Small Molecule IL-17A Modulators

Abstract

Disclosed herein are fused bicyclic compounds for use as small molecule IL-17A modulators. Disclosed herein are the use of such small molecule IL-17A modulators for use in reducing IL-17 activity by inhibition, and the use of such compounds for use in treating autoimmune or inflammatory diseases. The interleukin-17 (IL-17) family is a group of pro-inflammatory cytokines that are involved in tissue immune responses and play a critical role in chronic inflammation.

Description

[Technical field]

[0001] Disclosed herein are fused bicyclic compounds for use as small molecule IL-17A modulators. Disclosed herein are the use of such small molecule IL-17A modulators for use in reducing IL-17 activity by inhibition, and the use of such compounds for use in treating autoimmune or inflammatory diseases. [Background technology]

[0002] The interleukin-17 (IL-17) family is a group of pro-inflammatory cytokines that are involved in tissue immune responses and play a critical role in chronic inflammation. Secretion of IL-17 can stimulate the production of other pro-inflammatory cytokines (IL-1, IL-6, G-CSF, GM-CSF, and TNF) and chemokines (CXCL1, CXCL2, CXCL5, CCL2, CCL7, CCL20, and IL-8), matrix metalloproteinases (MMP1, MMP3, MMP9, and MMP13), and antimicrobial peptides (β-defensin, S-100 protein) (Frontiers in Immunology (2020) 11:947). The IL-17 family is composed of seven members, including IL17A-IL17F and vIL-17A. IL-17A, the most extensively studied basal member, is associated with host defense against various pathogenic microorganisms and tissue inflammation (Gene (2017) 614: 8-14). IL-17A consists of 155 amino acids, and the molecular weight of the homodimer is 30-35 kDa (European Respiratory Journal (2005): 159-172). IL-17F, the closest relative of IL-17A, shares approximately 50% amino acid sequence homology with IL-17A over its 163 amino acids and is often co-expressed with IL-17A (Immunity (2004): 467-476). Both IL-17A and IL-17F are secreted by helper T cells (Th17) and expressed as either homodimers or IL-17A / F heterodimers (European Respiratory Journal (2005): 159-172). The IL-17 receptor family consists of five members: IL-17RA, IL-17RB, IL-17RC, IL-17RD, and IL-17RE. All five receptors share a common cytoplasmic motif named the SEFIR domain (Frontiers in Immunology 11 (2020): 947). The signaling pathways of IL-17A and IL-17F are mediated by the same receptor complex, IL-17R, which consists of two subunits: IL-17RA and IL-17RG (Gene (2017) 614: 8-14).The corresponding receptors activate downstream pathways of these signaling pathways, including NFκB, MAPK and C / EBP, inducing the expression of antimicrobial peptides, cytokines and chemokines (Frontiers in Immunology (2020): 947). IL-17A promotes tissue inflammation and bone remodeling. IL-17A can act on various cell types: keratinocytes, endothelial cells, fibroblasts, osteoclasts, chondrocytes and osteoblasts (Archives of oral biology (2014): 897-905). Abnormal autoimmune responses, resulting in increased secretion of IL-17A, are found in many autoimmune diseases, including psoriasis, spondyloarthritis, rheumatoid arthritis, and multiple sclerosis (Gene (2017) 614: 8-14). One possible treatment for these diseases is to develop IL-17A inhibitors. Currently, several monoclonal antibodies targeting IL-17A have been approved by the FDA for the treatment of moderate to severe plaque psoriasis (Expert Opin. Biol. Ther. (2019), 19, 45-54): secukinumab (Cosentyx, Novartis), ixekizumab (Taltz, Eli Lilly), and brodalumab (Kyntheum, LEO Pharma / AstraZeneca). Bimekizumab (UCB) is a bispecific anti-IL-17A / IL-17F humanized monoclonal antibody that was just approved by the EC in 2021. However, monoclonal antibodies have several drawbacks, such as high cost, parenteral application, poor tissue penetration, and often long half-life (Chem. Biol. (2014) 21, 1102-1114), so the search for small molecules that should show the same biological outcomes is still ongoing. Several disclosures are known describing small molecules with IL-17A inhibitory activity (WO2014066726, WO2018229079, WO2019138017, WO2019223718, WO2020182666, WO2020011731, WO2020127685, WO2020163554, WO2021055376, WO2021098844, 2020163554 WO2020146194, WO2021204801, WO2021170627, WO2021098844, WO2021222404, WO2021220183). Currently, several small molecule inhibitors targeting the protein / protein interaction between IL-17A and IL-17RA are in clinical trials. Oral administration and flexible treatment schedules appear to be the main aspects prioritizing patient convenience. Small molecule drugs can be rapidly discontinued, which may allow for safety approval in the event of target-related adverse events.Thus, there is a continuing need for the development of structurally diverse small molecule IL-17A modulators, particularly those that are orally bioavailable. [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] Frontiers in Immunology(2020)11:947 [Non-Patent Document 2] Gene(2017)614:8-14 [Non-Patent Document 3] European Respiratory Journal(2005):159-172 [Non-Patent Document 4] Immunity(2004):467-476 [Non-Patent Document 5] European Respiratory Journal(2005):159-172 [Non-Patent Document 6] Archives of oral biology(2014):897-905 [Non-Patent Document 7] Expert Opin.Biol.Ther.(2019),19,45-54 [Non-Patent Document 8] Chem. Biol. (2014) 21, 1102-1114 [Patent documents]

[0004] [Patent Document 1] International Publication No. 2014 / 066726 [Patent Document 2] International Publication No. 2018 / 229079 [Patent Document 3] International Publication No. 2019 / 138017 [Patent Document 4] International Publication No. 2019 / 223718 [Patent Document 5] International Publication No. 2020 / 182666 [Patent Document 6] International Publication No. 2020 / 011731 [Patent Document 7] International Publication No. 2020 / 127685 [Patent Document 8] International Publication No. 2020 / 163554 [Patent Document 9] International Publication No. 2021 / 055376 [Patent Document 10] International Publication No. 2021 / 098844 Summary of the Invention

[0005] In one embodiment, disclosed herein is a fused bicyclic compound of formula (I). The embodiment includes the following aspects: Aspect 1. A compound of formula (I): [ka] or an N-oxide thereof, or a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated analog thereof, wherein: Cy1 is a 5-6 membered aromatic ring, said ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, said ring optionally containing at least one substituent R 3 is replaced by n3 is independently 0, 1, 2 or 3; Cy2 is a 4-8 membered saturated or partially or fully unsaturated ring, said ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur, said ring containing at least one substituent R 1 and / or R 2 is replaced by n1 is 0 or 1, n2 is 0, 1 or 2; n1 and n2 are not 0 at the same time, Cy1 and Cy2 are fused to each other, Cy3 is a 3-12 membered saturated or partially or fully unsaturated ring, said ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur, said ring optionally containing at least one substituent R 6 is replaced by n6 is independently 0, 1, 2, 3, 4, or 5, provided that valence theory is satisfied; X 1 is a single bond or -CR 9 R 10 - and R 1 is H or [ka] are independently selected from Where X 2 is N or C(R 15 ) and X 3 is -C(O)-, -S(O)- or -S(O)-, n11 and n12 each independently represent 1, 2, or 3; n14 is 0 or 1, R 15 is hydrogen, halogen, -C 1~8 Alkyl, -C3-C8 cycloalkyl, 3-8 membered heterocyclyl, -CN, -OR 15a , -NR 15a R 15b , or -NR 15a COR 15b Selected from -C 1~8 Each of the alkyl, C3-C8 cycloalkyl and 3- to 8-membered heterocyclyl optionally has at least one substituent R 15c is replaced by R 15a and R 15b are hydrogen and -C 1~8 Alkyl, -C 1~8 Haloalkyl, -C 2~8 Alkenyl, -C 2~8 Alkynyl, C 1~8 Alkoxy-C 1~8Alkyl-, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 aryl or 5-12 membered heteroaryl; 1~8 Alkyl, -C 1~8 Haloalkyl, -C 2~8 Alkenyl, -C 2~8 Alkynyl, C 1~8 Alkoxy-C 1~8 Alkyl-, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Each of the aryl and 5- to 12-membered heteroaryl optionally has at least one substituent R 15d is replaced by R 15c and R 15d are each independently halogen, -OH, -CN, oxo, -C 1~8 Alkyl, -C 1~8 Haloalkyl, -C 1~8 Alkoxy, -C 2~8 Alkenyl, -C 2~8 Alkynyl, -C3-C8 cycloalkyl, -C3-C8 halocycloalkyl, 3-8 membered heterocyclyl, -C6-C 12 aryl, or 5-12 membered heteroaryl; R 11a , R 11b , R 12a and R 12b are hydrogen, halogen, and -C, respectively. 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 Alkynyl, -C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Aryl, 5-12 membered heteroaryl, -CN, -OR 11c , -COR 11c , -CO2R 11c , -CONR 11c R 11d , -NR 11c R 11d or -NR 11c COR 11d are selected independently from -C 1~8Alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Each aryl or 5- to 12-membered heteroaryl may optionally contain at least one substituent R 11e or (R 11a and R 11b ), (R 12a and R 12b ), (R 11a and R 12a ), (R 11a and R 12b ), (R 11b and R 12a ) or (R 11b and R 12b ) together with the atom(s) to which they are attached form a 3-8 membered unsaturated or saturated ring, said ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, said ring optionally containing at least one substituent R 11f is replaced by R 11e , and R 11f are independently hydrogen, halogen, -C 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 Alkynyl, -C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Aryl, 5-12 membered heteroaryl, oxo (=O), -OR 11g , thioxo(=S), -SR 11g , -CN, -SO2R 11g , -SO2NR 11g R 11h , -COR 11g , -CO2R 11h , -CONR 11g R 11h , -NR 11g R 11h , -NR 11g COR 11h , -NR 11g CO2R 11h or -NR 11g SO2R 11h and -C 1~8 Alkyl, -C 1~8Alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Each aryl or 5- to 12-membered heteroaryl may optionally contain at least one substituent R 11i is replaced by R 11c , R 11d , R 11g and R 11h are hydrogen and -C 1~8 Alkyl, -C 1~8 Haloalkyl, -C 2~8 Alkenyl, -C 2~8 Alkynyl, C 1~8 Alkoxy-C 1~8 Alkyl-, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 aryl or 5-12 membered heteroaryl; 1~8 Alkyl, -C 1~8 Haloalkyl, -C 2~8 Alkenyl, -C 2~8 Alkynyl, C 1~8 Alkoxy-C 1~8 Alkyl-, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Each of the aryl and 5- to 12-membered heteroaryl optionally has at least one substituent R 11j is replaced by For each occurrence, R 11i and R 11j are each independently halogen, -OH, -CN, oxo, -C 1~8 Alkyl, -C 1~8 Haloalkyl, -C 1~8 Alkoxy, -C 2~8 Alkenyl, -C 2~8 Alkynyl, -C3-C8 cycloalkyl, -C3-C8 halocycloalkyl, 3-8 membered heterocyclyl, -C6-C 12 aryl, or 5-12 membered heteroaryl; -C 1~8 Alkyl, -C 1~8 Alkoxy, -C 2~8 Alkenyl, -C 2~8Alkynyl, -C3-C8 cycloalkyl, 3-8 membered heterocyclyl, -C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl optionally contains at least one substituent, halogen, -OH, -CN, oxo, -C 1~8 Alkyl, -C 1~8 Haloalkyl, -C 1~8 Alkoxy, -C 2~8 Alkenyl, -C 2~8 Alkynyl, -C3-C8 cycloalkyl, -C3-C8 halocycloalkyl, 3-8 membered heterocyclyl, -C6-C 12 substituted with aryl or 5-12 membered heteroaryl; R 13 , R 14a and R 14b are hydrogen and -C 1~8 independently selected from alkyl, -C3-C8 cycloalkyl, or 3-8 membered heterocyclyl; 1~8 Each of the alkyl, -C3-C8 cycloalkyl and 3- to 8-membered heterocyclyl optionally has at least one substituent R 13a is replaced by R 13a Each occurrence is independently halogen, -OH, -CN, oxo, -C 1~8 Alkyl, -C 1~8 Haloalkyl, -C 1~8 Alkoxy, -C 2~8 Alkenyl, -C 2~8 Alkynyl, -C3-C8 cycloalkyl, -C3-C8 halocycloalkyl, 3-8 membered heterocyclyl, -C6-C 12 aryl, or 5-12 membered heteroaryl; R 2 -H, -C 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 Alkynyl, -C3~C8 cycloalkyl, C6~C 12 Aryl, 5-12 membered heteroaryl, -CN, -COR 2a , -CO2R 2a , -CONR 2a R 2b , -NR2a R 2b , or -NR 2a COR 2b are selected independently from -C 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 Alkynyl, -C3~C8 cycloalkyl, C6~C 12 Each of the aryl and 5- to 12-membered heteroaryl optionally has at least one substituent R 2c or In the case of geminal or adjacent, two R 2 form, together with the carbon atom(s) attached thereto, a 3-8 membered unsaturated or saturated ring, said ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, said ring optionally containing at least one substituent R 2c is replaced by R 2a and R 2b are hydrogen and -C 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 Alkynyl, C3-C 12 Cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 aryl or 5-12 membered heteroaryl; 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 Alkynyl, C3-C 12 Cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Each of the aryl and 5- to 12-membered heteroaryl optionally has at least one substituent R 2d or R 2a and R 2b form, together with the nitrogen atom to which they are attached, a 3-8 membered unsaturated or saturated ring, said ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, said ring optionally containing at least one substituent R 2d is replaced by R 2c and R 2dare independently hydrogen, halogen, -C 1~8 Alkyl, -C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Aryl, 5-12 membered heteroaryl, oxo (=O), -OR 2e , -SR 2e , -CN, -COR 2e , -CO2R 2e , -CONR 2e R 2f , -NR 2e R 2f , -NR 2e COR 2f or -NR 2e CO2R 2f and -C 1~8 Alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Each aryl or 5- to 12-membered heteroaryl may optionally contain at least one substituent R 2g is replaced by R 2e and R 2f are hydrogen and -C 1~8 Alkyl, -C 1~8 Alkoxy, C 1~8 Alkoxy-C 1~8 Alkyl-, -C 2~8 Alkenyl, -C 2~8 Alkynyl, C3-C 12 Cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 aryl or 5-12 membered heteroaryl; 1~8 Alkyl, -C 1~8 Alkoxy, C 1~8 Alkoxy-C 1~8 Alkyl-, -C 2~8 Alkenyl, -C 2~8 Alkynyl, C3-C 12 Cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Each of the aryl and 5- to 12-membered heteroaryl optionally has at least one substituent R 2h is replaced by R 2g and R 2hare each independently a halogen, -OH, -C 1~8 Alkyl, -C 1~8 Haloalkyl, -C 1~8 Alkoxy, C 1~8 Alkoxy-C 1~8 Alkyl-, -C 2~8 Alkenyl, -C 2~8 Alkynyl, -C3-C8 cycloalkyl, -C3-C8 halocycloalkyl, 3-8 membered heterocyclyl, -C6-C 12 aryl, or 5-12 membered heteroaryl; When n1 and n2 are both 1, R 1 and R 2 is geminal or adjacent, R 3 is hydrogen, halogen, -C 1~8 Alkyl, -C 1~8 alkoxy, -C3-C8 cycloalkyl, or -CN, 1~8 Alkyl, -C 1~8 Each of the alkoxy and -C3-C8 cycloalkyl is optionally selected from halogen, -OH, -C 1~8 Alkyl, -C 1~8 Alkoxy, C 1~8 Alkoxy-C 1~8 Alkyl-, -C 2~8 Alkenyl, -C 2~8 Alkynyl, -C3-C8 cycloalkyl, 3-8 membered heterocyclyl, -C6-C 12 substituted with at least one substituent selected from aryl, or 5- to 12-membered heteroaryl; R 4 is oxo (=O) or thioxo (=S), or R 3 and R 4 form, together with the atoms to which they are attached, a 5-6 membered aromatic ring, said ring containing 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, said ring optionally containing at least one substituent R 3a is replaced by R 3a is hydrogen, halogen, -C 1~8Alkyl, -C 1~8 alkoxy, -C3-C8 cycloalkyl, or -CN, 1~8 Alkyl, -C 1~8 Each of the alkoxy and -C3-C8 cycloalkyl is optionally selected from halogen, -OH, -C 1~8 Alkyl, -C 1~8 Alkoxy, C 1~8 Alkoxy-C 1~8 Alkyl-, -C 2~8 Alkenyl, -C 2~8 Alkynyl, -C3-C8 cycloalkyl, 3-8 membered heterocyclyl, -C6-C 12 substituted with at least one substituent selected from aryl, or 5- to 12-membered heteroaryl; R 5 is C6~C 12 Aryl, 5-12 membered heteroaryl, -COR 5a , -CO2R 5a , -CONR 5a R 5b where C6 to C 12 Each of the aryl and 5- to 12-membered heteroaryl optionally has at least one substituent R 5c is replaced by R 5a and R 5b are respectively -C 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 Alkynyl, C3-C 12 Cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 aryl or 5-12 membered heteroaryl; 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 Alkynyl, C3-C 12 Cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Each of the aryl and 5- to 12-membered heteroaryl optionally has at least one substituent R 5d or R 5a and R 5bform, together with the atoms to which they are attached, a 3-8 membered unsaturated or saturated ring, said ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, said ring optionally containing at least one substituent R 5d is replaced by R 5c and R 5d are hydrogen, halogen, and -C, respectively, for each occurrence. 1~8 Alkyl, -C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Aryl, 5-12 membered heteroaryl, oxo (=O), -OR 5e , -SR 5e , -CN, -COR 5e , -CO2R 5e , -CONR 5e R 5f , -NR 5e R 5f , -NR 5e COR 5f or -NR 5e CO2R 5f are selected independently from -C 1~8 Alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Each aryl or 5- to 12-membered heteroaryl may optionally contain at least one substituent R 5g is replaced by R 5e and R 5f are hydrogen and -C 1~8 Alkyl, -C 1~8 Alkoxy, C 1~8 Alkoxy-C 1~8 Alkyl-, -C 2~8 Alkenyl, -C 2~8 Alkynyl, C3-C 12 Cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 aryl or 5-12 membered heteroaryl; 1~8 Alkyl, -C 1~8 Alkoxy, C 1~8 Alkoxy-C 1~8 Alkyl-, -C 2~8 Alkenyl, -C 2~8Alkynyl, C3-C 12 Cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Each of the aryl and 5- to 12-membered heteroaryl optionally has at least one substituent R 5h is replaced by R 5g and R 5h are halogen, -OH, -CN, and -C, respectively. 1~8 Alkyl, -C 1~8 Alkoxy, C 1~8 Alkoxy-C 1~8 Alkyl-, -C 2~8 Alkenyl, -C 2~8 Alkynyl, -C3-C8 cycloalkyl, 3-8 membered heterocyclyl, -C6-C 12 aryl, or 5-12 membered heteroaryl; R 6 is H, halogen, -C 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 Alkynyl, -C3~C8 cycloalkyl, C6~C 12 Aryl, 5-12 membered heteroaryl, -CN, -OR 6a , -NR 6a R 6b , -COR 6a , -CO2R 6a , -CONR 6a R 6b , -COR 6a or -NR 6a COR 6b and -C 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 Alkynyl, -C3~C8 cycloalkyl, C6~C 12 Each of the aryl and 5- to 12-membered heteroaryl optionally has at least one substituent R 6c is replaced by R 6a and R 6b are hydrogen and -C 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 Alkynyl, C3-C 12Cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 aryl or 5-12 membered heteroaryl; 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 Alkynyl, C3-C 12 Cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Each of the aryl and 5- to 12-membered heteroaryl optionally has at least one substituent R 6d is replaced by R 6c Each occurrence is independently hydrogen, halogen, or -C 1~8 Alkyl, -C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Aryl, 5-12 membered heteroaryl, oxo (=O), -OR 6e , -SR 6e , -CN, -COR 6e , -CO2R 6e , -CONR 6e R 6f , -NR 6e R 6f , -NR 6e COR 6f or -NR 6e CO2R 6f and -C 1~8 Alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Each aryl or 5- to 12-membered heteroaryl may optionally contain at least one substituent R 6g is replaced by R 6e and R 6f are hydrogen and -C 1~8 Alkyl, -C 1~8 Alkoxy, C 1~8 Alkoxy-C 1~8 Alkyl-, -C 2~8 Alkenyl, -C 2~8 Alkynyl, C3-C 12 Cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 aryl or 5-12 membered heteroaryl; R 6d and R 6g are halogen, -OH, and -C, respectively. 1~8 Alkyl, -C 1~8 Alkoxy, C 1~8 Alkoxy-C 1~8 Alkyl-, -C 2~8 Alkenyl, -C 2~8 Alkynyl, -C3-C8 cycloalkyl, 3-8 membered heterocyclyl, -C6-C 12 aryl, or 5-12 membered heteroaryl; R 7 and R 8 are each independently hydrogen; R 9 and R 10 are H, halogen, and -C, respectively. 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 Alkynyl, -C3~C8 cycloalkyl, C6~C 12 aryl or 5-12 membered heteroaryl; 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 Alkynyl, -C3~C8 cycloalkyl, C6~C 12 Each of the aryl and 5- to 12-membered heteroaryl optionally has at least one substituent R 9a is replaced by R 9a Each occurrence is independently a halogen, -OH, -C 1~8 Alkyl, -C 1~8 Alkoxy, C 1~8 Alkoxy-C 1~8 Alkyl-, -C 2~8 Alkenyl, -C 2~8 Alkynyl, -C3-C8 cycloalkyl, 3-8 membered heterocyclyl, -C6-C 12 aryl, or 5-12 membered heteroaryl).

[0006] Aspect 2. The compound according to aspect 1, having the formula (IIa)-(IIp): [ka] [ka] [ka] The compound (wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Cy3, n1, n2, n3, n6 and X 1 is defined as in embodiment 1).

[0007] Aspect 3. The compound according to aspect 1, having the formula (IIf1) to (IIf2): [ka] The compound (wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Cy3, n1, n2, n3, n6 and X 1 is defined as in embodiment 1).

[0008] Aspect 4. The compound according to aspect 1, having the formula (IIIa)-(IIIb): [ka] The compound (wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Cy1, Cy2, Cy3, n1, n2, n3, n6, R 9 and R 10 is defined as in embodiment 1).

[0009] Aspect 5. The compound according to aspect 1, having the formula (IVa)-(IVb): [ka] The compound (wherein X 1 , R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , Cy1, Cy2, Cy3, n1, n2, n3, n6, R 9 and R 10 is defined as in embodiment 1).

[0010] Aspect 6. The compound according to aspect 1, having the formula (Va)-(Vc): [ka] The compound (wherein X 1 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Cy1, Cy2, Cy3, n3, n6, R 9 and R 10 is defined as in embodiment 1).

[0011] Aspect 7. The compound according to aspect 1, comprising VIa [ka] and Preferably, VIb and VIc [ka] The compound (wherein X 1 , X 2 , X 3 , R 2, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Cy1, Cy2, Cy3, n2, n3, n6, R 11a , R 11b , R 12a , R 12b , R 13 , R 14a , R 14b , n11, n12 and n14 are defined as in embodiment 1).

[0012] Embodiment 8. A compound according to embodiment 1, comprising: [ka] and Preferably VIIc, VIId, VIIe, VIIf, VIIg or VIIh [ka] [ka] The compound (wherein X 2 , R 2a , R 3 , R 5 , R 6 , R 9 , R 10 , Cy1, Cy2, Cy3, n2, n3, n6, R 11a , R 11b , R 12a , R 12b , R 13 , R 14a , R 14b , n11, n12 and n14 are defined as in embodiment 1).

[0013] Embodiment 9. The compound of any one of the preceding embodiments, wherein Cy1 is a 5- or 6-membered aromatic ring, said ring containing 0, 1, or 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and said ring optionally contains 0, 1, 2, or 3 substituents R 3is replaced by Preferably, Cy1 is phenyl, pyridyl, thiophenyl, imidazolyl, furanyl or pyrazolyl, each of which optionally contains 0, 1 or 2 substituents R 3 The compound is substituted with

[0014] Aspect 10. A compound according to any one of the preceding aspects, wherein Cy2 is a 4-, 5-, 6-, 7-, or 8-membered saturated or partially or fully unsaturated ring, said ring containing 0, 1, 2, or 3 heteroatoms independently selected from nitrogen or oxygen, and said ring is further characterized by the presence of at least one substituent R 1 and / or R 2 is replaced by Preferably, Cy2 is a 5-, 6- or 7-membered saturated or partially or fully unsaturated ring, said ring containing 0, 1 or 2 heteroatoms independently selected from nitrogen or oxygen, said ring containing at least one substituent R 1 and / or R 2 The compound is substituted with

[0015] Embodiment 11. A compound according to any one of the preceding embodiments, [ka] The part is [ka] The compound is selected from the group consisting of

[0016] Aspect 12. A compound according to any one of the preceding aspects, wherein Cy3 is a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered saturated or partially or fully unsaturated ring, said ring containing 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur, said ring optionally containing 0, 1, 2, 3, 4, or 5 substituents R 6 is replaced by Preferably, Cy3 is a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered saturated or partially or fully unsaturated ring, said ring being monocyclic, bicyclic or tricyclic containing 0, 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur, said ring optionally containing 0, 1, 2, 3, 4 or 5 substituents R 6 is replaced by More preferably, [ka] The part is [ka] and Even more preferably, [ka] The part is [ka] The compound,

[0017] Aspect 13. A compound according to any one of the preceding aspects, wherein R 1 H, [ka] wherein R 11a , R 11b , R 12a , R 12b , R 13 , n11 and n12 are defined as in embodiment 1).

[0018] Aspect 14. A compound according to any one of the preceding aspects, wherein R 15is hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, -CN, -OR 15a , -NR 15a R 15b , or -NR 15a COR 15b wherein each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and 3- to 8-membered heterocyclyl optionally has at least one substituent R 15c is replaced by R 15a and R 15b are hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 1~8 Haloalkyl, -C 2~8 Alkenyl, -C 2~8 Alkynyl, C 1~8 Alkoxy-C 1~8 Alkyl-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, C6-C 12 aryl or 5-12 membered heteroaryl, and is independently selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2~8 Alkenyl, -C 2~8 Alkynyl, C 1~8 Alkoxy-C 1~8 Alkyl-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, C6-C 12 Each of the aryl and 5- to 12-membered heteroaryl optionally has at least one substituent R 15d is replaced by R 15c and R 15deach occurrence independently represents -F, -Cl, -Br, -I, -OH, -CN, oxo, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 1~8 Haloalkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2~8 Alkenyl, -C 2~8 The compound is alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C3-C8 halocycloalkyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl.

[0019] Aspect 15. A compound according to any one of the preceding aspects, wherein R 15 is selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, -CN, -OH, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy; Preferably, R 15 is selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl; More preferably, R 15 is selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl; Even more preferably, R 15 is selected from hydrogen.

[0020] Aspect 16. A compound according to any one of the preceding aspects, wherein R 11a , R 11b , R 12a and R 12bare hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, propenyl, allyl, but-3-en-1-yl, but-2-en-1-yl, but-1-en-1-yl, pent-4-en-1-yl, pent-3-en-1-yl, pent-2-en-1-yl, pent-1-en-1-yl, hex-5-en-1-yl, hex-4-en-1-yl, hex-3-en-1-yl, hex-2-en-1-yl, hex-1-en-1-yl, and hept-6-en-1-yl, respectively. hept-5-enyl, hept-4-enyl, hept-3-enyl, hept-2-enyl, hept-1-enyl, oct-7-enyl, oct-6-enyl, oct-5-enyl, oct-4-enyl, oct-3-enyl, oct-2-enyl, oct-1-enyl, ethynyl, prop-2-yn-1-yl, prop-1-yn-1-yl, but-3-yn-1-yl, but-2-yn-1-yl, but-1-yn-1-yl, pent-4-yn-1-yl, pent-3-yn-1-yl, pent- 2-yn-1-yl, pent-1-yn-1-yl, hex-5-yn-1-yl, hex-4-yn-1-yl, hex-3-yn-1-yl, hex-2-yn-1-yl, hex-1-yn-1-yl, hep-6-yn-yl, hep-5-yn-yl, hep-4-yn-yl, hep-3-yn-yl, hep-2-yn-yl, hep-1-yn-yl, oct-7-yn-yl, oct-6-yn-yl, oct-5-yn-yl, oct-4-yn-yl, oct-3-yn-yl, oct-2-yn-yl, oct-1-yn-yl, independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, aziridinyl, azetidinyl, pyrrolidinyl, dihydropyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, -CN, methyl, ethyl, propyl, butyl, pentyl,Hexyl, heptyl, octyl, vinyl, propenyl, allyl, but-3-en-1-yl, but-2-en-1-yl, but-1-en-1-yl, pent-4-en-1-yl, pent-3-en-1-yl, pent-2-en-1-yl, pent-1-en-1-yl, hex-5-en-1-yl, hex-4-en-1-yl, hex-3-en-1-yl, hex-2-en-1-yl, hex-1-en-1-yl, hept-6-en-yl, hept-5-en-yl, hept-4-en-yl, hept-3 -enyl, hept-2-enyl, hept-1-enyl, oct-7-enyl, oct-6-enyl, oct-5-enyl, oct-4-enyl, oct-3-enyl, oct-2-enyl, oct-1-enyl, ethynyl, prop-2-yn-1-yl, prop-1-yn-1-yl, but-3-yn-1-yl, but-2-yn-1-yl, but-1-yn-1-yl, pent-4-yn-1-yl, pent-3-yn-1-yl, pent-2-yn-1-yl, pent-1-yn 1-yn-yl, hex-5-yn-1-yl, hex-4-yn-1-yl, hex-3-yn-1-yl, hex-2-yn-1-yl, hex-1-yn-1-yl, hep-6-yn-yl, hep-5-yn-yl, hep-4-yn-yl, hep-3-yn-yl, hep-2-yn-yl, hep-1-yn-yl, oct-7-yn-yl, oct-6-yn-yl, oct-5-yn-yl, oct-4-yn-yl, oct-3-yn-yl, oct-2-yn-yl, oct-1-yn-yl, cyclo-yn-yl, Each of the arylpropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, aziridinyl, azetidinyl, pyrrolidinyl, dihydropyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl may optionally be selected from the group consisting of at least one substituent R, 11e is replaced by R 11erepresents, at each occurrence, independently, hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, propenyl, allyl, but-3-en-1-yl, but-2-en-1-yl, but-1-en-1-yl, pent-4-en-1-yl, pent-3-en-1-yl, pent-2-en-1-yl, pent-1-en-1-yl, hex-5-en-1-yl, hex-4-en-1-yl, hex-3-en-1-yl, hex-2-en-1-yl, hex-1-en-1-yl, Hept-6-en-yl, hept-5-en-yl, hept-4-en-yl, hept-3-en-yl, hept-2-en-yl, hept-1-en-yl, oct-7-en-yl, oct-6-en-yl, oct-5-en-yl, oct-4-en-yl, oct-3-en-yl, oct-2-en-yl, oct-1-en-yl, ethynyl, prop-2-yn-1-yl, prop-1-yn-1-yl, but-3-yn-1-yl, but-2-yn-1-yl, but-1-yn-1-yl, pent-4-yn-1-yl, penta -3-yn-1-yl, pent-2-yn-1-yl, pent-1-yn-1-yl, hex-5-yn-1-yl, hex-4-yn-1-yl, hex-3-yn-1-yl, hex-2-yn-1-yl, hex-1-yn-1-yl, hept-6-yn-yl, hept-5-yn-yl, hept-4-yn-yl, hept-3-yn-yl, hept-2-yn-yl, hept-1-yn-yl, oct-7-yn-yl, oct-6-yn-yl, oct-5-yn-yl, oct-4-yn-yl, oct-3-yn-yl, oct- 2-yn-yl, oct-1-yn-yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, aziridinyl, azetidinyl, pyrrolidinyl, dihydropyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxo(=O), -OR 11g, thioxo(=S), -SR 11g , -CN, -SO2R 11g , -SO2NR 11g R 11h , -COR 11g , -CO2R 11h , -CONR 11g R 11h , -NR 11g R 11h , -NR 11g COR 11h , -NR 11g CO2R 11h or -NR 11g SO2R 11hand are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, propenyl, allyl, but-3-en-1-yl, but-2-en-1-yl, but-1-en-1-yl, pent-4-en-1-yl, pent-3-en-1-yl, pent-2-en-1-yl, pent-1-en-1-yl, hex-5-en-1-yl, hex-4-en-1-yl, hex-3-en-1-yl, hex-2-en-1-yl, hex-1-en-1-yl, hept-6-en-yl, hept-5-en-1-yl, yl, hept-4-en-yl, hept-3-en-yl, hept-2-en-yl, hept-1-en-yl, oct-7-en-yl, oct-6-en-yl, oct-5-en-yl, oct-4-en-yl, oct-3-en-yl, oct-2-en-yl, oct-1-en-yl, ethynyl, prop-2-yn-1-yl, prop-1-yn-1-yl, but-3-yn-1-yl, but-2-yn-1-yl, but-1-yn-1-yl, pent-4-yn-1-yl, pent-3-yn-1-yl, pent-2-yn-1-yl 1-yn-yl, pent-1-yn-1-yl, hex-5-yn-1-yl, hex-4-yn-1-yl, hex-3-yn-1-yl, hex-2-yn-1-yl, hex-1-yn-1-yl, hep-6-yn-yl, hep-5-yn-yl, hep-4-yn-yl, hep-3-yn-yl, hep-2-yn-yl, hep-1-yn-yl, oct-7-yn-yl, oct-6-yn-yl, oct-5-yn-yl, oct-4-yn-yl, oct-3-yn-yl, oct-2-yn-yl, oct-1-yn-yl Each of the aryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, aziridinyl, azetidinyl, pyrrolidinyl, dihydropyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl may optionally be selected from the group consisting of aryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, aziridinyl, azetidinyl, pyrrolidinyl, dihydropyrrolidinyl, tetrahydrofuranyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl. 11i is replaced by R 11c , R 11d , R 11g and R 11h are hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 1~8 Haloalkyl, -C 2~8 Alkenyl, -C 2~8 Alkynyl, C 1~8 Alkoxy-C 1~8 independently selected from alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 1~8 Haloalkyl, -C 2~8 Alkenyl, -C 2~8 Alkynyl, C 1~8 Alkoxy-C 1~8 Each of alkyl-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, and 5- to 12-membered heteroaryl may optionally contain at least one substituent R 11j is replaced by For each occurrence, R 11i and R 11j are each independently -F, -Cl, -Br, -I, -OH, -CN, oxo, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 1~8Haloalkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, vinyl, propenyl, allyl, but-3-en-1-yl, but-2-en-1-yl, but-1-en-1-yl, pent-4-en-1-yl, pent-3-en-1-yl, pent-2-en-1-yl, pent-1-en-1-yl, hex-5-en-1-yl, hex-4-en-1-yl, hex-3-en-1-yl, hex-2-en-1-yl, hex-1-en-1-yl, hept-6-en-yl, hept-5-en-1-yl Hept-4-en-yl, hept-3-en-yl, hept-2-en-yl, hept-1-en-yl, oct-7-en-yl, oct-6-en-yl, oct-5-en-yl, oct-4-en-yl, oct-3-en-yl, oct-2-en-yl, oct-1-en-yl, ethynyl, prop-2-yn-1-yl, prop-1-yn-1-yl, but-3-yn-1-yl, but-2-yn-1-yl, but-1-yn-1-yl, pent-4-yn-1-yl, pent-3-yn-1-yl, pent-2-yn-1-yl , pent-1-yn-1-yl, hex-5-yn-1-yl, hex-4-yn-1-yl, hex-3-yn-1-yl, hex-2-yn-1-yl, hex-1-yn-1-yl, hept-6-yn-yl, hept-5-yn-yl, hept-4-yn-yl, hept-3-yn-yl, hept-2-yn-yl, hept-1-yn-yl, oct-7-yn-yl, oct-6-yn-yl, oct-5-yn-yl, oct-4-yn-yl, oct-3-yn-yl, oct-2-yn-yl, oct-1-yn-yl, cyclopropyl, cyclopropyl cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C3-C8 halocycloalkyl, aziridinyl, azetidinyl, pyrrolidinyl, dihydropyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl; methyl, ethyl, propyl, butyl, pentyl, hexyl,Heptyl, Octyl, -C, 1~8Haloalkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, vinyl, propenyl, allyl, but-3-en-1-yl, but-2-en-1-yl, but-1-en-1-yl, pent-4-en-1-yl, pent-3-en-1-yl, pent-2-en-1-yl, pent-1-en-1-yl, hex-5-en-1-yl, hex-4-en-1-yl, hex-3-en-1-yl, hex-2-en-1-yl, hex-1-en-1-yl, hept-6-en-yl, hept-5-en-1-yl Hept-4-yn-yl, hept-3-yn-yl, hept-2-yn-yl, hept-1-yn-yl, oct-7-yn-yl, oct-6-yn-yl, oct-5-yn-yl, oct-4-yn-yl, oct-3-yn-yl, oct-2-yn-yl, oct-1-yn-yl, ethynyl, prop-2-yn-1-yl, prop-1-yn-1-yl, but-3-yn-1-yl, but-2-yn-1-yl, but-1-yn-1-yl, pent-4-yn-1-yl, pent-3-yn-1-yl, pent-2-yn-1-yl cyclopropyl, pent-1-yn-1-yl, hex-5-yn-1-yl, hex-4-yn-1-yl, hex-3-yn-1-yl, hex-2-yn-1-yl, hex-1-yn-1-yl, hept-6-yn-yl, hept-5-yn-yl, hept-4-yn-yl, hept-3-yn-yl, hept-2-yn-yl, hept-1-yn-yl, oct-7-yn-yl, oct-6-yn-yl, oct-5-yn-yl, oct-4-yn-yl, oct-3-yn-yl, oct-2-yn-yl, oct-1-yn-yl, cyclopropyl, Each of cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C3-C8 halocycloalkyl, aziridinyl, azetidinyl, pyrrolidinyl, dihydropyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl may optionally have at least one substituent -F, -Cl,-Br, -I, -OH, -CN, oxo, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C, 1~8 Haloalkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2~8 Alkenyl, -C 2~8 The compound is substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C3-C8 halocycloalkyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl.

[0021] Aspect 17. A compound according to any one of the preceding aspects, wherein R 11a , R 11b , R 12a and R 12bare hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, propenyl, allyl, but-3-en-1-yl, but-2-en-1-yl, but-1-en-1-yl, pent-4-en-1-yl, pent-3-en-1-yl, pent-2-en-1-yl, pent-1-en-1-yl, hex-5-en-1-yl, hex-4-en-1-yl, hex-3-en-1-yl, hex-2-en-1-yl, hex-1-en-1-yl, and hept-6-en-1-yl, respectively. hept-5-enyl, hept-4-enyl, hept-3-enyl, hept-2-enyl, hept-1-enyl, oct-7-enyl, oct-6-enyl, oct-5-enyl, oct-4-enyl, oct-3-enyl, oct-2-enyl, oct-1-enyl, ethynyl, prop-2-yn-1-yl, prop-1-yn-1-yl, but-3-yn-1-yl, but-2-yn-1-yl, but-1-yn-1-yl, pent-4-yn-1-yl, pent-3-yn-1-yl, pent- 2-yn-1-yl, pent-1-yn-1-yl, hex-5-yn-1-yl, hex-4-yn-1-yl, hex-3-yn-1-yl, hex-2-yn-1-yl, hex-1-yn-1-yl, hep-6-yn-yl, hep-5-yn-yl, hep-4-yn-yl, hep-3-yn-yl, hep-2-yn-yl, hep-1-yn-yl, oct-7-yn-yl, oct-6-yn-yl, oct-5-yn-yl, oct-4-yn-yl, oct-3-yn-yl, oct-2-yn-yl, oct-1-yn-yl, independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, aziridinyl, azetidinyl, pyrrolidinyl, dihydropyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, -CN, methyl, ethyl, propyl, butyl, pentyl,Hexyl, heptyl, octyl, vinyl, propenyl, allyl, but-3-en-1-yl, but-2-en-1-yl, but-1-en-1-yl, pent-4-en-1-yl, pent-3-en-1-yl, pent-2-en-1-yl, pent-1-en-1-yl, hex-5-en-1-yl, hex-4-en-1-yl, hex-3-en-1-yl, hex-2-en-1-yl, hex-1-en-1-yl, hept-6-en-yl, hept-5-en-yl, hept-4-en-yl, hept-3 -enyl, hept-2-enyl, hept-1-enyl, oct-7-enyl, oct-6-enyl, oct-5-enyl, oct-4-enyl, oct-3-enyl, oct-2-enyl, oct-1-enyl, ethynyl, prop-2-yn-1-yl, prop-1-yn-1-yl, but-3-yn-1-yl, but-2-yn-1-yl, but-1-yn-1-yl, pent-4-yn-1-yl, pent-3-yn-1-yl, pent-2-yn-1-yl, pent-1-yn 1-yn-yl, hex-5-yn-1-yl, hex-4-yn-1-yl, hex-3-yn-1-yl, hex-2-yn-1-yl, hex-1-yn-1-yl, hep-6-yn-yl, hep-5-yn-yl, hep-4-yn-yl, hep-3-yn-yl, hep-2-yn-yl, hep-1-yn-yl, oct-7-yn-yl, oct-6-yn-yl, oct-5-yn-yl, oct-4-yn-yl, oct-3-yn-yl, oct-2-yn-yl, oct-1-yn-yl, cyclo-yn-yl, Each of the arylpropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, aziridinyl, azetidinyl, pyrrolidinyl, dihydropyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl may optionally be selected from the group consisting of at least one substituent R, 11e is replaced by R 11eis independently represented at each occurrence by hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, propenyl, allyl, but-3-en-1-yl, but-2-en-1-yl, but-1-en-1-yl, pent-4-en-1-yl, pent-3-en-1-yl, pent-2-en-1-yl, pent-1-en-1-yl, hex-5-en-1-yl, hex-4-en-1-yl, hex-3-en-1-yl, hex-2-en-1-yl, hex-1-en-1-yl, hept-6-en-yl, hept-5-en-yl, hept-4-en-yl, hept-3-en-yl, hept-2-en-yl, hept-1-en-yl, oct-7-en-yl, oct-6-en-yl, oct-5-en-yl, oct-4-en-yl, oct-3-en-yl, oct-2-en-yl, oct-1-en-yl, ethynyl, prop-2-yn-1-yl, prop-1-yn-1-yl, but-3-yn-1-yl, but-2-yn-1-yl, but-1-yn-1-yl, pent-4-yn-1-yl , pent-3-yn-1-yl, pent-2-yn-1-yl, pent-1-yn-1-yl, hex-5-yn-1-yl, hex-4-yn-1-yl, hex-3-yn-1-yl, hex-2-yn-1-yl, hex-1-yn-1-yl, hep-6-yn-yl, hep-5-yn-yl, hep-4-yn-yl, hep-3-yn-yl, hep-2-yn-yl, hep-1-yn-yl, oct-7-yn-yl, oct-6-yn-yl, oct-5-yn-yl, oct-4-yn-yl, oct-3-yn-yl aryl, oct-2-yn-yl, oct-1-yn-yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, aziridinyl, azetidinyl, pyrrolidinyl, dihydropyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, -OR 11g or -CN, R 11g is independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl; Preferably, R 11a , R 11b , R 12a and R 12b are respectively: H, -CH3, -CF3, -CH2CH3, -CH2CF3, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyrrolidinyl, tetrahydrofuranyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, phenyl, benzyl, vinyl, propenyl, allyl, but-3-en-1-yl, ethynyl, prop-2-yn-1-yl, prop-1-yn-1-yl, but-3-yn-1-yl, but-2-yn-1-yl, but-1-yn-1-yl, [ka] The compound is independently selected from:

[0022] Aspect 18. A compound according to any one of the preceding aspects, comprising (R 11a and R 11b ), (R 12a and R 12b ), (R 11a and R 12a ), (R 11a and R 12b ), (R 11b and R 12a ) or (R 11b and R 12b ) together with the carbon atoms to which they are attached form a 3-, 4-, 5-, 6- or 8-membered unsaturated or saturated ring, said ring containing 0, 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen or sulfur, said ring optionally containing at least one substituent R 11f is replaced by R 11fEach occurrence independently represents hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2~8 Alkenyl, -C 2~8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, C6-C 12 Aryl, 5-12 membered heteroaryl, oxo (=O), -OR 11g , thioxo(=S), -SR 11g , -CN, -SO2R 11g , -SO2NR 11g R 11h , -COR 11g , -CO2R 11h , -CONR 11g R 11h , -NR 11g R 11h , -NR 11g COR 11h , -NR 11g CO2R 11h or -NR 11g SO2R 11h and R 11g and R 11h are hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2~8 Alkenyl, -C 2~8 Alkynyl, C 1~8 Alkoxy-C 1~8 Alkyl-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, C6-C 12 aryl or 5-12 membered heteroaryl; For each occurrence, R 11i are independently -F, -Cl, -Br, -I, -OH, -CN, oxo, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 1~8 Haloalkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2~8 Alkenyl, -C2~8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C3-C8 halocycloalkyl, 3-8 membered heterocyclyl, -C6-C 12 aryl, or 5-12 membered heteroaryl; Preferably, (R 11a and R 11b ), (R 12a and R 12b ), (R 11a and R 12a ), (R 11a and R 12b ), (R 11b and R 12a ) or (R 11b and R 12b ) together with the carbon atoms to which they are attached form a 3-, 4-, 5-, 6- or 8-membered unsaturated or saturated ring; More preferably, (R 11a and R 11b ), (R 12a and R 12b ), (R 11a and R 12a ), (R 11a and R 12b ), (R 11b and R 12a ) or (R 11b and R 12b ) together with the carbon atom to which they are attached form a 3-, 4-, 5-, 6-, or 8-membered saturated ring.

[0023] Aspect 19. A compound according to any one of the preceding aspects, wherein R 13 , R 14a and R 14bare each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or 3- to 8-membered heterocyclyl, each of which may optionally be selected from at least one substituent R 13a is replaced by R 13a is independently selected for each occurrence from halogen, -OH, -CN, oxo, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C 1~8 Haloalkyl, -C 1~8 Alkoxy, -C 2~8 Alkenyl, -C 2~8 alkynyl, -C3-C8 halocycloalkyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl; Preferably, R 13 , R 14a and R 14b are each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or 3- to 8-membered heterocyclyl; More preferably, R 13 is hydrogen, methyl, ethyl, propyl or butyl; R 14a and R 14b are each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or 3- to 8-membered heterocyclyl; Even more preferably, R 13 is hydrogen and R 14a and R14b are each independently selected from hydrogen, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, and cyclopentyl.

[0024] Aspect 20. A compound according to any one of the preceding aspects, wherein R 1 teeth, [ka] The compound is selected from the group consisting of

[0025] Aspect 21. A compound according to any one of the preceding aspects, wherein R 2 is H, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2~8 Alkenyl, -C 2~8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, imidazopyridazinyl, imidazopyridinyl, -CN, -COR 2a , -CO2R 2a , -CONR 2a R 2b , -NR 2a R 2b , -NR 2a COR 2b independently selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2~8 Alkenyl, -C 2~8 Each of alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, imidazopyridazinyl and imidazopyridinyl may optionally be selected from the group consisting of at least one substituent R 2c is replaced by R2a and R 2b are hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2~8 Alkenyl, -C 2~8 independently selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, aziridinyl, azetidinyl, pyrrolidinyl, dihydropyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, imidazopyridazinyl, imidazopyridinyl, and methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2~8 Alkenyl, -C 2~8 Each of alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, aziridinyl, azetidinyl, pyrrolidinyl, dihydropyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, imidazopyridazinyl, imidazopyridinyl may optionally be selected from the group consisting of aryl, ... 2d or R 2a and R 2b form together with the carbon atoms to which they are attached a 3-, 4-, 5-, 6-, 7- or 8-membered unsaturated or saturated ring, said ring containing 0, 1, 2, 3 heteroatoms independently selected from nitrogen, oxygen or sulfur, said ring optionally containing at least one substituent R 2d is replaced by R 2c and R 2deach occurrence independently represents hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, imidazopyridazinyl, imidazopyridinyl, oxo (=O), -OR 2e , -SR 2e , -CN, -COR 2e , -CO2R 2e , -CONR 2e R 2f , -NR 2e R 2f , -NR 2e COR 2f or -NR 2e CO2R 2f wherein each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, imidazopyridazinyl, and imidazopyridinyl may optionally be selected from the group consisting of at least one substituent R 2g is replaced by R 2e and R 2f are hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, and C 1~8 Alkoxy-C 1~8 Alkyl-, -C 2~8 Alkenyl, -C 2~8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; and independently selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, C 1~8 Alkoxy-C 1~8 Alkyl-, -C 2~8 Alkenyl, -C 2~8 Each of alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl may optionally be substituted with at least one substituent R 2h is replaced by R 2g and R 2h each occurrence independently represents -F, -Cl, -Br, -I, -OH, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 1~8 Haloalkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, C 1~8 Alkoxy-C 1~8 Alkyl-, -C 2~8 Alkenyl, -C 2~8 The compound is alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C3-C8 halocycloalkyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl.

[0026] Aspect 22. A compound according to any one of the preceding aspects, wherein R 2is H, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, imidazopyridazinyl, imidazopyridinyl, -CN, -COR 2a , -CO2R 2a or -CONR 2a R 2b wherein each of methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, imidazopyridazinyl, imidazopyridinyl, optionally has at least one substituent R 2c is replaced by R 2a and R 2bare each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, aziridinyl, azetidinyl, pyrrolidinyl, dihydropyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, imidazopyridazinyl, and imidazopyridinyl; each of the aryl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, aziridinyl, azetidinyl, pyrrolidinyl, dihydropyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, imidazopyridazinyl, and imidazopyridinyl may optionally be selected from the group consisting of aryl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, aziridinyl, azetidinyl, pyrrolidinyl, dihydropyrrolidinyl, tetrahydrofuranyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, imidazopyridazinyl, and imidazopyridinyl, may optionally be selected from the group consisting of aryl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclopropyl, cyclopropyl, cyclopropyl, cyclopropyl, 2d or R 2a and R 2b form together with the carbon atoms to which they are attached a 3-, 4-, 5- or 6-membered unsaturated or saturated ring, said ring containing 0 or 1 heteroatom independently selected from nitrogen, oxygen or sulfur, said ring optionally containing at least one substituent R 2d is replaced by R 2c and R 2deach occurrence independently represents hydrogen (H or D), -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, imidazopyridazinyl, imidazopyridinyl, -OR 2e , -CN or -NR 2e R 2f wherein each of methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, imidazopyridazinyl, imidazopyridinyl may optionally be selected from the group consisting of at least one substituent R 2g is replaced by R 2e and R 2f are each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or phenyl, each of which may optionally be selected from at least one substituent R 2h is replaced by R 2g and R 2h is independently at each occurrence -F, -Cl, -Br, -I, -OH, methyl, ethyl, propyl, butyl, pentyl, hexyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; Preferably, R2 teeth, [ka] [ka] The compound,

[0027] Aspect 23. A compound according to any one of the preceding aspects, wherein R 3 is independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or -CN, where methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl , methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl are each optionally selected from the group consisting of -F, -Cl, -Br, -I, -OH, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, C 1~8 Alkoxy-C 1~8 Alkyl-, -C 2~8 Alkenyl, -C 2~8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, -C6-C 12 substituted with at least one substituent selected from aryl, or 5- to 12-membered heteroaryl; Preferably, R 3is independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or -CN; More preferably, R 3 are independently selected from hydrogen, -F, -Cl, -Br, and -I.

[0028] Aspect 24. A compound according to any one of the preceding aspects, wherein R 4 is oxo (=O).

[0029] Aspect 25. A compound according to any one of the preceding aspects, wherein R 3 and R 4 form, together with the carbon atoms to which they are attached, a 5-6 membered aromatic ring, said ring containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen or sulfur, said ring optionally containing at least one substituent R 3a is replaced by R 3a is independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -CN, where methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, Each of methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl is optionally selected from the group consisting of -F, -Cl, -Br, -I, -OH, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, C 1~8Alkoxy-C 1~8 Alkyl-, -C 2~8 Alkenyl, -C 2~8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, -C6-C 12 The compound is substituted with at least one substituent selected from aryl and 5- to 12-membered heteroaryl.

[0030] Aspect 26. A compound according to any one of the preceding aspects, wherein R 5 is phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzoxazolyl, benzimidazolyl, imidazopyridazinyl, imidazopyridinyl, -COR 5a , -CO2R 5a , or -CONR 5a R 5b wherein each of phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzoxazolyl, benzimidazolyl, imidazopyridazinyl or imidazopyridinyl may optionally be selected from the group consisting of at least one substituent R 5c is replaced by R 5a and R 5b are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C 2~8 Alkenyl, -C 2~8independently selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, oxadiazolyl, triazolyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzoxazolyl, benzimidazolyl, imidazopyridazinyl or imidazopyridinyl; methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2~8 Alkenyl, -C 2~8 Each of alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, oxadiazolyl, triazolyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzoxazolyl, benzimidazolyl, imidazopyridazinyl or imidazopyridinyl may optionally be selected from the group consisting of at least one substituent R 5d or R 5a and R 5b form together with the nitrogen atom to which they are attached a 3-, 4-, 5-, 6-, 7- or 8-membered unsaturated or saturated ring, said ring containing 0, 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen or sulfur, said ring optionally containing at least one substituent R 5d is replaced by R 5c and R 5d is represented, at each occurrence, by hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, imidazopyridazinyl, imidazopyridinyl, oxo (=O), -OR5e , -SR 5e , -CN, -COR 5e , -CO2R 5e , -CONR 5e R 5f , -NR 5e R 5f , -NR 5e COR 5f or -NR 5e CO2R 5f and each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, imidazopyridazinyl, or imidazopyridinyl may optionally be selected from at least one substituent R 5g is replaced by R 5e and R 5f are hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, and C 1~8 Alkoxy-C 1~8 Alkyl-, -C 2~8 Alkenyl, -C 2~8 independently selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzoxazolyl, benzimidazolyl, imidazopyridazinyl or imidazopyridinyl; methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, C 1~8 Alkoxy-C 1~8 Alkyl-, -C 2~8Alkenyl, -C 2~8 Each of alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzoxazolyl, benzimidazolyl, imidazopyridazinyl or imidazopyridinyl may optionally be selected from the group consisting of at least one substituent R 5h is replaced by R 5g and R 5h are halogen, -OH, -CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, and C 1~8 Alkoxy-C 1~8 Alkyl-, -C 2~8 Alkenyl, -C 2~8 The compound is independently selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl.

[0031] Aspect 27. A compound according to any one of the preceding aspects, wherein R 5 is pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzoxazolyl, benzimidazolyl, imidazopyridazinyl or imidazopyridinyl, wherein each of pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzoxazolyl, benzimidazolyl, imidazopyridazinyl, imidazopyridinyl, optionally contains at least one substituent R 5c is replaced by R 5cis independently selected at each occurrence from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, imidazopyridazinyl, imidazopyridinyl; Preferably, R 5 is benzoxazolyl, More preferably, R 5 teeth, [ka] The compound,

[0032] Aspect 28. A compound according to any one of the preceding aspects, wherein R 5 -COR 5a , -CO2R 5a , or -CONR 5a R 5b and Here, R 5a and R 5beach independently being methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, oxadiazolyl, triazolyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzoxazolyl, benzimidazolyl, imidazopyridazinyl, or imidazopyridinyl; wherein each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzoxazolyl, benzimidazolyl, imidazopyridazinyl or imidazopyridinyl may optionally be selected from at least one substituent R 5d is replaced by R 5d is represented for each occurrence by hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, imidazopyridazinyl, imidazopyridinyl, -OR 5e or -CN, each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, imidazopyridazinyl, or imidazopyridinyl may optionally be selected from at least one substituent R 5g is replaced by R 5e is selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzoxazolyl, benzimidazolyl, imidazopyridazinyl, or imidazopyridinyl; and Each of butyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzoxazolyl, benzimidazolyl, imidazopyridazinyl or imidazopyridinyl may optionally be further selected from the group consisting of at least one substituent R 5h is replaced by R 5g and R 5h are each independently selected from halogen, -OH, -CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, or 5-12 membered heteroaryl; Preferably, R 5 teeth, [ka] The compound is -COCH3 or -COCF3.

[0033] Aspect 29. A compound according to any one of the preceding aspects, wherein R 6is H, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2~8 Alkenyl, -C 2~8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, -CN, -OR 6a , -NR 6a R 6b , -COR 6a , -CO2R 6a , -CONR 6a R 6b , -COR 6a or -NR 6a COR 6b methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2~8 Alkenyl, -C 2~8 Each of alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl may optionally be selected from the group consisting of at least one substituent R 6c is replaced by R 6a and R 6b are hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2~8 Alkenyl, -C 2~8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2~8 Alkenyl, -C 2~8Each of alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl may optionally be substituted with at least one substituent R 6d is replaced by R 6c each occurrence independently represents hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, 5-12 membered heteroaryl, oxo (=O), -OR 6e , -SR 6e , -CN, -COR 6e , -CO2R 6e , -CONR 6e R 6f , -NR 6e R 6f , -NR 6e COR 6f or -NR 6e CO2R 6f wherein each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, and 5- to 12-membered heteroaryl may optionally be selected from the group consisting of at least one substituent R 6g is replaced by R 6e and R 6f are hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, and C 1~8 Alkoxy-C 1~8 Alkyl-, -C 2~8 Alkenyl, -C 2~8 independently selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; R 6d and R 6g are respectively -F, -Cl, -Br, -I, -OH, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, and C. 1~8 Alkoxy-C 1~8 Alkyl-, -C 2~8 Alkenyl, -C 2~8 The compound is independently selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl.

[0034] Aspect 30. A compound according to any one of the preceding aspects, wherein R 6 is H, -F, -Cl, -Br, -I, methyl, -CF3, ethyl, -CH2CF3, -CF2CH3, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, -CN, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, [ka] and Preferably, [ka] The part is [ka] The compound,

[0035] Aspect 31. A compound according to any one of the preceding aspects, wherein R 9 and R 10are H, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C 2~8 Alkenyl, -C 2~8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, or 5-12 membered heteroaryl; 2~8 Alkenyl, -C 2~8 Each of alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl or 5-12 membered heteroaryl optionally has at least one substituent R 9a is replaced by R 9a is independently selected from each occurrence halogen, -OH, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, C 1~8 Alkoxy-C 1~8 Alkyl-, -C 2~8 Alkenyl, -C 2~8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; Preferably, R 9 and R 10 are H, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C 2~8 Alkenyl, -C 2~8 independently selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, or 5-12 membered heteroaryl; More preferably, R 9 and R 10are each independently selected from H, methyl, ethyl, propyl, butyl, pentyl, cyclopropyl, cyclobutyl, and cyclopentyl; More preferably, R 9 and R 10 are each independently selected from H and cyclopropyl.

[0036] Aspect 32. The compound according to any one of the preceding aspects, wherein the compound is selected from: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0037] Aspect 33. A pharmaceutical composition comprising a compound according to any one of aspects 1 to 32, or a pharma- ceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof, together with a pharma- ceutically acceptable excipient.

[0038] Aspect 34. A method of decreasing IL-17 activity by inhibition, comprising administering to an individual a compound according to any one of aspects 1 to 32, including a compound of formula (I) or a specific compound exemplified herein, or a pharma- ceutically acceptable salt thereof.

[0039] Aspect 35. The method of aspect 34, wherein the disease is selected from cancer.

[0040] Aspect 36. Use of a compound according to any one of aspects 1 to 32, or a pharma- ceutically acceptable salt, stereoisomer, tautomer or prodrug thereof, in the preparation of a medicament for treating a disease that can be affected by IL-17.

[0041] Aspect 37. The use according to aspect 36, wherein the disease is an autoimmune disease or an inflammatory disease.

[0042] Aspect 38. The use according to aspect 37, wherein the disease is chronic inflammation, psoriasis, spondyloarthritis, rheumatoid arthritis or multiple sclerosis. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0043] The following terms have the indicated meanings throughout this specification:

[0044] As used in this specification, including the accompanying embodiments, singular terms such as "a," "an," and "the" include references to their corresponding plural forms unless the context clearly requires otherwise.

[0045] The term "or" is used to mean, and is used interchangeably with, the term "and / or," unless the context clearly requires otherwise.

[0046] The term "alkyl" refers to a hydrocarbon group selected from linear and branched chain saturated hydrocarbon groups containing 1 to 18 (such as 1 to 12, further such as 1 to 10, even further such as 1 to 8, or 1 to 6, or 1 to 4) carbon atoms. Alkyl groups containing 1 to 6 carbon atoms (i.e., C 1~6Examples of alkyl include, but are not limited to, methyl, ethyl, 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr"), 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or s-butyl ("s-Bu"), 1,1-dimethylethyl or t-butyl ("t-Bu"), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl groups.

[0047] The term "cycloalkyl" refers to a hydrocarbon group selected from saturated cyclic hydrocarbon groups, including monocyclic and polycyclic (eg, bicyclic and tricyclic) groups, including fused, bridged, or spirocycloalkyl.

[0048] The term "aryl," used alone or in combination with other terms, refers to a group selected from: 5- and 6-membered carbocyclic aromatic rings (e.g., phenyl), Bicyclic ring systems, such as 7-12 membered bicyclic ring systems in which at least one ring is carbocyclic and aromatic (e.g., naphthyl and indanyl), and Tricyclic ring systems, such as 10-15 membered tricyclic ring systems in which at least one ring is carbocyclic and aromatic (eg, fluorenyl).

[0049] The terms "aromatic hydrocarbon ring" and "aryl" are used interchangeably throughout this disclosure. In some embodiments, the monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 ring-forming carbon atoms (i.e., C 5~10aryl). Examples of monocyclic or bicyclic aromatic hydrocarbon rings include, but are not limited to, phenyl, naphth-1-yl, naphth-2-yl, anthracenyl, phenanthrenyl, and the like. In some embodiments, the aromatic hydrocarbon ring is a naphthalene ring (naphth-1-yl or naphth-2-yl) or a phenyl ring. In some embodiments, the aromatic hydrocarbon ring is a phenyl ring.

[0050] The term "aryl-alkyl-" refers to an alkyl group as defined above that is further substituted with an aryl group. Examples of aryl-alkyl groups include aryl-C, such as phenylethyl, or phenylmethyl (benzyl). 1~8 Examples of such alkyl groups include alkyl.

[0051] The term "heteroaryl" refers to a group selected from: a 5-, 6-, or 7-membered aromatic monocyclic ring containing at least one heteroatom (e.g., 1-4, or in some embodiments, 1-3, and in some embodiments, 1-2 heteroatoms) selected from nitrogen (N), sulfur (S), and oxygen (O), with the remaining ring atoms being carbon; a 7-12 membered bicyclic ring containing at least one heteroatom (e.g., 1-4, or in some embodiments 1-3, or in other embodiments 1 or 2 heteroatoms) selected from N, O, and S, with the remaining ring atoms being carbon, and at least one ring being aromatic, with at least one heteroatom being present in the aromatic ring; An 11-14 membered tricyclic ring containing at least one heteroatom (e.g., 1-4, or in some embodiments 1-3, or in other embodiments 1 or 2 heteroatoms) selected from N, O, and S, with the remaining ring atoms being carbon, and at least one ring being aromatic, with at least one heteroatom being present in the aromatic ring.

[0052] When the total number of S and O atoms in a heteroaryl group exceeds 1, the heteroatoms are not adjacent to one another. In some embodiments, the total number of S and O atoms in a heteroaryl group is 2 or less. In some embodiments, the total number of S and O atoms in an aromatic heterocycle is 1 or less. When a heteroaryl group contains more than one heteroatom ring member, the heteroatoms can be the same or different. Nitrogen atoms in the ring(s) of a heteroaryl group can be oxidized to form an N-oxide. As used herein, the term "C-linked heteroaryl" means that a heteroaryl group is attached to a core molecule by a bond originating from a C-atom of the heteroaryl ring.

[0053] The terms "aromatic heterocycle" and "heteroaryl" are used interchangeably throughout the disclosure herein. In some embodiments, a monocyclic or bicyclic aromatic heterocycle has 5, 6, 7, 8, 9, or 10 ring members, with 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O), and the remaining ring members are carbon. In some embodiments, a monocyclic or bicyclic aromatic heterocycle is a monocyclic or bicyclic ring containing 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O). In some embodiments, a monocyclic or bicyclic aromatic heterocycle is a monocyclic 5-6 membered heteroaryl ring having 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O). In some embodiments, the monocyclic or bicyclic aromatic heterocycle is a bicyclic, 8-10 membered heteroaryl ring having 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen.

[0054] "Heterocyclyl", "heterocycle" or "heterocyclic" are interchangeable and refer to a non-aromatic heterocyclyl group containing one or more heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring members, with the remaining ring members being carbon, including monocyclic, fused, bridged, and spiro rings (i.e., monocyclic, bridged, spiro, and fused heterocyclyl groups are encompassed). As used herein, the term "optionally oxidized sulfur" refers to S, SO, or SO2.

[0055] The compounds disclosed herein may contain asymmetric centers and therefore may exist as enantiomers. "Enantiomer" refers to two stereoisomers of a compound that are non-superimposable mirror images of each other. When the compounds disclosed herein have two or more asymmetric centers, they may further exist as diastereomers. Enantiomers and diastereomers belong to a broader class of stereoisomers. All such possible stereoisomers are intended to be included, as substantially pure separated enantiomers, racemic mixtures thereof, as well as diastereomeric mixtures. All stereoisomers of the compounds disclosed herein and / or their pharma-ceutically acceptable salts are intended to be included. Unless otherwise specifically stated, a reference to one isomer applies to any of the possible isomers. Whenever the composition of an isomer is not specified, all possible isomers are included.

[0056] As used herein, the term "substantially pure" means that the stereoisomer of interest contains 35% or less by weight (such as 30% or less by weight, even such as 25% or less by weight, even more such as 20% or less by weight) of any other stereoisomer(s). In some embodiments, the term "substantially pure" means that the stereoisomer of interest contains 10% or less by weight (e.g., 5% or less by weight, 1% or less by weight, etc.) of any other stereoisomer(s).

[0057] When the compounds disclosed herein contain olefinic double bonds, unless otherwise specified, such double bonds are meant to include both E and Z geometric isomers.

[0058] When the compounds disclosed herein contain a disubstituted cyclohexyl or cyclobutyl group, the substituents found on the cyclohexyl or cyclobutyl ring may adopt cis and trans configurations, where cis means that the two substituents on the carbon are both found on the top side, whereas trans means that the two substituents are on opposite sides.

[0059] It may be advantageous to separate reaction products from one another and / or from starting materials. The desired products of each step or series of steps are separated and / or purified (hereinafter separated) to the desired degree of homogeneity by techniques common in the art. Typically, such separation requires multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can include many methods, including, for example, reverse and normal phase, size exclusion, ion exchange, high, medium and low pressure liquid chromatography methods and equipment, small scale analytical, simulated moving bed ("SMB") and preparative thin or thick layer chromatography, as well as small scale thin layer techniques and flash chromatography. The skilled artisan will apply the technique most likely to achieve the desired separation.

[0060] "Diastereomer" refers to stereoisomers of a compound that have two or more chiral centers, but are not mirror images of one another. Diastereomeric mixtures can be separated into individual diastereomers based on their physical chemical differences by methods well known to those skilled in the art, such as chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture to a diastereomeric mixture by reaction with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and converting the individual diastereoisomers into the corresponding pure enantiomers (e.g., by hydrolysis). Enantiomers can also be separated by the use of chiral HPLC columns.

[0061] "Pharmaceutically acceptable salts" refers to salts that are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic responses, and the like, within the scope of sound medical judgment, and commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compounds disclosed herein, or separately, by reacting free base functional groups with a suitable organic acid, or acidic groups with a suitable base.

[0062] In addition, when the compounds disclosed herein are obtained as acid addition salts, the free base can be obtained by basifying a solution of the acid salt. Conversely, when the product is a free base, the addition salt (such as a pharma- ceutically acceptable addition salt) can be produced by dissolving the free base in a suitable organic solvent and / or water and treating the solution with an acid according to conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methods that can be used without undue experimentation to prepare non-toxic pharma-ceutically acceptable addition salts.

[0063] As defined herein, "a pharma- ceutically acceptable salt thereof" includes at least one salt of a compound of formula (I), and salts of stereoisomers of a compound of formula (I), such as enantiomeric and / or diastereomeric salts.

[0064] The terms "administration," "administering," "treating," and "treatment," as used herein, when applied to an animal, human, experimental subject, cell, tissue, organ, or bodily fluid, refer to contacting an exogenous pharmaceutical, therapeutic, diagnostic, or composition with the animal, human, subject, cell, tissue, organ, or bodily fluid. Treatment of a cell includes contact of a cell with a reagent, as well as contact of a fluid with a reagent, where the fluid is in contact with the cell. The terms "administration" and "treatment" also refer to in vitro and ex vivo treatment (e.g., of a cell) with a reagent, diagnostic, binding compound, or with another cell. The term "subject" as used herein includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, and rabbit), and most preferably a human.

[0065] The term "effective amount" or "therapeutically effective amount" refers to an amount of an active ingredient (such as a compound) sufficient to affect treatment for a disease, or at least one of the clinical symptoms of a disease or disorder, when administered to a subject. A "therapeutically effective amount" may vary depending on the compound, the disease, disorder, and / or symptoms of the disease or disorder, the severity of the disease, disorder, and / or symptoms of the disease or disorder, the age of the subject to be treated, and / or the weight of the subject to be treated. The appropriate amount in any given case may be apparent to one of skill in the art or may be determined by routine experimentation. In some embodiments, a "therapeutically effective amount" is an amount of at least one compound disclosed herein and / or at least one stereoisomer thereof, and / or at least one pharma- ceutically acceptable salt thereof, which is effective in "treating" a disease or disorder in a subject, as defined above. In the case of a combination therapy, a "therapeutically effective amount" refers to the total amount of the combination to effectively treat a disease, disorder, or condition.

[0066] The pharmaceutical composition comprising the compound disclosed herein can be administered to a subject in need thereof by oral, inhalation, rectal, parenteral or topical administration.For oral administration, the pharmaceutical composition can be a conventional solid formulation such as tablet, powder, granule, capsule and the like, a liquid formulation such as water or oil suspension, or other liquid formulation such as syrup, solution, suspension or the like, and for parenteral administration, the pharmaceutical composition can be a solution, an aqueous solution, an oil suspension concentrate, a lyophilized powder or the like.Preferably, the dosage form of the pharmaceutical composition is selected from tablet, coated tablet, capsule, suppository, nasal spray or injection, and more preferably, it is a tablet or capsule.The pharmaceutical composition can be administered in a single unit of precise dosage.In addition, the pharmaceutical composition can further comprise additional active ingredients.

[0067] All formulations of the pharmaceutical compositions disclosed herein can be prepared by conventional methods in the pharmaceutical field. For example, active ingredients can be mixed with one or more excipients to prepare desired formulations. "Pharmaceutically acceptable excipients" refers to conventional pharmaceutical carriers suitable for desired pharmaceutical formulations, such as diluents, vehicles (e.g., water, various organic solvents, etc.), fillers (e.g., starch, sucrose, etc.), binders (e.g., cellulose derivatives, alginates, gelatin, and polyvinylpyrrolidone (PVP)), wetting agents (e.g., glycerol), disintegrants (e.g., agar, calcium carbonate, and sodium bicarbonate), absorption enhancers (e.g., quaternary ammonium compounds), surfactants (e.g., hexadecanol), adsorption carriers (e.g., kaolin and bentonite), lubricants (e.g., talc, calcium stearate, magnesium stearate, polyethylene glycol, etc.). In addition, the pharmaceutical composition may further comprise other pharma- ceutically acceptable excipients such as dispersing agents, stabilizers, thickening agents, complexing agents, buffers, permeation enhancers, polymers, flavors, sweeteners, and dyes.

[0068] The term "disease" refers to any disease, ailment, illness, symptom or symptom, and is interchangeable with the terms "disorder" or "condition."

[0069] Throughout this specification and embodiments thereof, unless otherwise required by context, the term "comprise", as well as variations such as "comprises" and "comprising", are intended to specify the presence of the feature preceding the term, but do not exclude the presence or addition of one or more other features. As used herein, the term "comprise" may be replaced with the term "containing", "including" or, in some cases, "having".

[0070] Throughout this specification and embodiments thereunder, "C n~m The term " refers to a range inclusive of the endpoints, where n and m are integers and refer to the number of carbon atoms. Examples include 1~8 , C 1~6 , and the like.

[0071] Unless specifically defined elsewhere herein, all other technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs. EXAMPLES

[0072] The present invention is further illustrated by the following examples which illustrate, but do not limit, the present invention.

[0073] In the examples below, the following abbreviations are used: [Table 1-1] [Table 1-2] [Table 1-3]

[0074] The following examples are intended to be purely illustrative and should not be considered as limiting in any way. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should be accounted for. Temperatures are in degrees Celsius unless otherwise indicated. Reagents were purchased from commercial sources such as Sigma-Aldrich, Alfa Aesar, or TCI, and were used without further purification unless otherwise indicated.

[0075] Unless otherwise indicated, reactions described below were carried out under a positive pressure of nitrogen or argon or in anhydrous solvents using drying tubes, reaction flasks were fitted with rubber septa for the introduction of substrates and reagents via syringe, and glassware was oven-dried and / or heat-dried.

[0076] 1 1 H NMR spectra were recorded on a 400 MHz Agilent instrument. 1 HNMR spectra were obtained using CDCl3, CD2Cl2, CD3OD, DO, d6-DMSO, d6-acetone or (CD3)2CO as solvents and tetramethylsilane (0.00 ppm) or residual solvent (CDCl3: 7.25 ppm, CD3OD: 3.31 ppm, DO: 4.79 ppm, d6-DMSO: 2.50 ppm, d6-acetone: 2.05, (CD3)2CO: 2.05) as standards. When peak multiplicities are reported, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), qn (quintet), sx (sexlet), m (multiplet), br (broad line), dd (double doublet), dt (double triplet). Coupling constants given are reported in Hertz (Hz).

[0077] LC-MS spectrometer (Agilent 1260) Detector: MWD (190-400 nm), Mass detector: 6120 SQ

[0078] Mobile phase: A: acetonitrile containing 0.1% formic acid, B: water containing 0.1% formic acid

[0079] Column: Poroshell 120 EC-C18, 4.6 x 50 mm, 2.7 μm

[0080] Gradient Method: Flow rate: 1.8 mL / min [Table 2]

[0081] Preparative HPLC was performed on columns (150×21.2 mm ID, 5 μm, Gemini NX- C18) and (150×19 mm, 5 μm, SunFire Prep C18 OBD™) at different flow rates and injection volumes at room temperature with UV detection at 214 nm and 254 nm.

[0082] Combi Flash® was performed on a column (C18 spherical 20-35 μm) at different flow rates and injection volumes at room temperature with UV detection at 214 nm and 254 nm.

[0083] Preparation of intermediate (Int): Int A1: 5-((S)-2-amino-2-cyclohexylacetamido)-N-methyl-2-(6-oxo-5,7-diazaspiro[2.5]octan-5-yl)-2,3-dihydro-1H-indene-2-carboxamide Step 1: 2-Amino-N-methyl-2,3-dihydro-1H-indene-2-carboxamide [ka] A mixture of methyl 2-amino-2,3-dihydro-1H-indene-2-carboxylate (3.8 g, 20 mmol) in MeNH2 solution (33% in EtOH, wt, 20 mL) was heated to 80° C. in a sealed tube for 4 h. The reaction was cooled to ambient temperature and concentrated in vacuo to give the title compound (3.7 g, yield: 97.32%).

[0084] Step 2: 2-Amino-N-methyl-5-nitro-2,3-dihydro-1H-indene-2-carboxamide [ka] At 0°C, 2-amino-N-methyl-2,3-dihydro-1H-indene-2-carboxamide (3.7 g, 19.46 mmol, solution in 6 mL HOAc) was added slowly in one portion to a mixture of H2SO4 (3 mL) and HNO3 (3 mL) and stirred for 15 min. At 0°C, the reaction mixture was poured into NaHCO3 solution (aq, 200 mL) and then diluted with DCM (200 mL). The organic layer was separated, dried and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluent: DCM / MeOH (v / v) = 20 / 0 to 20 / 1) to give the title compound (3.28 g, yield: 71.56%).

[0085] Step 3: tert-Butyl (2-(methylcarbamoyl)-5-nitro-2,3-dihydro-1H-inden-2-yl)carbamate [ka] A mixture of 2-amino-N-methyl-5-nitro-2,3-dihydro-1H-indene-2-carboxamide (1.18 g, 5 mmol) and Boc2O (1.15 g, 5.25 mmol) in DCM (50 mL) was stirred overnight. The mixture was quenched with brine (50 mL), separated, and the organic phase was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (eluent: DCM / MeOH (v / v) = 50 / 1 to 20 / 1) to give the title product (1.31 g, yield: 77.52%). MS (ESI, m / e) [M+1] + 336.3.

[0086] Step 4: tert-Butyl (5-amino-2-(methylcarbamoyl)-2,3-dihydro-1H-inden-2-yl)carbamate [ka] A mixture of tert-butyl (2-(methylcarbamoyl)-5-nitro-2,3-dihydro-1H-inden-2-yl)carbamate (1.31 g, 3.90 mmol) and Pd / C (150 mg) in MeOH (50 mL) was bubbled with a H2 balloon and stirred overnight. The mixture was filtered, concentrated in vacuo, and purified by column chromatography on silica gel (eluent: DCM / MeOH (v / v) = 50 / 1 to 20 / 1) to give the title product (1.06 g, yield: 88.99%). MS (ESI, m / e) [M+1] + 306.0.

[0087] Step 5: tert-Butyl (5-((S)-2-(((benzyloxy)carbonyl)amino)-2-cyclohexylacetamido)-2-(methylcarbamoyl)-2,3-dihydro-1H-inden-2-yl)carbamate [ka] A mixture of (S)-2-(((benzyloxy)carbonyl)amino)-2-cyclohexylacetic acid (909 mg, 3.0 mmol), (5-amino-2-(methylcarbamoyl)-2,3-dihydro-1H-inden-2-yl)carbamate tert-butyl (915 mg, 3.0 mmol), HATU (1.14 g, 3.0 mmol) and TEA (606 mg, 6.0 mmol) in DCM (100 mL) was stirred at room temperature for 4 h. The mixture was quenched with aq. NaHCO3 (150 mL), separated and the organic phase was dried over Na2SO4 and concentrated in vacuum. The crude product was purified by column chromatography on silica gel (eluent: DCM / MeOH (v / v) = 50 / 1 to 20 / 1) to give the title product (1.41 g, yield: 80.67%). MS (ESI, m / e) [M+1] + 579.3.

[0088] Step 6: Benzyl ((1S)-2-((2-amino-2-(methylcarbamoyl)-2,3-dihydro-1H-inden-5-yl)amino)-1-cyclohexyl-2-oxoethyl)carbamate [ka] A mixture of tert-butyl (5-((S)-2-(((benzyloxy)carbonyl)amino)-2-cyclohexylacetamido)-2-(methylcarbamoyl)-2,3-dihydro-1H-inden-2-yl)carbamate (5 g, 8.6 mmol) and TFA (20 mL) in DCM (50 mL) was stirred at 20° C. for 2 h. The reaction mixture was then concentrated under reduced pressure. The residue was diluted with H2O (50 mL) and the aqueous phase was basified to pH ∼8-9 with Na2CO3. The mixture was extracted with EtOAc (50 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give ((1S)-2-((2-amino-2-(methylcarbamoyl)-2,3-dihydro-1H-inden-5-yl)amino)-1-cyclohexyl-2-oxoethyl)benzylcarbamate (4 g, crude). MS (ESI, m / e) [M+H] + 479.3.

[0089] Step 7: Benzyl ((1S)-2-((2-(((1-(((tert-butoxycarbonyl)amino)methyl)cyclopropyl)methyl)amino)-2-(methylcarbamoyl)-2,3-dihydro-1H-inden-5-yl)amino)-1-cyclohexyl-2-oxoethyl)carbamate [ka] To a solution of ((1S)-2-((2-amino-2-(methylcarbamoyl)-2,3-dihydro-1H-inden-5-yl)amino)-1-cyclohexyl-2-oxoethyl)benzylcarbamate (0.8 g, 1.7 mmol) and ((1-formylcyclopropyl)methyl)carbamate tert-butyl (0.5 g, 2.5 mmol) in DCM (15 mL) at 0° C., AcOH (0.2 g, 3.4 mmol) and NaBH(OAc) (0.931 g, 4.2 mmol) were added. The mixture was stirred at 25° C. for 3 h. The reaction mixture was then diluted with aq. NaHCO (20 mL), extracted with DCM (10 mL×3), washed with brine, dried over NaSO, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate (v / v) = 100 / 1 to 0 / 1) to obtain the title compound (0.65 g, yield: 59%).

[0090] Step 8: Benzyl ((1S)-2-((2-(((1-(aminomethyl)cyclopropyl)methyl)amino)-2-(methylcarbamoyl)-2,3-dihydro-1H-inden-5-yl)amino)-1-cyclohexyl-2-oxoethyl)carbamate [ka] A mixture of ((1S)-2-((2-(((1-(((tert-butoxycarbonyl)amino)methyl)cyclopropyl)methyl)amino)-2-(methylcarbamoyl)-2,3-dihydro-1H-inden-5-yl)amino)-1-cyclohexyl-2-oxoethyl)benzyl carbamate (0.65 g, 0.982 mmol) in HCl / EtOAc (10 mL) was stirred at 25° C. for 2 h. The reaction mixture was concentrated under reduced pressure to give ((1S)-2-((2-(((1-(aminomethyl)cyclopropyl)methyl)amino)-2-(methylcarbamoyl)-2,3-dihydro-1H-inden-5-yl)amino)-1-cyclohexyl-2-oxoethyl)benzyl carbamate (0.55 g, HCl salt). MS (ESI, m / e) [M+H] + 562.3.

[0091] Step 9: ((1S)-1-Cyclohexyl-2-((2-(methylcarbamoyl)-2-(6-oxo-5,7-diazaspiro[2.5]octan-5-yl)-2,3-dihydro-1H-inden-5-yl)amino)-2-oxoethyl)carbamate benzyl [ka] To a solution of ((1S)-2-((2-(((1-(aminomethyl)cyclopropyl)methyl)amino)-2-(methylcarbamoyl)-2,3-dihydro-1H-inden-5-yl)amino)-1-cyclohexyl-2-oxoethyl)benzylcarbamate (0.55 g, 0.98 mmol) in THF (10 mL) was added TEA (0.198 g, 1.9 mmol) and CDI (0.317 g, 1.9 mmol). The mixture was stirred at 60° C. for 8 h. The reaction mixture was poured into ice / water (10 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate (v / v) = 100 / 1 to 0 / 1) to give ((1S)-1-cyclohexyl-2-((2-(methylcarbamoyl)-2-(6-oxo-5,7-diazaspiro[2.5]octan-5-yl)-2,3-dihydro-1H-inden-5-yl)amino)-2-oxoethyl)benzyl carbamate (0.46 g, yield: 80%).

[0092] Step 10: 5-((S)-2-amino-2-cyclohexylacetamido)-N-methyl-2-(6-oxo-5,7-diazaspiro[2.5]octan-5-yl)-2,3-dihydro-1H-indene-2-carboxamide (Int A1) To a solution of ((1S)-1-cyclohexyl-2-((2-(methylcarbamoyl)-2-(6-oxo-5,7-diazaspiro[2.5]octan-5-yl)-2,3-dihydro-1H-inden-5-yl)amino)-2-oxoethyl)benzylcarbamate (0.41 g, 0.698 mmol) and MeNH2.H2O (1 mL) in MeOH (10 mL) was added Pd(OH)2 (0.1 g, 0.698 mmol). The mixture was stirred at 50 °C for 1 h under H2 (15 Psi). The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered and concentrated under reduced pressure to give 5-((S)-2-amino-2-cyclohexylacetamido)-N-methyl-2-(6-oxo-5,7-diazaspiro[2.5]octan-5-yl)-2,3-dihydro-1H-indene-2-carboxamide (280 mg, yield: 87%). 1 H NMR (400 MHz, DMSO-d6) δ ppm: 10.08 - 9.41 (m, 1 H), 7.50 (s, 1 H), 7.40 - 7.22 (m, 2 H), 7.06 (d, J = 8.4 Hz, 1 H), 6.42 (s, 1H), 3.55 - 3.39 (m, 3 H), 3.12 - 2.93 (m, 5 H), 2.91 - 2.81 (m, 2 H), 2.56 (d, J = 4.8 Hz, 3 H), 2.00 - 1.81 (m, 1 H), 1.69 (d, J = 10.0 Hz, 3 H), 1.62 - 1.45 (m, 3H), 1.23 - 0.97 (m, 5 H), 0.45 - 0.32 (m, 2 H), 0.19 - 0.44 (m, 2 H). MS (ESI, m / e) [M+H] + 454.3.

[0093] Int A2: 5-((S)-2-amino-2-cyclohexylacetamido)-2-((R)-4-isopropyl-2-oxoimidazolidin-1-yl)-N-methyl-2,3-dihydro-1H-indene-2-carboxamide Step 1: tert-butyl ((2R)-3-methyl-1-((2-(methylcarbamoyl)-5-nitro-2,3-dihydro-1H-inden-2-yl)amino)butan-2-yl)carbamate [ka] To a solution of 2-amino-N-methyl-5-nitro-2,3-dihydro-1H-indene-2-carboxamide (10 g, 42.51 mmol) and (R)-(3-methyl-1-oxobutan-2-yl) tert-butyl carbamate (15.4 g, 78.52 mmol) in MeOH (100 mL) was added NaBH3CN (5.17 g, 858.02 mmol). The mixture was stirred at 25° C. for 12 h. The reaction mixture was then concentrated under reduced pressure. The residue was diluted with water (50 mL) and extracted with DCM (50 mL×3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by preparative MPLC (SiO2 column, eluent: petroleum ether / ethyl acetate (v / v) = 10 / 1 to 0 / 1) to give tert-butyl ((2R)-3-methyl-1-((2-(methylcarbamoyl)-5-nitro-2,3-dihydro-1H-inden-2-yl)amino)butan-2-yl)carbamate (13 g, yield: 73%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.08 (d, J = 10.0 Hz, 2 H), 7.63 - 7.61 (m, 1 H), 7.34 (d, J = 8.0 Hz, 1 H), 7.19 (d, J = 3.2 Hz, 1 H), 4.31 (s, 1 H), 3.70 - 3.59 (m, 3 H), 3.44 (s, 1 H), 3.02 - 2.99 (m, 2 H), 2.88 (d, J = 4.8 Hz, 1 H), 2.58 - 2.55 (m, 1 H), 2.35 - 2.33 (m, 1 H), 1.68 - 1.66 (m, 2 H), 1.45 (s, 9 H), 0.89 - 0.85 (m, 6 H).

[0094] Step 2: 2-(((R)-2-amino-3-methylbutyl)amino)-N-methyl-5-nitro-2,3-dihydro-1H-indene-2-carboxamide [ka] To a solution of tert-butyl ((2R)-3-methyl-1-((2-(methylcarbamoyl)-5-nitro-2,3-dihydro-1H-inden-2-yl)amino)butan-2-yl)carbamate (7.8 g, 18.55 mmol) in DCM (80 mL) was added TFA (10 mL). The mixture was stirred at 20° C. for 13 h. After concentration to remove TFA, the reaction mixture was quenched with saturated NaHCO3 (50 mL) and then extracted with DCM (100 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by preparative MPLC (SiO2 column, eluent: petroleum ether / ethyl acetate (v / v) = 100 / 1 to 0 / 1) to give 2-(((R)-2-amino-3-methylbutyl)amino)-N-methyl-5-nitro-2,3-dihydro-1H-indene-2-carboxamide (4.5 g, yield: 76%). MS (ESI, m / e) [M+H] + 321.2.

[0095] Step 3: 2-((R)-4-isopropyl-2-oxoimidazolidin-1-yl)-N-methyl-5-nitro-2,3-dihydro-1H-indene-2-carboxamide [ka] A mixture of 2-(((R)-2-amino-3-methylbutyl)amino)-N-methyl-5-nitro-2,3-dihydro-1H-indene-2-carboxamide (4 g, 12.48 mmol), TEA (0.5 mL) and CDI (3.04 g, 18.73 mmol) in THF (40 mL) was stirred under reflux for 1 h. The reaction mixture was concentrated under reduced pressure, then diluted with water (50 mL) and extracted with DCM (50 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by preparative MPLC (SiO2 column, eluent: petroleum ether / ethyl acetate (v / v) = 100 / 1 to 0 / 1) to give 2-((R)-4-isopropyl-2-oxoimidazolidin-1-yl)-N-methyl-5-nitro-2,3-dihydro-1H-indene-2-carboxamide (3.5 g, yield: 80%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.08 (d, J = 7.2 Hz, 2 H), 7.69 (s, 1 H), 7.37 - 7.33 (m, 1 H), 7.12 (s, 1 H), 7.05 (s, 1 H), 4.75 (s, 1 H), 3.87 - 3.83 (m, 2 H), 3.63 - 3.55 (m, 2 H), 3.44 - 3.39 (m, 2 H), 3.14 - 3.12 (m, 1 H), 2.77 (d, J = 7.6 Hz, 3 H), 1.63 - 1.62 (m, 1 H), 0.89 - 0.83 (m, 6H).

[0096] Step 4: 5-amino-2-((R)-4-isopropyl-2-oxoimidazolidin-1-yl)-N-methyl-2,3-dihydro-1H-indene-2-carboxamide [ka] To a solution of 2-((R)-4-isopropyl-2-oxoimidazolidin-1-yl)-N-methyl-5-nitro-2,3-dihydro-1H-indene-2-carboxamide (8.1 g, 25.58 mmol) in CHOH (80 mL) was added Pd / C (1 g). The reaction mixture was purged with H three times and hydrogenated under H atmosphere (50 psi) at 50° C. for 12 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by preparative MPLC (SiO2 column, eluent: petroleum ether / ethyl acetate (v / v) = 100 / 1 to 0 / 1) to give 5-amino-2-((R)-4-isopropyl-2-oxoimidazolidin-1-yl)-N-methyl-2,3-dihydro-1H-indene-2-carboxamide (6.1 g, yield: 70%). MS (ESI, m / e) [M+H] + 317.3.

[0097] Step 5: tert-Butyl ((1S)-1-cyclohexyl-2-((2-((R)-4-isopropyl-2-oxoimidazolidin-1-yl)-2-(methylcarbamoyl)-2,3-dihydro-1H-inden-5-yl)amino)-2-oxoethyl)carbamate [ka] To a solution of 5-amino-2-((R)-4-isopropyl-2-oxoimidazolidin-1-yl)-N-methyl-2,3-dihydro-1H-indene-2-carboxamide (1.5 g, 4.74 mmol), TEA (719.59 mg, 7.11 mmol) and (S)-2-((tert-butoxycarbonyl)amino)-2-cyclohexylacetic acid (1.45 g, 5.69 mmol) in DCM (20 mL) at 0° C., HATU (2.16 g, 5.69 mmol) was added. The mixture was stirred at 20° C. for 3 h. The reaction mixture was then quenched with H2O (50 mL) and extracted with DCM (50 mL×3). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by preparative MPLC (SiO2 column, eluent: petroleum ether / ethyl acetate (v / v) = 100 / 1 to 1 / 1) to give tert-butyl ((1S)-1-cyclohexyl-2-((2-((R)-4-isopropyl-2-oxoimidazolidin-1-yl)-2-(methylcarbamoyl)-2,3-dihydro-1H-inden-5-yl)amino)-2-oxoethyl)carbamate (2.5 g, yield: 95%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.75 (s, 1 H), 7.52 - 7.45 (m, 2 H), 7.34 - 7.26 (m, 1 H), 7.16 - 7.08 (m, 1 H), 6.82 - 6.75 (m, 2 H), 3.92 - 3.90 (m, 1 H), 3.56 - 3.48 (m, 2 H), 3.21 - 3.18 (m, 2 H), 3.11 - 3.08 (m, 2 H), 2.90 - 2.88 (m, 1 H), 2.56 (d, J = 4.4 Hz, 3 H), 1.75 - 1.50 (m, 6 H), 1.42 (s, 9 H), 1.15 - 1.02 (m, 4 H), 0.74 - 0.65 (m, 6 H).

[0098] Step 6: 5-((S)-2-amino-2-cyclohexylacetamido)-2-((R)-4-isopropyl-2-oxoimidazolidin-1-yl)-N-methyl-2,3-dihydro-1H-indene-2-carboxamide (Int A2) A solution of tert-butyl ((1S)-1-cyclohexyl-2-((2-((R)-4-isopropyl-2-oxoimidazolidin-1-yl)-2-(methylcarbamoyl)-2,3-dihydro-1H-inden-5-yl)amino)-2-oxoethyl)carbamate (2.5 g, 4.5 mmol) and TFA (5 m) in DCM (20 mL) was stirred at 20° C. for 3 h. After concentration in vacuo to remove TFA, the reaction mixture was quenched with saturated NaHCO3 (50 mL) and extracted with DCM (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by preparative MPLC (SiO2 column, eluent: petroleum ether / ethyl acetate (v / v) = 100 / 1 to 0 / 1) to give 5-((S)-2-amino-2-cyclohexylacetamido)-2-((R)-4-isopropyl-2-oxoimidazolidin-1-yl)-N-methyl-2,3-dihydro-1H-indene-2-carboxamide (1270 mg, yield: 62%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.25 (s, 1 H), 7.55 - 7.44 (m, 4 H), 7.37 - 7.31 (m, 1 H), 7.15 (d, J = 8.0 Hz, 1 H), 6.77 (d, J = 11.2 Hz, 1 H), 3.60 - 3.48 (m, 3 H), 3.36 - 3.34 (m, 3 H), 3.22 - 3.16 (m, 2 H), 2.84 - 2.82 (m, 1 H), 2.56 (d, J = 4.4 Hz, 3 H), 1.75 - 1.50 (m, 6 H), 1.45 (s, 1 H), 1.15 - 1.02 (m, 5 H), 0.74 - 0.67 (m, 6 H). MS (ESI, m / e) [M+H] + 456.3.

[0099] Int A3: 5-((S)-2-amino-3,3-dicyclopropylpropanamido)-2-((R)-4-isopropyl-2-oxoimidazolidin-1-yl)-N-(o-tolyl)-2,3-dihydro-1H-indene-2-carboxamide Step 1: 5-amino-2-((R)-4-isopropyl-2-oxoimidazolidin-1-yl)-2,3-dihydro-1H-indene-2-carboxylate methyl [ka] To a solution of methyl 2-((R)-4-isopropyl-2-oxoimidazolidin-1-yl)-5-nitro-2,3-dihydro-1H-indene-2-carboxylate (5.9 g, 16.9 mmol, prepared by a similar procedure to 2-((R)-4-isopropyl-2-oxoimidazolidin-1-yl)-N-methyl-5-nitro-2,3-dihydro-1H-indene-2-carboxamide described in Int A2) in MeOH (60 mL) was added Raney Ni (0.6 g, 1.69 mmol) at room temperature under N2. The mixture was hydrogenated at 60° C. for 1 h under H2 atmosphere (15 psi). The reaction mixture was filtered through a celite pad and washed with MeOH (50 mL). The filtrate was concentrated in vacuo to give methyl 5-amino-2-((R)-4-isopropyl-2-oxoimidazolidin-1-yl)-2,3-dihydro-1H-indene-2-carboxylate (2.5 g, crude), which was used directly in the next step. MS (ESI, m / e) [M+H] + 318.1.

[0100] Step 2: 5-((S)-2-(((benzyloxy)carbonyl)amino)-3,3-dicyclopropylpropanamido)-2-((R)-4-isopropyl-2-oxoimidazolidin-1-yl)-2,3-dihydro-1H-indene-2-carboxylate methyl [ka] To a solution of methyl 5-amino-2-((R)-4-isopropyl-2-oxoimidazolidin-1-yl)-2,3-dihydro-1H-indene-2-carboxylate (2.5 g), DIEA (3.05 g, 23.6 mmol) and (S)-2-(((benzyloxy)carbonyl)amino)-3,3-dicyclopropylpropanoic acid (2.39 g, 7.88 mmol) in DCM (25 mL) at 0° C., HATU (3.0 g, 7.88 mmol) was added. The mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with water (30 mL) and then extracted with DCM (30 mL×3). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate (v / v) = 100 / 1 to 0 / 1) to give methyl 5-((S)-2-(((benzyloxy)carbonyl)amino)-3,3-dicyclopropylpropanamido)-2-((R)-4-isopropyl-2-oxoimidazolidin-1-yl)-2,3-dihydro-1H-indene-2-carboxylate (2.5 g, yield: 53%). MS (ESI, m / e) [M+H] + 603.3.

[0101] Step 3: 5-((S)-2-(((benzyloxy)carbonyl)amino)-3,3-dicyclopropylpropanamido)-2-((R)-4-isopropyl-2-oxoimidazolidin-1-yl)-2,3-dihydro-1H-indene-2-carboxylic acid [ka] To a solution of methyl 5-((S)-2-(((benzyloxy)carbonyl)amino)-3,3-dicyclopropylpropanamido)-2-((R)-4-isopropyl-2-oxoimidazolidin-1-yl)-2,3-dihydro-1H-indene-2-carboxylate (2.5 g, 4.13 mmol) in THF (47 mL) under N2, HO (10 mL), LiOH.HO (654 mg, 8.26 mmol) were added. The mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with HCl acid (30 mL, 0.5 M) with stirring and then extracted with EtOAc (35 mL x 3). The combined organic phase was washed with brine (40 mL), dried over anhydrous NaSO, filtered and concentrated in vacuo to give 5-((S)-2-(((benzyloxy)carbonyl)amino)-3,3-dicyclopropylpropanamido)-2-((R)-4-isopropyl-2-oxoimidazolidin-1-yl)-2,3-dihydro-1H-indene-2-carboxylic acid (1.0 g, yield: 50%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.5 (s, 1 H), 9.84 (s, 1 H), 7.23 - 7.53 (m, 8 H), 7.13 - 7.11 (m, 1 H), 6.75 (d, J = 2.4 Hz, 1 H), 5.06 (s, 2 H), 4.29 - 4.44 (m, 1 H), 3.42 - 3.52 (m, 2 H), 3.36 (s, 2 H), 3.16 - 3.24 (m, 1 H), 3.04 - 3.13 (m, 1 H), 1.50 - 1.47 (m, 1 H), 0.70 - 0.92 (m, 9H), 0.08 - 0.61 (m, 10 H). MS found: [M+H] + 589.4.

[0102] Step 4: ((2S)-1,1-dicyclopropyl-3-((2-((R)-4-isopropyl-2-oxoimidazolidin-1-yl)-2-(o-tolylcarbamoyl)-2,3-dihydro-1H-inden-5-yl)amino)-3-oxopropan-2-yl)carbamate benzyl [ka] To a solution of 5-((S)-2-(((benzyloxy)carbonyl)amino)-3,3-dicyclopropylpropanamido)-2-((R)-4-isopropyl-2-oxoimidazolidin-1-yl)-2,3-dihydro-1H-indene-2-carboxylic acid (0.15 g, 254.80 umol) in DCM (5 mL) at 0° C., o-toluidine (0.027 g, 0.255 mmol), DIEA (65.86 mg, 509.60 umol) and HATU (116.24 mg, 305.76 umol) were added. The mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with H2O (5 mL) and then extracted with DCM (5 mL×3). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by preparative TLC (silica gel, eluent: petroleum ether / ethyl acetate (v / v) = 5:1, R f =0.1) to give ((2S)-1,1-dicyclopropyl-3-((2-((R)-4-isopropyl-2-oxoimidazolidin-1-yl)-2-(o-tolylcarbamoyl)-2,3-dihydro-1H-inden-5-yl)amino)-3-oxopropan-2-yl)benzyl carbamate (0.105 g, yield: 61%).

[0103] Step 5: 5-((S)-2-amino-3,3-dicyclopropylpropanamido)-2-((R)-4-isopropyl-2-oxoimidazolidin-1-yl)-N-(o-tolyl)-2,3-dihydro-1H-indene-2-carboxamide (Int A3) To a solution of ((2S)-1,1-dicyclopropyl-3-((2-((R)-4-isopropyl-2-oxoimidazolidin-1-yl)-2-(o-tolylcarbamoyl)-2,3-dihydro-1H-inden-5-yl)amino)-3-oxopropan-2-yl)benzylcarbamate (0.105 g, 0.155 mmol) and MeNH2.H2O (0.1 mL) in MeOH (1 mL) at 20 °C under H2 was added Pd(OH)2 / C (0.1 g, 0.155 mmol). The mixture was stirred at 50 °C under H2 (20 Psi) atmosphere for 1 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by preparative TLC (silica gel, eluent: ethyl acetate / MeOH (v / v) = 10 / 1, R f =0.2) to give the title compound Int A3 (65 mg, yield: 77%). MS Found: [M+H] + 544.5.

[0104] Another key intermediate bearing a carboxamide group at position 2 of the 2,3-dihydro-1H-indene core fragment was synthesized following similar methods / procedures as intermediates Int A1 or Int A2 or Int A3 known to those skilled in the art and is listed in the table along with various aldehyde and amino acid substrates. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 3-9] [Table 3-10] [Table 3-11]

[0105] The protected amino acids or aldehydes are either commercially available, known in the literature, or can be synthesized as outlined in the preparations shown.

[0106] Int B1: 5-(5-amino-2-(1H-benzo[d]imidazol-2-yl)-2,3-dihydro-1H-inden-2-yl)-5,7-diazaspiro[2.5]octan-6-one Step 1: 5-nitro-2-(6-oxo-5,7-diazaspiro[2.5]octan-5-yl)-2,3-dihydro-1H-indene-2-carboxylic acid [ka] To a solution of N-methyl-5-nitro-2-(6-oxo-5,7-diazaspiro[2.5]octan-5-yl)-2,3-dihydro-1H-indene-2-carboxamide (2.1 g, 6.1 mol, prepared by a similar procedure to 2-((R)-4-isopropyl-2-oxoimidazolidin-1-yl)-N-methyl-5-nitro-2,3-dihydro-1H-indene-2-carboxamide described in Int A2) in DCM (15 mL) was added TFA (5 mL) and stirred at room temperature for 4 h. The reaction mixture was cooled to room temperature and concentrated in vacuo to remove TFA and solvent. The residue was diluted with DCM (50 mL) and washed with saturated NaHCO3 (20 mL) followed by saturated NH4Cl (20 mL). The organic solution was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give 5-nitro-2-(6-oxo-5,7-diazaspiro[2.5]octan-5-yl)-2,3-dihydro-1H-indene-2-carboxylic acid (2 g, yield: 98%). MS found: [M+H] + 332.4.

[0107] Step 2: N-(2-aminophenyl)-5-nitro-2-(6-oxo-5,7-diazaspiro[2.5]octan-5-yl)-2,3-dihydro-1H-indene-2-carboxamide [ka] To a solution of 5-nitro-2-(6-oxo-5,7-diazaspiro[2.5]octan-5-yl)-2,3-dihydro-1H-indene-2-carboxylic acid (0.5 g, 1.51 mmol), benzene-1,2-diamine (0.26 g, 1.51 mmol) and TEA (0.3 g, 3 mmol) in DCM (10 mL) at 0° C., HATU (0.0.65 g, 1.7 mmol) was added. The mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with water (15 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate (v / v) = 100 / 1 to 1 / 1) to give N-(2-aminophenyl)-5-nitro-2-(6-oxo-5,7-diazaspiro[2.5]octan-5-yl)-2,3-dihydro-1H-indene-2-carboxamide (0.18 g, yield: 28%). MS observed: [M+H] + 422.4.

[0108] Step 3: 5-(2-(1H-benzo[d]imidazol-2-yl)-5-nitro-2,3-dihydro-1H-inden-2-yl)-5,7-diazaspiro[2.5]octan-6-one [ka] A solution of N-(2-aminophenyl)-5-nitro-2-(6-oxo-5,7-diazaspiro[2.5]octan-5-yl)-2,3-dihydro-1H-indene-2-carboxamide (0.18 g, 0.45 mmol) in AcOH (8 mL) was heated to 50° C. and stirred for 4 h. The reaction mixture was diluted with water (15 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate (v / v) = 50 / 1 to 5 / 1) to give 5-(2-(1H-benzo[d]imidazol-2-yl)-5-nitro-2,3-dihydro-1H-inden-2-yl)-5,7-diazaspiro[2.5]octan-6-one (80 mg, yield: 44%). MS observed: [M+H] + 404.2.

[0109] Step 4: 5-(5-amino-2-(1H-benzo[d]imidazol-2-yl)-2,3-dihydro-1H-inden-2-yl)-5,7-diazaspiro[2.5]octan-6-one (Int B1) To a solution of 5-(2-(1H-benzo[d]imidazol-2-yl)-5-nitro-2,3-dihydro-1H-inden-2-yl)-5,7-diazaspiro[2.5]octan-6-one (80 mg, 0.09 mmol) in MeOH (10 mL) was added Raney Ni (11 mg) and NH3·H2O (1 mL) under N2. The suspension was degassed under vacuum and purged with H2 three times. The mixture was stirred at 50 °C under H2 atmosphere for 1 h. The reaction mixture was filtered and concentrated in vacuo to give 5-(5-amino-2-(1H-benzo[d]imidazol-2-yl)-2,3-dihydro-1H-inden-2-yl)-5,7-diazaspiro[2.5]octan-6-one (70 mg, yield: 54%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.89 (s, 1 H), 7.55 - 7.38 (m, 2 H), 7.07 (s, 2 H), 6.79 (d, J = 6.8 Hz, 1 H), 6.47 - 6.11 (m, 3 H), 4.79 (s, 2 H), 4.06 - 3.82 (m, 2 H), 3.27 - 3.09 (m, 4 H), 2.86 (d, J = 7.2 Hz, 2 H), 0.49 - 0.27, 4 H). [M+H] + 374.2.

[0110] Int B2: 5-(5-amino-2-(imidazo[1,2-a]pyridin-2-yl)-2,3-dihydro-1H-inden-2-yl)-5,7-diazaspiro[2.5]octan-6-one Step 1: Ethyl 5-bromo-2-((tert-butoxycarbonyl)amino)-2,3-dihydro-1H-indene-2-carboxylate [ka] To a solution of ethyl 2-amino-5-bromo-2,3-dihydro-1H-indene-2-carboxylate (4 g, 14.1 mmol) in DCM (60 mL) was added Boc2O (7.7 g, 35.3 mmol). The mixture was heated to reflux and stirred for 15 h. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by column chromatography on silica gel (eluent: EtOAc / PE (v / v) = 1 / 5) to give ethyl 5-bromo-2-((tert-butoxycarbonyl)amino)-2,3-dihydro-1H-indene-2-carboxylate (4.8 g, yield: 91%). MS (ESI) m / e [M-56+1] + 328.1.

[0111] Step 2: 5-Bromo-2-((tert-butoxycarbonyl)amino)-2,3-dihydro-1H-indene-2-carboxylic acid [ka] To a solution of ethyl 5-bromo-2-((tert-butoxycarbonyl)amino)-2,3-dihydro-1H-indene-2-carboxylate (3.45 g, 9.0 mmol) in THF (45 mL) was added NaOH solution (1.44 g in 15 mL H2O) dropwise with stirring at room temperature. The resulting mixture was heated to 55° C. and stirred for 16 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was diluted with water and the mixture was adjusted to pH ∼5 with HCl acid (1N) and then extracted with EtOAc (50×3 mL). The organic layer was washed with brine, dried and concentrated in vacuo. The crude product was stirred in EtOAc / PE (1:1) at room temperature for 10 min. The solid was collected by filtration and dried in vacuo to give 5-bromo-2-((tert-butoxycarbonyl)amino)-2,3-dihydro-1H-indene-2-carboxylic acid (3 g, yield: 93%). MS (ESI) m / e [M+23] + 378.1.

[0112] Step 3: tert-Butyl (5-bromo-2-(methoxy(methyl)carbamoyl)-2,3-dihydro-1H-inden-2-yl)carbamate [ka] To a solution of 5-bromo-2-((tert-butoxycarbonyl)amino)-2,3-dihydro-1H-indene-2-carboxylic acid (2.3 g, 6.5 mmol) in DCM (50 mL) was added N,O-dimethylhydroxylamine hydrochloride (698 mg, 7.1 mmol) and HATU (2.7 g, 7.1 mmol), DIPEA (3.3 g, 25.9 mmol) dropwise at room temperature. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with EtOAc. The organic layer was washed with saturated NaHCO3 solution (aq.) and brine, dried and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluent: EtOAc / PE (v / v)=1 / 2) to give tert-butyl (5-bromo-2-(methoxy(methyl)carbamoyl)-2,3-dihydro-1H-inden-2-yl)carbamate (2.3 g, yield: 88%). MS (ESI) m / e [M-56+1]+ 343.2.

[0113] Step 4: tert-Butyl (2-acetyl-5-bromo-2,3-dihydro-1H-inden-2-yl)carbamate [ka] To a solution of tert-butyl (5-bromo-2-(methoxy(methyl)carbamoyl)-2,3-dihydro-1H-inden-2-yl)carbamate (1.55 g, 3.9 mmol) in THF (25 mL) was added CH3MgCl (4 mL, 11.7 mmol) under N2 atmosphere below -10 °C. The resulting mixture was stirred at 0 °C for 1 h. The reaction mixture was poured into saturated aq. NH4Cl (30 mL) at 0 °C and then extracted with EtOAc (30 mL x 3). The combined organic layer was washed with brine, dried and concentrated in vacuum. The residue was purified by column chromatography on silica gel (eluent: EtOAc / PE (v / v) = 1 / 6) to give tert-butyl (2-acetyl-5-bromo-2,3-dihydro-1H-inden-2-yl)carbamate (1.3 g, yield: 94%). MS (ESI) m / e [M+23] + 376.1.

[0114] Step 5: tert-Butyl (5-bromo-2-(1-((trimethylsilyl)oxy)vinyl)-2,3-dihydro-1H-inden-2-yl)carbamate [ka] tert-Butyl (2-acetyl-5-bromo-2,3-dihydro-1H-inden-2-yl)carbamate (1.1 g, 3.1 mmol) was dissolved in THF (15 mL) and cooled to -70°C under N2 atmosphere. To this solution was added LDA (3.1 mL, 6.2 mmol) dropwise with stirring at -70°C under N2 atmosphere. The resulting mixture was stirred for 30 min, followed by addition of TMSCl (680 mg, 6.2 mmol) at -70°C. After further stirring at -60°C for 1 h, the reaction mixture was quenched with NH4Cl (aq.) below -20°C and then diluted with EtOAc. The organic layer was separated, washed with water and brine, dried and concentrated in vacuo to give the crude product (1.5 g), which was used directly in the next step.

[0115] Step 6: tert-Butyl (5-bromo-2-(2-bromoacetyl)-2,3-dihydro-1H-inden-2-yl)carbamate [ka] To a solution of tert-butyl (5-bromo-2-(1-((trimethylsilyl)oxy)vinyl)-2,3-dihydro-1H-inden-2-yl)carbamate (1.5 g, crude) in THF (20 mL) at 0° C., NBS (625 mg, 3.5 mmol) was added in portions. The mixture was stirred at 0° C. for 1 h. The reaction mixture was quenched with NaHCO3 (aq.) and diluted with EtOAc (30 mL). The organic layer was separated, washed with water and brine, dried and concentrated. The residue was purified by column chromatography on silica gel (eluent: EtOAc / PE (v / v)=1 / 7) to give tert-butyl (5-bromo-2-(2-bromoacetyl)-2,3-dihydro-1H-inden-2-yl)carbamate (740 mg, yield: 55% for two steps). MS (ESI) m / e [M+23] + 456.1.

[0116] Step 7: tert-Butyl (5-bromo-2-(imidazo[1,2-a]pyridin-2-yl)-2,3-dihydro-1H-inden-2-yl)carbamate [ka] A solution of tert-butyl (5-bromo-2-(2-bromoacetyl)-2,3-dihydro-1H-inden-2-yl)carbamate (740 mg, 1.72 mmol) and pyridin-2-amine (162 mg, 1.72 mmol) in MeOH (10 mL) was heated to 80° C. and stirred under N2 atmosphere for 24 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluent: EtOAc / PE (v / v)=1 / 2) to give tert-butyl (5-bromo-2-(imidazo[1,2-a]pyridin-2-yl)-2,3-dihydro-1H-inden-2-yl)carbamate (250 mg, yield: 34%). MS (ESI) m / e [M+1] + 428.2.

[0117] Step 8: 5-Bromo-2-(imidazo[1,2-a]pyridin-2-yl)-2,3-dihydro-1H-inden-2-amine [ka] To a solution of tert-butyl (5-bromo-2-(imidazo[1,2-a]pyridin-2-yl)-2,3-dihydro-1H-inden-2-yl)carbamate (250 mg, 0.59 mmol) in DCM (16 mL) at room temperature, HCl (4N in dioxane, 4 mL) was added dropwise. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was then concentrated in vacuo to give 5-bromo-2-(imidazo[1,2-a]pyridin-2-yl)-2,3-dihydro-1H-inden-2-amine (180 mg, crude) as the HCl salt. MS (ESI) m / e [M+1] + 328.1.

[0118] Step 9: tert-Butyl ((1-(((5-bromo-2-(imidazo[1,2-a]pyridin-2-yl)-2,3-dihydro-1H-inden-2-yl)amino)methyl)cyclopropyl)-methyl)carbamate [ka] A mixture of 5-bromo-2-(imidazo[1,2-a]pyridin-2-yl)-2,3-dihydro-1H-inden-2-amine (180 mg, 0.55 mmol) and tert-butyl ((1-formylcyclopropyl)methyl)carbamate (154 mg, 0.77 mmol) in DCM (10 mL) was stirred at room temperature for 1 h. To this mixture was then added NaBH3CN (351 mg, 1.66 mmol) in portions at 0° C. The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with NaHCO3 (aq.) and extracted with EtOAc (30 mL). The organic layer was washed with brine, dried and concentrated in vacuo. The residue was purified by preparative TLC (eluent: DCM / EtOAc (v / v)=1 / 1) to give tert-butyl ((1-(((5-bromo-2-(imidazo[1,2-a]pyridin-2-yl)-2,3-dihydro-1H-inden-2-yl)amino)methyl)cyclopropyl)-methyl)carbamate (200 mg, yield: 67% for two steps). MS (ESI) m / e [M+1] + 511.3.

[0119] Step 10: N-((1-(aminomethyl)cyclopropyl)methyl)-5-bromo-2-(imidazo[1,2-a]pyridin-2-yl)-2,3-dihydro-1H-inden-2-amine [ka] To a solution of tert-butyl ((1-(((5-bromo-2-(imidazo[1,2-a]pyridin-2-yl)-2,3-dihydro-1H-inden-2-yl)amino)methyl)cyclopropyl)-methyl)carbamate (200 mg, 0.39 mmol) in DCM (9 mL) at 0° C., HCl (4N in dioxane, 3 mL) was added dropwise. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was then concentrated to give N-((1-(aminomethyl)cyclopropyl)methyl)-5-bromo-2-(imidazo[1,2-a]pyridin-2-yl)-2,3-dihydro-1H-inden-2-amine HCl salt (200 mg, crude), which was used directly in the next step. MS (ESI) m / e [M+1] + 411.2.

[0120] Step 11: 5-(5-bromo-2-(imidazo[1,2-a]pyridin-2-yl)-2,3-dihydro-1H-inden-2-yl)-5,7-diazaspiro[2.5]octan-6-one [ka] To a solution of N-((1-(aminomethyl)cyclopropyl)methyl)-5-bromo-2-(imidazo[1,2-a]pyridin-2-yl)-2,3-dihydro-1H-inden-2-amine (200 mg) and TEA (1 mL) in THF (10 mL) was added CDI (198 mg, 1.22 mmol). The mixture was heated to 60° C. and stirred for 1 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed with water and brine, dried and concentrated in vacuo. The crude product was purified by preparative TLC (eluent: DCM / MeOH (v / v) = 15 / 1) to give 5-(5-bromo-2-(imidazo[1,2-a]pyridin-2-yl)-2,3-dihydro-1H-inden-2-yl)-5,7-diazaspiro[2.5]octan-6-one (100 mg, yield: 58% for two steps). MS (ESI) m / e [M+1] + 437.2.

[0121] Step 12: 5-(5-((diphenylmethylene)amino)-2-(imidazo[1,2-a]pyridin-2-yl)-2,3-dihydro-1H-inden-2-yl)-5,7-diazaspiro[2.5]octan-6-one [ka] To a solution of 5-(5-bromo-2-(imidazo[1,2-a]pyridin-2-yl)-2,3-dihydro-1H-inden-2-yl)-5,7-diazaspiro[2.5]octan-6-one (100 mg, 0.23 mmol) in dioxane (15 mL) was added diphenylmethanimine (62.3 mg, 0.34 mmol), Pd2dba3 (21 mg, 0.02 mmol), Xantphos (27 mg, 0.04 mmol) and Cs2CO3 (150 mg, 0.46 mmol). The mixture was degassed with N2, heated to 100 °C and then stirred under N2 atmosphere for 6 h. The reaction mixture was cooled to room temperature and diluted with DCM / MeOH (v / v=15 / 1). After filtering off the solid, the filtrate was concentrated and purified by preparative TLC (eluent: DCM / MeOH (v / v)=20 / 1) to give 5-(5-((diphenylmethylene)amino)-2-(imidazo[1,2-a]pyridin-2-yl)-2,3-dihydro-1H-inden-2-yl)-5,7-diazaspiro[2.5]octan-6-one (58 mg, yield: 47%). MS (ESI) m / e [M+1] + 538.4.

[0122] Step 13: 5-(5-amino-2-(imidazo[1,2-a]pyridin-2-yl)-2,3-dihydro-1H-inden-2-yl)-5,7-diazaspiro[2.5]octan-6-one (Int B2) To a solution of 5-(5-((diphenylmethylene)amino)-2-(imidazo[1,2-a]pyridin-2-yl)-2,3-dihydro-1H-inden-2-yl)-5,7-diazaspiro[2.5]octan-6-one (58 mg, 0.11 mmol) in THF (5 mL) at room temperature was added HCl (3N, 1 mL) and stirred for 30 min. The resulting reaction mixture was poured into saturated aq. NaHCO3 and then extracted with EA (30 x 3 mL). The combined organic layers were washed with brine, dried, filtered and concentrated in vacuo. The residue was purified by preparative TLC (eluent: DCM / MeOH (v / v)=10 / 1) to give 5-(5-amino-2-(imidazo[1,2-a]pyridin-2-yl)-2,3-dihydro-1H-inden-2-yl)-5,7-diazaspiro[2.5]octan-6-one (22 mg, yield: 55%). MS (ESI) m / e [M+1] + 374.3.

[0123] Int C1: (4S)-1-(1-(6-amino-2,3-dihydrobenzofuran-2-yl)ethyl)-4-(trifluoromethyl)imidazolidin-2-one Step 1: 1-(6-nitrobenzofuran-2-yl)ethan-1-one [ka] To a solution of 2-hydroxy-4-nitrobenzaldehyde (2 g, 12 mmol) and 1-chloropropan-2-one (1.1 g, 12 mmol) in CH3CN (20 mL) was added K2CO3 (3.3 g, 24 mmol). The mixture was stirred at room temperature for 4 h. The reaction mixture was poured into water (40 mL) and then extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluent: PE / EA (v / v) = 100 / 1 to 10 / 1) to give 1-(6-nitrobenzofuran-2-yl)ethanone (0.61 g, yield: 25%). MS (ESI) m / e [M+1] + 206.2.

[0124] Step 2: (S)-1,1,1-trifluoro-3-((1-(6-nitrobenzofuran-2-yl)ethylidene)amino)propan-2-amine [ka] To a solution of 1-(6-nitrobenzofuran-2-yl)ethanone (0.4 g, 1.9 mmol) and (S)-3,3,3-trifluoropropane-1,2-diamine hydrochloride (0.164 g, 2.9 mmol) in DCM (10 mL) was added TEA (0.101 g, 19.5 mmol) and 4A MS (1 g). The mixture was stirred at 45 °C for 3 h. After the reaction mixture was filtered, the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluent: PE / EA (v / v) = 100 / 1 to 0 / 1) to obtain (S)-3,3,3-trifluoro-N1-(1-(6-nitrobenzofuran-2-yl)ethylidene)propane-1,2-diamine (0.5 g, yield: 81%). MS (ESI) m / e [M+1] + 316.1.

[0125] Step 3: (2S)-3,3,3-trifluoro-N1-(1-(6-nitrobenzofuran-2-yl)ethyl)propane-1,2-diamine [ka] To a solution of (S)-3,3,3-trifluoro-N1-(1-(6-nitrobenzofuran-2-yl)ethylidene)propane-1,2-diamine (0.5 g, 1.6 mmol) in MeOH (10 mL) was added NaBH3CN (1 g, 16 mmol). The mixture was stirred at 70 °C for 12 h. The mixture was poured into water (20 mL) and then extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified and the crude product was purified by column chromatography on silica gel (eluent: DCM / CH3OH (v / v) = 100 / 1 to 10 / 1) to give (2S)-3,3,3-trifluoro-N1-(1-(6-nitrobenzofuran-2-yl)ethyl)propane-1,2-diamine (0.32 g, yield: 64%). MS (ESI) m / e [M+1] + 318.2.

[0126] Step 4: (4S)-1-(1-(6-nitrobenzofuran-2-yl)ethyl)-4-(trifluoromethyl)imidazolidin-2-one [ka] To a solution of (2S)-3,3,3-trifluoro-N1-(1-(6-nitrobenzofuran-2-yl)ethyl)propane-1,2-diamine (1.2 g, 3.8 mmol) in THF (15 mL) at 20° C., CDI (0.92 g, 5.7 mmol) and TEA (0.5 mL) were added. The mixture was stirred at 60° C. for 6 h. The reaction mixture was diluted with EtOAc (30 mL) and then washed with brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography on silica gel (eluent: PE / EAE (v / v)=100 / 1 to 10 / 1) to give (4S)-1-(1-(6-nitrobenzofuran-2-yl)ethyl)-4-(trifluoromethyl)imidazolidin-2-one (0.34 g, yield: 26%). MS (ESI) m / e [M+1] + 344.3.

[0127] Step 5: (4S)-1-(1-(6-amino-2,3-dihydrobenzofuran-2-yl)ethyl)-4-(trifluoromethyl)imidazolidin-2-one (Int C1) [ka] To a solution of (4S)-1-(1-(6-nitrobenzofuran-2-yl)ethyl)-4-(trifluoromethyl)imidazolidin-2-one (0.32 g, 0.932 mmol) in i-PrOH (5 mL) at room temperature was added Pd / C (0.1 g, 0.932 mmol). The mixture was heated to 50° C., stirred and hydrogenated under an atmosphere of H2 (15 Psi) for 2 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give (4S)-1-(1-(6-amino-2,3-dihydrobenzofuran-2-yl)ethyl)-4-(trifluoromethyl)imidazolidin-2-one (282 mg). 1 H NMR (400 MHz, CDCl3) δ ppm 7.02 - 6.84 (m, 1 H), 6.79 - 6.12 (m, 2 H), 5.10 - 4.92 (m, 1 H), 4.91 - 4.72 (m, 1 H), 4.20 - 4.09 (m, 1 H), 4.06 - 3.90 (m, 1 H), 3.83 - 3.66 (m, 1 H), 3.65 - 3.49 (m, 2 H), 3.48 - 2.80 (m, 1 H), 1.58 - 1.12 (m, 3 H). MS (ESI, m / e) [M+H] + 316.1.

[0128] Example 32: N-((1S)-cyclohexyl(6-((R)-4-ethyl-2-oxoimidazolidin-1-yl)-6-(methylcarbamoyl)-1,5,6,7-tetrahydroindeno[5,6-d]imidazol-2-yl)methyl)-4-methyl-1,2,5-oxadiazole-3-carboxamide [ka] Step 1: 2-Amino-N-methyl-5,6-dinitro-2,3-dihydro-1H-indene-2-carboxamide [ka] To a mixture of H2SO4 (100 mL) and HNO3 (25 mL) was added 2-amino-N-methyl-2,3-dihydro-1H-indene-2-carboxamide (19 g, 100 mmol, dissolved in 10 mL HOAc) slowly in one portion at 0°C. After addition, the mixture was stirred at room temperature for 4 h. The reaction mixture was carefully poured into saturated NaHCO3 (aq, 500 mL) at 0-10°C, and then extracted with DCM (500 mL). The organic layer was separated and purified by silica gel column chromatography (eluent: DCM to DCM / MeOH (v / v) = 20 / 1) to give the title compound (16.81 g, yield: 60.0%).

[0129] Step 2: tert-Butyl (2-(methylcarbamoyl)-5,6-dinitro-2,3-dihydro-1H-inden-2-yl)carbamate [ka] A mixture of 2-amino-N-methyl-5,6-dinitro-2,3-dihydro-1H-indene-2-carboxamide (16.81 g, 60 mmol) and Boc2O (26.16 g) in DCM (200 mL) was stirred at room temperature overnight. The reaction mixture was diluted with PE (200 mL), washed with brine (500 mL), dried over Na2SO4, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (eluent: DCM / MeOH (v / v) = 50 / 1 to 20 / 1) to give the title product (19.76 g, yield: 86.7%). MS (ESI, m / e) [M+1] + 381.3.

[0130] Step 3: tert-Butyl (5,6-diamino-2-(methylcarbamoyl)-2,3-dihydro-1H-inden-2-yl)carbamate [ka] A mixture of tert-butyl (2-(methylcarbamoyl)-5,6-dinitro-2,3-dihydro-1H-inden-2-yl)carbamate (19.76 g, 52 mmol) and Pd / C (1.5 g) in MeOH (500 mL) was bubbled with a H2 balloon and stirred under H2 atmosphere overnight. The reaction mixture was filtered, and the filtrate was concentrated in vacuo and then purified by column chromatography on silica gel (eluent: DCM / MeOH (v / v) = 50 / 1 to 20 / 1) to give the title compound (14.7 g, yield: 88.46%). MS (ESI, m / e) [M+1] + 321.3.

[0131] Step 4: ((1S)-2-((6-amino-2-((tert-butoxycarbonyl)amino)-2-(methylcarbamoyl)-2,3-dihydro-1H-inden-5-yl)amino)-1-cyclohexyl-2-oxoethyl)carbamate benzyl [ka] A mixture of (S)-2-(((benzyloxy)carbonyl)amino)-2-cyclohexylacetic acid (13.4 g, 46 mmol), (5,6-diamino-2-(methylcarbamoyl)-2,3-dihydro-1H-inden-2-yl)carbamate tert-butyl (14.70 g, 46 mmol), HATU (19 g, 50 mmol) and TEA (10 g, 100 mmol) in DCM (500 mL) was stirred at room temperature overnight. The reaction mixture was quenched with NaHCO3 (aq, 500 mL). The organic layer was separated, washed with brine (500 mL), dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (eluent: DCM / MeOH (v / v) = 50 / 1 to 20 / 1) to give the title compound (9.0 g, yield: 32.95%). MS (ESI, m / e) [M+1] + 594.3.

[0132] Step 5: ((1S)-(6-((tert-butoxycarbonyl)amino)-6-(methylcarbamoyl)-1,5,6,7-tetrahydroindeno[5,6-d]imidazol-2-yl)(cyclohexyl)methyl)carbamate benzyl [ka] A mixture of ((1S)-2-((6-amino-2-((tert-butoxycarbonyl)amino)-2-(methylcarbamoyl)-2,3-dihydro-1H-inden-5-yl)amino)-1-cyclohexyl-2-oxoethyl)benzylcarbamate (9.0 g) and AcOH (50 mL) was heated to 100° C. and stirred overnight. The reaction mixture was concentrated in vacuo, and the residue was diluted with NaHCO3 (aq, 250 mL), extracted with DCM (250 mL), washed with brine (500 mL), dried over Na2SO4, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (eluent: DCM / MeOH (v / v)=50 / 1-20 / 1) to give the title compound (1.63 g, yield: 39.36%). MS (ESI, m / e) [M+1] + 576.3.

[0133] Step 6: ((1S)-(6-amino-6-(methylcarbamoyl)-1,5,6,7-tetrahydroindeno[5,6-d]imidazol-2-yl)(cyclohexyl)methyl)carbamate benzyl [ka] To a solution of ((1S)-(6-((tert-butoxycarbonyl)amino)-6-(methylcarbamoyl)-1,5,6,7-tetrahydroindeno[5,6-d]imidazol-2-yl)(cyclohexyl)methyl)benzylcarbamate (5.0 g, 8.69 mmol) in DCM (100 mL) was added HCl acid (4 M in dioxane, 100 mL). The mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with NaHCO3 (aq, 250 mL) and extracted with DCM (250 mL). The organic layer was washed with brine (200 mL), dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (eluent: DCM / MeOH (v / v) = 50 / 1 to 20 / 1) to give the title compound (1.63 g, yield: 39.36%). MS (ESI, m / e) [M+1] + 476.2.

[0134] Step 7: Benzyl ((1S)-(6-(((R)-2-((tert-butoxycarbonyl)amino)butyl)amino)-6-(methylcarbamoyl)-1,5,6,7-tetrahydroindeno[5,6-d]imidazol-2-yl)(cyclohexyl)methyl)carbamate [ka] A mixture of ((1S)-(6-amino-6-(methylcarbamoyl)-1,5,6,7-tetrahydroindeno[5,6-d]imidazol-2-yl)(cyclohexyl)methyl)benzylcarbamate (300 mg, 0.63 mmol), (R)-(3-methyl-1-oxobutan-2-yl)tert-butylcarbamate (252 mg, 1.26 mmol) and NaBH(OAc)3 (267 mg, 1.26 mmol) in DCM (50 mL) was stirred at room temperature for 2 h. The reaction mixture was quenched with NaHCO3 (aq, 100 mL) and extracted with DCM (50 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluent: DCM / MeOH (v / v) = 50 / 1). ((1S)-(6-(((R)-2-((tert-butoxycarbonyl)amino)butyl)amino)-6-(methylcarbamoyl)-1,5,6,7-tetrahydroindeno[5,6-d]imidazol-2-yl)(cyclohexyl)methyl)benzyl carbamate (310 mg, yield: 71.4%) was obtained. MS (ESI, m / e) [M+1] + 647.4.

[0135] Step 8: ((1S)-(6-(((R)-2-aminobutyl)amino)-6-(methylcarbamoyl)-1,5,6,7-tetrahydroindeno[5,6-d]imidazol-2-yl)(cyclohexyl)methyl)carbamate benzyl [ka] A mixture of ((1S)-(6-(((R)-2-((tert-butoxycarbonyl)amino)butyl)amino)-6-(methylcarbamoyl)-1,5,6,7-tetrahydroindeno[5,6-d]imidazol-2-yl)(cyclohexyl)methyl)benzyl carbamate (310 mg, 0.45 mmol) and TFA (2 mL) in DCM (5 mL) was stirred for 2 h. The mixture was concentrated in vacuo to give ((1S)-(6-(((R)-2-aminobutyl)amino)-6-(methylcarbamoyl)-1,5,6,7-tetrahydroindeno[5,6-d]imidazol-2-yl)(cyclohexyl)methyl)benzyl carbamate (236 mg, crude), which was used directly in the next step. MS (ESI, m / e) [M+1] + 547.3.

[0136] Step 9: ((1S)-Cyclohexyl(6-((R)-4-ethyl-2-oxoimidazolidin-1-yl)-6-(methylcarbamoyl)-1,5,6,7-tetrahydroindeno[5,6-d]imidazol-2-yl)methyl)benzyl carbamate [ka] A mixture of ((1S)-(6-(((R)-2-aminobutyl)amino)-6-(methylcarbamoyl)-1,5,6,7-tetrahydroindeno[5,6-d]imidazol-2-yl)(cyclohexyl)methyl)benzylcarbamate (236 mg, 0.44 mmol), TEA (0.5 mL) and CDI (142 mg, 0.88 mmol) in THF (20 mL) was heated to 60 °C and stirred for 2 h. The reaction mixture was quenched with brine (50 mL) and extracted with EA (50 × 2 mL). The combined layers were dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (eluent: DCM / MeOH (v / v) = 50 / 1 to 20 / 1). ((1S)-cyclohexyl(6-((R)-4-ethyl-2-oxoimidazolidin-1-yl)-6-(methylcarbamoyl)-1,5,6,7-tetrahydroindeno[5,6-d]imidazol-2-yl)methyl)benzyl carbamate (236 mg, yield: 93.18%) was obtained. MS (ESI, m / e) [M+1] + 573.3.

[0137] Step 10: 2-((S)-amino(cyclohexyl)methyl)-6-((R)-4-ethyl-2-oxoimidazolidin-1-yl)-N-methyl-1,5,6,7-tetrahydroindeno[5,6-d]imidazole-6-carboxamide [ka] A mixture of ((1S)-cyclohexyl(6-((R)-4-ethyl-2-oxoimidazolidin-1-yl)-6-(methylcarbamoyl)-1,5,6,7-tetrahydroindeno[5,6-d]imidazol-2-yl)methyl)benzylcarbamate (236 mg, 0.41 mmol) in MeOH (50 mL) and Pd / C (20 mg) was bubbled with a H2 balloon and stirred overnight under H2 atmosphere for deprotection. The reaction mixture was then filtered and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography on silica gel (eluent: DCM / MeOH (v / v) = 50 / 1 to 20 / 1) to give the title amine compound (142 mg, yield: 55.66%). MS (ESI, m / e) [M+1] + 439.3.

[0138] Step 11: N-((1S)-cyclohexyl(6-((R)-4-ethyl-2-oxoimidazolidin-1-yl)-6-(methylcarbamoyl)-1,5,6,7-tetrahydroindeno[5,6-d]imidazol-2-yl)methyl)-4-methyl-1,2,5-oxadiazole-3-carboxamide (Example 32) To a solution of 2-((S)-amino(cyclohexyl)methyl)-6-((R)-4-ethyl-2-oxoimidazolidin-1-yl)-N-methyl-1,5,6,7-tetrahydroindeno[5,6-d]imidazole-6-carboxamide (22 mg, 0.05 mmol) in DCM (10 mL) was added 4-methyl-1,2,5-oxadiazole-3-carboxylic acid (7 mg, 0.05 mmol), HATU (19 mg, 0.05 mmol) and TEA (10 mg, 0.1 mmol). The mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with aq. NaHCO3 (50 mL) and diluted with DCM (20 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (eluent: DCM / MeOH (v / v) = 50 / 1 to 20 / 1) to obtain the title compound (13 mg, yield: 47.4%). 1H NMR (400 MHz, DMSO-d6) δ ppm: 12.20 (br, 1H), 9.42 (d, J = 8.8 Hz, 1H), 7.55-7.25 (m, 3H), 6.69 (s, 1H), 5.05 (t, J = 8.4 Hz, 1H), 3.65-3.40 (m, 4H), 3.32-3.23 (m, 2H), 2.93-2.87 (m, 1H), 2.58 (d, J = 4.4 Hz, 3H), 2.10-1.55 (m, 5H), 1.42-1.27 (m, 3H), 1.21-0.95 (m, 5H), 0.71 (t, J = 7.2 Hz, 3H). MS (ESI, m / e) [M+1] + 549.4.

[0139] Example 145: N-((1S)-1-cyclohexyl-2-((6-(methylcarbamoyl)-6-(6-oxo-5,7-diazaspiro[2.5]octan-5-yl)-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide [ka] Step 1: 9,12-Dioxa-1,3-diazadispiro[4.2.4 8 .2 5 ]Tetradecane-2,4-dione [ka] A mixture of 1,4-dioxaspiro[4.5]decan-8-one (9.55 g, 61.2 mmol), NaCN (3 g, 61.2 mmol) and (NH4)2CO3 (23.5 g, 244.8 mmol) in HO (100 mL) and EtOH (5 mL) was stirred at 60 °C overnight. The reaction mixture was cooled to room temperature and left for 1 day. The precipitate was filtered and the cake was then dried in air to give 9,12-dioxa-1,3-diazadispiro[4.2.4]decan-8-one (9.55 g, 61.2 mmol), NaCN (3 g, 61.2 mmol) and (NH4)2CO3 (23.5 g, 244.8 mmol). 8 .2 5 ]Tetradecane-2,4-dione (7.38 g, crude) was obtained.1 H NMR (400 MHz, DMSO-d6) δ ppm: 10.59 (s, 1H), 8.44 (s, 1H), 3.87 (s, 4H), 1.95-1.78 (m, 2H), 1.73-1.69 (m, 4H), 1.59-1.56 (m, 2H).

[0140] Step 2: 8-Amino-1,4-dioxaspiro[4.5]decane-8-carboxylic acid [ka] In a sealed tube, 9,12-dioxa-1,3-diazadispiro[4.2.4] in NaOH solution (6N, 15 mL) was 8 .2 5 A solution of 8-amino-1,4-dioxaspiro[4.5]decane-8-dione (2 g) was stirred at 140° C. for 3 h. The reaction mixture was cooled to room temperature and acidified with 6N HCl acid to pH=4. After the mixture was concentrated in vacuo to remove the solvent, the residue was dissolved in DCM / MeOH=10 / 1 (80 mL) and stirred for 10 min. The mixture was filtered and the filtrate was concentrated to give 8-amino-1,4-dioxaspiro[4.5]decane-8-carboxylic acid (1.13 g, crude). MS (ESI) m / e [M+1] + 202.1

[0141] Step 3: 8-(((benzyloxy)carbonyl)amino)-1,4-dioxaspiro[4.5]decane-8-carboxylic acid [ka] A mixture of 8-amino-1,4-dioxaspiro[4.5]decane-8-carboxylic acid (1.13 g), CbzCl (966 mg) and EtN (1.15 g, 3.06 mmol) in THF (30 mL) and HO (30 mL) was stirred at room temperature for 3 h. The reaction mixture was diluted with MTBE (30 mL) and stirred for 10 min. The aqueous phase was collected and concentrated in vacuo. The resulting solid was dried in air to give 8-(((benzyloxy)carbonyl)amino)-1,4-dioxaspiro[4.5]decane-8-carboxylic acid (1.86 g, crude). MS (ESI) m / e [M+1] + 337.1.

[0142] Step 4: Benzyl (8-(methylcarbamoyl)-1,4-dioxaspiro[4.5]decan-8-yl)carbamate [ka] A mixture of 8-(((benzyloxy)carbonyl)amino)-1,4-dioxaspiro[4.5]decane-8-carboxylic acid (1.86 g), methylamine hydrochloride (385 mg, 5.7 mmol), HATU (2.17 g, 5.7 mmol) and Et3N (1.15 g, 11.4 mmol) in DCM (60 mL) was stirred at room temperature overnight. The reaction mixture was concentrated and then the residue was purified by column chromatography on silica gel (eluent: DCM / MeOH (v / v) = 50 / 1). Benzyl (8-(methylcarbamoyl)-1,4-dioxaspiro[4.5]decane-8-yl)carbamate (1.77 g) was obtained. MS (ESI) m / e [M+1] + 349.2.

[0143] Step 5: Benzyl (1-(methylcarbamoyl)-4-oxocyclohexyl)carbamate [ka] A solution of (8-(methylcarbamoyl)-1,4-dioxaspiro[4.5]decan-8-yl)benzylcarbamate (1.77 g, 5.7 mmol) in TFA (10 mL) was stirred at room temperature for 3 h. The reaction mixture was concentrated to remove TFA. The residue was neutralized with aq. NaHCO3 and then extracted with DCM (50 mL x 3). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. (1-(methylcarbamoyl)-4-oxocyclohexyl)benzylcarbamate (615 mg, crude) was obtained. MS (ESI) m / e [M+1] + 305.1

[0144] Step 6: tert-butyl 2-amino-6-(((benzyloxy)carbonyl)amino)-6-(methylcarbamoyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate [ka] A mixture of benzyl (1-(methylcarbamoyl)-4-oxocyclohexyl)carbamate (615 mg, 2.02 mmol), tert-butyl 2-cyanoacetate (500 mg, 2.02 mmol), sulfur (65 mg, 2.02 mmol) and morpholine (176 mg, 2.02 mmol) in EtOH (25 mL) was stirred at 80° C. overnight. The mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by preparative TLC (eluent: EA / PE (v / v)=1 / 1). 2-amino-6-(((benzyloxy)carbonyl)amino)-6-(methylcarbamoyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate tert-butyl (287 mg) was obtained. MS (ESI) m / e [M+1] + 460.3.

[0145] Step 7: Benzyl (2-amino-6-(methylcarbamoyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-6-yl)carbamate [ka] To a solution of tert-butyl 2-amino-6-(((benzyloxy)carbonyl)amino)-6-(methylcarbamoyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (287 mg, 0.625 mmol) in THF (30 mL) was added HCl acid (6N, 10 mL). The mixture was stirred at 60° C. for 4 h. After cooling to room temperature, the reaction mixture was neutralized with aq. NaHCO3 and then extracted with DCM (50 mL×3). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuum. The residue was purified by preparative TLC (eluent: MeOH / DCM (v / v)=1 / 10) to give benzyl (2-amino-6-(methylcarbamoyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-6-yl)carbamate (237 mg). MS (ESI) m / e [M+1] + 360.2.

[0146] Step 8: Benzyl (2-((S)-2-((tert-butoxycarbonyl)amino)-2-cyclohexylacetamido)-6-(methylcarbamoyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-6-yl)carbamate [ka] To a solution of benzyl (2-amino-6-(methylcarbamoyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-6-yl)carbamate (237 mg, 0.625 mmol) in DCM (15 mL) was added (S)-2-((tert-butoxycarbonyl)amino)-2-cyclohexylacetic acid (161 mg, 0.625 mmol), HATU (238 mg, 0.625 mmol) and Et3N (189 mg, 1.875 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was purified by preparative TLC (MeOH / DCM=1 / 10). (2-((S)-2-((tert-butoxycarbonyl)amino)-2-cyclohexylacetamido)-6-(methylcarbamoyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-6-yl)benzylcarbamate (223 mg) was obtained. MS (ESI) m / e [M+1] + 599.3.

[0147] Step 9: Benzyl (2-((S)-2-amino-2-cyclohexylacetamido)-6-(methylcarbamoyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-6-yl)carbamate [ka] A solution of (2-((S)-2-((tert-butoxycarbonyl)amino)-2-cyclohexylacetamido)-6-(methylcarbamoyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-6-yl)benzylcarbamate (223 mg, 0.372 mmol) in TFA (5 mL) was stirred at room temperature for 1 h. The reaction was concentrated in vacuo to give the crude title compound (300 mg). MS (ESI) m / e [M+1] + 499.4.

[0148] Step 10: Benzyl (2-((S)-2-cyclohexyl-2-(1-methyl-1H-pyrazole-5-carboxamido)acetamido)-6-(methylcarbamoyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-6-yl)carbamate [ka] To a solution of benzyl (2-((S)-2-amino-2-cyclohexylacetamido)-6-(methylcarbamoyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-6-yl)carbamate (300 mg) in DCM (15 mL) was added 1-methyl-1H-pyrazole-5-carboxylic acid (47 mg, 0.372 mmol), HATU (141 mg, 0.372 mmol) and EtN (190 mg, 1.86 mmol). The mixture was stirred at room temperature for 48 h. The reaction mixture was concentrated in vacuo. The residue was purified by preparative TLC (eluent: MeOH / DCM (v / v) = 1 / 10) to give (2-((S)-2-cyclohexyl-2-(1-methyl-1H-pyrazole-5-carboxamido)acetamido)-6-(methylcarbamoyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-6-yl)benzylcarbamate (90 mg). MS (ESI) m / e [M+1] + 607.4.

[0149] Step 11: N-((1S)-2-((6-amino-6-(methylcarbamoyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-1-cyclohexyl-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide [ka] To a solution of (2-((S)-2-cyclohexyl-2-(1-methyl-1H-pyrazole-5-carboxamido)acetamido)-6-(methylcarbamoyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-6-yl)benzylcarbamate (80 mg, 0.13 mmol) in DCM (10 mL) was added TMSI (1 mL, 1 mol / L). The mixture was stirred at room temperature for 30 min. The reaction mixture was neutralized with aq. NaHCO3 and extracted with DCM (50 mL x 3). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. N-((1S)-2-((6-amino-6-(methylcarbamoyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-1-cyclohexyl-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (63 mg, crude) was obtained. MS (ESI) m / e [M+1] + 473.2.

[0150] Step 12: tert-butyl ((1-(((2-((S)-2-cyclohexyl-2-(1-methyl-1H-pyrazole-5-carboxamido)acetamido)-6-(methylcarbamoyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-6-yl)amino)methyl)cyclopropyl)methyl)carbamate [ka] A mixture of N-((1S)-2-((6-amino-6-(methylcarbamoyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-1-cyclohexyl-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (30 mg, 0.063 mmol), tert-butyl ((1-formylcyclopropyl)methyl)carbamate (13 mg, 0.063 mmol) and NaBH(OAc)3 (14 mg, 0.063 mmol) in DCM (10 mL) was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. The residue was purified by preparative TLC (eluent: MeOH / DCM (v / v) = 1 / 15) to give the desired product (10 mg). MS (ESI) m / e [M+1]+ 656.5.

[0151] Step 13: N-((1S)-2-((6-(((1-(aminomethyl)cyclopropyl)methyl)amino)-6-(methylcarbamoyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-1-cyclohexyl-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide [ka] A mixture of ((1-(((2-((S)-2-cyclohexyl-2-(1-methyl-1H-pyrazole-5-carboxamido)acetamido)-6-(methylcarbamoyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-6-yl)amino)methyl)cyclopropyl)methyl)tert-butylcarbamate (10 mg) in TFA (2 mL) was stirred at room temperature for 30 min. The reaction was concentrated to give the desired product (10 mg) as a white solid. MS (ESI) m / e [M+1] + 556.4.

[0152] Step 14: N-((1S)-1-cyclohexyl-2-((6-(methylcarbamoyl)-6-(6-oxo-5,7-diazaspiro[2.5]octan-5-yl)-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 145) To a solution of N-((1S)-2-((6-(((1-(aminomethyl)cyclopropyl)methyl)amino)-6-(methylcarbamoyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-1-cyclohexyl-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (10 mg) and Et3N (30 mg) in DMF (2 mL) was added CDI (3 mg). The mixture was stirred at 60° C. for 2 h. The reaction mixture was concentrated in vacuo and the residue was purified by preparative TLC (eluent: MeOH / DCM (v / v)=1 / 15). The title compound Example 145 (2 mg) was obtained. MS (ESI) m / e [M+1] + 582.2.

[0153] Example 170: N-((1S)-1-cyclohexyl-2-((2-isopropyl-2-(6-oxo-5,7-diazaspiro[2.5]octan-5-yl)-2,3-dihydro-1H-inden-5-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide [ka] Step 1: 6-Bromo-2-isopropyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate methyl [ka] To a solution of methyl 6-bromo-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (27 g) in dry DMF (250 ml) was added sodium hydride (8 g of a 60% suspension in oil, 200 mmol) in portions over 20 min under N2 protection. The mixture was stirred for 45 min. 2-Iodopropane (34 g, 200 mmol) was added dropwise over 15 min and then the mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between EA (150 mL) and HCl acid (2N, 50 mL). The organic layer was separated, dried and concentrated in vacuum. The crude product was purified by column chromatography on silica gel (eluent: PE / EA (v / v) = 10 / 1). Methyl 6-bromo-2-isopropyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (10 g, yield: 33%) was obtained. MS (ESI, m / e) [M+1] + 311.0 / 313.0.

[0154] Step 2: Methyl 6-((diphenylmethylene)amino)-2-isopropyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate [ka] A mixture of methyl 6-bromo-2-isopropyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (3.11 g, 10 mmol), diphenylmethanimine (2.7 g, 15 mmol), BINAP (1.87 g, 0.3 mmol), Pd2(dba)3 (1.4 g, 0.15 mmol) and Cs2CO3 (10 g, 30 mmol) in toluene (50 mL) was degassed with N2. The mixture was heated to 100 °C and stirred under N2 atmosphere for 12 h. The reaction mixture was cooled to room temperature and washed with H2O, brine. The organic layer was dried over MgSO4, filtered and concentrated in vacuum. The residue was purified by column chromatography on silica gel (eluent: hexane / EtOAc (v / v) = 10 / 1). Methyl 6-((diphenylmethylene)amino)-2-isopropyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (2.2 g, yield: 53.5%) was obtained. MS (ESI, m / e) [M+1] + 412.1

[0155] Step 3: 6-amino-2-isopropyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate methyl [ka] Methyl 6-((diphenylmethylene)amino)-2-isopropyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (2.2 g) was dissolved in HCl acid (1N, 15 mL) and stirred for 1 h. The reaction mixture was basified with aq.NaHCO3 to pH=8-9 and extracted with EtOAc (30 mL×3). The combined organic layers were washed with H2O, brine, dried over MgSO4, filtered and concentrated in vacuum. The residue was purified by column chromatography on silica gel (eluent: hexane / EtOAc (v / v)=1 / 1). Methyl 6-amino-2-isopropyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (1 g, yield: 76.9%) was obtained. MS (ESI, m / e) [M+1] + 248.1.

[0156] Step 4: 6-Amino-1-hydroxy-2-isopropyl-2,3-dihydro-1H-indene-2-carboxylate methyl [ka] To a solution of methyl 6-amino-2-isopropyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (1 g, 4 mmol) in MeOH (50 mL) at 0° C., NaBH4 (154 mg, 12 mmol) was added in portions. The reaction mixture was stirred for 1 h and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was dried over MgSO4 and concentrated in vacuo. Methyl 6-amino-1-hydroxy-2-isopropyl-2,3-dihydro-1H-indene-2-carboxylate (1 g, crude) was obtained. MS (ESI, m / e) [M+1] + 250.1.

[0157] Step 5: 5-Amino-2-isopropyl-2,3-dihydro-1H-indene-2-carboxylate methyl [ka] To a solution of methyl 6-amino-1-hydroxy-2-isopropyl-2,3-dihydro-1H-indene-2-carboxylate (249 mg, 1 mmol) in TFA (10 mL) was added triethylsilane (2 mL). The mixture was stirred at room temperature for 1 h. After the reaction mixture was concentrated to remove TFA, the residue was dissolved in DCM (25 mL) and washed with saturated aq. NaHCO3. The organic layer was dried over MgSO4 and concentrated in vacuo. Methyl 5-amino-2-isopropyl-2,3-dihydro-1H-indene-2-carboxylate (240 mg, crude) was obtained. MS (ESI, m / e) [M+1] + 234.1.

[0158] Step 6: 5-((S)-2-((tert-butoxycarbonyl)amino)-2-cyclohexylacetamido)-2-isopropyl-2,3-dihydro-1H-indene-2-carboxylate methyl ester [ka] To a solution of methyl 5-amino-2-isopropyl-2,3-dihydro-1H-indene-2-carboxylate (466 mg, 2 mmol) in DCM (25 mL) was added (S)-2-((tert-butoxycarbonyl)amino)-2-cyclohexylacetic acid (819 mg, 3 mmol), HATU (1.35 g, 3.6 mmol) and TEA (1 mL). The mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated to remove the solvent and the residue was purified by preparative TLC (eluent: DCM / MeOH (v / v) = 15:1). 5-((S)-2-((tert-butoxycarbonyl)amino)-2-cyclohexylacetamido)-2-isopropyl-2,3-dihydro-1H-indene-2-carboxylate (623 mg, yield: 56%) was obtained. MS (ESI, m / e) [M+1] + 473.3.

[0159] Step 7: 5-((S)-2-amino-2-cyclohexylacetamido)-2-isopropyl-2,3-dihydro-1H-indene-2-carboxylate methyl [ka] Methyl 5-((S)-2-((tert-butoxycarbonyl)amino)-2-cyclohexylacetamido)-2-isopropyl-2,3-dihydro-1H-indene-2-carboxylate (623 mg, 1.32 mmol) was dissolved in HCl solution (10 mL, 2M in dioxane) and stirred at room temperature for 1 h. After concentration of the reaction mixture in vacuo to remove the solvent, the HCl salt of methyl 5-((S)-2-amino-2-cyclohexylacetamido)-2-isopropyl-2,3-dihydro-1H-indene-2-carboxylate (491 mg, crude) was obtained. MS (ESI, m / e) [M+1] + 373.1.

[0160] Step 8: 5-((S)-2-cyclohexyl-2-(1-methyl-1H-pyrazole-5-carboxamido)acetamido)-2-isopropyl-2,3-dihydro-1H-indene-2-carboxylate methyl [ka] To a solution of methyl 5-((S)-2-amino-2-cyclohexylacetamido)-2-isopropyl-2,3-dihydro-1H-indene-2-carboxylate (491 mg, crude) and TEA (1.0 mL) in DCM (25 mL) was added 1-methyl-1H-pyrazole-5-carboxylic acid (200 mg, 1.58 mmol) and HATU (752 mg, 1.98 mmol). The mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with aq. NaHCO3 (50 mL) and diluted with DCM (20 mL). The organic layer was dried over Na2SO4 and concentrated in vacuum. The residue was purified by preparative TLC (eluent: DCM / MeOH (v / v) = 15:1). Methyl 5-((S)-2-cyclohexyl-2-(1-methyl-1H-pyrazole-5-carboxamido)acetamido)-2-isopropyl-2,3-dihydro-1H-indene-2-carboxylate (200 mg, yield: 32%) was obtained. MS (ESI, m / e) [M+1] + 481.1.

[0161] Step 9: 5-((S)-2-cyclohexyl-2-(1-methyl-1H-pyrazole-5-carboxamido)acetamido)-2-isopropyl-2,3-dihydro-1H-indene-2-carboxylic acid [ka] To a solution of methyl 5-((S)-2-cyclohexyl-2-(1-methyl-1H-pyrazole-5-carboxamido)acetamido)-2-isopropyl-2,3-dihydro-1H-indene-2-carboxylate (200 mg, 0.42 mmol) in methanol (5 mL) was added aq.NaOH (2 mL, 1.0 N). The mixture was stirred at room temperature overnight. The reaction mixture was acidified to pH=5-6 with diluted HCl acid and extracted with EtOAc (15 mL×3). The organic layer was washed with H2O, brine, dried over MgSO4, filtered and concentrated in vacuum. 5-((S)-2-cyclohexyl-2-(1-methyl-1H-pyrazole-5-carboxamido)acetamido)-2-isopropyl-2,3-dihydro-1H-indene-2-carboxylic acid (100 mg, crude) was obtained. MS (ESI, m / e) [M+1] + 467.0.

[0162] Step 10: N-((1S)-2-((2-amino-2-isopropyl-2,3-dihydro-1H-inden-5-yl)amino)-1-cyclohexyl-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide [ka] To a solution of 5-((S)-2-cyclohexyl-2-(1-methyl-1H-pyrazole-5-carboxamido)acetamido)-2-isopropyl-2,3-dihydro-1H-indene-2-carboxylic acid (60 mg, 0.13 mmol) in toluene (5 mL) was added DPPA (53 mg) and TEA (0.1 mL). The mixture was heated to 90° C. and stirred for 1 h. The reaction mixture was cooled and concentrated to remove the solvent. The residue was dissolved in HCl acid (5 mL, 1N) and then stirred for 1 h. The mixture was basified to pH 9 with aq. NaHCO3 and extracted with EtOAc (10 mL×3). The organic layer was washed with H2O, brine, dried over MgSO4, filtered and concentrated in vacuum. The residue was purified by column chromatography on silica gel (eluent: hexane / EtOAc (v / v)=1 / 1). N-((1S)-2-((2-amino-2-isopropyl-2,3-dihydro-1H-inden-5-yl)amino)-1-cyclohexyl-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (30 mg, yield: 54%) was obtained. MS (ESI, m / e) [M+1] + 438.1.

[0163] Step 11: ((1-(((5-((S)-2-cyclohexyl-2-(1-methyl-1H-pyrazole-5-carboxamido)acetamido)-2-isopropyl-2,3-dihydro-1H-inden-2-yl)amino)methyl)cyclopropyl)methyl)carbamate tert-butyl [ka] A mixture of N-((1S)-2-((2-amino-2-isopropyl-2,3-dihydro-1H-inden-5-yl)amino)-1-cyclohexyl-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (30 mg, 0.069 mmol), tert-butyl ((1-formylcyclopropyl)methyl)carbamate (14 mg, 0.069 mmol) and NaBH(OAc)3 (50 mg) in DCM (5 mL) was stirred at room temperature for 1 h. The reaction mixture was diluted with DCM (15 mL) and then washed with H2O, brine. The organic layer was separated, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by preparative TLC (eluent: DCM / MeOH (v / v) = 15:1). ((1-(((5-((S)-2-cyclohexyl-2-(1-methyl-1H-pyrazole-5-carboxamido)acetamido)-2-isopropyl-2,3-dihydro-1H-inden-2-yl)amino)methyl)cyclopropyl)methyl)tert-butyl carbamate (20 mg, yield: 47%) was obtained. MS (ESI, m / e) [M+1] + 621.1.

[0164] Step 12: N-((1S)-2-((2-(((1-(aminomethyl)cyclopropyl)methyl)amino)-2-isopropyl-2,3-dihydro-1H-inden-5-yl)amino)-1-cyclohexyl-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide [ka] tert-Butyl ((1-(((5-((S)-2-cyclohexyl-2-(1-methyl-1H-pyrazole-5-carboxamide)acetamido)-2-isopropyl-2,3-dihydro-1H-inden-2-yl)amino)methyl)cyclopropyl)methyl)carbamate (20 mg) was dissolved in HCl solution (10 mL, 2M in dioxane) and stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo to give the HCl salt of N-((1S)-2-((2-(((1-(aminomethyl)cyclopropyl)methyl)amino)-2-isopropyl-2,3-dihydro-1H-inden-5-yl)amino)-1-cyclohexyl-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (20 mg, crude). MS (ESI, m / e) [M+1] + 521.3.

[0165] Step 13: N-((1S)-1-cyclohexyl-2-((2-isopropyl-2-(6-oxo-5,7-diazaspiro[2.5]octan-5-yl)-2,3-dihydro-1H-inden-5-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 170) To a solution of methyl N-((1S)-2-((2-(((1-(aminomethyl)cyclopropyl)methyl)amino)-2-isopropyl-2,3-dihydro-1H-inden-5-yl)amino)-1-cyclohexyl-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (20 mg) and TEA (0.5 mL) in THF (5 mL) was added CDI (20 mg). The mixture was heated to reflux and stirred for 3 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by preparative TLC (eluent: DCM / MeOH (v / v)=15:1). The title compound (10 mg, yield: 28.6% for two steps) was obtained. 1H NMR (400 MHz, DMSO-d6) δ ppm:10.05 (s, 1H), 8.45 (d, J = 8.0 Hz, 1H), 7.45 (t, J = 8.6 Hz, 2H), 7.29 (s, 1H), 7.04 (d, J = 10.4 Hz, 2H), 6.05 (s, 1H), 4.44-4.31 (m, 1H), 4.03 (s, 3H), 3.21-2.92 (m, 4H), 2.86 (s, 2H), 2.67 (s, 2H), 1.94-1.49 (m, 8H), 128-1.15 (m, 4H), 0.70 (d, J = 6.6 Hz, 6H), 0.52-0.38 (m, 4H). MS (ESI, m / e) [M+1] + 547.7.

[0166] Example 212: N-((2S)-1,1-dicyclopropyl-3-((2-isopropyl-2-(2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)-2,3-dihydro-1H-inden-5-yl)amino)-3-oxopropan-2-yl)-4-methyl-1,2,5-oxadiazole-3-carboxamide [ka] Step 1: 2-isopropyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate methyl [ka] To a solution of methyl 1-oxo-2,3-dihydro-1H-indene-2-carboxylate (14 g, 73.6 mmol) in dry DMF (250 ml) at 0° C., sodium hydride (8.8 g of a 60% suspension in oil, 222 mmol) was added portionwise over 20 min. The mixture was stirred for another 45 min, after which 2-iodopropane (25 g, 148 mmol) was added dropwise over 15 min. The mixture was then heated to 90° C. and stirred for 18 h. The reaction mixture was cooled to room temperature, then poured into ice / water (100 mL) and extracted with EA (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluent: PE / EA (v / v)=10 / 1). Methyl 2-isopropyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (8 g, 50%) was obtained. MS (ESI, m / e) [M+1] + 233.1.

[0167] Step 2: 1-Hydroxy-2-isopropyl-2,3-dihydro-1H-indene-2-carboxylate methyl [ka] To a solution of methyl 2-isopropyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (1.8 g, 7.8 mmol) in MeOH (50 mL) at 0° C. was added NaBH4 (1.2 g, 32 mmol) in portions. The mixture was stirred for 1 h and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. Methyl 1-hydroxy-2-isopropyl-2,3-dihydro-1H-indene-2-carboxylate (1.8 g, crude) was obtained, which was used directly in the next step. MS (ESI, m / e) [M-17] + 217.1.

[0168] Step 3: 2-isopropyl-2,3-dihydro-1H-indene-2-carboxylate methyl [ka] To a solution of methyl 1-hydroxy-2-isopropyl-2,3-dihydro-1H-indene-2-carboxylate (1.7 g, 7.2 mmol) in TFA (25 mL) was added triethylsilane (5 mL). The mixture was stirred at room temperature for 1 h. The reaction mixture was then concentrated under reduced pressure to remove the solvent. The residue was dissolved in DCM (25 mL) and washed with saturated aq. NaHCO3 (10 mL). The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. Methyl 2-isopropyl-2,3-dihydro-1H-indene-2-carboxylate (1.5 g, crude) was obtained, which was used directly in the next step. MS (ESI, m / e) [M+1] + 219.1.

[0169] Step 4: 2-Isopropyl-2,3-dihydro-1H-indene-2-carboxylic acid [ka] To a solution of methyl 2-isopropyl-2,3-dihydro-1H-indene-2-carboxylate (218 mg, 1 mmol) in methanol (3 mL) was added aq.NaOH (1.0 N, 2 mL, 2 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was then acidified with HCl acid (2.0 N) and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine, H2O, dried over MgSO4, filtered and concentrated in vacuo. 2-Isopropyl-2,3-dihydro-1H-indene-2-carboxylic acid (200 mg, crude) was obtained. MS (ESI, m / e) [M+1] + 205.1.

[0170] Step 5: 2-Isopropyl-2,3-dihydro-1H-inden-2-amine [ka] To a solution of 2-isopropyl-2,3-dihydro-1H-indene-2-carboxylic acid (1.2 g, 6.8 mmol) in toluene (25 mL) was added DPPA (2.75 g) and TEA (3 mL). The mixture was heated to 90° C. and stirred for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted in HCl acid (1N, 15 mL) and then stirred for 1 h. The mixture was basified to pH 8-9 with aq. NaHCO3 and extracted with EtOAc (10 mL×3). The combined organic layers were washed with H2O, brine, dried over MgSO4, filtered and concentrated in vacuum. The residue was purified by column chromatography on silica gel (eluent: hexane / EtOAc (v / v)=4 / 1). 2-Isopropyl-2,3-dihydro-1H-indene-2-amine (700 mg, yield: 69%) was obtained. MS (ESI, m / e) [M+1] + 176.1

[0171] Step 6: tert-Butyl (1,1,1-trifluoro-3-((2-isopropyl-2,3-dihydro-1H-inden-2-yl)amino)-3-oxopropan-2-yl)carbamate [ka] To a mixture of 2-(((benzyloxy)carbonyl)amino)-3,3,3-trifluoropropanoic acid (1.17 g, 4.8 mmol), HATU (1.98 g, 5.2 mmol) in DCM (30 mL) was added 2-isopropyl-2,3-dihydro-1H-inden-2-amine (700 mg, 4 mmol) and TEA (1.6 g, 15.4 mmol) at 0° C. The mixture was stirred at room temperature for 1.5 h. The reaction mixture was diluted with DCM and quenched with aq. NaHCO3. The organic layer was washed with brine, dried and concentrated in vacuum. The residue was purified by column chromatography on silica gel (eluent: hexane / EtOAc (v / v) = 5 / 1). (1,1,1-trifluoro-3-((2-isopropyl-2,3-dihydro-1H-inden-2-yl)amino)-3-oxopropan-2-yl)carbamic acid tert-butyl ester (750 mg, yield: 46%) was obtained. MS (ESI, m / e) [M+1] + 401.1.

[0172] Step 7: tert-Butyl (1,1,1-trifluoro-3-((2-isopropyl-2,3-dihydro-1H-inden-2-yl)amino)propan-2-yl)carbamate [ka] To a solution of tert-butyl (1,1,1-trifluoro-3-((2-isopropyl-2,3-dihydro-1H-inden-2-yl)amino)-3-oxopropan-2-yl)carbamate (750 mg, 1.8 mmol) in THF (10 mL) was added dropwise BH3-Me2S (10 mL). The mixture was heated to 70° C. and stirred for 4 h. The reaction mixture was quenched with MeOH (10 mL). After removal of the solvent, the residue was purified by column chromatography on silica gel (eluent: hexane / EtOAc (v / v)=4 / 1). To obtain tert-butyl (1,1,1-trifluoro-3-((2-isopropyl-2,3-dihydro-1H-inden-2-yl)amino)propan-2-yl)carbamate (500 mg, 72%). MS (ESI, m / e) [M+1] + 387.2

[0173] Step 8: 3,3,3-Trifluoro-N 1 -(2-isopropyl-2,3-dihydro-1H-inden-2-yl)propane-1,2-diamine [ka] To a solution of tert-butyl (1,1,1-trifluoro-3-((2-isopropyl-2,3-dihydro-1H-inden-2-yl)amino)propan-2-yl)carbamate (500 mg) in THF was added HCl in dioxane (2M, 10 mL). The mixture was stirred at room temperature for 1 h. After removing the solvent in vacuo, 3,3,3-trifluoro-N 1 -(2-isopropyl-2,3-dihydro-1H-inden-2-yl)propane-1,2-diamine salt (450 mg, crude) was obtained and used directly in the next step.

[0174] Step 9: 1-(2-isopropyl-2,3-dihydro-1H-inden-2-yl)-4-(trifluoromethyl)imidazolidin-2-one [ka] To a solution of 3,3,3-trifluoro-N1-(2-isopropyl-2,3-dihydro-1H-inden-2-yl)propane-1,2-diamine (400 mg, 1.4 mmol) and TEA (1.5 mL) in THF (15 mL) was added CDI (324 mg, 2 mmol). The mixture was heated to reflux and stirred for 3 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane / EtOAc (v / v) = 5 / 1). 1-(2-isopropyl-2,3-dihydro-1H-inden-2-yl)-4-(trifluoromethyl)imidazolidin-2-one (150 mg, yield: 34% for two steps) was obtained. MS (ESI, m / e) [M+1] + 313.0.

[0175] Step 10: 1-(2-isopropyl-5-nitro-2,3-dihydro-1H-inden-2-yl)-4-(trifluoromethyl)imidazolidin-2-one [ka] To a mixture of H2SO4 (2 mL) and HNO3 (3 mL) was added a solution of 1-(2-isopropyl-2,3-dihydro-1H-inden-2-yl)-4-(trifluoromethyl)imidazolidin-2-one (80 mg, 0.25 mmol) in HOAc (2 mL) in one portion at 0°C. The mixture was stirred at 0°C for 5 min, then quenched with saturated aq. NaHCO3 (10 mL) and extracted with DCM (10 mL x 3). The organic layer was washed with H2O, brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluent: hexane / EtOAc (v / v) = 4 / 1). 1-(2-isopropyl-5-nitro-2,3-dihydro-1H-inden-2-yl)-4-(trifluoromethyl)imidazolidin-2-one (40 mg, yield: 44%) was obtained. MS (ESI, m / e) [M+1] + 358.0.

[0176] Step 11: 1-(5-amino-2-isopropyl-2,3-dihydro-1H-inden-2-yl)-4-(trifluoromethyl)imidazolidin-2-one [ka] To a solution of 1-(2-isopropyl-5-nitro-2,3-dihydro-1H-inden-2-yl)-4-(trifluoromethyl)imidazolidin-2-one (40 mg, 0.11 mmol) in MeOH (10 mL) was added Pd / C (10 mg). The mixture was stirred under H2 atmosphere for 1 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give 1-(5-amino-2-isopropyl-2,3-dihydro-1H-inden-2-yl)-4-(trifluoromethyl)imidazolidin-2-one (40 mg, crude). MS (ESI, m / e) [M+1] + 328.0.

[0177] Step 12: tert-butyl ((2S)-1,1-dicyclopropyl-3-((2-isopropyl-2-(2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)-2,3-dihydro-1H-inden-5-yl)amino)-3-oxopropan-2-yl)carbamate [ka] To a solution of 1-(5-amino-2-isopropyl-2,3-dihydro-1H-inden-2-yl)-4-(trifluoromethyl)imidazolidin-2-one (40 mg, 0.11 mmol) in DCM was added (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid (30 mg, 0.11 mmol), HATU (63 mg, 0.17 mmol) and TEA (0.1 mL). The mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated and purified by preparative TLC to give tert-butyl ((2S)-1,1-dicyclopropyl-3-((2-isopropyl-2-(2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)-2,3-dihydro-1H-inden-5-yl)amino)-3-oxopropan-2-yl)carbamate (30 mg, yield: 47%). MS (ESI, m / e) [M+1] + 579.1.

[0178] Step 13: (2S)-2-Amino-3,3-dicyclopropyl-N-(2-isopropyl-2-(2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)-2,3-dihydro-1H-inden-5-yl)propanamide [ka] To a solution of tert-butyl ((2S)-1,1-dicyclopropyl-3-((2-isopropyl-2-(2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)-2,3-dihydro-1H-inden-5-yl)amino)-3-oxopropan-2-yl)carbamate (30 mg) in THF was added HCl in dioxane (2M, 10 mL). The mixture was stirred at room temperature for 1 h. After removing the solvent in vacuo, (2S)-2-amino-3,3-dicyclopropyl-N-(2-isopropyl-2-(2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)-2,3-dihydro-1H-inden-5-yl)propanamide (20 mg, crude) was obtained. MS (ESI, m / e) [M+1] + 479.1.

[0179] Step 14: N-((2S)-1,1-dicyclopropyl-3-((2-isopropyl-2-(2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)-2,3-dihydro-1H-inden-5-yl)amino)-3-oxopropan-2-yl)-4-methyl-1,2,5-oxadiazole-3-carboxamide (Example 212) To a solution of (2S)-2-amino-3,3-dicyclopropyl-N-(2-isopropyl-2-(2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)-2,3-dihydro-1H-inden-5-yl)propanamide (20 mg, 0.042 mmol) in DCM (10 mL) was added 4-methyl-1,2,5-oxadiazole-3-carboxylic acid (5 mg, 0.042 mmol), HATU (24 mg, 0.063 mmol) and TEA (0.1 mL). The mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated to remove the solvent. The residue was purified by preparative TLC (eluent: DCM / CH3OH (v / v)=20 / 1). The title compound Example 212 (8 mg, yield: 32%) was obtained. 1H NMR (400 MHz, DMSO-d6) δ ppm:10.06 (s, 1H), 9.02 (d, J = 8.8 Hz, 1H), 7.46 (d, J = 7.8 Hz, 1H), 7.33 (d, J = 8.2 Hz, 1H), 7.22 (s, 1H), 7.12 (d, J = 8.0 Hz, 1H), 4.89-4.80 (m, 1H), 4.24 (s, 1H), 3.65 (d, J = 10.6 Hz, 1H), 3.49-3.41 (m, 2H), 3.09-3.01 (m, 3H), 2.59-2.53 (m, 1H), 2.48 (s, 3H), 0.94-0.76 (m, 9H), 0.50-0.11 (m, 8H). MS (ESI, m / e) [M+1] + 589.5.

[0180] Example 238 N-((2S)-1,1-dicyclopropyl-3-((2-((R)-4-isopropyl-2-oxoimidazolidin-1-yl)-2-(2,2,2-trifluoro-1-hydroxyethyl)-2,3-dihydro-1H-inden-5-yl)amino)-3-oxopropan-2-yl)-4-methyl-1,2,5-oxadiazole-3-carboxamide [ka] Step 1: (R)-1-(2-(hydroxymethyl)-2,3-dihydro-1H-inden-2-yl)-4-isopropylimidazolidin-2-one [ka] To a solution of methyl (R)-2-(4-isopropyl-2-oxoimidazolidin-1-yl)-2,3-dihydro-1H-indene-2-carboxylate (430 mg, 1.4 mmol, prepared by a similar procedure as 2-((R)-4-isopropyl-2-oxoimidazolidin-1-yl)-N-methyl-5-nitro-2,3-dihydro-1H-indene-2-carboxamide described in intermediate A2) in THF (8 mL) at 0° C., LAH solution (2.5 M, 1.5 mL, 3.7 mmol) was added dropwise with stirring under N2 atmosphere. After addition, the mixture was stirred at 0° C. for 1 h. The reaction mixture was quenched with aq. Na2SO4 and extracted with EA (15 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative TLC (eluent: DCM / MeOH (v / v)=20 / 1) to give (R)-1-(2-(hydroxymethyl)-2,3-dihydro-1H-inden-2-yl)-4-isopropylimidazolidin-2-one (270 mg, yield: 69%). MS (ESI) m / e [M+1] + 275.1.

[0181] Step 2: (R)-2-(4-isopropyl-2-oxoimidazolidin-1-yl)-2,3-dihydro-1H-indene-2-carbaldehyde [ka] To a solution of (R)-1-(2-(hydroxymethyl)-2,3-dihydro-1H-inden-2-yl)-4-isopropylimidazolidin-2-one (270 mg, 1.0 mmol) in DCM (20 mL). The resulting solution was cooled to 0° C. under nitrogen atmosphere and Dess-Martin reagent (636 mg, 1.5 mmol) was added in portions at 0° C. under nitrogen atmosphere. The mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with aq. Na2S2O3 (5 mL) at 0° C., then diluted with aq. NaHCO3 (10 mL) and extracted with EA (15 mL×3). The combined organic layers were washed with brine, dried and concentrated in vacuo. The residue was purified by preparative TLC (eluent: DCM / MeOH (v / v)=30 / 1) to give (R)-2-(4-isopropyl-2-oxoimidazolidin-1-yl)-2,3-dihydro-1H-indene-2-carbaldehyde (240 mg, yield: 88%). MS (ESI) m / e [M+1] + 273.1.

[0182] Step 3: (4R)-4-Isopropyl-1-(2-(2,2,2-trifluoro-1-((trimethylsilyl)oxy)ethyl)-2,3-dihydro-1H-inden-2-yl)imidazolidin-2-one [ka] To a solution of (R)-2-(4-isopropyl-2-oxoimidazolidin-1-yl)-2,3-dihydro-1H-indene-2-carbaldehyde (240 mg, 0.88 mmol) in THF (10 mL) under nitrogen atmosphere was added CsF (174 mg, 1.15 mmol). The resulting mixture was cooled to 0° C. To this mixture was added TMS-CF3 (163 mg, 1.15 mmol). The mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with EtOAc (50 mL) and then washed with brine. The organic layer was separated, dried over Na2SO4, and concentrated in vacuo. (4R)-4-Isopropyl-1-(2-(2,2,2-trifluoro-1-((trimethylsilyl)oxy)ethyl)-2,3-dihydro-1H-inden-2-yl)imidazolidin-2-one (300 mg, crude) was obtained and used directly in the next step.

[0183] Step 4: (4R)-4-Isopropyl-1-(2-(2,2,2-trifluoro-1-hydroxyethyl)-2,3-dihydro-1H-inden-2-yl)imidazolidin-2-one [ka] (4R)-4-Isopropyl-1-(2-(2,2,2-trifluoro-1-((trimethylsilyl)oxy)ethyl)-2,3-dihydro-1H-inden-2-yl)imidazolidin-2-one (300 mg, crude) was dissolved in THF (10 mL) and cooled to 0° C. To this solution was added TBAF (0.1 mL, 1 M). The mixture was stirred at 0° C. for 1 h. The reaction mixture was diluted with EtOAc (50 mL) and then washed with brine. The organic layer was separated, dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative TLC (eluent: DCM / MeOH (v / v) = 25 / 1) to give (4R)-4-isopropyl-1-(2-(2,2,2-trifluoro-1-hydroxyethyl)-2,3-dihydro-1H-inden-2-yl)imidazolidin-2-one (60 mg, yield: 20% for two steps). MS (ESI) m / e [M+1] + 343.2.

[0184] Step 5: (4R)-1-(5-amino-2-(2,2,2-trifluoro-1-hydroxyethyl)-2,3-dihydro-1H-inden-2-yl)-4-isopropylimidazolidin-2-one [ka] To a mixture of H2SO4 (1 mL) and HNO3 (1.5 mL) was added a solution of (4R)-4-isopropyl-1-(2-(2,2,2-trifluoro-1-hydroxyethyl)-2,3-dihydro-1H-inden-2-yl)imidazolidin-2-one (60 mg) in AcOH (2 mL) in one portion at -5°C. The mixture was stirred at -5°C for another 5 min. The reaction mixture was poured into water / ice and then extracted with EtOAc (15 mL x 3). The combined organic layers were washed with water, aq. NaHCO3 and brine, dried and concentrated in vacuo. (4R)-1-(5-amino-2-(2,2,2-trifluoro-1-hydroxyethyl)-2,3-dihydro-1H-inden-2-yl)-4-isopropylimidazolidin-2-one (70 mg, crude) was obtained. The crude nitro product was dissolved in MeOH (10 mL), stirred and hydrogenated with H2 in the presence of Pd / C (35 mg) at room temperature for 1 h to give (4R)-1-(5-amino-2-(2,2,2-trifluoro-1-hydroxyethyl)-2,3-dihydro-1H-inden-2-yl)-4-isopropylimidazolidin-2-one (40 mg, crude). MS (ESI) m / e [M+1] + 358.3.

[0185] Step 6: ((2S)-1,1-dicyclopropyl-3-((2-((R)-4-isopropyl-2-oxoimidazolidin-1-yl)-2-(2,2,2-trifluoro-1-hydroxyethyl)-2,3-dihydro-1H-inden-5-yl)amino)-3-oxopropan-2-yl)carbamate benzyl [ka] To a solution of (4R)-1-(5-amino-2-(2,2,2-trifluoro-1-hydroxyethyl)-2,3-dihydro-1H-inden-2-yl)-4-isopropylimidazolidin-2-one (40 mg, crude) in DCM (5 mL) was added (S)-2-(((benzyloxy)carbonyl)amino)-3,3-dicyclopropylpropanoic acid (34 mg, 0.11 mmol), DIPEA (43.4 mg, 0.34 mmol) and HATU (55.4 mg, 0.15 mmol). The mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with DCM (15 mL) and then washed with aq. NaHCO3. The organic layer was washed with brine, dried and concentrated in vacuum. The crude product was purified by preparative TLC (eluent: EA / PE (v / v) = 1 / 1). ((2S)-1,1-dicyclopropyl-3-((2-((R)-4-isopropyl-2-oxoimidazolidin-1-yl)-2-(2,2,2-trifluoro-1-hydroxyethyl)-2,3-dihydro-1H-inden-5-yl)amino)-3-oxopropan-2-yl)benzyl carbamate (30 mg, yield: 42%) was obtained. MS (ESI) m / e [M+1] + 643.5.

[0186] Step 7: (2S)-2-Amino-3,3-dicyclopropyl-N-(2-((R)-4-isopropyl-2-oxoimidazolidin-1-yl)-2-(2,2,2-trifluoro-1-hydroxyethyl)-2,3-dihydro-1H-inden-5-yl)propanamide [ka] To a solution of ((2S)-1,1-dicyclopropyl-3-((2-((R)-4-isopropyl-2-oxoimidazolidin-1-yl)-2-(2,2,2-trifluoro-1-hydroxyethyl)-2,3-dihydro-1H-inden-5-yl)amino)-3-oxopropan-2-yl)benzylcarbamate (30 mg, 0.05 mmol) in MeOH was added Pd / C (30 mg). The mixture was then degassed with H2 and stirred at room temperature under H2 atmosphere for 1 h. The reaction mixture was diluted with DCM and filtered. The filtrate was concentrated to give (2S)-2-amino-3,3-dicyclopropyl-N-(2-((R)-4-isopropyl-2-oxoimidazolidin-1-yl)-2-(2,2,2-trifluoro-1-hydroxyethyl)-2,3-dihydro-1H-inden-5-yl)propanamide (29 mg, crude). MS (ESI) m / e [M+1] + 509.4.

[0187] Step 8: N-((2S)-1,1-dicyclopropyl-3-((2-((R)-4-isopropyl-2-oxoimidazolidin-1-yl)-2-(2,2,2-trifluoro-1-hydroxyethyl)-2,3-dihydro-1H-inden-5-yl)amino)-3-oxopropan-2-yl)-4-methyl-1,2,5-oxadiazole-3-carboxamide (Example 238) To a solution of (2S)-2-amino-3,3-dicyclopropyl-N-(2-((R)-4-isopropyl-2-oxoimidazolidin-1-yl)-2-(2,2,2-trifluoro-1-hydroxyethyl)-2,3-dihydro-1H-inden-5-yl)propanamide (29 mg, crude) in DCM (5 mL) was added 4-methyl-1,2,5-oxadiazole-3-carboxylic acid (7.3 mg, 0.06 mmol), DIPEA (22 mg, 0.17 mmol) and HATU (33 mg, 0.09 mmol). The mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with DCM (15 mL) and then washed with aq. NaHCO3. The organic layer was washed with brine, dried and concentrated in vacuum. The residue was first purified by preparative TLC. The crude product was then purified by preparative HPLC (mobile phase: MeCN / water (0.1% FA), column: SunFire, elution: 60%-80% MeCN) to give the title compound Example 238 (8.16 mg, 28% for two steps). 1 H NMR (400 MHz, DMSO-d6) δ ppm: 10.12 (s, 1H), 9.05 (d, J = 8.8 Hz, 1H), 7.54-7.50 (m, 1H), 7.43-7.32 (m, 1H), 7.24-7.11 (m, 1H), 6.90-6.76 (m, 1H), 4.87-4.75 (m, 2H), 3.53-3.38 (m, 3H), 3.31-3.14 (m, 4H), 2.97-2.89 (m, 1H), 2.49 (s, 3H), 1.37-1.24 (m, 1H), 0.93-0.67 (m, 3H), 0.63-0.50 (m, 6H), 0.49-0.35 (m, 2H), 0.33-0.08 (m, 6H). MS (ESI) m / e [M+1] + 619.5.

[0188] Example 256: N-((2S)-1,1-dicyclopropyl-3-oxo-3-((2-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)-2,3-dihydrobenzofuran-6-yl)amino)propan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide [ka] Step 1: 2-(2,2-dimethoxyethoxy)-4-nitrobenzaldehyde [ka] To a solution of 2-hydroxy-4-nitrobenzaldehyde (10 g, 29.92 mmol) in DMA (100 mL) at room temperature, 2-bromo-1,1-dimethoxyethane (40 g, 239.35 mmol), K2CO3 (33 g, 239.35 mmol) were added slowly. The mixture was stirred at 140° C. for 12 h. The reaction mixture was poured into ice-water (500 mL). The precipitate was collected by filtration and washed with water (500 mL). After the cake was dried in vacuum, 2-(2,2-dimethoxyethoxy)-4-nitrobenzaldehyde (10 g, yield: 66%) was obtained. 1 H NMR (400 MHz, CDCl3) δ ppm 10.55 (s, 1 H), 8.04 - 7.96 (m, 1 H), 7.94 - 7.86 (m, 2 H), 4.81 (t, J = 5.2 Hz, 1 H), 4.23 (d, J = 5.2 Hz, 2 H), 3.52 - 3.44 (m, 6H).

[0189] Step 2: 6-Nitrobenzofuran-2-carbaldehyde [ka] A solution of 2-(2,2-dimethoxyethoxy)-4-nitrobenzaldehyde (10 g, 39.18 mmol) in AcOH (100 mL) was heated to 60° C. and stirred for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was poured into saturated aq. Na2CO3 solution (100 mL) and then extracted with DCM (100 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuum. 6-Nitrobenzofuran-2-carbaldehyde (6 g, yield: 80%) was obtained. 1 H NMR (400 MHz, CDCl3) δ ppm 9.99 (s, 1 H), 8.52 (s, 1 H), 8.28 (dd, J = 2.0, 8.8 Hz, 1 H), 7.92 (d, J = 8.8 Hz, 1 H), 7.65 (d, J = 0.4 Hz, 1 H).

[0190] Step 3: (S)-3,3,3-trifluoro-N 1 -((6-nitrobenzofuran-2-yl)methyl)propane-1,2-diamine [ka] To a solution of 6-nitrobenzofuran-2-carbaldehyde (2 g, 10.46 mmol) in i-PrOH (40 mL) at 20° C., (S)-3,3,3-trifluoropropane-1,2-diamine hydrochloride (2.58 g, 15.70 mmol) and TEA (4.24 g, 41.85 mmol) were added. The mixture was stirred at 60° C. for 2 h. After TLC showed that the aldehyde reactant was completely consumed, AcOH (3.14 g, 52.30 mmol) and NaBH3CN (1.64 g, 26.16 mmol) were added to the reaction mixture (containing mainly the imine intermediate of (S)-1,1,1-trifluoro-3-(((6-nitrobenzofuran-2-yl)methylene)amino)propan-2-amine in i-PrOH) at 0° C. After the addition, the reaction mixture was stirred at 80° C. for another 12 h. The reaction mixture was cooled and then poured into saturated aq. NaHCO3 solution (20 mL) and extracted with DCM (50 mL×3). The combined layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate (v / v)=100 / 1 to 0 / 1). (S)-3,3,3-trifluoro-N 1 -((6-nitrobenzofuran-2-yl)methyl)propane-1,2-diamine (2.3 g, 70% yield) was obtained. 1 H NMR (400 MHz, CDCl3) δ ppm 8.37 (d, J = 1.2 Hz, 1 H), 8.18 (dd, J = 2.0, 8.4 Hz, 1 H), 7.63 (d, J = 8.4 Hz, 1H), 6.74 (s, 1 H), 4.05 (s, 2 H), 3.36 (s, 1H), 3.37 (s, 1H), 3.00 (dd, J = 3.6, 12.4 Hz, 1H), 2.75 (dd, J = 8.8, 12.0 Hz, 1H). MS (ESI, m / e) [M+1] + 303.2.

[0191] Step 4: (S)-1-((6-nitrobenzofuran-2-yl)methyl)-4-(trifluoromethyl)imidazolidin-2-one [ka] (S)-3,3,3-trifluoro-N 1 To a solution of -((6-nitrobenzofuran-2-yl)methyl)propane-1,2-diamine (2.3 g, 7.58 mmol) was added CDI (1.84 g, 11.38 mmol). The mixture was stirred at 80° C. for 2 h. The reaction mixture was cooled, poured into water (20 mL) and extracted with DCM (20 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The crude product was purified by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate (v / v)=50 / 1 to 1 / 1). (S)-1-((6-nitrobenzofuran-2-yl)methyl)-4-(trifluoromethyl)imidazolidin-2-one (1.5 g, yield: 60%) was obtained. 1 H NMR (400 MHz, CDCl3) δ ppm 8.42 - 8.35 (m, 1 H), 8.23 ​​- 8.15 (m, 1 H), 7.67 - 7.62 (m, 1 H), 6.81 - 6.75 (m, 1 H), 5.01 - 4.94 (m, 1 H), 4.68 - 4.54 (m, 1 H), 4.24 - 4.17 (m, 1 H), 3.84 - 3.62 (m, 2 H).

[0192] Step 5: (4S)-1-((6-amino-2,3-dihydrobenzofuran-2-yl)methyl)-4-(trifluoromethyl)imidazolidin-2-one [ka] To a solution of (S)-1-((6-nitrobenzofuran-2-yl)methyl)-4-(trifluoromethyl)imidazolidin-2-one (1.5 g, 4.56 mmol) in i-PrOH (10 mL) at room temperature, Pd / C (180 mg) was added. The mixture was stirred and hydrogenated under H2 atmosphere (50 psi) at 50 °C for 12 h. The reaction mixture was filtered and concentrated in vacuum. The crude product was purified by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate (v / v) = 100 / 1 to 0 / 1). (4S)-1-((6-amino-2,3-dihydrobenzofuran-2-yl)methyl)-4-(trifluoromethyl)imidazolidin-2-one (810 mg, yield: 59%) was obtained. 1 H NMR (400 MHz, CDCl3) δ ppm 6.92 (d, J = 7.6 Hz, 1 H), 6.30 - 6.11 (m, 2 H), 5.16 - 4.88 (m, 2 H), 4.18 - 4.07 (m, 1 H), 3.84 - 3.71 (m, 1 H), 3.67 - 3.54 (m, 3 H), 3.47 - 3.29 (m, 1 H), 3.18 (ddd, J = 3.2, 9.6, 15.2 Hz, 1H), 2.86 (dt, J = 7.2, 16.4 Hz, 1 H). MS (ESI, m / e) [M+1] + 302.1.

[0193] Step 6: Benzyl ((2S)-1,1-dicyclopropyl-3-oxo-3-((2-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)-2,3-dihydrobenzofuran-6-yl)amino)propan-2-yl)carbamate [ka] To a solution of (4S)-1-((6-amino-2,3-dihydrobenzofuran-2-yl)methyl)-4-(trifluoromethyl)imidazolidin-2-one (301 mg, 1.0 mmol) in DCM (100 mL) was added (S)-2-(((benzyloxy)carbonyl)amino)-3,3-dicyclopropylpropanoic acid (303 mg, 1.0 mmol), HATU (380 mg, 1.0 mmol) and TEA (202 mg, 2.0 mmol). The mixture was stirred at room temperature for 4 h. Then the reaction mixture was quenched with NaHCO3 (aq, 150 mL). The organic layer was separated, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (eluent: DCM / MeOH (v / v) = 50 / 1). Obtained benzyl ((2S)-1,1-dicyclopropyl-3-oxo-3-((2-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)-2,3-dihydrobenzofuran-6-yl)amino)propan-2-yl)carbamate (469 mg, 80%). MS (ESI, m / e) [M+1] + 587.2.

[0194] Step 7: (2S)-2-Amino-3,3-dicyclopropyl-N-(2-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)-2,3-dihydrobenzofuran-6-yl)propanamide [ka] A mixture of ((2S)-1,1-dicyclopropyl-3-oxo-3-((2-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)-2,3-dihydrobenzofuran-6-yl)amino)propan-2-yl)benzylcarbamate (469 mg, 0.8 mmol) and Pd / C (50 mg) in MeOH (50 mL) was bubbled with a H2 balloon and stirred for 2 h. The mixture was filtered and concentrated in vacuo to give the crude product (2S)-2-amino-3,3-dicyclopropyl-N-(2-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)-2,3-dihydrobenzofuran-6-yl)propanamide (226 mg, crude), which was used directly in the next step. MS (ESI, m / e) [M+1] + 453.2.

[0195] Step 8: N-((2S)-1,1-dicyclopropyl-3-oxo-3-((2-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)-2,3-dihydrobenzofuran-6-yl)amino)propan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (Example 256) To a solution of (2S)-2-amino-3,3-dicyclopropyl-N-(2-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)-2,3-dihydrobenzofuran-6-yl)propanamide (226 mg, 0.5 mmol) in DCM (50 mL) was added 1-isopropyl-1H-pyrazole-5-carboxylic acid (14 mg, 0.09 mmol), HATU (40 mg, 0.09 mmol) and DIEA (23 mg, 0.18 mmol). The mixture was stirred at room temperature for 4 h. The reaction mixture was quenched with saturated aq. NaHCO3 (50 mL). The organic layer was separated, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative TLC (eluent: MeOH / DCM (v / v) = 1 / 20) to give the crude product. The crude product was purified by preparative HPLC to give N-((2S)-1,1-dicyclopropyl-3-oxo-3-((2-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)-2,3-dihydrobenzofuran-6-yl)amino)propan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (16.85 mg, 32.3%). 1 H NMR (400 MHz, DMSO-d6) δ ppm: 10.09 (d, J = 5.0 Hz, 1H), 8.42 (d, J = 8.7 Hz, 1H), 7.52-7.50 (m, 2H), 7.18 (d, J = 4.4 Hz, 1H), 7.10 (t, J = 8.4 Hz, 1H), 7.00 (d, J = 7.8 Hz, 1H), 6.92 (s, 1H), 5.44-5.37 (m, 1H), 4.95-4.93 (m, 1H), 4.76 (t, J = 8.2 Hz, 1H), 4.35 (s, 1H), 3.79-3.66 (m, 1H), 3.58-3.37 (m, 2H), 3.30-3.14 (m, 2H), 2.87-2.82 (m, 1H), 1.38-1.33 (m, 6H), 0.89-0.67 (m, 3H), 0.45-0.06 (m, 8H). MS (ESI, m / e) [M+1] + 589.5.

[0196] Example 261: N-((2S)-1,1-dicyclopropyl-3-((2-((R)-4-isopropyl-2-oxoimidazolidin-1-yl)-2-(o-tolylcarbamoyl)-2,3-dihydro-1H-inden-5-yl)amino)-3-oxopropan-2-yl)-4-methyl-1,2,5-oxadiazole-3-carboxamide [ka] To a solution of 5-((S)-2-amino-3,3-dicyclopropylpropanamido)-2-((R)-4-isopropyl-2-oxoimidazolidin-1-yl)-N-(o-tolyl)-2,3-dihydro-1H-indene-2-carboxamide (65 mg, 0.12 mmol) in DCM (5 mL) at 0° C., 4-methyl-1,2,5-oxadiazole-3-carboxylic acid (23 mg, 0.18 mmol), HATU (68 mg, 0.18 mmol) and DIEA (31 mg, 0.24 mmol) were added. The mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with water (3 mL) and extracted with DCM (5 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC (column: Phenomenex Luna C18 75*30mm*3um, mobile phase: [water (NH4HCO3)-ACN], B%: 40%~70%, 8 min). N-((2S)-1,1-dicyclopropyl-3-((2-((R)-4-isopropyl-2-oxoimidazolidin-1-yl)-2-(o-tolylcarbamoyl)-2,3-dihydro-1H-inden-5-yl)amino)-3-oxopropan-2-yl)-4-methyl-1,2,5-oxadiazole-3-carboxamide (15.5mg, yield: 19.8%) was obtained. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.10 (s, 1 H), 9.07 - 8.96 (m, 2 H), 7.56 - 7.47 (m, 1 H), 7.46 - 7.32 (m, 2 H), 7.19 (d, J = 7.6 Hz, 2 H), 7.16 - 7.10 (m, 1 H), 7.08 - 7.03 (m, 1 H), 7.02 (s, 1 H), 4.86 (t, J = 8.0 Hz, 1 H), 3.70 (t, J = 17.6 Hz, 1 H), 3.62 - 3.49 (m, 2 H), 3.48 - 3.38 (m, 1H), 3.30 - 3.25 (m, 1 H), 3.22 (d, J = 16.4 Hz, 1 H), 2.94 (td, J = 7.6, 12.4 Hz, 1 H), 2.49 (s, 3 H), 2.17 (s, 3 H), 1.55 - 1.42 (m, 1 H), 0.93 - 0.84 (m, 1 H), 0.82 - 0.68 (m, 8 H), 0.52 - 0.36 (m, 2 H), 0.34 - 0.11 (m, 6 H). MS (ESI, m / e) [M+1] + 654.2.

[0197] Example 279: N-((2S)-1,1-dicyclopropyl-3-((2-(2-hydroxypropan-2-yl)-2-(2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)-2,3-dihydro-1H-inden-5-yl)amino)-3-oxopropan-2-yl)-4-methyl-1,2,5-oxadiazole-3-carboxamide [ka] Step 1: 2-(2-amino-2,3-dihydro-1H-inden-2-yl)propan-2-ol [ka] Methyl 2-amino-2,3-dihydro-1H-indene-2-carboxylate (1 g, 5.2 mmol) was dissolved in THF (20 mL) and cooled to 0° C. under N2 atmosphere. CH3MgBr (26.2 mL, 26.2 mmol) was added dropwise to this solution under stirring below 10° C. The mixture was warmed to room temperature and stirred for 30 min. At 0° C., the reaction mixture was quenched with aq. NH4Cl and extracted with DCM (30 mL×3). The combined organic layers were washed with brine, dried and concentrated in vacuum. The residue was purified by column chromatography on silica gel (eluent: DCM / MeOH (v / v)=10 / 1). 2-(2-amino-2,3-dihydro-1H-inden-2-yl)propan-2-ol (980 mg, yield: 98%) was obtained. MS (ESI) m / e [M+1] + 192.2.

[0198] Step 2: Benzyl (1,1,1-trifluoro-3-((2-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-inden-2-yl)amino)-3-oxopropan-2-yl)carbamate [ka] To a mixture of 2-(((benzyloxy)carbonyl)amino)-3,3,3-trifluoropropanoic acid (1.4 g, 5.1 mmol), EDCI (2.5 g, 12.8 mmol) and HOBt (727 mg, 5.4 mmol) in DCM (30 mL) at 0° C., 2-(2-amino-2,3-dihydro-1H-inden-2-yl)propan-2-ol (980 mg, 5.1 mmol) and TEA (1.6 g, 15.4 mmol) were added. The mixture was allowed to warm to room temperature and stirred for 1.5 h. The reaction mixture was diluted with DCM and quenched with NaHCO3 (aq.). The organic layer was washed with brine, dried and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluent: PE / EA (v / v)=1 / 1). Benzyl (1,1,1-trifluoro-3-((2-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-inden-2-yl)amino)-3-oxopropan-2-yl)carbamate (400 mg, yield: 17%) was obtained. MS (ESI) m / e [M+1] + 451.3.

[0199] Step 3: Benzyl (1,1,1-trifluoro-3-((2-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-inden-2-yl)amino)propan-2-yl)carbamate [ka] Benzyl (1,1,1-trifluoro-3-((2-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-inden-2-yl)amino)-3-oxopropan-2-yl)carbamate (400 mg, 0.89 mmol) was added with stirring in BH3-THF (1M, 10 mL). The mixture was heated to 60° C. and stirred for 6 h. The reaction mixture was cooled to room temperature and quenched with MeOH (5 mL) at 0° C. The mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluent: DCM / MeOH (v / v)=25 / 1). Benzyl (1,1,1-trifluoro-3-((2-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-inden-2-yl)amino)propan-2-yl)carbamate (110 mg, yield: 28%) was obtained. MS (ESI) m / e [M+1] + 437.3.

[0200] Step 4: Benzyl (3-((2-(2-((tert-butyldimethylsilyl)oxy)propan-2-yl)-2,3-dihydro-1H-inden-2-yl)amino)-1,1,1-trifluoropropan-2-yl)carbamate [ka] To a solution of benzyl (1,1,1-trifluoro-3-((2-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-inden-2-yl)amino)propan-2-yl)carbamate (110 mg, 0.25 mmol) in DCM (5 mL) was added dropwise 2,6-lutidine (40.5 mg, 0.38 mmol) and TBS-OTf (86.6 mg, 0.33 mmol) under N2 atmosphere at 0°C. The mixture was stirred at 0°C for 1 h. The reaction mixture was quenched with aq. NaHCO3 (10 mL) at 0°C and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine, dried and concentrated in vacuum. The residue was purified by column chromatography on silica gel (eluent: PE / EA (v / v) = 3 / 1). Benzyl (3-((2-(2-((tert-butyldimethylsilyl)oxy)propan-2-yl)-2,3-dihydro-1H-inden-2-yl)amino)-1,1,1-trifluoropropan-2-yl)carbamate (110 mg, yield: 79%) was obtained. MS (ESI) m / e [M+1] + 551.4.

[0201] Step 5: N 1 -(2-(2-((tert-butyldimethylsilyl)oxy)propan-2-yl)-2,3-dihydro-1H-inden-2-yl)-3,3,3-trifluoropropane-1,2-diamine [ka] To a solution of benzyl (3-((2-(2-((tert-butyldimethylsilyl)oxy)propan-2-yl)-2,3-dihydro-1H-inden-2-yl)amino)-1,1,1-trifluoropropan-2-yl)carbamate (110 mg, 0.2 mmol) in MeOH (5 mL) was added Pd / C (55 mg). The mixture was then degassed with H2 and stirred at room temperature under H2 atmosphere for 1 h. The reaction mixture was diluted with DCM (5 mL) and then filtered. The filtrate was concentrated in vacuo. N 1-(2-(2-((tert-butyldimethylsilyl)oxy)propan-2-yl)-2,3-dihydro-1H-inden-2-yl)-3,3,3-trifluoropropane-1,2-diamine (84 mg, crude) was obtained and used directly in the next step. MS (ESI) m / e [M+1] + 417.4.

[0202] Step 6: 1-(2-(2-((tert-butyldimethylsilyl)oxy)propan-2-yl)-2,3-dihydro-1H-inden-2-yl)-4-(trifluoromethyl)imidazolidin-2-one [ka] N in THF (6 mL) at room temperature 1 To a solution of -(2-(2-((tert-butyldimethylsilyl)oxy)propan-2-yl)-2,3-dihydro-1H-inden-2-yl)-3,3,3-trifluoropropane-1,2-diamine (84 mg, 0.2 mmol) was added CDI (82 mg, 0.5 mmol) and TEA (102 mg, 1.0 mmol). The mixture was heated to 60° C. and stirred for 2 h. The reaction mixture was then cooled to room temperature, diluted with EtOAc (20 mL) and washed with brine. The organic layer was dried and concentrated in vacuo. The residue was purified by preparative TLC (eluent: EtOAc / DCM (v / v)=2 / 1). Obtained 1-(2-(2-((tert-butyldimethylsilyl)oxy)propan-2-yl)-2,3-dihydro-1H-inden-2-yl)-4-(trifluoromethyl)imidazolidin-2-one (80 mg, crude). MS (ESI) m / e [M+1] + 443.3.

[0203] Step 7: 1-(2-(2-hydroxypropan-2-yl)-5-nitro-2,3-dihydro-1H-inden-2-yl)-4-(trifluoromethyl)imidazolidin-2-one [ka] To a mixture of H2SO4 (2 mL) and HNO3 (3 mL) was added a solution of (1-(2-(2-((tert-butyldimethylsilyl)oxy)propan-2-yl)-2,3-dihydro-1H-inden-2-yl)-4-(trifluoromethyl)imidazolidin-2-one (80 mg) in AcOH (2 mL) in one portion at -5°C. The mixture was stirred at -5°C for another 5 min. The reaction mixture was poured into water / ice and then extracted with EtOAc (15 mL x 3). The combined organic layers were washed with water, aq. NaHCO3 and brine, dried and concentrated in vacuo to give 1-(2-(2-hydroxypropan-2-yl)-5-nitro-2,3-dihydro-1H-inden-2-yl)-4-(trifluoromethyl)imidazolidin-2-one (50 mg, crude). MS (ESI) m / e [M+23] + 374.2.

[0204] Step 8: 1-(5-amino-2-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-inden-2-yl)-4-(trifluoromethyl)imidazolidin-2-one [ka] To a solution of 1-(2-(2-hydroxypropan-2-yl)-5-nitro-2,3-dihydro-1H-inden-2-yl)-4-(trifluoromethyl)imidazolidin-2-one (50 mg, crude) in MeOH (6 mL) was added Pd / C (30 mg). The mixture was then degassed with H2 and stirred at room temperature for 1 h. The reaction mixture was diluted with DCM (15 mL) and filtered. The filtrate was concentrated in vacuo to give 1-(5-amino-2-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-inden-2-yl)-4-(trifluoromethyl)imidazolidin-2-one (40 mg, crude). MS (ESI) m / e [M+1] + 344.2.

[0205] Step 9: ((2S)-1,1-dicyclopropyl-3-((2-(2-hydroxypropan-2-yl)-2-(2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)-2,3-dihydro-1H-inden-5-yl)amino)-3-oxopropan-2-yl)carbamate benzyl [ka] To a solution of 1-(5-amino-2-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-inden-2-yl)-4-(trifluoromethyl)imidazolidin-2-one (40 mg, 0.11 mmol) in DCM (5 mL) was added (S)-2-(((benzyloxy)carbonyl)amino)-3,3-dicyclopropylpropanoic acid (35 mg, 0.11 mmol), DIPEA (45 mg, 0.35 mmol) and HATU (66 mg, 0.17 mmol). The mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with DCM (15 mL) and washed with aq. NaHCO3. The organic layer was washed with brine, dried and concentrated in vacuum. The residue was purified by preparative TLC (eluent: EtOAc / DCM (v / v) = 1 / 1). ((2S)-1,1-dicyclopropyl-3-((2-(2-hydroxypropan-2-yl)-2-(2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)-2,3-dihydro-1H-inden-5-yl)amino)-3-oxopropan-2-yl)benzyl carbamate was obtained (30 mg, 41% yield in 3 steps). MS (ESI) m / e [M+1] + 629.1.

[0206] Step 10: (2S)-2-amino-3,3-dicyclopropyl-N-(2-(2-hydroxypropan-2-yl)-2-(2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)-2,3-dihydro-1H-inden-5-yl)propanamide [ka] To a solution of ((2S)-1,1-dicyclopropyl-3-((2-(2-hydroxypropan-2-yl)-2-(2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)-2,3-dihydro-1H-inden-5-yl)amino)-3-oxopropan-2-yl)benzylcarbamate (30 mg, 0.05 mmol) in MeOH (6 mL) was added Pd / C (30 mg). The mixture was then degassed with H2 and stirred under H2 atmosphere for 1 h. The reaction mixture was diluted with DCM (10 mL) and filtered. The filtrate was concentrated in vacuo. (2S)-2-amino-3,3-dicyclopropyl-N-(2-(2-hydroxypropan-2-yl)-2-(2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)-2,3-dihydro-1H-inden-5-yl)propanamide (28 mg, crude) was obtained. MS (ESI) m / e [M+1] + 495.2.

[0207] Step 11: N-((2S)-1,1-dicyclopropyl-3-((2-(2-hydroxypropan-2-yl)-2-(2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)-2,3-dihydro-1H-inden-5-yl)amino)-3-oxopropan-2-yl)-4-methyl-1,2,5-oxadiazole-3-carboxamide (Example 279) [ka] To a solution of (2S)-2-amino-3,3-dicyclopropyl-N-(2-(2-hydroxypropan-2-yl)-2-(2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)-2,3-dihydro-1H-inden-5-yl)propanamide (28 mg, crude) in DCM (5 mL) was added 4-methyl-1,2,5-oxadiazole-3-carboxylic acid (7.3 mg, 0.06 mmol), DIPEA (22 mg, 0.17 mmol) and HATU (33 mg, 0.09 mmol). The mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with DCM (15 mL) and then washed with aq. NaHCO3. The organic layer was washed with brine, dried and concentrated in vacuum. The residue was first purified by preparative TLC. The crude product was further purified by preparative HPLC (mobile phase: MeCN / water (0.1% FA), column: SunFire, elution: 50%-68% MeCN) to give the title compound Example 279 (10 mg, yield: 29% for two steps). 1 H NMR (400 MHz, DMSO-d6) δ ppm:10.06 (s, 1H), 9.01 (d, J = 8.8 Hz, 1H), 7.46 (t, J = 9.4 Hz, 1H), 7.34-7.30 (m, 2H), 7.12 (d, J = 7.8 Hz, 1H), 5.21 (s, 1H), 4.85 (t, J = 7.8 Hz, 1H), 4.23 (s, 1H), 3.83-3.57 (m, 3H), 3.43-3.18 (m, 3H), 2.48 (s, 3H), 1.10 (s, 6H), 0.93-0.62 (m, 3H), 0.52-0.11 (m, 8H). MS (ESI) m / e [M+1] + 605.2.

[0208] Other examples were synthesized according to methods similar to those known to those skilled in the art, such as Example 32 or Example 170, Example 212, Example 238, Example 256, Example 261, and Example 279. The corresponding compound names, structures, and spectral data are shown in the table. [Table 4-1]

Table 4-2

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Table 4-4

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change

[0209] Biotechnology: The biological activity of the compounds of the present disclosure is measured by using the assay described herein.Values ​​may vary depending on the day-to-day performance of the assay, and such variations are known to those skilled in the art.These results show that the compounds of the present disclosure can inhibit the biological action of IL-17A.

[0210] Human IL-17A biochemical assay Compounds disclosed herein were tested in a homogeneous time-resolved fluorescence-based assay for blocking human IL-17A (catalog: C774, novoprotein) protein to its receptor human IL-17RA (catalog: CI53, novoprotein). 0.4 nM recombinant human IL-17A protein was pre-incubated with serially diluted compounds disclosed herein (maximum concentration 10 uM, 2.7-fold serial dilution, 10 points) in assay buffer containing 20 mM HEPES (pH 7.5), 50 mM NaCl, 0.1% BSA, 0.2 mM DTT, 0.005% Tween® 20 for 3 hours at room temperature. 0.3 nM recombinant human IL-17RA was then added to the plate and incubated for an additional hour at room temperature. Then, MAb Anti-6His Tb cryptate Gold (Cat: 61HI2TLB, Cisbio Bioassays) and MAb Anti Human IgG-XL665 (Cat: 61HFCXLB, Cisbio Bioassays) were added to the plate and incubated for another hour at room temperature. HTRF signals (excitation 337 nm, emission 620 nm / 665 nm) were read on a BMG PHERAstar FSX instrument. The inhibition percentage of human IL-17A interaction with its receptor human IL-17RA was calculated based on the ratio of fluorescence at 620 nm to fluorescence at 665 nm with increasing concentrations of compounds. The IC50 of each compound was derived by fitting the data to a four-parameter logistic equation by Dotmatics.

[0211] GROα release assay in human colorectal adenocarcinoma epithelial cells The purpose of this assay is to test the ability of compounds to neutralize IL17A protein. IL17 can stimulate human epithelial cells to secrete GROα. The ability of one compound of the present invention to neutralize IL-17-induced GROα secretion from human colorectal adenocarcinoma epithelial cell line HT-29 is tested in this assay.

[0212] HT-29 cells (human colorectal adenocarcinoma epithelial cells, ATCC) were stimulated with IL-17A (Novoprotein, #C774) at a final concentration of 10ng / mL. The resulting GROα response was measured using an ELISA kit from Invitrogen (#88-52122). HT-29 cells were cultured in complete medium (McCoy's 5A medium + 10% FBS) and maintained in tissue culture flasks using standard techniques. On day 1, cells were detached by using TrypLE (Gibco, #12605036) and neutralized with complete medium. Cells were centrifuged at 11,00 rpm for 4 minutes. The cell pellet was resuspended in complete medium and 50,000 HT-29 cells were seeded into a 96-well assay plate (Corning, 3599) in 135μL of complete medium per well. Cells were incubated overnight at 37°C / 5% CO2 to allow them to adhere to the plates. On the second day, 4-fold serial dilutions of test compounds were prepared in DMSO. The highest concentration of compound was 10 μM. 2 μL of serially diluted compounds were transferred from the serial dilution plate to the reagent plate. Each well of the reagent plate contained 198 μL of complete medium containing 100 ng / mL IL-17A. Compounds were incubated with IL-17A for 15 minutes. 15 μL of the mixture was transferred from the reagent plate to the cell assay plate. Plates were incubated for 48 hours at 37°C / 5% CO2. After incubation, on the fourth day, GROα levels were measured by GROα ELISA as per the manufacturer's instructions. 50 μL of supernatant was collected from the assay plate and transferred to an ELISA plate. ELISA plates were read at 450 nm in a microplate reader and compared to a standard curve.

[0213] Data was processed using GraphPad Prism. GROα concentrations were calculated from the standard curve. IC50s were determined using the equation log concentration (inhibitor) vs. response and a four-parameter fit. [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5]

[0214] It is to be understood that if any prior art publication is referred to herein, such reference is not an admission in any country that such publication forms part of the general knowledge in the art. The disclosures of all publications, patents, patent applications, and published patent applications referred to herein by an identified citation are incorporated herein by reference in their entirety.

[0215] Although the foregoing invention has been described in some detail by way of illustration and example, for purposes of clarity of understanding, it will be apparent to those skilled in the art that certain minor changes and modifications may be made. Accordingly, the descriptions and examples should not be construed as limiting the scope of the invention.

Claims

1. Compound of formula (I): 【Chemistry 175】 or its N-oxide, or a pharmaceutically acceptable salt thereof, or its stereoisomer, or its deuterated analog (in the formula, Cy1 is a 5-6 membered aromatic ring, the ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the ring optionally contains at least one substituent R ３ It has been replaced with, n3 is independently 0, 1, 2, or 3. Cy2 is a 4-8 member saturated ring or a partially or fully unsaturated ring, the ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur, and the ring comprising at least one substituent R １ and / or R ２ It has been replaced with, n1 is either 0 or 1, n2 is 0, 1, or 2. n1 and n2 are not both 0 at the same time. Cy1 and Cy2 are condensed with each other. Cy3 is a 3- to 12-membered saturated ring or a partially or fully unsaturated ring, wherein the ring contains 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur, and the ring optionally has at least one substituent R ６ It has been replaced with, n6 is independently 0, 1, 2, 3, 4, or 5, provided that it satisfies valence theory. X １ is a single bond or -CR ９ R １０ - and R １ H or 【Chemistry 176】 Selected independently from, Here, X ２ is N or C(R １５ ), and X ３ is -C(O)-, -S(O)-, or -S(O) ２ - and n11 and n12 are independently 1, 2, or 3. n14 is either 0 or 1. R １５ is hydrogen, halogen, -C １～８ Alkyl, -C ３ ~C ８ Cycloalkyl, 3- to 8-membered heterocyclyl, -CN, -OR １５ａ , -NR １５ａ R １５ｂ , or -NR １５ａ COR １５ｂ Selected from, -C １～８ Alkyl, C ３ ~C ８ Each of the cycloalkyl and 3- to 8-membered heterocyclyl groups may optionally have at least one substituent R １５ｃ It has been replaced with, R １５ａ and R １５ｂ These are hydrogen and -C, respectively. １～８ Alkyl, -C １～８ Haloalkyl, -C ２～８ Alkenyl, -C ２～８ Alkinyl, C １～８ Alkoxy-C １～８ Alkyl-, C ３ ~C ８ Cycloalkyl, 3-8 membered heterocyclyl, C ６ ~C １２ Independently selected from aryl or 5- to 12-membered heteroaryls, -C １～８ Alkyl, -C １～８ Haloalkyl, -C ２～８ Alkenyl, -C ２～８ Alkinyl, C １～８ Alkoxy-C １～８ Alkyl-, C ３ ~C ８ Cycloalkyl, 3-8 membered heterocyclyl, C ６ ~C １２ Each of the aryl and 5- to 12-membered heteroaryls may optionally have at least one substituent R １５ｄ It has been replaced with, R １５ｃ and R １５ｄ Each instance independently represents halogen, -OH, -CN, oxo, and -C. １～８ Alkyl, -C １～８ Haloalkyl, -C １～８ Alkoxy, -C ２～８ Alkenyl, -C ２～８ Alkinyl, -C ３ ~C ８ Cycloalkyl, -C ３ ~C ８ Halocycloalkyl, 3-8 member heterocyclyl, -C ６ ~C １２ It is an aryl or a 5- to 12-membered heteroaryl. R １１ａ , R １１ｂ , R １２ａ and R １２ｂ These are hydrogen, halogen, and -C, respectively. １～８ Alkyl, -C ２～８ Alkenyl, -C ２～８ Alkinyl, -C ３ ~C ８ Cycloalkyl, 3-8 membered heterocyclyl, C ６ ~C １２ Aryl, 5- to 12-membered heteroaryl, -CN, -OR １１ｃ , -COR １１ｃ , -CO ２ R １１ｃ , -CONR １１ｃ R １１ｄ , -NR １１ｃ R １１ｄ or -NR １１ｃ COR １１ｄ Selected independently from, -C １～８ Alkyl, C ３ ~C ８ Cycloalkyl, 3-8 membered heterocyclyl, C ６ ~C １２ Each of the aryl or 5- to 12-membered heteroaryl is optionally comprised of at least one substituent R １１ｅ It is replaced with, or (R １１ａ and R １１ｂ ), (R １２ａ and R １２ｂ ), (R １１ａ and R １２ａ ), (R １１ａ and R １２ｂ ), (R １１ｂ and R １２ａ ), or (R １１ｂ and R １２ｂ ) together with the atom(s) to which they are attached form a 3- to 8-membered unsaturated or saturated ring, said ring containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen or sulfur, said ring being optionally substituted with at least one substituent R １１ｆ . R １１ｅ , and R １１ｆ Each instance independently represents hydrogen, halogen, and -C. １～８ Alkyl, -C ２～８ Alkenyl, -C ２～８ Alkinyl, -C ３ ~C ８ Cycloalkyl, 3-8 membered heterocyclyl, C ６ ~C １２ Aryl, 5-12 member heteroaryl, oxo (=O), -OR １１ｇ , thioxo(=S), -SR １１ｇ -CN, -SO ２ R １１ｇ , -SO ２ NR １１ｇ R １１ｈ , -COR １１ｇ , -CO ２ R １１ｈ , -CONR １１ｇ R １１ｈ , -NR １１ｇ R １１ｈ , -NR １１ｇ COR １１ｈ , -NR １１ｇ CO ２ R １１ｈ or -NR １１ｇ SO ２ R １１ｈ And, -C １～８ Alkyl, -C １～８ Alkoxy, C ３ ~C ８ Cycloalkyl, 3-8 membered heterocyclyl, C ６ ~C １２ Each of the aryl or 5- to 12-membered heteroaryl is optionally comprised of at least one substituent R １１ｉ It has been replaced with, R １１ｃ , R １１ｄ , R １１ｇ and R １１ｈ These are hydrogen and -C, respectively. １～８ Alkyl, -C １～８ Haloalkyl, -C ２～８ Alkenyl, -C ２～８ Alkinyl, C １～８ Alkoxy-C １～８ Alkyl-, C ３ ~C ８ Cycloalkyl, 3-8 membered heterocyclyl, C ６ ~C １２ Independently selected from aryl or 5- to 12-membered heteroaryls, -C １～８ Alkyl, -C １～８ Haloalkyl, -C ２～８ Alkenyl, -C ２～８ Alkinyl, C １～８ Alkoxy-C １～８ Alkyl-, C ３ ~C ８ Cycloalkyl, 3-8 membered heterocyclyl, C ６ ~C １２ Each of the aryl and 5- to 12-membered heteroaryls may optionally have at least one substituent R １１ｊ It has been replaced with, Each time it appears, R １１ｉ and R １１ｊ These are, independently, halogen, -OH, -CN, oxo, and -C. １～８ Alkyl, -C １～８ Haloalkyl, -C １～８ Alkoxy, -C ２～８ Alkenyl, -C ２～８ Alkinyl, -C ３ ~C ８ Cycloalkyl, -C ３ ~C ８ Halocycloalkyl, 3-8 member heterocyclyl, -C ６ ~C １２ It is an aryl or a 5- to 12-membered heteroaryl, -C １～８ Alkyl, -C １～８ Alkoxy, -C ２～８ Alkenyl, -C ２～８ Alkinyl, -C ３ ~C ８ Cycloalkyl, 3-8 membered heterocyclyl, -C ６ ~C １２ Each aryl or 5- to 12-membered heteroaryl may optionally have at least one substituent halogen, -OH, -CN, oxo, or -C １～８ Alkyl, -C １～８ Haloalkyl, -C １～８ Alkoxy, -C ２～８ Alkenyl, -C ２～８ Alkinyl, -C ３ ~C ８ Cycloalkyl, -C ３ ~C ８ Halocycloalkyl, 3-8 member heterocyclyl, -C ６ ~C １２ Substituted with aryl or 5- to 12-membered heteroaryl compounds, R １３ , R １４ａ and R １４ｂ These are hydrogen and -C, respectively. １～８ Alkyl, -C ３ ~C ８ Independently selected from cycloalkyl or 3- to 8-membered heterocyclyl, -C １～８ Alkyl, -C ３ ~C ８ Each of the cycloalkyl and 3- to 8-membered heterocyclyl groups may optionally have at least one substituent R １３ａ It has been replaced with, R １３ａ Each instance independently represents halogen, -OH, -CN, oxo, and -C. １～８ Alkyl, -C １～８ Haloalkyl, -C １～８ Alkoxy, -C ２～８ Alkenyl, -C ２～８ Alkinyl, -C ３ ~C ８ Cycloalkyl, -C ３ ~C ８ Halocycloalkyl, 3-8 member heterocyclyl, -C ６ ~C １２ It is an aryl or a 5- to 12-membered heteroaryl. R ２ H, -C １～８ Alkyl, -C ２～８ Alkenyl, -C ２～８ Alkinyl, -C ３ ~C ８ Cycloalkyl, C ６ ~C １２ Aryl, 5- to 12-membered heteroaryl, -CN, -COR ２ａ , -CO ２ R ２ａ , -CONR ２ａ R ２ｂ , -NR ２ａ R ２ｂ , or -NR ２ａ COR ２ｂ Selected independently from, -C １～８ Alkyl, -C ２～８ Alkenyl, -C ２～８ Alkinyl, -C ３ ~C ８ Cycloalkyl, C ６ ~C １２ Each of the aryl and 5- to 12-membered heteroaryls may optionally have at least one substituent R ２ｃ It is replaced with, or If they are geominal or adjacent, two R ２ These atoms, together with the carbon atoms (or more) bonded to them, form a 3- to 8-membered unsaturated or saturated ring, the ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the ring optionally having at least one substituent R ２ｃ It has been replaced with, R ２ａ and R ２ｂ These are hydrogen and -C, respectively. １～８ Alkyl, -C ２～８ Alkenyl, -C ２～８ Alkinyl, C ３ ~C １２ Cycloalkyl, 3-8 membered heterocyclyl, C ６ ~C １２ Independently selected from aryl or 5- to 12-membered heteroaryls, -C １～８ Alkyl, -C ２～８ Alkenyl, -C ２～８ Alkinyl, C ３ ~C １２ Cycloalkyl, 3-8 membered heterocyclyl, C ６ ~C １２ Each of the aryl and 5- to 12-membered heteroaryls may optionally have at least one substituent R ２ｄ It is replaced with, or R ２ａ and R ２ｂ These atoms, together with the nitrogen atoms bonded to them, form a 3- to 8-membered unsaturated or saturated ring, the ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the ring optionally having at least one substituent R ２ｄ It has been replaced with, R ２ｃ and R ２ｄ Each instance independently represents hydrogen, halogen, and -C. １～８ Alkyl, -C ３ ~C ８ Cycloalkyl, 3-8 membered heterocyclyl, C ６ ~C １２ Aryl, 5-12 member heteroaryl, oxo (=O), -OR ２ｅ ,-SR ２ｅ -CN, -COR ２ｅ , -CO ２ R ２ｅ , -CONR ２ｅ R ２ｆ , -NR ２ｅ R ２ｆ , -NR ２ｅ COR ２ｆ or -NR ２ｅ CO ２ R ２ｆ And, -C １～８ Alkyl, C ３ ~C ８ Cycloalkyl, 3-8 membered heterocyclyl, C ６ ~C １２ Each of the aryl or 5- to 12-membered heteroaryl is optionally comprised of at least one substituent R ２ｇ It has been replaced with, R ２ｅ and R ２ｆ These are hydrogen and -C, respectively. １～８ Alkyl, -C １～８ Alkoxy, C １～８ Alkoxy-C １～８ Alkyl-, -C ２～８ Alkenyl, -C ２～８ Alkinyl, C ３ ~C １２ Cycloalkyl, 3-8 membered heterocyclyl, C ６ ~C １２ Independently selected from aryl or 5- to 12-membered heteroaryls, -C １～８ Alkyl, -C １～８ Alkoxy, C １～８ Alkoxy-C １～８ Alkyl-, -C ２～８ Alkenyl, -C ２～８ Alkinyl, C ３ ~C １２ Cycloalkyl, 3-8 membered heterocyclyl, C ６ ~C １２ Each of the aryl and 5- to 12-membered heteroaryls may optionally have at least one substituent R ２ｈ It has been replaced with, R ２ｇ and R ２ｈ Each instance independently represents halogen, -OH, and -C. １～８ Alkyl, -C １～８ Haloalkyl, -C １～８ Alkoxy, C １～８ Alkoxy-C １～８ Alkyl-, -C ２～８ Alkenyl, -C ２～８ Alkinyl, -C ３ ~C ８ Cycloalkyl, -C ３ ~C ８ Halocycloalkyl, 3-8 member heterocyclyl, -C ６ ~C １２ It is an aryl or a 5- to 12-membered heteroaryl. If both n1 and n2 are 1, then R １ and R ２ is geminal or adjacent, R ３ is hydrogen, halogen, -C １～８ Alkyl, -C １～８ Alkoxy, -C ３ ~C ８ A cycloalkyl group, or a group independently selected from -CN, where -C １～８ Alkyl, -C １～８ Alkoxy and -C ３ ~C ８ Each of the cycloalkyl groups can be optionally a halogen, -OH, or -C. １～８ Alkyl, -C １～８ Alkoxy, C １～８ Alkoxy-C １～８ Alkyl-, -C ２～８ Alkenyl, -C ２～８ Alkinyl, -C ３ ~C ８ Cycloalkyl, 3-8 membered heterocyclyl, -C ６ ~C １２ Substituted with at least one substituent selected from aryl or 5- to 12-membered heteroaryl groups, R ４ is either oxo (=O) or thioxo (=S), or R ３ and R ４ These atoms, together with the atoms bonded to them, form a 5-6 membered aromatic ring, the ring containing 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the ring optionally having at least one substituent R ３ａ It has been replaced with, R ３ａ is hydrogen, halogen, -C １～８ Alkyl, -C １～８ Alkoxy, -C ３ ~C ８ A cycloalkyl group, or a group independently selected from -CN, where -C １～８ Alkyl, -C １～８ Alkoxy and -C ３ ~C ８ Each of the cycloalkyl groups can be optionally a halogen, -OH, or -C. １～８ Alkyl, -C １～８ Alkoxy, C １～８ Alkoxy-C １～８ Alkyl-, -C ２～８ Alkenyl, -C ２～８ Alkinyl, -C ３ ~C ８ Cycloalkyl, 3-8 membered heterocyclyl, -C ６ ~C １２ Substituted with at least one substituent selected from aryl or 5- to 12-membered heteroaryl groups, R ５ C ６ ~C １２ Aryl, 5-12 member heteroaryl, -COR ５ａ , -CO ２ R ５ａ , -CONR ５ａ R ５ｂ And here, C ６ ~C １２ Each of the aryl and 5- to 12-membered heteroaryls may optionally have at least one substituent R ５ｃ It has been replaced with, R ５ａ and R ５ｂ These are, respectively, -C １～８ Alkyl, -C ２～８ Alkenyl, -C ２～８ Alkinyl, C ３ ~C １２ Cycloalkyl, 3-8 membered heterocyclyl, C ６ ~C １２ Independently selected from aryl or 5- to 12-membered heteroaryls, -C １～８ Alkyl, -C ２～８ Alkenyl, -C ２～８ Alkinyl, C ３ ~C １２ Cycloalkyl, 3-8 membered heterocyclyl, C ６ ~C １２ Each of the aryl and 5- to 12-membered heteroaryls may optionally have at least one substituent R ５ｄ It is replaced with, or R ５ａ and R ５ｂ These atoms, together with the atoms bonded to them, form a 3- to 8-membered unsaturated or saturated ring, the ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the ring optionally comprising at least one substituent R ５ｄ It has been replaced with, R ５ｃ and R ５ｄ Each instance represents hydrogen, halogen, and -C, respectively. １～８ Alkyl, -C ３ ~C ８ Cycloalkyl, 3-8 membered heterocyclyl, C ６ ~C １２ Aryl, 5-12 member heteroaryl, oxo (=O), -OR ５ｅ ,-SR ５ｅ -CN, -COR ５ｅ , -CO ２ R ５ｅ , -CONR ５ｅ R ５ｆ , -NR ５ｅ R ５ｆ , -NR ５ｅ COR ５ｆ or -NR ５ｅ CO ２ R ５ｆ Selected independently from, -C １～８ Alkyl, C ３ ~C ８ Cycloalkyl, 3-8 membered heterocyclyl, C ６ ~C １２ Each of the aryl or 5- to 12-membered heteroaryl is optionally comprised of at least one substituent R ５ｇ It has been replaced with, R ５ｅ and R ５ｆ These are hydrogen and -C, respectively. １～８ Alkyl, -C １～８ Alkoxy, C １～８ Alkoxy-C １～８ Alkyl-, -C ２～８ Alkenyl, -C ２～８ Alkinyl, C ３ ~C １２ Cycloalkyl, 3-8 membered heterocyclyl, C ６ ~C １２ Independently selected from aryl or 5- to 12-membered heteroaryls, -C １～８ Alkyl, -C １～８ Alkoxy, C １～８ Alkoxy-C １～８ Alkyl-, -C ２～８ Alkenyl, -C ２～８ Alkinyl, C ３ ~C １２ Cycloalkyl, 3-8 membered heterocyclyl, C ６ ~C １２ Each of the aryl and 5- to 12-membered heteroaryls may optionally have at least one substituent R ５ｈ It has been replaced with, R ５ｇ and R ５ｈ These are halogen, -OH, -CN, and -C, respectively. １～８ Alkyl, -C １～８ Alkoxy, C １～８ Alkoxy-C １～８ Alkyl-, -C ２～８ Alkenyl, -C ２～８ Alkinyl, -C ３ ~C ８ Cycloalkyl, 3-8 membered heterocyclyl, -C ６ ~C １２ Independently selected from aryls or 5- to 12-membered heteroaryls, R ６ H, halogen, -C １～８ Alkyl, -C ２～８ Alkenyl, -C ２～８ Alkinyl, -C ３ ~C ８ Cycloalkyl, C ６ ~C １２ Aryl, 5- to 12-membered heteroaryl, -CN, -OR ６ａ , -NR ６ａ R ６ｂ , -COR ６ａ , -CO ２ R ６ａ , -CONR ６ａ R ６ｂ , -COR ６ａ or -NR ６ａ COR ６ｂ And, -C １～８ Alkyl, -C ２～８ Alkenyl, -C ２～８ Alkinyl, -C ３ ~C ８ Cycloalkyl, C ６ ~C １２ Each of the aryl and 5- to 12-membered heteroaryls may optionally have at least one substituent R ６ｃ It has been replaced with, R ６ａ and R ６ｂ These are hydrogen and -C, respectively. １～８ Alkyl, -C ２～８ Alkenyl, -C ２～８ Alkinyl, C ３ ~C １２ Cycloalkyl, 3-8 membered heterocyclyl, C ６ ~C １２ Independently selected from aryl or 5- to 12-membered heteroaryls, -C １～８ Alkyl, -C ２～８ Alkenyl, -C ２～８ Alkinyl, C ３ ~C １２ Cycloalkyl, 3-8 membered heterocyclyl, C ６ ~C １２ Each of the aryl and 5- to 12-membered heteroaryls may optionally have at least one substituent R ６ｄ It has been replaced with, R ６ｃ Each instance, independently, hydrogen, halogen, and -C appear. １～８ Alkyl, -C ３ ~C ８ Cycloalkyl, 3-8 membered heterocyclyl, C ６ ~C １２ Aryl, 5-12 member heteroaryl, oxo (=O), -OR ６ｅ ,-SR ６ｅ -CN, -COR ６ｅ , -CO ２ R ６ｅ , -CONR ６ｅ R ６ｆ , -NR ６ｅ R ６ｆ , -NR ６ｅ COR ６ｆ or -NR ６ｅ CO ２ R ６ｆ And, -C １～８ Alkyl, C ３ ~C ８ Cycloalkyl, 3-8 membered heterocyclyl, C ６ ~C １２ Each of the aryl or 5- to 12-membered heteroaryl is optionally comprised of at least one substituent R ６ｇ It has been replaced with, R ６ｅ and R ６ｆ These are hydrogen and -C, respectively. １～８ Alkyl, -C １～８ Alkoxy, C １～８ Alkoxy-C １～８ Alkyl-, -C ２～８ Alkenyl, -C ２～８ Alkinyl, C ３ ~C １２ Cycloalkyl, 3-8 membered heterocyclyl, C ６ ~C １２ Independently selected from aryl or 5- to 12-membered heteroaryl groups, R ６ｄ and R ６ｇ These are halogen, -OH, and -C, respectively. １～８ Alkyl, -C １～８ Alkoxy, C １～８ Alkoxy-C １～８ Alkyl-, -C ２～８ Alkenyl, -C ２～８ Alkinyl, -C ３ ~C ８ Cycloalkyl, 3-8 membered heterocyclyl, -C ６ ~C １２ Independently selected from aryls or 5- to 12-membered heteroaryls, R ７ and R ８ Each of them is independently hydrogen, R ９ and R １０ These are H, halogen, and -C, respectively. １～８ Alkyl, -C ２～８ Alkenyl, -C ２～８ Alkinyl, -C ３ ~C ８ Cycloalkyl, C ６ ~C １２ Independently selected from aryl or 5- to 12-membered heteroaryls, -C １～８ Alkyl, -C ２～８ Alkenyl, -C ２～８ Alkinyl, -C ３ ~C ８ Cycloalkyl, C ６ ~C １２ Each of the aryl and 5- to 12-membered heteroaryls may optionally have at least one substituent R ９ａ It has been replaced with, R ９ａ Each instance independently represents halogen, -OH, and -C. １～８ Alkyl, -C １～８ Alkoxy, C １～８ Alkoxy-C １～８ Alkyl-, -C ２～８ Alkenyl, -C ２～８ Alkinyl, -C ３ ~C ８ Cycloalkyl, 3-8 membered heterocyclyl, -C ６ ~C １２ (An aryl, or a heteroaryl with 5 to 12 members).

2. The compound according to claim 1, wherein formulas (IIa) to (IIp), (IIf1) to (IIf2), (IIIa) to (IIIb), (IVa) to (IVb), (Va) to (Vc), (VIa) to (VIc) and (VIia) to (VIih): 【Chemistry 177】 【Chemistry 178】 【Chemistry 179】 【Chemical 301】 【Chemical 302】 【Chemical 303】 【Chemical 304】 【Chemical 305】 A compound selected from (wherein R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , Cy1, Cy2, Cy3, n1, n2, n3, n6, n11, n12, n14, R 2a , R 3 , R 5 , R 6 , R 9 , R 10 , R 11a , R 11b , R 12a , R 12b , R 13 , R 14a , R 14b ,X １ (where X2 and X3 are defined as in claim 1).

3. The compound according to Claim 1, wherein Cy1 is a 5 or 6-membered aromatic ring, the ring comprises 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or sulfur, and the ring optionally comprises 0, 1, 2 or 3 substituents R ３ It has been replaced with, Preferably, Cy1 is phenyl, pyridyl, thiophenyl, imidazolyl, furanil, or pyrazolyl, and each of phenyl, pyridyl, thiophenyl, imidazolyl, furanil, or pyrazolyl is optionally 0, 1, or 2 substituents R ３ The compound, which is substituted with [the compound].

4. The compound according to claim 1, wherein Cy2 is a 4, 5, 6, 7, or 8-membered saturated ring or a partially or fully unsaturated ring, the ring comprising 0, 1, 2, or 3 heteroatoms independently selected from nitrogen or oxygen, and the ring comprising at least one substituent R １ and / or R ２ It has been replaced with, Preferably, Cy2 is a 5, 6, or 7-membered saturated ring or a partially or fully unsaturated ring, the ring comprising 0, 1, or 2 heteroatoms independently selected from nitrogen or oxygen, and the ring comprising at least one substituent R １ and / or R ２ The compound, which is substituted with [the compound].

5. The compound according to claim 1, 【Chemical 189】 The part is, 【Chemistry 190】 The compound selected from the above.

6. The compound according to Claim 1, wherein Cy3 is a 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12-membered saturated ring or a partially or fully unsaturated ring, the ring comprising 0, 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur, and the ring optionally comprising 0, 1, 2, 3, 4 or 5 substituents R ６ It has been replaced with, Preferably, Cy3 is a 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12-membered saturated ring or a partially or fully unsaturated ring, wherein the ring is a monocyclic, dicyclic, or tricyclic ring containing 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur, and the ring optionally contains 0, 1, 2, 3, 4, or 5 substituents R ６ It has been replaced with, more, 【Chemistry 191】 The part is, 【Chemistry 192】 And, Even more preferably, 【Chemistry 193】 The part is, 【Chemistry 194】 The aforementioned compound.

7. The compound according to claim 1, R １ H, 【Chemistry 195】 A compound (where R is independently selected from) １１ａ , R １１ｂ , R １２ａ , R １２ｂ , R １３ (where n11 and n12 are defined as in claim 1).

8. The compound according to claim 1, R １５ The elements are hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, -CN, -OR １５ａ , -NR １５ａ R １５ｂ , -NR １５ａ COR １５ｂ Selected from -OH, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, and octoxy, each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and 3- to 8-membered heterocyclyls, optionally has at least one substituent R １５ｃ It has been replaced with, R １５ａ and R １５ｂ These are hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C, respectively. １～８ Haloalkyl, -C ２～８ Alkenyl, -C ２～８ Alkinyl, C １～８ Alkoxy-C １～８ Alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, C ６ ~C １２ Independently selected from aryl or 5- to 12-membered heteroaryls, including methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, and -C. ２～８ Alkenyl, -C ２～８ Alkinyl, C １～８ Alkoxy-C １～８ Alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, C ６ ~C １２ Each of the aryl and 5- to 12-membered heteroaryls may optionally have at least one substituent R １５ｄ It has been replaced with, R １５ｃ and R １５ｄ Each instance independently represents -F, -Cl, -Br, -I, -OH, -CN, oxo, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C. １～８ Haloalkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C ２～８ Alkenyl, -C ２～８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C ３ ~C ８ The compound is a halocycloalkyl, a 3- to 8-membered heterocyclyl, a phenyl, or a 5- to 12-membered heteroaryl.

9. The compound according to claim 1, R １１ａ , R １１ｂ , R １２ａ and R １２ｂ These are, respectively, hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, propenyl, allyl, buta-3-en-1-yl, buta-2-en-1-yl, buta-1-en-1-yl, penta-4-en-1-yl, penta-3-en-1-yl, penta-2-en-1-yl, penta-1-en-1-yl, hexa-5-en-1-yl, hexa-4-en-1-yl, hexa-3-en-1-yl, hexa-2-en-1-yl, hexa-1-en-1-yl, hepta-6-en-yl Hepta-5-enyl, hepta-4-enyl, hepta-3-enyl, hepta-2-enyl, hepta-1-enyl, octa-7-enyl, octa-6-enyl, octa-5-enyl, octa-4-enyl, octa-3-enyl, octa-2-enyl, octa-1-enyl, ethinyl, propane-2-in-1yl, propane-1-in-1yl, butane-3-in-1yl, butane-2-in-1yl, butane-1-in-1yl, penta-4-in-1yl, penta-3-in-1yl, penta- 2-in-1-il, penta-1-in-1-il, hexa-5-in-1-il, hexa-4-in-1-il, hexa-3-in-1-il, hexa-2-in-1-il, hexa-1-in-1-il, hepta-6-in-il, hepta-5-in-il, hepta-4-in-il, hepta-3-in-il, hepta-2-in-il, hepta-1-in-il, octa-7-in-il, octa-6-in-il, octa-5-in-il, octa-4-in-il, octa-3-in-il, octa-2-in-il, octa-1-in-il, Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, azilidinyl, azetidinyl, pyrrolidinyl, dihydropyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridadinyl, pyrimidinyl, pyrazinyl, independently selected from -CN, methyl, ethyl, propyl, butyl, pentyl,Hexyl, heptyl, octyl, vinyl, propenyl, allyl, buta-3-en-1-yl, buta-2-en-1-yl, buta-1-en-1-yl, penta-4-en-1-yl, penta-3-en-1-yl, penta-2-en-1-yl, penta-1-en-1-yl, hexa-5-en-1-yl, hexa-4-en-1-yl, hexa-3-en-1-yl, hexa-2-en-1-yl, hexa-1-en-1-yl, hepta-6-en-yl, hepta-5-en-yl, hepta-4-en-yl, hepta-3 -en-yl, hepta-2-en-yl, hepta-1-en-yl, octa-7-en-yl, octa-6-en-yl, octa-5-en-yl, octa-4-en-yl, octa-3-en-yl, octa-2-en-yl, octa-1-en-yl, ethinyl, propane-2-in-1-yl, propane-1-in-1-yl, butane-3-in-1-yl, butane-2-in-1-yl, butane-1-in-1-yl, penta-4-in-1-yl, penta-3-in-1-yl, penta-2-in-1-yl, penta-1-yl n-1-il, hexa-5-in-1-il, hexa-4-in-1-il, hexa-3-in-1-il, hexa-2-in-1-il, hexa-1-in-1-il, hepta-6-in-il, hepta-5-in-il, hepta-4-in-il, hepta-3-in-il, hepta-2-in-il, hepta-1-in-il, octa-7-in-il, octa-6-in-il, octa-5-in-il, octa-4-in-il, octa-3-in-il, octa-2-in-il, octa-1-in-il, sik Ropropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, azilidinyl, azetidinyl, pyrrolidinyl, dihydropyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridadinyl, pyrimidinyl, and pyrazinyl each optionally have at least one substituent R, １１ｅ It has been replaced with, R １１ｅ Each instance independently contains hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, propenyl, allyl, buta-3-en-1-yl, buta-2-en-1-yl, buta-1-en-1-yl, penta-4-en-1-yl, penta-3-en-1-yl, penta-2-en-1-yl, penta-1-en-1-yl, hexa-5-en-1-yl, hexa-4-en-1-yl, hexa-3-en-1-yl, hexa-2-en-1-yl, hexa-1-en-1-yl, Hepta-6-en-yl, hepta-5-en-yl, hepta-4-en-yl, hepta-3-en-yl, hepta-2-en-yl, hepta-1-en-yl, octa-7-en-yl, octa-6-en-yl, octa-5-en-yl, octa-4-en-yl, octa-3-en-yl, octa-2-en-yl, octa-1-en-yl, ethinyl, propane-2-in-1-yl, propane-1-in-1-yl, butane-3-in-1-yl, butane-2-in-1-yl, butane-1-in-1-yl, penta-4-in-1-yl, penta -3-in-1-il, penta-2-in-1-il, penta-1-in-1-il, hexa-5-in-1-il, hexa-4-in-1-il, hexa-3-in-1-il, hexa-2-in-1-il, hexa-1-in-1-il, hepta-6-in-il, hepta-5-in-il, hepta-4-in-il, hepta-3-in-il, hepta-2-in-il, hepta-1-in-il, octa-7-in-il, octa-6-in-il, octa-5-in-il, octa-4-in-il, octa-3-in-il, octa- 2-in-yl, octa-1-in-yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, azilidinyl, azetidinyl, pyrrolidinyl, dihydropyrrolidinyl, tetrahydrofuranil, dihydrofuranil, oxazolidinyl, piperidinyl, piperazinyl, morpholinil, tetrahydropyranil, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanil, thiophenyl, thiazolyl, pyridinyl, pyridadinyl, pyrimidinyl, pyrazinyl, oxo(=O), -OR １１ｇ , thioxo(=S), -SR １１ｇ -CN, -SO ２ R １１ｇ , -SO ２ NR １１ｇ R １１ｈ , -COR １１ｇ , -CO ２ R １１ｈ , -CONR １１ｇ R １１ｈ , -NR １１ｇ R １１ｈ , -NR １１ｇ COR １１ｈ , -NR １１ｇ CO ２ R １１ｈ or -NR １１ｇ SO ２ R １１ｈ These include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, propenyl, allyl, buta-3-en-1-yl, buta-2-en-1-yl, buta-1-en-1-yl, penta-4-en-1-yl, penta-3-en-1-yl, penta-2-en-1-yl, penta-1-en-1-yl, hexa-5-en-1-yl, hexa-4-en-1-yl, hexa-3-en-1-yl, hexa-2-en-1-yl, hexa-1-en-1-yl, hepta-6-en-yl, hepta-5-en- Il, hepta-4-en-yl, hepta-3-en-yl, hepta-2-en-yl, hepta-1-en-yl, octa-7-en-yl, octa-6-en-yl, octa-5-en-yl, octa-4-en-yl, octa-3-en-yl, octa-2-en-yl, octa-1-en-yl, ethinyl, propane-2-in-1-yl, propane-1-in-1-yl, butane-3-in-1-yl, butane-2-in-1-yl, butane-1-in-1-yl, penta-4-in-1-yl, penta-3-in-1-yl, penta-2-in-yl n-1-il, penta-1-in-1-il, hexa-5-in-1-il, hexa-4-in-1-il, hexa-3-in-1-il, hexa-2-in-1-il, hexa-1-in-1-il, hepta-6-in-il, hepta-5-in-il, hepta-4-in-il, hepta-3-in-il, hepta-2-in-il, hepta-1-in-il, octa-7-in-il, octa-6-in-il, octa-5-in-il, octa-4-in-il, octa-3-in-il, octa-2-in-il, octa-1-i Each of the following is optionally substituted R: yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, azilidinyl, azetidinyl, pyrrolidinyl, dihydropyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridadinyl, pyrimidinyl, and pyrazinyl. １１ｉ It has been replaced with, R １１ｃ , R １１ｄ , R １１ｇ and R １１ｈ These are hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C, respectively. １～８ Haloalkyl, -C ２～８ Alkenyl, -C ２～８ Alkinyl, C １～８ Alkoxy-C １～８ Alkyl-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, independently selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C １～８ Haloalkyl, -C ２～８ Alkenyl, -C ２～８ Alkinyl, C １～８ Alkoxy-C １～８ Each of alkyl-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, and 5- to 12-membered heteroaryl may optionally have at least one substituent R １１ｊ It has been replaced with, Each time it appears, R １１ｉ and R １１ｊ These are independently -F, -Cl, -Br, -I, -OH, -CN, oxo, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C. １～８ Haloalkyl, Methoxy, Ethoxy, Propoxy, Butoxy, Pentoxy, Hexoxy, Heptoxy, Octoxy, Vinyl, Propenyl, Allyl, Buta-3-en-1-yl, Buta-2-en-1-yl, Buta-1-en-1-yl, Penta-4-en-1-yl, Penta-3-en-1-yl, Penta-2-en-1-yl, Penta-1-en-1-yl, Hexa-5-en-1-yl, Hexa-4-en-1-yl, Hexa-3-en -1-yl, hexa-2-en-1-yl, hexa-1-en-1-yl, hepta-6-en-yl, hepta-5-en-yl, hepta-4-en-yl, hepta-3-en-yl, hepta-2-en-yl, hepta-1-en-yl, octa-7-en-yl, octa-6-en-yl, octa-5-en-yl, octa-4-en-yl, octa-3-en-yl, octa-2-en-yl, octa-1-en-yl, ethinyl, propane -2-in-1-yl, prop-1-in-1-yl, bu-3-in-1-yl, bu-2-in-1-yl, bu-1-in-1-yl, penta-4-in-1-yl, penta-3-in-1-yl, penta-2-in-1-yl, penta-1-in-1-yl, hexa-5-in-1-yl, hexa-4-in-1-yl, hexa-3-in-1-yl, hexa-2-in-1-yl, hexa-1-in-1-yl, hepta-6-in-yl -Il, hept-5-in-Il, hept-4-in-Il, hept-3-in-Il, hept-2-in-Il, hept-1-in-Il, octa-7-in-Il, octa-6-in-Il, octa-5-in-Il, octa-4-in-Il, octa-3-in-Il, octa-2-in-Il, octa-1-in-Il, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C ３ ~C ８ Halocycloalkyl, azilidinyl, azetidinyl, pyrrolidinyl, dihydropyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridadinyl, pyrimidinyl, pyrazinyl, and methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C １～８ Haloalkyl, Methoxy, Ethoxy, Propoxy, Butoxy, Pentoxy, Hexoxy, Heptoxy, Octoxy, Vinyl, Propenyl, Allyl, Buta-3-en-1-yl, Buta-2-en-1-yl, Buta-1-en-1-yl, Penta-4-en-1-yl, Penta-3-en-1-yl, Penta-2-en-1-yl, Penta-1-en-1-yl, Hexa-5-en-1-yl, Hexa-4-en-1-yl, Hexa-3-en -1-yl, hexa-2-en-1-yl, hexa-1-en-1-yl, hepta-6-en-yl, hepta-5-en-yl, hepta-4-en-yl, hepta-3-en-yl, hepta-2-en-yl, hepta-1-en-yl, octa-7-en-yl, octa-6-en-yl, octa-5-en-yl, octa-4-en-yl, octa-3-en-yl, octa-2-en-yl, octa-1-en-yl, ethinyl, propane -2-in-1-yl, prop-1-in-1-yl, bu-3-in-1-yl, bu-2-in-1-yl, bu-1-in-1-yl, penta-4-in-1-yl, penta-3-in-1-yl, penta-2-in-1-yl, penta-1-in-1-yl, hexa-5-in-1-yl, hexa-4-in-1-yl, hexa-3-in-1-yl, hexa-2-in-1-yl, hexa-1-in-1-yl, hepta-6-in-yl -Il, hept-5-in-Il, hept-4-in-Il, hept-3-in-Il, hept-2-in-Il, hept-1-in-Il, octa-7-in-Il, octa-6-in-Il, octa-5-in-Il, octa-4-in-Il, octa-3-in-Il, octa-2-in-Il, octa-1-in-Il, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C ３ ~C ８ Each of the following is optionally substituted: halocycloalkyl, azilidinyl, azetidinyl, pyrrolidinyl, dihydropyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridadinyl, pyrimidinyl, and pyrazinyl, with at least one substituent -F, -Cl, -Br, -I, -OH, -CN, oxo, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C １～８ Haloalkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C ２～８ Alkenyl, -C ２～８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C ３ ~C ８ The compound is substituted with a halocycloalkyl, a 3- to 8-membered heterocyclyl, a phenyl, or a 5- to 12-membered heteroaryl.

10. The compound according to claim 1, R １１ａ , R １１ｂ , R １２ａ and R １２ｂ These are, respectively, hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, propenyl, allyl, buta-3-en-1-yl, buta-2-en-1-yl, buta-1-en-1-yl, penta-4-en-1-yl, penta-3-en-1-yl, penta-2-en-1-yl, penta-1-en-1-yl, hexa-5-en-1-yl, hexa-4-en-1-yl, hexa-3-en-1-yl, hexa-2-en-1-yl, hexa-1-en-1-yl, hepta-6-en-yl Hepta-5-enyl, hepta-4-enyl, hepta-3-enyl, hepta-2-enyl, hepta-1-enyl, octa-7-enyl, octa-6-enyl, octa-5-enyl, octa-4-enyl, octa-3-enyl, octa-2-enyl, octa-1-enyl, ethinyl, propane-2-in-1yl, propane-1-in-1yl, butane-3-in-1yl, butane-2-in-1yl, butane-1-in-1yl, penta-4-in-1yl, penta-3-in-1yl, penta- 2-in-1-il, penta-1-in-1-il, hexa-5-in-1-il, hexa-4-in-1-il, hexa-3-in-1-il, hexa-2-in-1-il, hexa-1-in-1-il, hepta-6-in-il, hepta-5-in-il, hepta-4-in-il, hepta-3-in-il, hepta-2-in-il, hepta-1-in-il, octa-7-in-il, octa-6-in-il, octa-5-in-il, octa-4-in-il, octa-3-in-il, octa-2-in-il, octa-1-in-il, Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, azilidinyl, azetidinyl, pyrrolidinyl, dihydropyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridadinyl, pyrimidinyl, pyrazinyl, independently selected from -CN, methyl, ethyl, propyl, butyl, pentyl,Hexyl, heptyl, octyl, vinyl, propenyl, allyl, buta-3-en-1-yl, buta-2-en-1-yl, buta-1-en-1-yl, penta-4-en-1-yl, penta-3-en-1-yl, penta-2-en-1-yl, penta-1-en-1-yl, hexa-5-en-1-yl, hexa-4-en-1-yl, hexa-3-en-1-yl, hexa-2-en-1-yl, hexa-1-en-1-yl, hepta-6-en-yl, hepta-5-en-yl, hepta-4-en-yl, hepta-3 -en-yl, hepta-2-en-yl, hepta-1-en-yl, octa-7-en-yl, octa-6-en-yl, octa-5-en-yl, octa-4-en-yl, octa-3-en-yl, octa-2-en-yl, octa-1-en-yl, ethinyl, propane-2-in-1-yl, propane-1-in-1-yl, butane-3-in-1-yl, butane-2-in-1-yl, butane-1-in-1-yl, penta-4-in-1-yl, penta-3-in-1-yl, penta-2-in-1-yl, penta-1-yl n-1-il, hexa-5-in-1-il, hexa-4-in-1-il, hexa-3-in-1-il, hexa-2-in-1-il, hexa-1-in-1-il, hepta-6-in-il, hepta-5-in-il, hepta-4-in-il, hepta-3-in-il, hepta-2-in-il, hepta-1-in-il, octa-7-in-il, octa-6-in-il, octa-5-in-il, octa-4-in-il, octa-3-in-il, octa-2-in-il, octa-1-in-il, sik Ropropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, azilidinyl, azetidinyl, pyrrolidinyl, dihydropyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridadinyl, pyrimidinyl, and pyrazinyl each optionally have at least one substituent R, １１ｅ It has been replaced with, R １１ｅ Each instance independently contains hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, propenyl, allyl, buta-3-en-1-yl, buta-2-en-1-yl, buta-1-en-1-yl, penta-4-en-1-yl, penta-3-en-1-yl, penta-2-en-1-yl, penta-1-en-1-yl, hexa-5-en-1-yl, hexa-4-en-1-yl, hexa-3-en-1-yl, hexa-2-en-1-yl, hexa-1-en-1-yl Hepta-6-enyl, hepta-5-enyl, hepta-4-enyl, hepta-3-enyl, hepta-2-enyl, hepta-1-enyl, octa-7-enyl, octa-6-enyl, octa-5-enyl, octa-4-enyl, octa-3-enyl, octa-2-enyl, octa-1-enyl, ethinyl, propane-2-in-1yl, propane-1-in-1yl, butane-3-in-1yl, butane-2-in-1yl, butane-1-in-1yl, penta-4-in-1yl , penta-3-in-1-il, penta-2-in-1-il, penta-1-in-1-il, hexa-5-in-1-il, hexa-4-in-1-il, hexa-3-in-1-il, hexa-2-in-1-il, hexa-1-in-1-il, hepta-6-in-il, hepta-5-in-il, hepta-4-in-il, hepta-3-in-il, hepta-2-in-il, hepta-1-in-il, octa-7-in-il, octa-6-in-il, octa-5-in-il, octa-4-in-il, octa-3-in-il , octa-2-in-yl, octa-1-in-yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, azilidinyl, azetidinyl, pyrrolidinyl, dihydropyrrolidinyl, tetrahydrofuranil, dihydrofuranil, oxazolidinyl, piperidinyl, piperazinyl, morpholinil, tetrahydropyranil, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanil, thiophenyl, thiazolyl, pyridinyl, pyridadinyl, pyrimidinyl, pyrazinyl, -OR １１ｇ or -CN, R １１ｇ This is independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl. Preferably, R １１ａ , R １１ｂ , R １２ａ and R １２ｂ These are H and -CH, respectively. ３ , -CF ３ ien-CH ２ CH ３ ien-CH ２ CF ３ n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyrrolidinyl, tetrahydrofuranil, oxazolidinyl, piperidinyl, piperazinyl, morpholinil, tetrahydropyranil, phenyl, benzyl, vinyl, propenyl, allyl, buta-3-en-1-yl, ethinyl, propa-2-in-1-yl, propa-1-in-1-yl, buta-3-in-1-yl, buta-2-in-1-yl, buta-1-in-1-yl, 【Chemistry 196】 The compound, selected independently from the above.

11. The compound according to claim 1, (R １１ａ and R １１ｂ ), (R １２ａ and R １２ｂ ), (R １１ａ and R １２ａ ), (R １１ａ and R １２ｂ ), (R １１ｂ and R １２ａ ) or (Note １１ｂ and R １２ｂ ) together with the carbon atoms bonded to them form a 3, 4, 5, 6, or 8-membered unsaturated or saturated ring, wherein the ring contains 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the ring optionally has at least one substituent R １１ｆ It has been replaced with, R １１ｆ Each instance independently represents hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C. ２～８ Alkenyl, -C ２～８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, C ６ ~C １２ Aryl, 5-12 member heteroaryl, oxo (=O), -OR １１ｇ , thioxo(=S), -SR １１ｇ -CN, -SO ２ R １１ｇ , -SO ２ NR １１ｇ R １１ｈ , -COR １１ｇ , -CO ２ R １１ｈ , -CONR １１ｇ R １１ｈ , -NR １１ｇ R １１ｈ , -NR １１ｇ COR １１ｈ , -NR １１ｇ CO ２ R １１ｈ or -NR １１ｇ SO ２ R １１ｈ And, R １１ｇ and R １１ｈ These are hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C, respectively. ２～８ Alkenyl, -C ２～８ Alkinyl, C １～８ Alkoxy-C １～８ Alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, C ６ ~C １２ Independently selected from aryl or 5- to 12-membered heteroaryl groups, Each time it appears, R １１ｉ These are independently -F, -Cl, -Br, -I, -OH, -CN, oxo, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C １～８ Haloalkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C ２～８ Alkenyl, -C ２～８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C ３ ~C ８ Halocycloalkyl, 3-8 member heterocyclyl, -C ６ ~C １２ It is an aryl or a 5- to 12-membered heteroaryl. Preferably, (R １１ａ and R １１ｂ ), (R １２ａ and R １２ｂ ), (R １１ａ and R １２ａ ), (R １１ａ and R １２ｂ ), (R １１ｂ and R １２ａ ) or (Note １１ｂ and R １２ｂ ) together with the carbon atoms bonded to them form a 3, 4, 5, 6, or 8-membered unsaturated or saturated ring. More preferably, (R １１ａ and R １１ｂ ), (R １２ａ and R １２ｂ ), (R １１ａ and R １２ａ ), (R １１ａ and R １２ｂ ), (R １１ｂ and R １２ａ ) or (Note １１ｂ and R １２ｂ The compound wherein the carbon atoms bonded to them form a saturated ring of 3, 4, 5, 6, or 8 members.

12. The compound according to claim 1, R １３ , R １４ａ and R １４ｂ Each of these is independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or a 3- to 8-membered heterocycline, and each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or a 3- to 8-membered heterocycline is optionally given at least one substituent R １３ａ It has been replaced with, R １３ａ Each instance independently represents halogen, -OH, -CN, oxo, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C １～８ Haloalkyl, -C １～８ Alkoxy, -C ２～８ Alkenyl, -C ２～８ Alkinyl, -C ３ ~C ８ Halocycloalkyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl, Preferably, R １３ , R １４ａ and R １４ｂ Each is independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or a 3- to 8-membered heterocycline. More specifically, R １３ R is hydrogen, methyl, ethyl, propyl, or butyl, １４ａ and R １４ｂ Each is independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or a 3- to 8-membered heterocycline. More preferably, R １３ is hydrogen, and R １４ａ and R １４ｂ The compounds are each independently selected from hydrogen, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, and cyclopentyl.

13. The compound according to claim 1, R １ teeth, 【Chemistry 197】 【Chemistry 198】 The compound selected from the above.

14. The compound according to claim 1, R ２ H, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２～８ Alkenyl, -C ２～８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridadinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, imidazopyridazinyl, imidazopyridinyl, -CN, -COR ２ａ , -CO ２ R ２ａ , -CONR ２ａ R ２ｂ , -NR ２ａ R ２ｂ , -NR ２ａ COR ２ｂ Independently selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２～８ Alkenyl, -C ２～８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridadinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, imidazopyridazinyl, and imidazopyridinyl each optionally have at least one substituent R ２ｃ It has been replaced with, R ２ａ and R ２ｂ These are hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C, respectively. ２～８ Alkenyl, -C ２～８ Independently selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, azilidinyl, azetidinyl, pyrrolidinyl, dihydropyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridadinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, imidazopyridazinyl, imidazopyridinyl, and methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２～８ Alkenyl, -C ２～８ Each of the following compounds may optionally have at least one substituent R: alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, azilidinyl, azetidinyl, pyrrolidinyl, dihydropyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridadinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, imidazopyridazinyl, imidazopyridinyl. ２ｄ It is replaced with, or R ２ａ and R ２ｂ These atoms, together with the carbon atoms bonded to them, form a 3, 4, 5, 6, 7, or 8-membered unsaturated or saturated ring, the ring comprising 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the ring optionally comprising at least one substituent R ２ｄ It has been replaced with, R ２ｃ and R ２ｄ Each instance independently represents hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridadinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, imidazopyridazinyl, imidazopyridinyl, oxo (=O), -OR ２ｅ ,-SR ２ｅ -CN, -COR ２ｅ , -CO ２ R ２ｅ , -CONR ２ｅ R ２ｆ , -NR ２ｅ R ２ｆ , -NR ２ｅ COR ２ｆ or -NR ２ｅ CO ２ R ２ｆ Each of the following is optionally a substituent R: methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridadinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, imidazopyridazinyl, imidazopyridinyl. ２ｇ It has been replaced with, R ２ｅ and R ２ｆ These are hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, and C, respectively. １～８ Alkoxy-C １～８ Alkyl-, -C ２～８ Alkenyl, -C ２～８ A molecule independently selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl molecules, and containing the following compounds: methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, C １～８ Alkoxy-C １～８ Alkyl-, -C ２～８ Alkenyl, -C ２～８ Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl compounds may optionally have at least one substituent R ２ｈ It has been replaced with, R ２ｇ and R ２ｈ Each instance independently represents -F, -Cl, -Br, -I, -OH, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C. １～８ Haloalkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, C １～８ Alkoxy-C １～８ Alkyl-, -C ２～８ Alkenyl, -C ２～８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C ３ ~C ８ The compound is a halocycloalkyl, a 3- to 8-membered heterocyclyl, a phenyl, or a 5- to 12-membered heteroaryl.

15. The compound according to claim 1, R ２ H, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridadinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, imidazopyridazinyl, imidazopyridinyl, -CN, -COR ２ａ , -CO ２ R ２ａ or -CONR ２ａ R ２ｂ Independently selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridadinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, imidazopyridazinyl, and imidazopyridinyl, each optionally has at least one substituent R ２ｃ It has been replaced with, R ２ａ and R ２ｂ Each of these is independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, azilidinyl, azetidinyl, pyrrolidinyl, dihydropyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridadinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, imidazopyridazinyl, and imidazopyridinyl. Each of the following is optionally substituted R: ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, azilidinyl, azetidinyl, pyrrolidinyl, dihydropyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridadinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, imidazopyridazinyl, imidazopyridinyl. ２ｄ It is replaced with, or R ２ａ and R ２ｂ These atoms, together with the carbon atoms bonded to them, form a 3, 4, 5, or 6-membered unsaturated or saturated ring, the ring comprising 0 or 1 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the ring optionally comprising at least one substituent R ２ｄ It has been replaced with, R ２ｃ and R ２ｄ is, for each occurrence, independently hydrogen (H or D), -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, imidazopyridazinyl, imidazopyridinyl, -OR ２ｅ , -CN or -NR ２ｅ R ２ｆ where each of methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, imidazopyridazinyl, imidazopyridinyl is optionally substituted with at least one substituent R ２ｇ and R ２ｅ and R ２ｆ Each of these is independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or phenyl, and each of methyl, ethyl, propyl, butyl, pentyl, hexyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or phenyl is optionally accompanied by at least one substituent R ２ｈ It has been replaced with, R ２ｇ and R ２ｈ Each instance is independently -F, -Cl, -Br, -I, -OH, methyl, ethyl, propyl, butyl, pentyl, hexyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. Preferably, R ２ is 【Chemistry 199】 【Chemistry 200】 The aforementioned compound.

16. The compound according to claim 1, R ３ is independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or -CN, where methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl Each of the following can be optionally selected: -F, -Cl, -Br, -I, -OH, methyl, ethyl, propyl, butyl, pentoxy, hexoxy, heptoxy, octoxy, C １～８ Alkoxy-C １～８ Alkyl-, -C ２～８ Alkenyl, -C ２～８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, -C ６ ~C １２ Substituted with at least one substituent selected from aryl or 5- to 12-membered heteroaryl groups, Preferably, R ３ is independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or -CN. More specifically, R ３ The compound is independently selected from hydrogen, -F, -Cl, -Br, and -I.

17. The compound according to claim 1, R ４ The compound is oxo (=O).

18. The compound according to claim 1, R ３ and R ４ These atoms, together with the carbon atoms bonded to them, form a 5-6 membered aromatic ring, the ring comprising 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the ring optionally comprising at least one substituent R ３ａ It has been replaced with, R ３ａ is independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -CN, where methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, Each of the following can be optionally selected: -F, -Cl, -Br, -I, -OH, methyl, ethyl, propyl, butyl, pentoxy, hexoxy, heptoxy, octoxy, C １～８ Alkoxy-C １～８ Alkyl-, -C ２～８ Alkenyl, -C ２～８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, -C ６ ~C １２ The compound is substituted with at least one substituent selected from aryl or 5- to 12-membered heteroaryl groups.

19. The compound according to claim 1, R ５ Phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridadinyl, pyrimidinyl, pyrazinyl, benzoxazolyl, benzimidazolyl, imidazopyridazinyl, imidazopyridinyl, -COR ５ａ , -CO ２ R ５ａ , or -CONR ５ａ R ５ｂ Here, each of phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridadinyl, pyrimidinyl, pyrazinyl, benzoxazolyl, benzimidazolyl, imidazopyridazinyl, or imidazopyridinyl is optionally paired with at least one substituent R ５ｃ It has been replaced with, R ５ａ and R ５ｂ These are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C, respectively. ２～８ Alkenyl, -C ２～８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, oxadiazolyl, triazolyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridadinyl, pyrimidinyl, pyrazinyl, benzoxazolyl, benzimidazolyl, imidazopyridazinyl or imidazopyridinyl, independently selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２～８ Alkenyl, -C ２～８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, oxadiazolyl, triazolyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridadinyl, pyrimidinyl, pyrazinyl, benzoxazolyl, benzimidazolyl, imidazopyridazinyl, or imidazopyridinyl, each of which optionally has at least one substituent R ５ｄ It is replaced with, or R ５ａ and R ５ｂ These atoms, together with the nitrogen atoms bonded to them, form a 3, 4, 5, 6, 7, or 8-membered unsaturated or saturated ring, the ring comprising 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the ring optionally comprising at least one substituent R ５ｄ It has been replaced with, R ５ｃ and R ５ｄ Each instance of these is hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridadinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, imidazopyridazinyl, imidazopyridinyl, oxo (=O), -OR ５ｅ ,-SR ５ｅ -CN, -COR ５ｅ , -CO ２ R ５ｅ , -CONR ５ｅ R ５ｆ , -NR ５ｅ R ５ｆ , -NR ５ｅ COR ５ｆ or -NR ５ｅ CO ２ R ５ｆ Independently selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridadinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, imidazopyridazinyl, or imidazopyridinyl, each optionally has at least one substituent R ５ｇ It has been replaced with, R ５ｅ and R ５ｆ are each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, C １～８ alkoxy-C １～８ alkyl-, -C ２～８ alkenyl, -C ２～８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzoxazolyl, benzimidazolyl, imidazopyridazinyl or imidazopyridinyl, and each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, C １～８ alkoxy-C １～８ alkyl-, -C ２～８ alkenyl, -C ２～８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzoxazolyl, benzimidazolyl, imidazopyridazinyl or imidazopyridinyl is optionally substituted with at least one substituent R ５ｈ and R ５ｇ and R ５ｈ These are halogen, -OH, -CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, and C, respectively. １～８ Alkoxy-C １～８ Alkyl-, -C ２～８ Alkenyl, -C ２～８ The compound is independently selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl.

20. The compound according to claim 1, R ５ is pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanil, thiophenyl, thiazolyl, pyridinyl, pyridadinyl, pyrimidinyl, pyrazinyl, benzoxazolyl, benzimidazolyl, imidazopyridazinyl, or imidazopyridinyl, where each of pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanil, thiophenyl, thiazolyl, pyridinyl, pyridadinyl, pyrimidinyl, pyrazinyl, benzoxazolyl, benzimidazolyl, imidazopyridazinyl, or imidazopyridinyl is optionally coupled with at least one substituent R ５ｃ It has been replaced with, R ５ｃ Each instance is independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridadinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, imidazopyridazinyl, and imidazopyridinyl. Preferably, R ５ It is benzoxazolyl, More specifically, R ５ teeth, 【Chemical Engineering 201】 The aforementioned compound.

21. The compound according to claim 1, R ５ is -COR ５ａ , -CO ２ R ５ａ , or -CONR ５ａ R ５ｂ And, Here, R ５ａ and R ５ｂ Each of these is independently derived from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, oxadiazolyl, triazolyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridadinyl, pyrimidinyl, pyrazinyl, benzoxazolyl, benzimidazolyl, imidazopyridazinyl, or imidazopyridinyl. Each of the following is selected: methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridadinyl, pyrimidinyl, pyrazinyl, benzoxazolyl, benzimidazolyl, imidazopyridazinyl, or imidazopyridinyl, optionally, at least one substituent R ５ｄ It has been replaced with, R ５ｄ Each instance of these is hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridadinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, imidazopyridazinyl, imidazopyridinyl, -OR ５ｅ Alternatively, independently selected from -CN, each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridadinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, imidazopyridazinyl, or imidazopyridinyl may optionally have at least one substituent R ５ｇ It has been replaced with, R ５ｅ The compounds are selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridadinyl, pyrimidinyl, pyrazinyl, benzoxazolyl, benzimidazolyl, imidazopyridazinyl, or imidazopyridinyl, and include methyl, ethyl, propyl, butyl, pentyl, hexyl, and Butyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridadinyl, pyrimidinyl, pyrazinyl, benzoxazolyl, benzimidazolyl, imidazopyridazinyl, or imidazopyridinyl may optionally have at least one substituent R ５ｈ It has been replaced with, R ５ｇ and R ５ｈ Each is independently selected from halogen, -OH, -CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, or 5-12 membered heteroaryls. Preferably, R ５ teeth, 【Chemical Engineering 202】 - COCH ３ or -COCF ３ The aforementioned compound.

22. The compound according to claim 1, R ６ H, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２～８ Alkenyl, -C ２～８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridadinyl, pyrimidinyl, pyrazinyl, -CN, -OR ６ａ , -NR ６ａ R ６ｂ , -COR ６ａ , -CO ２ R ６ａ , -CONR ６ａ R ６ｂ , -COR ６ａ or -NR ６ａ COR ６ｂ These are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C. ２～８ Alkenyl, -C ２～８ Each of the following compounds may optionally have at least one substituent R: alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridadinyl, pyrimidinyl, and pyrazinyl. ６ｃ It has been replaced with, R ６ａ and R ６ｂ These are hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C, respectively. ２～８ Alkenyl, -C ２～８ A selection independently from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl, and including methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２～８ Alkenyl, -C ２～８ Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl compounds may optionally have at least one substituent R ６ｄ It has been replaced with, R ６ｃ Each instance independently contains hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, 5-12 membered heteroaryl, oxo (=O), -OR ６ｅ ,-SR ６ｅ -CN, -COR ６ｅ , -CO ２ R ６ｅ , -CONR ６ｅ R ６ｆ , -NR ６ｅ R ６ｆ , -NR ６ｅ COR ６ｆ or -NR ６ｅ CO ２ R ６ｆ Each of the following is optionally a substituent R: methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, and 5-12 membered heteroaryl. ６ｇ It has been replaced with, R ６ｅ and R ６ｆ These are hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, and C, respectively. １～８ Alkoxy-C １～８ Alkyl-, -C ２～８ Alkenyl, -C ２～８ Independently selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl, R ６ｄ and R ６ｇ These are, respectively, -F, -Cl, -Br, -I, -OH, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, and C. １～８ Alkoxy-C １～８ Alkyl-, -C ２～８ Alkenyl, -C ２～８ The compound is independently selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl.

23. The compound according to claim 1, R ６ H, -F, -Cl, -Br, -I, methyl, -CF ３ ethyl, -CH ２ CF ３ , -CF ２ CH ３ ,propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, pyridinyl, pyridadinyl, pyrimidinyl, pyrazinyl, -CN, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, 【Chemical 203】 And, Preferably, 【Chemical 204】 The part is, 【Chemical 205】 The aforementioned compound.

24. The compound according to claim 1, R ９ and R １０ These are H, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C respectively. ２～８ Alkenyl, -C ２～８ Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, or 5-12 membered heteroaryls are independently selected, and include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２～８ Alkenyl, -C ２～８ Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, or 5- to 12-membered heteroaryls may optionally have at least one substituent R ９ａ It has been replaced with, R ９ａ Each instance independently contains halogen, -OH, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, and C. １～８ Alkoxy-C １～８ Alkyl-, -C ２～８ Alkenyl, -C ２～８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl. Preferably, R ９ and R １０ These are H, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C respectively. ２～８ Alkenyl, -C ２～８ Independently selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, or 5-12 membered heteroaryls, More specifically, R ９ and R １０ Each of these is independently selected from H, methyl, ethyl, propyl, butyl, pentyl, cyclopropyl, cyclobutyl, and cyclopentyl. More specifically, R ９ and R １０ The compounds are each independently selected from H and cyclopropyl.

25. The compound according to claim 1, wherein the compound is selected from the following: 【Chemical 206】 【Chemical 207】 【Chemical 208】 【Chemical Engineering 209】 【Chemical 210】 【Chemistry 211】 【Chemical Engineering 212】 【Chemistry 213】 【Chemical 214】 【Chemical 215】 【Chemical 216】 【Chemical 217】 【Chemistry 218】 【Chemical 219】 【Chemical 220】 【Chemistry 221】 【Chemistry 222】 【Chemistry 223】 【Chemistry 224】 【Chemical 225】 【Chemistry 226】 【Chemistry 227】 【Chemistry 228】 【Chemistry 229】

26. A pharmaceutical composition comprising a compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof, together with a pharmaceutically acceptable excipient.

27. ​​A composition for reducing IL-17 activity by inhibition, wherein the composition comprises a compound according to any one of claims 1 to 25, which comprises a compound of formula (I) or a specific compound exemplified in the claims, or a pharmaceutically acceptable salt thereof, and the composition is administered to an individual.

28. The composition according to claim 27 for treating a disease that may be affected by IL-17, wherein the disease is selected from cancer.

29. A composition for treating a disease that may be affected by IL-17, wherein the composition comprises a compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer or prodrug, wherein the disease is an autoimmune disease, an inflammatory disease, chronic inflammation, psoriasis, spondyloarthritis, rheumatoid arthritis or multiple sclerosis.

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