5-amino-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide derivative as a PRMT5 MTA synergistic inhibitor

Abstract

This disclosure relates to the 5-amino-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide derivative of formula (I), MTAP DEL The present invention provides for the use of the compound to selectively inhibit the activity of PRMT5 in cooperation with MTA in tumors with mutations, and for use in pharmaceutical compositions for treating various diseases, including cancer. TIFF2026511698000719.tif35156

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the benefit of priority from International Application PCT / CN2023 / 085078 filed on 30 March 2023, International Application PCT / CN2023 / 110807 filed on 2 August 2023, and International Application PCT / CN2024 / 080582 filed on 7 March 2024, the entire contents of which are incorporated herein by reference.

[0002] This disclosure relates to 5-amino-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide derivatives, such as MTAP. DEL The present invention provides a use for selectively inhibiting the activity of PRMT5, which cooperates with methylthioadenosine (MTA), in tumors with mutations, and a pharmaceutical composition containing the compound. [Background technology]

[0003] Epigenetic modification is a process that alters the primary DNA sequence and can change genetic output. Epigenetic modification plays a crucial role in gene expression and regulation, protein production in multiple dimensions, and cell differentiation. Typically, this process is reversible and selective for DNA, its regulatory proteins such as histones, and other proteins such as transcription factors [Bradbury, EM, BioEssays, 1992, 14(1):pp.9-16]. Protein methyltransferases (PMTs), consisting of two subfamilies named PKMTs (protein lysine methyltransferases) and PRMTs (protein arginine methyltransferases), are central players in epigenetic modification [Copeland, RA, et al., Oncogene, 2012, 32(8):pp.939-46]. PMTs are associated with various human diseases and are considered candidate therapeutic targets [Copeland, RA, et al., Oncogene, 2012, 32(8):pp.939-46].

[0004] As its name suggests, PRMT catalyzes the methylation of arginine residues in proteins. In addition to their primary function of histone tail methylation, PRMT also targets other cellular proteins such as NAB2p, FOXO1, PABP1, and Sm D1 [Bedford, MT, et al., Molecular Cell, 2005, 18(3): pp. 263-72]. The nine mammalian PRMTs, classified by their products, can be divided into three subtypes: Type I (PRMT1, PRMT2, PRMT3, PRMT4, PRMT6, and PRMT8) catalyze aDMA (asymmetric dimethylated arginine) formation, Type II (PRMT5, PRMT9) catalyze sDMA (symmetric dimethylated arginine) formation, and Type III (PRMT7) catalyzes MMA (monomethylated arginine) formation [Yang, Y., et al., Nature Reviews Cancer, 2012, 13(1): pp. 37-50]. In addition, Type I / II PRMTs can also catalyze MMA formation as an intermediate for aDMA and sDMA. PRMTs contain a pocket for interacting with their cofactor SAM (S-adenosylmethionine) and an adjacent pocket for interacting with arginine residues on the protein, i.e., a SAM pocket and a substrate pocket. The methylation process involves transferring an activated methyl group from the cofactor SAM to the guanidino group on the arginine residue. N It involves two different mechanisms. [Bedford, MT, et al., Molecular Cell, 2005, 18(3):pp.263-72]. The byproduct of this process is SAH (S-adenosyl-L-homocysteine).

[0005] The overall intracellular arginine level is approximately 1500:3:2:1 for Arg:aDMA:MMA:sDMA, and PRMT5 is responsible for the majority of sDMA formation [Dhar, S., et al., Scientific Reports, 2013, 3:1311]. In contrast to PRMT1, the main type I PRMT that functions independently within cells, PRMT5 binds to MEP50 (methirosomal protein 50) and forms a heterocomplex that is often increased in cancer cells and correlates with poor patient survival [Gao, G., et al., Nucleic Acids Research, 2019, 47(10):pp.5038-48]. PRMT5 promotes tumorigenesis through various mechanisms. PRMT5 is a potent repressor of numerous genes. When PRMT5 methylates histone H2a and H4 on Arg3 and histone H3 on Arg8, it represses gene transcripts involved in differentiation, transformation, cell cycle progression, and tumor suppression [Karkhanis, V., et al., Trends in Biochemical Sciences, 2011, 36(12):pp.633-41]. In addition to its epigenetic role, PRMT5 may also regulate RNA-binding proteins such as splicing factors. For example, a reproducible event was observed in PRMT5 knockout mice, in which case exon 6 skipping of MDM4 (mouse double microchromosome 4) occurred, leading to p53 release and upregulation of the p53 pathway [Gerhart, SV, et al., Scientific Reports, 2018, 8:9711]. In addition, PRMT5 can directly influence key proliferation pathways through direct methylation of p53 [Jansson, M., et al., Nature Cell Biology, 2008, 10(12): pp. 1431-9], EGFR [Hsu, J.-M., et al., Nature Cell Biology, 2011, 13(2): pp. 174-81], PI3K [Wei, T.-YW, et al., Cellular Signaling, 2014, 26(12): pp. 2940-50], and others.Therefore, PRMT5 has a strong potential to be a clinically relevant target.

[0006] On the other hand, PRMT5 is present in essential genes in normal tissues, and systemic inhibition of PRMT5 can lead to significant susceptibility to disease, particularly hematological toxicity [Ahnert, JR, et al., Journal of Clinical Oncology, 2021, 39(15-suppl): p.3019]. Therefore, strategies to selectively block PRMT5 activity within tumor cells are needed for safer therapies.

[0007] Homozygous deletion of the tumor-depressing factor CDKN2A (cyclin-dependent kinase inhibitor 2A) occurs in approximately 15% of all tumor types. Interestingly, the mutation is frequently accompanied by co-deletion of adjacent genes located in 9p21, including the gene encoding MTAP (methylthioadenosine phosphorylase) [Firestone, RS, et al., Journal of American Chemical Society, 2017, 139(39):p.13754-60]. As a result of MTAP deletion, MTA (methylthioadenosine), a substrate of MTAP, accumulates. MTA is a weak ligand / inhibitor of PRMT5, structurally related to SAM and occupying the same pocket as SAM. The formation of the MTA-PRMT5 complex provides an opportunity for further PRMT5 inhibition through the formation of a tertiary complex. In this way, the correlation between the absence of MTAP and PRMT5 dependence is established by MTA concentration levels, leading to precise oncological therapies. Currently, most clinically-stage PRMT5 inhibitors are unable to differentiate normal cells from cancer cells based on either SAM / MTA competitive mechanisms (JNJ64619178, PF06939999, PRT543, and PRT811) or non-MTA competitive mechanisms (GSK3326595). Therefore, there is a continuing unmet medical need for potent and selective MTA-cooperative PRMT5 inhibitors. [Prior art documents] [Non-patent literature]

[0008]

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Summary of the Invention

[0009] One object of the present invention is to provide a PRMT5 - inhibiting compound, as well as methods for its preparation and use.

[0010] Aspect 1. A compound of formula (I):

Chemical Formula

[0011] In one embodiment, R 1 and R 2 is -C 1~8 Alkyl, -C3~C8 cycloalkyl, -C3~C 12 A cycloalkenyl and a 3-12 membered heterocyclyl are independently selected, and the -C 1~8 Alkyl, -C3~C8 cycloalkyl, -C3~C 12 Each of the cycloalkenyl and 3-12 membered heterocyclyl has at least one substituent R 1a It can be arbitrarily replaced with R. 1a It is defined as described above.

[0012] In one embodiment, R1 and R 2 is -C 1~8 Each alkyl is independently selected, and the -C 1~8 Alkyl has at least one substituent R 1a It can be arbitrarily replaced with R. 1a It is defined as described above. Preferably, R 1 and R 2 is -C 1~4 Each alkyl is independently selected, and the -C 1~8 Alkyl has at least one substituent R 1a It can be arbitrarily replaced with R. 1a It is defined as described above. More preferably, R 1 and R 2 Each of the methyl, ethyl, and propyl (isopropyl or n-propyl) atoms is independently selected from methyl, ethyl, and propyl (isopropyl or n-propyl), and each of the methyl, ethyl, and propyl (isopropyl or n-propyl) atoms has at least one substituent R 1a It can be arbitrarily replaced with R. 1a R is defined as described above. In one embodiment, R 1 The substituents are methyl, ethyl, propyl (isopropyl or n-propyl), and butyl (n-butyl, sec-butyl, isobutyl, or tert-butyl), and each of the methyl, ethyl, propyl (isopropyl or n-propyl), and butyl (n-butyl, sec-butyl, isobutyl, or tert-butyl) has at least one substituent R 1a It is arbitrarily replaced with R 1a R is defined as described above. In one embodiment, R 1aThe substituents are phenyl, pyrimidinyl, tetrahydro-2H-pyranyl, pyridazinyl, pyrazinyl, triazolyl (preferably 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl), pyridinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, dihydrophlopyridinyl, or tetrahydrophlopyridinyl, and each of the phenyl, pyrimidinyl, tetrahydro-2H-pyranyl, pyridazinyl, pyrazinyl, triazolyl (preferably 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl), pyridinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, dihydrophlopyridinyl, or tetrahydrophlopyridinyl has at least one substituent R 1d It is arbitrarily replaced with R 1d R is defined as described above. In one embodiment, R 1 teeth [ka] Y is N or CH, n4 is 0, 1, 2, 3 or 4, preferably n4 is 1, 2 or 3. In one embodiment, R 1 teeth, [ka] That is the case.

[0013] In one embodiment, R 1 teeth [ka] Y is N or CH, preferably 0, 1 or 2 occurrences of Y are N and the rest are CH, more preferably 0 or 1 occurrences of Y are N and the rest are CH, R 1a is hydrogen or C 1~8 It is alkyl, preferably R 1a is hydrogen, methyl, ethyl, propyl (isopropyl or n-propyl), or butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), and more preferably R 1aR is hydrogen, methyl, ethyl, or propyl (isopropyl or n-propyl), 1d C is optionally substituted with a halo, a methyl atom substituted with one or more halos, or a fluorocarbon. 3~5 A cycloalkyl group, or a group independently selected from -CN, preferably R 1d n4 is independently selected from -F, -Br, -I, -CF3, cyclopropyl, fluorocyclopropyl, cyclobutyl, or -CN, and n4 is 0, 1, 2, 3, or 4, preferably n4 is 1, 2, or 3. In further embodiments, R 1 teeth, [ka] That is the case.

[0014] In one embodiment, R 1 and R 2These include methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, chromanil, isochromanil, dihydropyranopyridinyl (preferably 5,8-dihydro-6H-pyrano[3,4-b]pyridinyl, 3,4-dihydro-2H-pyrano[3,2-b]pyridinyl, or 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl), pyrimidinyl, tetrahydroxypropyl Each of the following is independently selected: dro-2H-pyranil, pyridazinil, pyrazinil, dihydroflopyridinil (preferably 2,3-dihydroflop[2,3-b]pyridinil), tetrahydronaphthalenil (preferably 1,2,3,4-tetrahydronaphthalenil), benzo[d]thiazolyl, pyridinil, quinolinil, isoquinolinil, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranil, tetrahydroquinolinil, tetrahydronaphthyl, dihydroflopyridinil, or tetrahydroflopyridinil. Methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, chromanil, isochromanil, dihydropyranopyridinyl (preferably 5,8-dihydro-6H-pyrano[3,4-b]pyridinyl, 3,4-dihydro-2H-pyrano[3,2-b]pyridinyl, or 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl), pyrimidinyl, tetrahydro- Each of 2H-pyranyl, pyridadinyl, pyrazinyl, dihydrophlopyridinyl (preferably 2,3-dihydrophlo[2,3-b]pyridinyl), tetrahydronaphthalenyl (preferably 1,2,3,4-tetrahydronaphthalenyl), benzo[d]thiazolyl, pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrophlopyridinyl, or tetrahydrophlopyridinyl has at least one substituent R 1a It can be arbitrarily replaced with R. 1a It is defined as described above.

[0015] In one embodiment, R 1 is a 3- to 12-membered heterocycline, and the 3- to 12-membered heterocycline has at least one substituent R 1a It is arbitrarily replaced with R 1a It is defined as described above. Preferably, R 1 is a 6-10 member heterocycline, and the 6-10 member heterocycline has at least one substituent R 1a It is arbitrarily replaced with R 1a R is defined as described above. In one embodiment, R 1 is a 3- to 12-membered heterocycline, and the 3- to 12-membered heterocycline has at least one substituent R 1a It is arbitrarily replaced with R 2 These are 3-12 member heterocyclines, -C6-C 12 -C is further substituted with aryl, 5-12 member heteroaryls. 1~8 Alkyl, and the 3-12 member heterocyclyl, -C6-C 12 Each of the aryl and 5-12 member heteroaryl has at least one substituent R 1d It is optionally replaced by R. Preferably, 2 -C is further substituted with a 5-10 member heterocyclyl, phenyl, or 5-6 member heteroaryl. 1~4 The alkyl group is such that each of the 5-10 member heterocyclyl, phenyl, and 5-6 member heteroaryl groups has at least one substituent R 1d It can be arbitrarily replaced with.

[0016] In one embodiment, R 1 is a 3- to 12-membered heterocycline, and the 3- to 12-membered heterocycline has at least one substituent R 1a It is arbitrarily replaced with R 1a R is defined as described above. In one embodiment, R 1 is tetrahydropyranyl, and the tetrahydropyranyl has at least one substituent R 1a It is arbitrarily replaced with R 1a It is defined as described above. Preferably, R 1a is -C 1~8It is an alkoxy, more preferably R 1a is methoxy or ethoxy. In one embodiment, R 1 teeth [ka] And R 1b is -C 1~8 It is alkyl, preferably R 1b It is either methyl or ethyl.

[0017] In one embodiment, R 1 is a 3-12 member heterocyclyl, preferably R 1 is tetrahydroquinolinyl, and the tetrahydroquinolinyl has at least one substituent R 1a It is arbitrarily replaced with R 1a R is defined as described above. In one embodiment, R 1a is H. In one embodiment, R 1 teeth, [ka] That is the case.

[0018] In one embodiment, R 1 is a 3-12 member heterocyclyl, preferably R 1 is chromanil or isochromanil, and each of the chromanil or isochromanil has at least one substituent R 1a It is arbitrarily replaced with R 1a R is defined as described above. In one embodiment, R 1a is H. In one embodiment, R 1a is -F, -CH3, or -CF3. In one embodiment, R 1 teeth, [ka] In one embodiment, R 1 teeth [ka] And R1a This includes methyl, ethyl, propyl, halo, methyl substituted with one or more halos, and C 3~5 A cycloalkyl group, or one independently selected from -CN, or two R groups bonded to the same atom. 1a C 3~5 A cycloalkyl group is formed, preferably R 1a is hydrogen, methyl, ethyl, -F, -Cl, -Br, -I, -CF3, cyclopropyl, or -CN, or two R atoms bonded to the same atom. 1a The compound forms a cyclopropyl group, where n5 is 0, 1, 2, 3, 4, or 5, preferably n5 is 1, 2, 3, 4, or 5, more preferably n5 is 1, 2, 3, or 4, and even more preferably n5 is 1, 2, or 3.

[0019] R 1a teeth, [ka] of [ka] Partially on or [ka] of [ka] It can be a substituent(s) on a part.

[0020] In one embodiment, R 1 is benzyl, pyridylmethyl, pyridadinylmethyl, pyrimidinylmethyl, pyrazinylmethyl, 1-pyridylethyl, 1-pyridazinylethyl, 1-pyridinylethyl, or 1-pyradinylethyl, and each of the benzyl, pyridylmethyl, pyridadinylmethyl, pyrimidinylmethyl, pyrazinylmethyl, 1-pyridylethyl, 1-pyridazinylethyl, 1-pyridinylethyl, or 1-pyradinylethyl has at least one substituent R 1d It is arbitrarily replaced with R1d R is defined as described above. In one embodiment, R 1d These are, independently, hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), phenyl, pyrimidinyl, tetrahydro-2H-pyranyl, pyridadinyl, pyrazinyl, triazolyl (preferably 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl), pyridinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrophlopyridinyl, tetrahydrophlopyridinyl, -OR 1f , -SO2R 1f or -CN, and each of the methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), phenyl, pyrimidinyl, tetrahydro-2H-pyranyl, pyridadinyl, pyrazinyl, triazolyl (preferably 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl), pyridinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrophlopyridinyl, or tetrahydrophlopyridinyl has at least one substituent R 1h It is arbitrarily replaced with R 1f Each of the following is independently selected from hydrogen, methyl, ethyl, propyl (isopropyl or n-propyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or phenyl, and each of the methyl, ethyl, propyl (isopropyl or n-propyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or phenyl has at least one substituent R 1i It is arbitrarily replaced with R 1h and R 1iEach of these is independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -OH, or -CN.

[0021] In one embodiment, R 2 C 1~8 It is alkyl. In one embodiment, R 2 is methyl, ethyl, propyl (isopropyl or n-propyl), or butyl (n-butyl, sec-butyl, isobutyl or tert-butyl). In one embodiment, R 2 is methyl, ethyl, or propyl (isopropyl or n-propyl). In one embodiment, R 2 It is methyl.

[0022] Embodiment 2. The compound is of formula (IIa) or (IIb): [ka] The compound is of the form of formula (IIc) or (IId): [ka] The compound is of the form (IIe), (IIf), (IIg), or (IIh): [ka] It is of the form, and in the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 However, the compound as defined in Embodiment 1.

[0023] Embodiment 3. The compound is of formula (IIIa): [ka] The compound is preferably of formula (IIIb): [ka] The compound is of the form of formula (IIIc): [ka] The compound is of the form (IIId), (IIIe), (IIIf), or (IIIg): [ka] The compound is of the formula (IIIh), (IIIi), (IIIj), or (IIIk): [ka] The formula is such that n1 is 0, 1, 2, or 3, preferably n1 is 1 or 2, and more preferably n1 is 1. R 1a , R 1b , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 The compound according to Embodiment 1, wherein L is as defined in Embodiment 1.

[0024] Embodiment 4. The compound is of formula (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (IVg), or (IVh): [ka] [ka] The compound is of the form (IVi), (IVj), (IVk), (IVl), (IVm), (IVn), (IVo), (IVp), (IVq), (IVr), (IVs), (IVt), (IVu), or (IVv): [ka] [ka] The formula is such that n2 is 0, 1, 2, or 3, preferably n2 is 0, 1, or 2. R 1a , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 The compound according to Embodiment 1, wherein L is as defined in Embodiment 1. 1a teeth, [ka] Among these, they can be substituted at any position that satisfies valence theory.

[0025] Embodiment 5. The compound is of formula (Va): [ka] The formula is such that n3 is 0, 1, 2, 3 or 4, preferably n3 is 1, 2 or 3. Each occurrence of X is independently either N or CH, preferably 0, one or two occurrences of X are N, and the rest are CH. R 1a , R 1d , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 And L is as defined in Embodiment 1, Preferably, the compound is of the formula (Vb), (Vc), (Vd), (Ve), or (Vf): [ka] The formula is such that n3 is 0, 1, 2, or 3, preferably n3 is 1 or 2, and more preferably n3 is 1. R 1a , R 1d , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 And L is as defined in Embodiment 1, More preferably, the compound is of the formula (Vg), (Vh), (Vi), (Vj), (Vk), (Vl), (Vm), (Vn), or (Vo): [ka] The compound is of the formula (Vp), (Vq), (Vr), (Vs), (Vt), (Vu), (Vv), (Vw), (Vx), (Vy), or (Vz): [ka] [ka] It is of the form, and in the formula, R 1a , R 1d , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 The compound according to Embodiment 1, wherein L is as defined in Embodiment 1.

[0026] Apparatus 6. Compound of formula (VI): [ka] or its N-oxide, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, or deuterated analog, wherein in the formula, R 1 and R 2However, hydrogen, -C 1~8 Alkyl, -C3~C8 cycloalkyl, -C3~C 12 Cycloalkenyl, 3-12 member heterocyclyl, -C6-C 12 Each is independently selected from aryls and 5-12 member heteroaryls, and the -C 1~8 Alkyl, -C3~C8 cycloalkyl, 3~12 member heterocyclyl, -C6~C 12 Each of the aryl and 5-12 member heteroaryl has at least one substituent R 1a It can be arbitrarily replaced with, or R 1 and R 2 However, together with the nitrogen atom to which they are bonded, they form a 3- to 8-membered unsaturated or saturated ring, the ring containing 0 to 3 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the ring having at least one substituent R 1a It is arbitrarily replaced with, R 1a However, hydrogen, halogen, deuterium, and -C are produced independently. 1~8 Alkyl, -C3~C8 cycloalkyl, -C3~C 12 Cycloalkenyl, 3-12 member heterocyclyl, -C6-C 12 Aryl, 5-12 member heteroaryl, -OR 1b , -SO2R 1b -SO2NR 1b R 1c , -COR 1b , -CO2R 1b ,-CONR 1b R 1c , -NR 1b R 1c , -NR 1b COR 1c , -NR 1b CO2R 1c , -NR 1b SO2R 1c , oxo, or -CN, and the aforementioned -C 1~8 Alkyl, -C3~C8 cycloalkyl, -C3~C 12 Cycloalkenyl, 3-12 member heterocyclyl, -C6-C 12 Each of the aryl and 5-12 member heteroaryl has at least one substituent R1d It can be arbitrarily replaced with, or 2 R 1a However, together with the atom(s) to which they are bonded, they form a 3- to 8-membered unsaturated or saturated ring, and the ring contains 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the ring contains at least one substituent R 1d It is arbitrarily replaced with, R 1b and R 1c However, hydrogen, -C 1~8 Alkyl, -C3~C8 cycloalkyl, 3~12 member heterocyclyl, -C6~C 12 Each is independently selected from aryls and 5-12 member heteroaryls, and the -C 1~8 Alkyl, -C3~C8 cycloalkyl, 3~12 member heterocyclyl, -C6~C 12 Each of the aryl and 5-12 member heteroaryl has at least one substituent R 1e It is arbitrarily replaced with, R 1d and R 1e However, each is independently hydrogen, halogen, and -C 1~8 Alkyl, -C3~C8 cycloalkyl, -C3~C 12 Cycloalkenyl, 3-12 member heterocyclyl, -C6-C 12 Aryl, 5-12 member heteroaryl, -OR 1f , -SO2R 1f -SO2NR 1f R 1g , -COR 1f , -CO2R 1f ,-CONR 1f R 1g , -NR 1f R 1g , -NR 1f COR 1g , -NR 1f CO2R 1g , -NR 1f SO2R 1g , oxo, or -CN, and the -C 1~8 Alkyl, -C3~C8 cycloalkyl, -C3~C 12 Cycloalkenyl, 3-12 member heterocyclyl, -C6-C 12Each of the aryl and 5-12 member heteroaryl has at least one substituent R 1h It is arbitrarily replaced with, R 1f and R 1g However, hydrogen, -C 1~8 Alkyl, -C3~C8 cycloalkyl, 3~12 member heterocyclyl, -C6~C 12 Each is independently selected from aryls and 5-12 member heteroaryls, and the -C 1~8 Alkyl, -C3~C8 cycloalkyl, 3~12 member heterocyclyl, -C6~C 12 Each of the aryl and 5-12 member heteroaryl has at least one substituent R 1i It is arbitrarily replaced with, R 1h and R 1i However, each is independently hydrogen, halogen, and -C 1~8 Alkyl, -C3~C8 cycloalkyl, -C3~C 12 Cycloalkenyl, 3-12 member heterocyclyl, -C6-C 12 Aryl, 5-12 member heteroaryl, -OR 1j , -SO2R 1j -SO2NR 1j R 1k , -COR 1j , -CO2R 1j ,-CONR 1j R 1k , -NR 1j R 1k , -NR 1j COR 1k , -NR 1j CO2R 1k , -NR 1j SO2R 1k , oxo, or -CN, and the -C 1~8 Alkyl, -C3~C8 cycloalkyl, -C3~C 12 Cycloalkenyl, 3-12 member heterocyclyl, -C6-C 12 Each of the aryl and 5-12 member heteroaryl groups is a halogen, -C 1~8 Alkyl, -C 1~8 Alkoxy, -C 2~8 Alkenyl, -C 2~8Alkinyl, -C3~C8 cycloalkyl, 3~8 membered heterocyclyl, -C6~C 12 Optionally substituted with at least one substituent selected from the group consisting of aryl, 5-12 member heteroaryl, -CN, -OH, -NH2, or oxo, R 1j and R 1k However, hydrogen, -C 1~8 Alkyl, -C3~C8 cycloalkyl, 3~12 member heterocyclyl, -C6~C 12 Each is independently selected from aryls and 5-12 member heteroaryls, and the -C 1~8 Alkyl, -C3~C8 cycloalkyl, 3~12 member heterocyclyl, -C6~C 12 Each of the aryl and 5-12 member heteroaryl groups is a halogen, -C 1~8 Alkyl, -C 1~8 Alkoxy, -C 2~8 Alkenyl, -C 2~8 Alkinyl, -C3~C8 cycloalkyl, 3~8 membered heterocyclyl, -C6~C 12 Optionally substituted with at least one substituent selected from the group consisting of aryl, 5-12 member heteroaryl, -CN, -OH, -NH2, or oxo, R 6 and R 7 The compound, or its N-oxide, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, or deuterated analog, each independently selected from hydrogen or methyl.

[0027] Embodiment 7. The compound is of formula (VIIa): [ka] In the formula, n4 is 0, 1, 2, 3 or 4, preferably n4 is 1, 2 or 3. Each occurrence of Y is independently either N or CH, preferably 0, one or two occurrences of Y are N, and the rest are CH. R 1a , R 1d , R 2 , R 6 and R7 However, as defined in aspect 6, Preferably, the compound is of formula (VIIb), (VIIc), (VIId), (VIIe), or (VIIf): [ka] In the formula, n4 is 0, 1, 2, or 3, preferably n4 is 1 or 2, and more preferably n4 is 1. R 1a , R 1d , R 2 , R 6 and R 7 However, as defined in aspect 6, More preferably, the compound is of formula (VIIg), (VIIh), (VIIi), (VIIj), (VIIk), (VIIl), (VIIm), (VIIn), (VIIo), (VIIp), or (VIIq): [ka] And in the formula, R 1a , R 1d , R 2 , R 6 and R 7 However, the compound according to Embodiment 6, as defined in Embodiment 6.

[0028] Embodiment 8. The compound is of formula (VIIIa): [ka] In the formula, n5 is 0, 1, 2, 3 or 4, preferably n5 is 1, 2 or 3. Z 1 and Z 2 However, they are independently selected from O or CH2, Z 3 and Z 4 However, they are selected independently from N or CH, R 1a , R 6 and R 7 However, as defined in aspect 6, Preferably, the compound is of formula (VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIg), (VIIIh), (VIIIi), (VIIIj), (VIIIk), (VIIIl), (VIIIm), (VIIIn), or (VIIIo): [ka] [ka] In the formula, n5 is 0, 1, 2, or 3, preferably n5 is 1 or 2. R 1a , R 1d , R 2 , R 6 and R 7 However, as defined in aspect 6, R 1a but, [ka] The compound according to embodiment 6, which can be substituted at any position that satisfies valence theory.

[0029] Appearance 9.R 1 and R 2 However, hydrogen, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C3~C 12Each of the following is independently selected from cycloalkenyls, 3-12 member heterocyclyls, phenyls, and 5-12 member heteroaryls, and each of the methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-12 member heterocyclyls, phenyls, and 5-12 member heteroaryls has at least one substituent R 1a It can be arbitrarily replaced with, or R 1 and R 2 However, together with the nitrogen atoms bonded to them, they form a 3, 4, 5, 6, 7, or 8-membered unsaturated or saturated ring, wherein the ring contains 0, 1, 2, or 3 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the ring has at least one substituent R 1a It is arbitrarily replaced with, R 1a However, independently, hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C3~C 12 Cycloalkenyl, 3-12 member heterocyclyl, phenyl, 5-12 member heteroaryl, -OR 1b , -SO2R 1b -SO2NR 1b R 1c , -COR 1b , -CO2R 1b ,-CONR 1b R 1c , -NR 1b R 1c , -NR 1b COR 1c , -NR 1b CO2R 1c , -NR 1b SO2R 1c, oxo, or -CN, and the aforementioned methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C3~C 12 Each of the cycloalkenyl, 3-12 member heterocyclyl, phenyl, or 5-12 member heteroaryl has at least one substituent R 1d It can be arbitrarily replaced with, or 2 R 1a However, together with the atom(s) to which they are bonded, they form a 3, 4, 5, 6, 7, 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 has at least one substituent R 1d It is arbitrarily replaced with, R 1b and R 1c However, each of the following is independently selected from hydrogen, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-12 member heterocyclyl, phenyl, or 5-12 member heteroaryl, and each of the above methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-12 member heterocyclyl, phenyl, or 5-12 member heteroaryl has at least one substituent R 1e It is arbitrarily replaced with, R 1d and R 1eHowever, each is independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C3~C 12 Cycloalkenyl, 3-12 member heterocyclyl, phenyl, 5-12 member heteroaryl, -OR 1f , -SO2R 1f -SO2NR 1f R 1g , -COR 1f , -CO2R 1f ,-CONR 1f R 1g , -NR 1f R 1g , -NR 1f COR 1g , -NR 1f CO2R 1g , -NR 1f SO2R 1g , oxo, or -CN, and the aforementioned methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C3~C 12 Each of the cycloalkenyl, 3-12 member heterocyclyl, phenyl, and 5-12 member heteroaryl has at least one substituent R 1h It is arbitrarily replaced with, R 1f and R 1gHowever, each of the following is independently selected from hydrogen, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-12 member heterocyclyl, phenyl, or 5-12 member heteroaryl, and each of the above methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-12 member heterocyclyl, phenyl, or 5-12 member heteroaryl has at least one substituent R 1i It is arbitrarily replaced with, R 1h and R 1i However, each is independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C3~C 12 Cycloalkenyl, 3-12 member heterocyclyl, phenyl, 5-12 member heteroaryl, -OR 1j , -SO2R 1j -SO2NR 1j R 1k , -COR 1j , -CO2R 1j ,-CONR 1j R 1k , -NR 1j R 1k , -NR 1j COR 1k , -NR 1j CO2R 1k , -NR 1j SO2R 1k, oxo, or -CN, and the aforementioned methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C3~C 12 Each of the cycloalkenyl, 3-12 member heterocyclyl, phenyl, and 5-12 member heteroaryl has at least one substituent -F, -Cl, -Br, -I, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2~8 Alkenyl, -C 2~8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, 5-12 membered heteroaryl, -CN, -OH, -NH2 or oxo optionally substituted, R 1j and R 1k However, each is independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-12 member heterocyclyl, phenyl, and 5-12 member heteroaryl. Each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-12 member heterocyclyl, phenyl, and 5-12 member heteroaryl compounds has at least one substituent -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2~8 Alkenyl, -C 2~8A compound according to any one of the prior embodiments, optionally substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, 5-12 membered heteroaryl, -CN, -OH, -NH2, or oxo.

[0030] Appearance 10.R 1 and R 2However, hydrogen, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, chromanil, isochromanil, dihydropyranopyridinyl (preferably 5,8-dihydro-6H-pyrano[3,4-b]pyridinyl, 3,4-dihydro-2H-pyrano[3,2-b]pyridinyl, or 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl) ), pyrimidinil, tetrahydro-2H-pyranil, pyridadinil, pyrazinil, dihydroflopyridinil (preferably 2,3-dihydroflop[2,3-b]pyridinil), tetrahydronaphthalenil (preferably 1,2,3,4-tetrahydronaphthalenil), benzo[d]thiazolyl, triazolyl (preferably 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl), pyridinil, quinolinil, isoquinolinil, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranil, Each of the following is independently selected from tetrahydroquinolinyl, tetrahydronaphthyl, dihydrophlopyridinyl, or tetrahydrophlopyridinyl: methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, chromanil, isochromanil, dihydropyranopyridinyl (preferably 5,8-dihydro-6H-pyrano[3,4-b]pyridinyl (Nyl, 3,4-dihydro-2H-pyrano[3,2-b]pyridine or 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl), pyrimidinyl, tetrahydro-2H-pyranyl, pyridadinyl, pyrazinyl, dihydroflopyridinyl (preferably 2,3-dihydroflopyridinyl), tetrahydronaphthalenyl (preferably 1,2,3,4-tetrahydronaphthalenyl), benzo[d]thiazolyl, triazolyl (preferably 1H-1,2,4-triazolyl, 4H-1,2,Each of the following substituents (4-triazolyl), pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrophlopyridinyl, or tetrahydrophlopyridinyl) has at least one substituent R, 1a It can be arbitrarily replaced with, or R 1 and R 2 However, together with the nitrogen atoms bonded to them, they form a 3, 4, 5, 6, 7, or 8-membered unsaturated or saturated ring, wherein the ring contains 0, 1, 2, or 3 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the ring has at least one substituent R 1a It is arbitrarily replaced with, R 1a However, independently, hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, chromanil, isochromanil, dihydropyranopyridinyl (preferably 5,8-dihydro-6H-pyrano[3,4-b]pyridinyl, 3,4-dihydro-2H-pyrano[3,2-b]pyridinyl, or 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl), pyrimidi Nyl, tetrahydro-2H-pyranil, pyridadinil, pyrazinil, dihydroflopyridinil (preferably 2,3-dihydroflop[2,3-b]pyridinil), tetrahydronaphthalenil (preferably 1,2,3,4-tetrahydronaphthalenil), benzo[d]thiazolyl, triazolyl (preferably 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl), pyridinil, quinolinil, isoquinolinil, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranil, tetrahydroquinolinil, tetrahydronaphthyl, tetrahydroflopyridinil, -OR 1b , -SO2R 1b -SO2NR 1b R 1c , -COR 1b , -CO2R 1b ,-CONR1b R 1c , -NR 1b R 1c , -NR 1b COR 1c , -NR 1b CO2R 1c , -NR 1b SO2R 1c , oxo, or -CN, and the aforementioned methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, chromanil, isochromanil, dihydropyranopyridine (preferably 5,8-dihydro-6H-pyrano[3,4-b]pyridinyl, 3,4-dihydro-2H-pyrano[3,2-b]pyridinyl, or 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl), pyrimidinil, tetrahydro-2H-pyranil Each of pyridadinyl, pyrazinyl, dihydroflopyridinyl (preferably 2,3-dihydroflop[2,3-b]pyridinyl), tetrahydronaphthalenyl (preferably 1,2,3,4-tetrahydronaphthalenyl), benzo[d]thiazolyl, triazolyl (preferably 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl), pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydroflopyridinyl, or tetrahydroflopyridinyl has at least one substituent R 1d It can be arbitrarily replaced with, or 2 R 1a However, together with the atom(s) to which they are bonded, they form a 3, 4, 5, or 6-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 has at least one substituent R 1d It is arbitrarily replaced with, R 1b and R 1cHowever, hydrogen, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, chromanil, isochromanil, dihydropyranopyridinyl (preferably 5,8-dihydro-6H-pyrano[3,4-b]pyridinyl, 3,4-dihydro-2H-pyrano[3,2-b]pyridine or 7,8-dihydro- 5H-pyrano[4,3-b]pyridinyl), pyrimidinyl, tetrahydro-2H-pyranyl, pyridadinyl, pyrazinyl, dihydroflopyridinyl (preferably 2,3-dihydroflopyridinyl), tetrahydronaphthalenyl (preferably 1,2,3,4-tetrahydronaphthalenyl), benzo[d]thiazolyl, triazolyl (preferably 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl), pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, Each of the following is independently selected from tetrahydroquinolinyl, tetrahydronaphthyl, dihydrophlopyridinyl, or tetrahydrophlopyridinyl: methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, chromanil, isochromanil, dihydropyranopyridinyl (preferably 5,8-dihydro Ro-6H-pyrano[3,4-b]pyridinyl, 3,4-dihydro-2H-pyrano[3,2-b]pyridinyl or 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl), pyrimidinyl, tetrahydro-2H-pyranyl, pyridadinyl, pyrazinyl, dihydroflopyridinyl (preferably 2,3-dihydroflopyridinyl), tetrahydronaphthalenyl (preferably 1,2,3,4-tetrahydronaphthalenyl), benzo[d]thiazolyl, triazolyl (preferably 1H-1,2,4-triazolyl, 4H-1,2Each of the following substituents (4-triazolyl), pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrophlopyridinyl, or tetrahydrophlopyridinyl) has at least one substituent R, 1e It is arbitrarily replaced with, R 1d and R 1e However, each is independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), phenyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, chromanil, isochromanil, dihydropyranopyridinyl (preferably 5,8-dihydro-6H-pyrano[3,4-b]pyridinyl, 3,4-dihydro-2H-pyrano[3,2-b]pyridinyl, or 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl), pyrimidinyl, tert Rahydro-2H-pyranyl, pyridadinyl, pyrazinyl, dihydroflopyridinyl (preferably 2,3-dihydroflop[2,3-b]pyridinyl), tetrahydronaphthalenyl (preferably 1,2,3,4-tetrahydronaphthalenyl), benzo[d]thiazolyl, triazolyl (preferably 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl), pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydroflopyridinyl, tetrahydroflopyridinyl, -OR 1f , -SO2R 1f , -COR 1f , -CO2R 1f ,-CONR 1f R 1g , -NR 1f R 1g , -NR 1f COR 1g , -NR 1f CO2R 1g, oxo, or -CN, and the aforementioned methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, chromanil, isochromanil, dihydropyranopyridine (preferably 5,8-dihydro-6H-pyrano[3,4-b]pyridinyl, 3,4-dihydro-2H-pyrano[3,2-b]pyridinyl, or 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl), pyrimidinil, tetrahydro-2H-pyranil Each of pyridadinyl, pyrazinyl, dihydroflopyridinyl (preferably 2,3-dihydroflop[2,3-b]pyridinyl), tetrahydronaphthalenyl (preferably 1,2,3,4-tetrahydronaphthalenyl), benzo[d]thiazolyl, triazolyl (preferably 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl), pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydroflopyridinyl, or tetrahydroflopyridinyl has at least one substituent R 1h It is arbitrarily replaced with, R 1f and R 1gHowever, hydrogen, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, chromanil, isochromanil, dihydropyranopyridinyl (preferably 5,8-dihydro-6H-pyrano[3,4-b]pyridinyl, 3,4-dihydro-2H-pyrano[3,2-b]pyridine or 7,8-dihydro- 5H-pyrano[4,3-b]pyridinyl), pyrimidinyl, tetrahydro-2H-pyranyl, pyridadinyl, pyrazinyl, dihydroflopyridinyl (preferably 2,3-dihydroflopyridinyl), tetrahydronaphthalenyl (preferably 1,2,3,4-tetrahydronaphthalenyl), benzo[d]thiazolyl, triazolyl (preferably 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl), pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, Each of the following is independently selected from tetrahydroquinolinyl, tetrahydronaphthyl, dihydrophlopyridinyl, or tetrahydrophlopyridinyl: methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, chromanil, isochromanil, dihydropyranopyridinyl (preferably 5,8-dihydro Ro-6H-pyrano[3,4-b]pyridinyl, 3,4-dihydro-2H-pyrano[3,2-b]pyridinyl or 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl), pyrimidinyl, tetrahydro-2H-pyranyl, pyridadinyl, pyrazinyl, dihydroflopyridinyl (preferably 2,3-dihydroflopyridinyl), tetrahydronaphthalenyl (preferably 1,2,3,4-tetrahydronaphthalenyl), benzo[d]thiazolyl, triazolyl (preferably 1H-1,2,4-triazolyl, 4H-1,2Each of the following substituents (4-triazolyl), pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrophlopyridinyl, or tetrahydrophlopyridinyl) has at least one substituent R, 1i It is arbitrarily replaced with, R 1h and R 1i However, each is independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, chromanil, isochromanil, dihydropyranopyridinyl (preferably 5,8-dihydro-6H-pyrano[3,4-b]pyridinyl, 3,4-dihydro-2H-pyrano[3,2-b]pyridinyl, or 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl) Pyrimidinyl, tetrahydro-2H-pyranil, pyridadinyl, pyrazinyl, dihydroflopyridinyl (preferably 2,3-dihydroflop[2,3-b]pyridinyl), tetrahydronaphthalenyl (preferably 1,2,3,4-tetrahydronaphthalenyl), benzo[d]thiazolyl, triazolyl (preferably 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl), pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranil, tetrahydroquinolinyl, tetrahydronaphthyl, dihydroflopyridinyl, tetrahydroflopyridinyl, -OR 1j , -COR 1j , -CO2R 1j ,-CONR 1j R 1k , -NR 1j R 1k , -NR 1j COR 1k , -NR 1j CO2R 1k, oxo, or -CN, and the aforementioned methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, chromanil, isochromanil, dihydropyranopyridinyl (preferably 5,8-dihydro-6H-pyrano[3,4-b]pyridinyl, 3,4-dihydro-2H-pyrano[3,2-b]pyridinyl, or 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl), pyrimidinyl, tetrahydro-2H-pyranil, pyridadinyl, pyrazinyl, dihydroflopyridinyl (preferably 2,3-dihydroflopyridinyl), tetrahydro Each of the following compounds may have at least one substituent: ronaphthalenyl (preferably 1,2,3,4-tetrahydronaphthalenyl), benzo[d]thiazolyl, triazolyl (preferably 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl), pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrophlopyridinyl, or tetrahydrophlopyridinyl, -F, -Cl, -Br, -I, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2~8 Alkenyl, -C 2~8 Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrophlopyridinyl, tetrahydrophlopyridinyl, optionally substituted with -CN, -OH, -NH2 or oxo, R 1j and R 1kHowever, hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, chromanil, isochromanil, dihydropyranopyridinyl (preferably 5,8-dihydro-6H-pyrano[3,4-b]pyridinyl, 3,4-dihydro-2H-pyrano[3,2-b]pyridinyl, or 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl), pyrimidinyl tetrahydro-2H-pyranyl, pyridadinyl, pyrazinyl, dihydroflopyridinyl (preferably 2,3-dihydroflop[2,3-b]pyridinyl), tetrahydronaphthalenyl (preferably 1,2,3,4-tetrahydronaphthalenyl), benzo[d]thiazolyl, triazolyl (preferably 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl), pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, Each of the following is independently selected from tetrahydroquinolinyl, tetrahydronaphthyl, dihydrophlopyridinyl, or tetrahydrophlopyridinyl: methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, chromanil, isochromanil, dihydropyranopyridinyl (preferably 5,8-dihydro-6H-pyrano[3,4-b]pyridinyl, 3,4-di Hydro-2H-pyrano[3,2-b]pyridine or 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl), pyrimidinyl, tetrahydro-2H-pyranyl, pyridadinyl, pyrazinyl, dihydroflopyridinyl (preferably 2,3-dihydroflopyridinyl), tetrahydronaphthalenyl (preferably 1,2,3,4-tetrahydronaphthalenyl), benzo[d]thiazolyl, triazolyl (preferably 1H-1,2,4-triazolyl, 4H-1,2Each of the following (4-Triazolyl), pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrophlopyridinyl, or tetrahydrophlopyridinyl) has at least one substituent -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C, 2~8 Alkenyl, -C 2~8 Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrophlopyridinyl, tetrahydrophlopyridinyl, optionally substituted with -CN, -OH, -NH2 or oxo, Preferably, R 1 and R 2However, hydrogen, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, chromanil, isochromanil, dihydropyranopyridinyl (preferably 5,8-dihydro-6H-pyrano[3,4-b]pyridinyl, 3,4-dihydro-2H-pyrano[3,2-b]pyridinyl, or 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl) ), pyrimidinil, tetrahydro-2H-pyranil, pyridadinil, pyrazinil, dihydroflopyridinil (preferably 2,3-dihydroflop[2,3-b]pyridinil), tetrahydronaphthalenil (preferably 1,2,3,4-tetrahydronaphthalenil), benzo[d]thiazolyl, triazolyl (preferably 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl), pyridinil, quinolinil, isoquinolinil, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranil, Each of the following is independently selected from tetrahydroquinolinyl, tetrahydronaphthyl, dihydrophlopyridinyl, or tetrahydrophlopyridinyl: methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, chromanil, isochromanil, dihydropyranopyridinyl (preferably 5,8-dihydro-6H-pyrano[3,4-b]pyridinyl (Nyl, 3,4-dihydro-2H-pyrano[3,2-b]pyridine or 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl), pyrimidinyl, tetrahydro-2H-pyranyl, pyridadinyl, pyrazinyl, dihydroflopyridinyl (preferably 2,3-dihydroflopyridinyl), tetrahydronaphthalenyl (preferably 1,2,3,4-tetrahydronaphthalenyl), benzo[d]thiazolyl, triazolyl (preferably 1H-1,2,4-triazolyl, 4H-1,2,Each of the following substituents (4-triazolyl), pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrophlopyridinyl, or tetrahydrophlopyridinyl) has at least one substituent R, 1a It can be arbitrarily replaced with, or R 1 and R 2 However, together with the nitrogen atoms bonded to them, they form a 3, 4, 5, 6, 7, or 8-membered unsaturated or saturated ring, wherein the ring contains 0, 1, 2, or 3 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the ring has at least one substituent R 1a It is arbitrarily replaced with, R 1a However, independently, hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, chromanil, isochromanil, dihydropyranopyridinyl (preferably 5,8-dihydro-6H-pyrano[3,4-b]pyridinyl, 3,4-dihydro-2H-pyrano[3,2-b]pyridinyl, or 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl), pyrimidinyl, tetrahydro-2H-pyranil, pyrida Dinyl, pyrazinyl, dihydroflopyridinyl (preferably 2,3-dihydroflop[2,3-b]pyridinyl), tetrahydronaphthalenyl (preferably 1,2,3,4-tetrahydronaphthalenyl), benzo[d]thiazolyl, triazolyl (preferably 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl), pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranil, tetrahydroquinolinyl, tetrahydronaphthyl, dihydroflopyridinyl (preferably 2,3-dihydroflop[2,3-b]pyridinyl), tetrahydroflopyridinyl, -OR 1bor -CN, and the methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, chromanil, isochromanil, dihydropyranopyridinyl (preferably 5,8-dihydro-6H-pyrano[3,4-b]pyridinyl, 3,4-dihydro-2H-pyrano[3,2-b]pyridinyl, or 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl), pyrimidinyl, tetrahydro-2H-pyranil, py Each of lidazinyl, pyrazinyl, dihydroflopyridinyl (preferably 2,3-dihydroflop[2,3-b]pyridinyl), tetrahydronaphthalenyl (preferably 1,2,3,4-tetrahydronaphthalenyl), benzo[d]thiazolyl, triazolyl (preferably 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl), pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydroflopyridinyl, or tetrahydroflopyridinyl has at least one substituent R 1d It can be arbitrarily replaced with, or 2 R 1a However, together with the atom(s) to which they are bonded, they form a 3, 4, 5, or 6-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 has at least one substituent R 1d It is arbitrarily replaced with, R 1b However, each is independently hydrogen, methyl, ethyl, propyl (isopropyl or n-propyl), cyclopropyl, or cyclobutyl. R 1dHowever, each is independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, chromanil, isochromanil, dihydropyranopyridinyl (preferably 5,8-dihydro-6H-pyrano[3,4-b]pyridinyl, 3,4-dihydro-2H-pyrano[3,2-b]pyridinyl, or 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl), pyrimidinyl, teto Rahydro-2H-pyranyl, pyridadinyl, pyrazinyl, dihydroflopyridinyl (preferably 2,3-dihydroflop[2,3-b]pyridinyl), tetrahydronaphthalenyl (preferably 1,2,3,4-tetrahydronaphthalenyl), benzo[d]thiazolyl, triazolyl (preferably 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl), pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydroflopyridinyl, tetrahydroflopyridinyl, -OR 1f , -NR 1f R 1g , -NR 1f COR 1g , oxo, -SO2R 1for -CN, and the methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, chromanil, isochromanil, dihydropyranopyridinyl (preferably 5,8-dihydro-6H-pyrano[3,4-b]pyridinyl, 3,4-dihydro-2H-pyrano[3,2-b]pyridinyl, or 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl), pyrimidinyl, tetrahydro-2H-pyranil, py Each of lidazinyl, pyrazinyl, dihydroflopyridinyl (preferably 2,3-dihydroflop[2,3-b]pyridinyl), tetrahydronaphthalenyl (preferably 1,2,3,4-tetrahydronaphthalenyl), benzo[d]thiazolyl, triazolyl (preferably 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl), pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydroflopyridinyl, or tetrahydroflopyridinyl has at least one substituent R 1h It is arbitrarily replaced with, R 1f and R 1gHowever, hydrogen, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, chromanil, isochromanil, dihydropyranopyridinyl (preferably 5,8-dihydro-6H-pyrano[3,4-b]pyridinyl, 3,4-dihydro-2H-pyrano[3,2-b]pyridine, or 7,8-dihydro-5H-pyrano[4,3-b] Pyridinyl), pyrimidinyl, tetrahydro-2H-pyranyl, pyridadinyl, pyrazinyl, dihydroflopyridinyl (preferably 2,3-dihydroflop[2,3-b]pyridinyl), tetrahydronaphthalenyl (preferably 1,2,3,4-tetrahydronaphthalenyl), benzo[d]thiazolyl, triazolyl (preferably 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl), pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, Each of the following is independently selected from tetrahydroquinolinyl, tetrahydronaphthyl, dihydrophlopyridinyl, or tetrahydrophlopyridinyl: methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, chromanil, isochromanil, dihydropyranopyridinyl (preferably 5,8-dihydro-6H-pyrano[3,4- b)pyridinyl, 3,4-dihydro-2H-pyrano[3,2-b]pyridinyl or 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl), pyrimidinyl, tetrahydro-2H-pyranyl, pyridadinyl, pyrazinyl, dihydroflopyridinyl (preferably 2,3-dihydroflop[2,3-b]pyridinyl), tetrahydronaphthalenyl (preferably 1,2,3,4-tetrahydronaphthalenyl), benzo[d]thiazolyl, triazolyl (preferably 1H-1,2,4-triazolyl, 4H-1,2,Each of the following substituents (4-triazolyl), pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrophlopyridinyl, or tetrahydrophlopyridinyl) has at least one substituent R, 1i It is arbitrarily replaced with, R 1h and R 1i However, each is independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, chromanil, isochromanil, dihydropyranopyridinyl (preferably 5,8-dihydro-6H-pyrano[3,4-b]pyridinyl, 3,4-dihydro-2H-pyrano[3,2-b]pyridinyl, or 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl), pyrimidinyl, tetrahydro-2 H-pyranyl, pyridadinyl, pyrazinyl, dihydroflopyridinyl (preferably 2,3-dihydroflopyridinyl [2,3-b]pyridinyl), tetrahydronaphthalenyl (preferably 1,2,3,4-tetrahydronaphthalenyl), benzo[d]thiazolyl, triazolyl (preferably 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl), pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydroflopyridinyl, tetrahydroflopyridinyl, -OH, or -CN. Comfortable, R 1 and R 2However, hydrogen, methyl, ethyl, propyl (isopropyl or n-propyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, chromanil, isochromanil, dihydropyranopyridinyl (preferably 5,8-dihydro-6H-pyrano[3,4-b]pyridinyl, 3,4-dihydro-2H-pyrano[3,2-b]pyridinyl, or 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl), pyrimidinyl, tetrahydro-2H-pyrinopyridinyl Ranyl, pyridazinyl, pyrazinyl, dihydroflopyridinyl (preferably 2,3-dihydroflop[2,3-b]pyridinyl), tetrahydronaphthalenyl (preferably 1,2,3,4-tetrahydronaphthalenyl), benzo[d]thiazolyl, pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranil, tetrahydroquinolinyl, tetrahydronaphthyl, dihydroflopyridinyl or tetrahydroflopyridyl Each of the following is independently selected from nyl: methyl, ethyl, propyl (isopropyl or n-propyl), phenyl, chromanil, isochromanil, dihydropyranopyridinyl (preferably 5,8-dihydro-6H-pyrano[3,4-b]pyridinyl, 3,4-dihydro-2H-pyrano[3,2-b]pyridinyl, or 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl), pyrimidinyl, tetrahydro-2H-pyranyl, pyridadinyl, pyrazinyl, dihy Each of droflopyridinyl (preferably 2,3-dihydroflop[2,3-b]pyridinyl), tetrahydronaphthalenyl (preferably 1,2,3,4-tetrahydronaphthalenyl), benzo[d]thiazolyl, pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydroflopyridinyl, or tetrahydroflopyridinyl has at least one substituent R 1a It can be arbitrarily replaced with, or R 1 and R 2 However, together with the nitrogen atom to which they are bonded, they form a 6-membered unsaturated or saturated ring, and the ring has at least one substituent R 1a It is arbitrarily replaced with, R1a However, independently, hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (isopropyl or n-propyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrimidinyl, pyridadinyl, pyrazinyl, dihydroflopyridinyl (preferably 2,3-dihydroflopyridinyl), benzo[d]thiazolyl, pyridinyl, quinolinyl, isoquinolinyl, thiazolyl, -OR 1b or -CN, and each of the methyl, ethyl, propyl (isopropyl or n-propyl), phenyl, pyrimidinyl, pyridadinyl, pyrazinyl, dihydroflopyridinyl (preferably 2,3-dihydroflop[2,3-b]pyridinyl), benzo[d]thiazolyl, pyridinyl, quinolinyl, isoquinolinyl, or thiazolyl has at least one substituent R 1d It is arbitrarily replaced with, R 1b However, each is independently hydrogen, methyl, ethyl, propyl (isopropyl or n-propyl), cyclopropyl, or cyclobutyl. R 1d However, each independently is hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), phenyl, pyrimidinyl, tetrahydro-2H-pyranyl, pyridadinyl, pyrazinyl, triazolyl (preferably 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl), pyridinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrophlopyridinyl, tetrahydrophlopyridinyl, -OR 1f , -SO2R 1for -CN, and each of the methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), phenyl, pyrimidinyl, tetrahydro-2H-pyranyl, pyridadinyl, pyrazinyl, triazolyl (preferably 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl), pyridinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrophlopyridinyl, or tetrahydrophlopyridinyl has at least one substituent R 1h It is arbitrarily replaced with, R 1f However, each of the following is independently selected from hydrogen, methyl, ethyl, propyl (isopropyl or n-propyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or phenyl, and each of the methyl, ethyl, propyl (isopropyl or n-propyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or phenyl has at least one substituent R 1i It is arbitrarily replaced with, R 1h and R 1i The compound according to any one of the prior art, wherein each of the elements is independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -OH, or -CN.

[0031] Appearance 11.R 1 and R 2 However, -C 1~8 Alkyl, -C3~C8 cycloalkyl, -C3~C 12 A cycloalkenyl and a 3-12 membered heterocyclyl are independently selected, and the -C 1~8 Alkyl, -C3~C8 cycloalkyl, -C3~C 12 Each of the cycloalkenyl and 3-12 membered heterocyclyl has at least one substituent R 1aIt can be arbitrarily replaced with, or R 1 and R 2 However, together with the nitrogen atom to which they are bonded, they form a 3- to 8-membered unsaturated or saturated ring, the ring containing 0 to 3 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the ring having at least one substituent R 1a It is arbitrarily replaced with, R 1a However, hydrogen, halogen, deuterium, and -C are produced independently. 1~8 Alkyl, -C3~C8 cycloalkyl, -C6~C 12 Aryl, 5-12 member heteroaryl, -OR 1b Alternatively, -CN, and the aforementioned -C 1~8 Alkyl, -C3~C8 cycloalkyl, -C6~C 12 Each of the aryl and 5-12 member heteroaryl has at least one substituent R 1d It can be arbitrarily replaced with, or 2 R 1a However, together with the atom(s) to which they are bonded, they form a 3- to 8-membered unsaturated or saturated ring, and the ring contains 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the ring contains at least one substituent R 1d It is arbitrarily replaced with, R 1b However, hydrogen, -C 1~8 Each alkyl is independently selected, and the -C 1~8 The alkyl group has at least one substituent R 1e It is arbitrarily replaced with, R 1d and R 1e However, each is independently hydrogen, halogen, and -C 1~8 Alkyl, -C3~C8 cycloalkyl, -C6~C 12 Aryl, 5-12 member heteroaryl, -OR 1f , -SO2R 1f or -CN, and the -C 1~8 Alkyl, -C6~C 12 Each of the aryl and 5-12 member heteroaryl has at least one substituent R 1h It is arbitrarily replaced with, R1f However, hydrogen, -C 1~8 Alkyl and -C3~C8 cycloalkyl are independently selected, and the -C 1~8 Each of the alkyl and -C3~C8 cycloalkyl groups has at least one substituent R 1i It is arbitrarily replaced with, R 1h and R 1i However, each is independently hydrogen, halogen, and -C 1~8 Alkyl or -CN, Preferably, R 1 and R 2 However, each is independently selected from methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, chromanil, isochromanil, pyridinyl, quinolinil, isoquinolinil, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranil, tetrahydroquinolinil, tetrahydronaphthyl, dihydrophlopyridinyl, or tetrahydrophlopyridinyl, and the above Each of methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, chromanil, isochromanil, pyridinyl, quinolinil, isoquinolinil, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranil, tetrahydroquinolinil, tetrahydronaphthyl, dihydrophlopyridinyl, or tetrahydrophlopyridinyl has at least one substituent R 1a It can be arbitrarily replaced with, or R 1 and R 2 However, together with the nitrogen atoms bonded to them, they form a 3, 4, 5, 6, 7, or 8-membered unsaturated or saturated ring, wherein the ring contains 0, 1, 2, or 3 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the ring has at least one substituent R 1a It is arbitrarily replaced with, R 1aHowever, independently, hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridinyl, pyrimidinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydroflopyridinyl (preferably 2,3-dihydroflopyridinyl), tetrahydroflopyridinyl, -OR 1b or -CN, and each of the methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridinyl, pyrimidinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrophlopyridinyl, or tetrahydrophlopyridinyl has at least one substituent R 1d It can be arbitrarily replaced with, or 2 R 1a However, together with the atom(s) to which they are bonded, they form a 3, 4, 5, or 6-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 has at least one substituent R 1d It is arbitrarily replaced with, R 1b each of the following is independently selected from hydrogen, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl and octyl, and each of the methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl and octyl has at least one substituent R 1e It is arbitrarily replaced with, R1d and R 1e However, each is independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrophlopyridinyl, tetrahydrophlopyridinyl, -OR 1f , -SO2R 1f or -CN, and each of the methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, phenyl, pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrophlopyridinyl, or tetrahydrophlopyridinyl has at least one substituent R 1h It is arbitrarily replaced with, R 1f However, each of the following is independently selected from hydrogen, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, and each of the above methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl has at least one substituent R 1i It is arbitrarily replaced with, R 1h and R 1iThe compound according to any one of the prior arts, wherein each is independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, or -CN.

[0032] Appearance 12.R 1 and R 2 However, -Me, -Et, -Pr (-nPr or -isoPr), -Bu [ka] Pentil [ka] -CF3, -CH2CF3, [ka] [ka] [ka] [ka] [ka] [ka] They are either selected independently from each other, or R 1 and R 2 However, along with the nitrogen atoms to which they are bonded, [ka] A compound according to any one of the prior embodiments, which forms a compound.

[0033] Embodiment 13. The compound according to any one of the prior embodiments, wherein L is a single bond.

[0034] Appearance 13'.R 1a However, hydrogen, methyl, ethyl, propyl, halo, methyl substituted with one or more halos, C 3~5 A cycloalkyl group, or one independently selected from -CN, or two R groups bonded to the same atom. 1a However, C 3~5 A cycloalkyl group is formed, preferably R 1a However, either hydrogen, methyl, ethyl, -F, -Cl, -Br, -I, -CF3, cyclopropyl, or -CN is independently selected, or two R atoms bonded to the same atom. 1a The compound according to any one of the prior embodiments, wherein it forms a cyclopropyl group.

[0035] Appearance 13''.R 1d However, hydrogen, halo, C 1~4 Alkyl, C substituted with one or more halos 1~4 alkyl, -OH substituted C 1~4 Alkyl, -OC 1~4 Alkyl, -OC substituted with one or more halos 1~4 C optionally substituted with alkyl or fluoro groups 3~5 Cycloalkyl, -SO2-C 1~4 Independently selected from alkyl or -CN, preferably R 1d The compound according to any one of the prior embodiments, wherein the compound is selected from hydrogen, -F, -Br, -Cl, -I, methyl, ethyl, propyl, butyl, -CF3, hydroxypropyl, methoxy, trifluoromethoxy, cyclopropyl, fluorocyclopropyl, cyclobutyl, -SO2CH3, or -CN.

[0036] Appearance 13'''.R 2 C 1~8 It is alkyl, preferably R 2 is methyl, ethyl, propyl (isopropyl or n-propyl), or butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), and more preferably R 2is methyl, ethyl, or propyl (isopropyl or n-propyl), and more preferably R 2 A compound according to any one of the prior art embodiments, wherein the compound is methyl.

[0037] Appearance 14.R 3 The following are selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -CN, -OH, or -NH2, and the aforementioned methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclo Each of butyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl is optionally substituted with at least one substituent selected from -F, -Cl, -Br, -I, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or 3- to 8-membered heterocyclines. Preferably, R 3 However, it is selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -CN, -OH or -NH2, Comfortable, R 3However, it is selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -CN, -OH, Furthermore, R 3 However, it is selected from hydrogen, -F, -Cl, methyl, ethyl, propyl (isopropyl or n-propyl), and butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), Furthermore, R 3 A compound according to any one of the prior art embodiments, wherein hydrogen is selected.

[0038] Appearance 15.R 4 , R 5 , R 6 , R 7 , R 8 and R 9However, each is independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, and the aforementioned methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, Each of cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl is -F, -Cl, -Br, -I, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 member heterocyclyl, phenyl, 5-12 member heteroaryl, oxo, -CN, -OR 4a , -SO2R 4a -SO2NR 4a R 4b , -COR 4a , -CO2R 4a ,-CONR 4a R 4b , -NR 4a R 4b , -NR 4a COR 4b , -NR 4a CO2R 4b , or -NR 4a SO2R 4b Optionally substituted with at least one substituent selected from, R 4a and R 4bHowever, each is independently hydrogen, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 member heterocyclyl, phenyl, or 5-12 member heteroaryl, and the aforementioned methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, Each of hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl is at least one -F, -Cl, -Br, -I, -OH, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-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 Optionally substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl, Preferably, R 4 , R 5 , R 6 , R 7 , R 8 and R 9 However, each is independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl. Comfortable, R 4 , R5 , R 6 , R 7 , R 8 and R 9 However, each is independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (isopropyl or n-propyl), cyclopropyl, and cyclobutyl. Furthermore, R 4 , R 5 , R 6 , R 7 , R 8 and R 9 The compound according to any one of the prior arts, wherein each is independently selected from hydrogen, -F, -Cl, -Br, -I, and methyl.

[0039] Appearance 15'. Compound of formula (VIIIp): [ka] or its N-oxide, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, or deuterated analog thereof, or its N-oxide, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a deuterated analog thereof, wherein in the formula, R 1a ' is independently selected from hydrogen, methyl, or ethyl, R 1a Is '' hydrogen, or R 1a 'and R 1a '' along with the atoms to which they are bonded, C 3~5 Forming a cycloalkyl group, n5' is 0, 1, or 2. R 1a , R 2 , R 6 , and R 7 However, the compound, or its N-oxide, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, or deuterated analog thereof, as defined in any one of the prior embodiments.

[0040] In one embodiment: R 1a This is a halo, a methyl molecule substituted with one or more halos, C 3~5 Independently selected from cycloalkyl or -CN, preferably -F, -Cl, -Br, -I, -CF3, cyclopropyl or -CN, R 2 is C 1~8 It is alkyl, preferably methyl, R 6 is hydrogen or methyl, preferably hydrogen. R 7 It is hydrogen.

[0041] Appearance 15''. Compound of formula (VIIr): [ka] Or its N-oxide, or a pharmaceutically acceptable salt thereof, or its stereoisomer, or its tautomer, or its deuterated analog, wherein Y' is N or C(R 1d ) and R 1a , R 1d , R 2 , R 6 , and R 7 However, the compound, or its N-oxide, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a deuterated analog thereof, as defined in any one of the prior art.

[0042] In one embodiment: R 1a is hydrogen or methyl, R 1d C is optionally substituted with hydrogen, halo, methyl or fluoro, or methyl with one or more halos. 3~5 Independently selected from cycloalkyl or -CN, preferably hydrogen, -F, -Br, -I, -CF3, cyclopropyl, fluorocyclopropyl, cyclobutyl or -CN, R 2 is C 1~8It is an alkyl group, preferably methyl, ethyl, or propyl. R 6 is hydrogen or methyl, R 7 It is hydrogen.

[0043] In one embodiment, Y' is N. In one embodiment, Y' is C(R 1d )

[0044] Embodiment 16. The compound is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] A compound according to any one of the prior art, selected from the above.

[0045] Embodiment 17. A pharmaceutical composition comprising a compound described in any one of Embodiments 1 to 16, or its N-oxide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analog thereof, and a pharmaceutically acceptable excipient.

[0046] In one embodiment, the pharmaceutical composition is for use as described herein, for example, in any one of embodiments 18 to 22.

[0047] Embodiment 18. A method for reducing or inhibiting PRMT5 activity, comprising administering an effective amount of a compound according to any one of Embodiments 1 to 16, or its N-oxide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analog thereof, to a subject requiring such reduction.

[0048] Aspect 19. A method for treating a disease regulated by PRMT5, comprising administering an effective amount of a compound according to any one of Aspects 1 to 16, or its N-oxide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analog thereof, to a subject in need thereof.

[0049] Embodiment 20. Use of the compound described in any one of Embodiments 1 to 16, or its N-oxide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analog thereof, in the preparation of a pharmaceutical for treating a disease modulated by PRMT5.

[0050] Embodiment 21. The method according to Embodiment 19 or the use according to Embodiment 20, wherein the disease is cancer.

[0051] Embodiment 22. The method according to Embodiment 19 or the use according to Embodiment 20, wherein the disease is an MTAP-null solid tumor, including lung cancer, bladder cancer, melanoma, pancreatic cancer, esophageal cancer, gastric adenocarcinoma, breast cancer, and glioblastoma. [Modes for carrying out the invention]

[0052] The following terms have the meanings set forth throughout this specification:

[0053] Unless otherwise defined elsewhere in this specification, all other technical and scientific terms used herein have meanings that are generally understood by those skilled in the art to which the present invention pertains.

[0054] The following terms have the meanings set forth throughout this specification:

[0055] As used herein, including in the attached claims, singular words such as "a," "an," and "the" refer to multiple objects corresponding to them unless the context clearly indicates otherwise.

[0056] The term "or" means "and / or" and is used interchangeably unless the context explicitly indicates otherwise.

[0057] The term "alkyl" includes hydrocarbon groups selected from linear and branched saturated hydrocarbon groups containing 1 to 18 carbon atoms, for example, 1 to 12, even 1 to 10, even 1 to 8, or 1 to 6, or 1 to 4 carbon atoms. 1~6 Examples of alkyl groups 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. If there is no opposite definition, then "C 1~8 "Alkyl" refers to a hydrocarbon group selected from linear and branched saturated hydrocarbon groups containing 1 to 8 carbon atoms, and "C 1~8 "Alkyl" also refers to a group of 1 to 6 carbon atoms (C 1~6 Alkyl) or 1 to 4 carbon atoms (C 1~4This also includes hydrocarbon groups selected from linear and branched saturated hydrocarbon groups, including alkyl groups.

[0058] The term "propyl" includes 1-propyl or n-propyl ("n-Pr"), and 2-propyl or isopropyl ("i-Pr").

[0059] The term "butyl" includes 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or s-butyl ("s-Bu"), and 1,1-dimethylethyl or t-butyl ("t-Bu").

[0060] The term "pentyl" includes 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, and 2-methyl-1-butyl. The term "pentyl" is [ka] It also includes.

[0061] The term "hexyl" includes 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.

[0062] The term "alkylene" refers to a group containing a divalent alkyl group, formed by removing two hydrogen atoms from an alkane. Alkylenes include, but are not limited to, methylene, ethylene, and propylene.

[0063] The term "halogen" includes fluoro(F), chloro(Cl), bromo(Br), and iodine(I).

[0064] The terms "H" or "hydrogen" as disclosed herein include hydrogen and non-radioactive isotope hydrogen.

[0065] The term "alkenyl" includes hydrocarbon groups selected from linear and branched hydrocarbon groups, which include at least one C=C double bond and 2 to 18 carbon atoms, for example, 2 to 8 carbon atoms, and further, for example, 2 to 6 carbon atoms. Alkenyl groups, for example, C 2-6 Examples of alkenyls include, but are not limited to, ethenyl or vinyl, propa-1-enyl, propa-2-enyl, 2-methylprop-1-enyl, buta-1-enyl, buta-2-enyl, buta-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-dienyl, hexa-1-enyl, hexa-2-enyl, hexa-3-enyl, hexa-4-enyl, and hexa-1,3-dienyl groups.

[0066] The term "alkenylene" refers to a divalent alkyl group formed by removing two hydrogen atoms from an alkane. Examples of alkenylenes include vinylidene and butenylene, but the term is not limited to these.

[0067] The term "alkynyl" includes hydrocarbon groups selected from linear and branched hydrocarbon groups containing at least one C≡C triple bond and 2 to 18 carbon atoms, for example, 2 to 8, and even more, for example, 2 to 6. 2-6 Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl, and 3-butynyl groups.

[0068] The term "alkynylene" refers to a divalent alkynyl group formed by removing two hydrogen atoms from an alkyne. Alkenylenes include, but are not limited to, ethynylene.

[0069] The term "cycloalkyl" includes hydrocarbon groups selected from saturated cyclic hydrocarbon groups, including condensed, crosslinked, or spirocycloalkyl groups, as well as monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups.

[0070] For example, a cycloalkyl group may contain 3 to 12 carbon atoms, for example, 3 to 10, even more for example, 3 to 8, even more for example, 3 to 6, 3 to 5, or 3 to 4 carbon atoms. Furthermore, for example, a cycloalkyl group may be selected from monocyclic groups containing 3 to 12 carbon atoms, for example, 3 to 10, even more for 3 to 8, or 3 to 6 carbon atoms. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl groups. In particular, saturated monocyclic cycloalkyl groups (e.g., C 3-8 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In preferred embodiments, the cycloalkyl group is a monocyclic ring containing 3 to 6 carbon atoms, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. 3-6 (Abbreviated as cycloalkyl). Examples of bicyclic cycloalkyl groups include those having 7 to 12 ring atoms arranged as fused bicyclic rings selected from the [4,4], [4,5], [5,5], [5,6], and [6,6] ring systems, or as bridging bicyclic rings selected from bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane. Further examples of bicyclic cycloalkyl groups include those arranged as bicyclic rings selected from the [5,6] and [6,6] ring systems.

[0071] The term "spirocycloalkyl" refers to a cyclic structure that contains carbon atoms and is formed by at least two rings sharing one atom.

[0072] The term "condensed cycloalkyl" refers to a bicyclic cycloalkyl group as defined herein, which is saturated and formed by two or more rings sharing two adjacent atoms.

[0073] The term "crosslinked cycloalkyl" refers to a cyclic structure formed by two rings containing carbon atoms and sharing two non-adjacent atoms. The term "7-10 membered crosslinked cycloalkyl" includes a cyclic structure containing 7-12 carbon atoms and formed by two rings sharing two non-adjacent atoms.

[0074] Examples of condensed cycloalkyls, condensed cycloalkenyls, or condensed cycloalkynyls include bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl, bicyclo[3.1.0]hexyl, bicyclo[4.1.0]heptyl, bicyclo[3.3.0]octyl, bicyclo[4.2.0]octyl, decalin, and benzo3- to 8-membered cycloalkyls, benzoC 4-6 Examples include, but are not limited to, cycloalkenyl, 2,3-dihydro-1H-indenyl, 1H-indenyl, 1,2,3,4-tetralyl, and 1,4-dihydronaphthyl. Preferred embodiments are 8-9 membered condensed rings, referring to cyclic structures containing 8-9 ring atoms within the range of the above examples.

[0075] The term “aryl,” when used alone or in combination with other terms, Five- and six-membered carbocyclic aromatic rings, such as phenyl; Bicyclic ring systems, for example, 7-12 membered bicyclic ring systems, wherein at least one ring is a carbon ring and an aromatic ring, such bicyclic ring systems, for example, naphthyl and indanyl and A tricyclic ring system, such as a 10-15 member tricyclic ring system, wherein at least one ring is a carbon ring and an aromatic ring, and the tricyclic ring system includes a group selected from, for example, fluorenyl.

[0076] The terms “aromatic hydrocarbon ring” and “aryl” are used interchangeably throughout this disclosure. In some embodiments, a monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 ring-forming carbon atoms (i.e., C 5-10It has an aryl group. Examples of monocyclic or bicyclic aromatic hydrocarbon rings include, but are not limited to, phenyl, naphtho-1-yl, naphtho-2-yl, anthracenyl, and phenantrenyl. In some embodiments, the aromatic hydrocarbon ring is a naphthalene ring (naphtho-1-yl or naphtho-2-yl) or a phenyl ring. In some embodiments, the aromatic hydrocarbon ring is a phenyl ring.

[0077] Specifically, the term "bicyclic fused aryl" refers to a bicyclic aryl ring as defined herein. A typical bicyclic fused aryl is naphthalene.

[0078] The term "heteroaryl" refers to a group selected from the following: A 5, 6, or 7-membered aromatic monocyclic ring comprising at least one heteroatom selected from nitrogen (N), sulfur (S), and oxygen (O), e.g., 1 to 4 heteroatoms, or in some embodiments 1 to 3 heteroatoms, or in some embodiments 1 to 2 heteroatoms, with the remaining ring atoms being carbon; A 7-12 membered bicyclic ring comprising at least one heteroatom selected from N, O, and S, e.g., 1-4 heteroatoms, or 1-3 heteroatoms in some embodiments, or 1 or 2 heteroatoms in other embodiments, the remaining ring atoms being carbon, at least one ring being aromatic, and at least one heteroatom present in the aromatic ring, and A tricyclic ring with 11 to 14 members, comprising at least one heteroatom (e.g., 1 to 4, or in some embodiments 1 to 3, or in other embodiments 1 or 2) selected from N, O, and S, the remaining ring atoms being carbon, at least one ring being aromatic, and at least one heteroatom located within an aromatic ring.

[0079] If the total number of S and O atoms in a heteroaryl group is greater than 1, those heteroatoms are not adjacent to each other. 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 heteroring is 1 or less. If a heteroaryl group contains two or more heteroatom ring members, the heteroatoms may be the same or different. Nitrogen atoms in the ring(s) of a heteroaryl group may be oxidized to form N-oxides.

[0080] More specifically, the term “bicyclic condensed heteroaryl” refers to a 7- to 12-membered, preferably 7- to 10-membered, more preferably 9 or 10-membered condensed bicyclic heteroaryl ring as defined herein. Typically, bicyclic condensed heteroaryls are 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 6-membered, or 6-membered / 7-membered bicyclic. The groups can be bonded to the rest of the molecule via either ring.

[0081] "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, and including monocyclic, condensed, bridging, and spirocyclic groups, i.e., monocyclic, heterocyclyl, bridging heterocyclyl, spiroheterocyclyl, and condensed heterocyclic groups.

[0082] The term “at least one substituent” as disclosed herein includes 1 to 4 substituents, such as 1 to 3, and further 1 or 2, as long as the theory of valence is satisfied. For example, “at least one substituent F” as disclosed herein includes 1 to 4 substituents F, such as 1 to 3, and further 1 or 2.

[0083] The term "divalent" refers to a linking group that can form a covalent bond with two other parts. For example, a "divalent cycloalkyl group" refers to a cycloalkyl group obtained by removing two hydrogens from the corresponding cycloalkane to form a linking group. The terms "divalent aryl group," "divalent heterocyclyl group," or "divalent heteroaryl group" should be understood similarly.

[0084] The compounds disclosed herein may have chiral centers and therefore may exist as enantiomers. “Enantiomer” refers to two stereoisomers of a compound that are mirror images of each other and cannot be superimposed. If a compound disclosed herein has two or more chiral centers, they may also exist as diastereomers. Enantiomers and diastereomers belong to a broader classification of stereoisomers. All such possible stereoisomers are intended to be included, such as substantially pure decomposed enantiomers, their racemic mixtures, and mixtures of diastereomers. All stereoisomers of the compounds disclosed herein and / or their pharmaceutically acceptable salts are intended to be included. Unless otherwise specified, a reference to one isomer applies to any of the possible isomers. Whenever the isomer composition is not specified, all possible isomers are included.

[0085] Where a compound disclosed herein contains an olefinic double bond, unless otherwise specified, such double bond is intended to include both E and Z geometric isomers.

[0086] If the compounds disclosed herein contain a disubstituted cyclic ring system, the substituents present in such a ring system can be in cis or trans configuration. The cis configuration means that both substituents are located above the arrangement of the two substituents on the carbon, while the trans configuration means that both substituents are located on opposite sides. For example, the disubstituted cyclic ring system may be a cyclohexyl or cyclobutyl ring.

[0087] It may be advantageous to separate reaction products from each other and / or from the starting materials. The desired products from each step or series of steps may be separated and / or purified (hereinafter, separated) to a desired degree of homogeneity by techniques common in the art. Typically, such separations include multiphase extraction, crystallization from a solvent or solvent mixture, distillation, condensation, or column chromatography. Chromatography can include any number of methods, for example, reversed-phase and normal-phase, size exclusion, ion exchange, high, medium, and low-pressure liquid chromatography methods and apparatus, small-scale analysis, simulated moving bed ("SMB") and preparative thin-layer or thick-layer chromatography, as well as small-scale thin-layer and flash techniques. Those skilled in the art will be able to select and apply the technique that is most likely to achieve the desired separation.

[0088] A "diastereomer" refers to a stereoisomer of a compound that has two or more chiral centers but is not a mirror image of one another. A mixture of diastereomers can be separated into their individual diastereomers based on their physicochemical differences by methods well known to those skilled in the art, such as chromatography and / or fractional recrystallization. Enantiomers can be separated by converting the enantiomer mixture into a diastereomer mixture by reaction with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Moscher acid chloride), separating the diastereomers, and converting the individual diastereoisomers into their corresponding pure enantiomers (e.g., by hydrolysis). Enantiomers can also be separated by the use of a chiral HPLC column.

[0089] A single stereoisomer, for example, a substantially pure enantiomer, can be obtained by the resolution of a racemic mixture using methods such as the formation of a diastereomer with an optically active resolution agent (Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. New York: John Wiley & Sons, Inc., 1994; L. Hmuller, CH, et al. “Flash column chromatographyic resolution of enantiomers: Selective review.” J. Chromatogr., 113(3)(1975): pp.283-302). The racemic mixture of chiral compounds of the present invention can be separated and isolated by any preferred method including (1) formation of an ionic diastereomer salt by the chiral compound and separation by fractional crystallization or other methods, (2) formation of a diastereomer compound by a chiral derivatizing reagent, separation of the diastereomer and conversion to a pure stereoisomer, and (3) direct separation of substantially pure or concentrated stereoisomers under chiral conditions. Wainer, Irving W., Ed. Drug See Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker, Inc., 1993.

[0090] Some of the compounds disclosed herein may exist at different hydrogen bonding sites, known as tautomers. For example, a compound containing a carbonyl-CH2C(O)- group (keto form) may undergo tautomerism to form a hydroxyl-CH=C(OH)- group (enol form). Where applicable, both keto and enol forms are intended to be included individually and as mixtures thereof.

[0091] A "prodrug" refers to a derivative of an active drug that requires conversion in the body to release the active drug. In certain embodiments, the conversion is enzymatic. Prodrugs are often, though not always, pharmacologically inactive until they are converted to the active drug.

[0092] A "pharmaceutically acceptable salt" means a salt that, within the bounds of sound medical judgment, is suitable for use in contact with human and lower animal tissues without excessive toxicity, irritation, or allergic reactions, and that corresponds to a reasonable benefit / risk ratio. A pharmaceutically acceptable salt may be prepared separately in situ during the final isolation and purification of the compounds disclosed herein, or by reacting a free base functional group with a suitable organic acid, or by reacting an acidic group with a suitable base. This term also includes stereoisomers (enantiomers and / or diastereomers), tautomers, and salts of prodrugs of the compounds of the present invention.

[0093] 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 acid. Conversely, when the product is a free base, addition salts such as pharmaceutically acceptable addition salts can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, following conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize a variety of synthetic methods that can be used without excessive experimentation to prepare non-toxic, pharmaceutically acceptable addition salts.

[0094] In this specification, the terms “administer,” “administer,” “treat,” and “treat” mean, when applied to animals, humans, experimental subjects, cells, tissues, organs, or biological fluids, the contact of an exogenous drug, therapeutic agent, diagnostic agent, or composition with an animal, human, subject, cell, tissue, organ, or biological fluid. Treatment of cells includes the contact of a reagent with cells, as well as the contact of a reagent with a fluid, where the fluid comes into contact with the cells. The terms “administer” and “treat” also mean, for example, in vitro and ex vivo treatment of cells, with a reagent, diagnostic agent, conjugate compound, or with another cell. In this specification, the term “subject” includes any living organism, preferably an animal, more preferably a mammal (e.g., rats, mice, dogs, cats, and rabbits), most preferably a human.

[0095] The term “effective dose” or “therapeutic dose” refers to the amount of an active ingredient, such as a compound, that is sufficient to have an effect on such treatment for a disease, disorder, or symptom when administered to a subject to treat a disease, disorder, or symptom of a disease or disorder. “Therapeutic dose” can vary depending on the compound, the disease, disorder, and / or the symptoms of the disease or disorder, the severity of the disease, disorder, and / or the symptoms of the disease or disorder, the age of the subject being treated, and / or the weight of the subject being treated. An appropriate amount in any given case may be obvious to those skilled in the art or can be determined by customary experimentation. In some embodiments, “therapeutic dose” is the amount of at least one compound disclosed herein and / or at least one stereoisomer thereof, and / or at least one pharmaceutically acceptable salt thereof, which is effective for “treatment” of a disease or disorder in a subject, as defined herein. In the case of combination therapy, “therapeutic dose” refers to the total amount of the combination substance for effective treatment of a disease, disorder, or condition.

[0096] The term “disease” refers to any illness, discomfort, disorder, symptom, or adaptation, and may be interchangeable with the terms “disorder” or “condition.”

[0097] Throughout this specification and the following claims, unless contextually required, the term “comprise,” and variations such as “comprises” and “comprising,” are intended to identify the presence of a subsequent feature, but not to exclude the presence or addition of one or more other features. As used herein, the term “comprising” may be replaced by the terms “containing,” “including,” or, in some cases, “having.”

[0098] Throughout this specification and the following claims, "C n-mThe term "x" indicates a range that includes the endpoint, where n and m are integers and represent the number of carbon atoms. For example, C 1~8 , C 1~6 These are some examples.

[0099] Figures herein showing substituents(s) attached to a cyclic group (e.g., aryl, heteroaryl, cycloalkyl, fused cyclic, spirocyclic groups) via inter-ring atom bonds mean, unless otherwise specified, that substituents(s) may be attached to the cyclic group at any ring position on any ring in the cyclic group (e.g., any ring in a fused cyclic group), provided that such substitution results in a stable compound.

[0100] Unless otherwise defined elsewhere in this specification, all other technical and scientific terms used herein have meanings that are generally understood by those skilled in the art to which this invention pertains. [Examples]

[0101] General synthesis The compounds and salts disclosed herein can be prepared using known organic synthesis techniques and can be synthesized according to any of a number of possible synthetic routes.

[0102] The reactions for preparing the compounds disclosed herein may be carried out in suitable solvents that can be readily selected by those skilled in the art of organic synthesis. Suitable solvents may be substantially inactive with the starting materials, intermediates, or products at the temperature in which the reaction is carried out, for example, at temperatures varying from the boiling point of the solvent. A given reaction may be carried out in one solvent or a mixture of solvents.

[0103] The selection of an appropriate protecting group can be easily determined by those skilled in the art. Some protection / deprotection steps are not shown in the synthetic scheme and may be incorporated before, after, or between any of the steps. The protecting groups shown in the synthetic scheme may or may not be used depending on the reaction conditions. The order of the reactions may vary, but similar results will be obtained.

[0104] The reaction can be monitored according to any suitable method known in the art, such as NMR, UV, HPLC, LC-MS, and TLC. The compound can be purified by various methods, including preparative HPLC and silica gel chromatography. Unless otherwise specified, a buffered acetonitrile / water system is used for preparative HPLC, and a PE / ÃO or DCM / MeOH system is used as the mobile phase for silica gel chromatography (including column chromatography and preparative TLC). The NMR spectrum is recorded using a Bruker or Varian instrument with a preset pulse sequence.

[0105] Scheme I [ka] For example, the compound of formula (I) can be formed as shown in scheme I. Compounds (i) and (ii) can be coupled to each other by transition metal catalytic coupling to obtain compound (iii). Compound (iii) can be deprotected to obtain compound (iv). Compound (iv) can be cyclized intramolecularly to obtain compound (v). Compound (v) can be saponified to obtain compound (vi). Compound (vi) can be coupled with compound (vii) to obtain compound (viii) [i.e., formula (I)].

[0106] Scheme II [ka] For example, the compound of formula (I) can be formed as shown in scheme II. Compound (i) can be subjected to dehydration cyclization to obtain compound (ii). Compound (ii) can be saponified to obtain compound (iii). Compound (iii) can be coupled with compound (iv) to obtain compound (v) [i.e., formula (I)].

[0107] Scheme III [ka] For example, the compound of formula (I) can be formed as shown in scheme III. Compound (i) can be halogenated to obtain compound (ii). Compound (ii) can be reacted with compound (iii) via the enamine-Heck reaction to obtain compound (iv). Compound (iv) can be aminated to obtain compound (v). Compound (v) can be saponified to obtain compound (vi). Compound (vi) can be coupled with compound (vii) to obtain compound (viii) [i.e., formula (I)].

[0108] Scheme IV [ka] For example, the compound of formula (I) can be formed as shown in scheme IV. Compound (i) can be aminated, for example, via a metal-catalyzed coupling reaction, to obtain compound (ii). Compound (ii) can be halogenated to obtain compound (iii). Compounds (iii) and (iv) can be coupled to each other by transition metal-catalyzed coupling to obtain compound (v). Compound (v) can be deprotected to obtain compound (vi). Compound (vi) can be intramolecularly cyclized to obtain compound (vii). Compound (vii) can be saponified to obtain compound (viii). Compound (viii) can be coupled with compound (ix), followed by any deprotection, to obtain compound (x) [i.e., formula (I)].

[0109] Scheme V [ka] For example, the compound of formula (I) can be formed as shown in scheme V. Compound (i) can be condensed with compound (ii) to obtain compound (iii). Compound (iii) can be aminated, for example, via a metal-catalyzed coupling reaction to obtain compound (iv). Compound (iv) can be deprotected to obtain compound (v). Compound (v) can be intramolecularly cyclized to obtain compound (vi). Compound (vi) can be saponified to obtain compound (vii). Compound (vii) can be coupled with compound (viii), followed by any deprotection, to obtain compound (ix) [i.e., formula (I)].

[0110] Scheme VI [ka] For example, the compound of formula (I) can be formed as shown in scheme VI. Compound (i) can be condensed with compound (ii) to obtain compound (iii). Compound (iii) can be deprotected to obtain compound (iv). Compound (iv) can be intramolecularly cyclized to obtain compound (v). Compound (v) can be saponified to obtain compound (vi). Compound (vi) can be coupled with compound (vii), followed by any deprotection, to obtain compound (viii) [i.e., formula (I)]. [Table 2-1] [Table 2-2]

[0111] Example 1: (R)-5-amino-N-((3',5'-difluoro-[3,4'-bipyridine]-6-yl)methyl)-N-(5,6,7,8-tetrahydroquinoline-8-yl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Step 1: 3',5'-difluoro-[3,4'-bipyridine]-6-carbaldehyde [ka] To a mixture of 3,5-difluoro-4-iodopyridine (0.85 g, 3.53 mmol) in dioxane (17 mL), toluene (8.5 mL), and water (8.5 mL), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picoline aldehyde (1.64 g, 7.05 mmol), K3PO4 (2.25 g, 10.6 mmol), and Pd(dppf)Cl2 (258 mg, 0.35 mmol) were added at 20°C. The mixture was stirred at 85°C for 3 hours. The mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE:Â=1:0~1:1) to obtain the title compound (0.70 g, 90%). LC-MS (M+H) + =221.2.

[0112] Step 2: (R)-N-((3',5'-difluoro-[3,4'-bipyridine]-6-yl)methyl)-5,6,7,8-tetrahydroquinoline-8-amine [ka] To a solution of (R)-5,6,7,8-tetrahydroquinoline-8-amine (525 mg, 3.54 mmol) in DCM (13 mL), NaBH(OAc)3 (939 mg, 4.43 mmol), MeOH (0.13 mL), and 3',5'-difluoro-[3,4'-bipyridine]-6-carbaldehyde (0.65 g, 2.95 mmol) were added. The mixture was stirred at 20°C for 1 hour and then poured into saturated NaHCO3 (50 mL). The mixture was extracted with DCM (50 mL x 3). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC to obtain the title compound (216 mg, 21%). LC-MS (M+H) + =353.2.

[0113] Step 3: 4-amino-1H-pyrrole-2-carboxylate ethyl carboxylate [ka] To a solution of ethyl 4-nitro-1H-pyrrole-2-carboxylate (9.0 g, 48.9 mmol) in MeOH (100 mL), Pd / C (10%, 5.2 g, 4.89 mmol) was added. The mixture was stirred under hydrogen (15 psi) at 25°C for 12 hours. The mixture was filtered through a short celite pad. The filtrate was concentrated under vacuum to obtain the title compound (7 g, 93%). LC-MS (M+H) + = 155.2.

[0114] Step 4: 4-((tert-butoxycarbonyl)amino)-1H-pyrrole-2-ethyl carboxylate [ka] To a solution of ethyl 4-amino-1H-pyrrole-2-carboxylate (7.0 g, 45.4 mmol) in DCM (80 mL), Boc2O (14.9 g, 68.1 mmol) and Et3N (13.8 g, 136 mmol) were added. The mixture was stirred at 25°C for 1 hour. The mixture was diluted with water (100 mL) and then extracted with DCM (50 mL x 3). The combined organic layer was washed with brine (50 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE:HCl = 1:0~1:1) to obtain the title compound (8.0 g, 69%). LCMS (M+Ht-Bu) + = 199.2.

[0115] Step 5: 5-Bromo-4-((tert-butoxycarbonyl)amino)-1H-pyrrole-2-carboxylate ethyl carboxylate [ka] 4-((tert-butoxycarbonyl)amino)-1H-pyrrole-2-carboxylate ethyl (7.0 g, 27.5 mmol) was dissolved in DCM (35 mL) and NBS (4.90 g, 27.5 mmol) was added. The mixture was stirred at 25°C for 2 hours. The mixture was diluted with water (50 mL) and then extracted with DCM (30 mL x 3). The combined organic layer was washed with brine (30 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE: Depositphotos = 5:1) to obtain the title compound (6.0 g, 65%). LCMS (M+H-tBu) + = 277.1.

[0116] Step 6: 4-Cyano-2,5-dihydrofuran-3-yltrifluoromethanesulfonate [ka] To a solution of 4-oxotetrahydrofuran-3-carbonitrile (10.0 g, 90.0 mmol) in DCM (100 mL), DIPEA (14.0 g, 108 mmol) and Tf2O (25.4 g, 90.0 mmol) were added at -78°C, and the mixture was stirred at -78°C for 1 hour. The reaction mixture was diluted with water (100 mL), warmed to room temperature, and then extracted with DCM (50 mL x 3). The combined organic layer was washed with brine (50 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE:siRNA = 1:0~3:1) to obtain the title compound (10.0 g, 46%). 1 H NMR (400 MHz, CDCl3) δ 4.95-4.60 (m, 4H).

[0117] Step 7: 4-((tert-butoxycarbonyl)amino)-5-(4-cyano-2,5-dihydrofuran-3-yl)-1H-pyrrole-2-carboxylate ethyl and 5-amino-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylate ethyl [ka] To a solution of 5-bromo-4-((tert-butoxycarbonyl)amino)-1H-pyrrole-2-carboxylate ethyl (13.0 g, 39.0 mmol) and BPD (19.8 g, 78.0 mmol) in THF (200 mL), Pd2(dba)3 (1.79 g, 1.95 mmol), KOAc (11.5 g, 117 mmol), and XPhos (1.86 g, 3.9 mmol) were added. The mixture was stirred at 75 °C for 3 hours and then cooled to room temperature. The solid was filtered off, and the filtrate was concentrated under vacuum. The crude substance was redissolved in dioxane (150 mL) and water (30 mL), and then 4-cyano-2,5-dihydrofuran-3-yltrifluoromethanesulfonate (17.9 g, 73.6 mmol), Pd(dppf)Cl2 (2.69 g, 3.68 mmol), and K2CO3 (12.7 g, 92.0 mmol) were added. The mixture was degassed, purged three times with nitrogen, and then stirred at 80°C for 12 hours. The mixture was cooled to room temperature, diluted with water (400 mL), and extracted with siRNA (300 mL x 3). The combined organic layer was washed with brine (100 mL x 2), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (PE / siRNA = 1 / 0 to 3 / 1) to obtain the following compounds:

[0118] 4-((tert-butoxycarbonyl)amino)-5-(4-cyano-2,5-dihydrofuran-3-yl)-1H-pyrrole-2-carboxylate ethyl (7.0g, 52%). LCMS (M+Ht-Bu) + = 292.1.

[0119] 5-amino-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylate ethyl (2.0g, 21%). LCMS (M+H) + = 248.2.

[0120] Step 8: 5-amino-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylate methyl [ka] 4-((tert-butoxycarbonyl)amino)-5-(4-cyano-2,5-dihydrofuran-3-yl)-1H-pyrrole-2-carboxylate ethyl (0.70 g, 2.02 mmol) was added to a HCl-MeOH (3 M, 10 mL) solution at 25°C and stirred for 1 hour. The mixture was concentrated under vacuum. The residue was redissolved in MeOH (5 mL) and K2CO3 (1.28 g, 9.27 mmol) was added. The mixture was stirred at 50°C for 2 hours and cooled to room temperature, and the solid was filtered off. The filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (PE / Depositphotos = 2 / 1 to 3 / 1, then Depositphotos / MeOH = 5 / 1) to obtain the title compound (0.40 g, 85%). 1 H NMR (400 MHz, DMSO-d6) δ 11.84 (br s, 1H), 6.85 (s, 1H), 5.70 (s, 2H), 5.19-5.09 (m, 2H), 4.97-4.88 (m, 2H), 3.85 (s, 3H). LCMS (M+H) + = 234.2.

[0121] Step 9: 5-amino-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid [ka] 5-amino-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylate methyl (0.40 g, 1.72 mmol) was dissolved in THF (4 mL), MeOH (0.8 mL), and water (0.8 mL), to which LiOH·H2O (108 mg, 2.57 mmol) was added. The mixture was stirred at 45°C for 4 hours and then cooled to room temperature. The mixture was diluted with H2O (10 mL) and then washed with RINKAN (15 mL x 3). The aqueous phase was freeze-dried to obtain the residue. The residue was purified by preparative HPLC to obtain the title compound (80 mg, 21%). LCMS (M+H) + = 220.1.

[0122] Step 10: (R)-5-amino-N-((3',5'-difluoro-[3,4'-bipyridine]-6-yl)methyl)-N-(5,6,7,8-tetrahydroquinoline-8-yl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide 5-amino-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid (100 mg, 0.45 mmol) and (R)-N-((3',5'-difluoro-[3,4'-bipyridine]-6-yl)methyl)-5,6,7,8-tetrahydroquinoline-8-amine (158 mg, 0.45 mmol) were dissolved in DMF (2 mL), to which DIPEA (0.25 mL, 1.35 mmol) and HATU (171 mg, 0.45 mmol) were added. The mixture was stirred at 25°C for 12 hours. The reaction mixture was diluted with water (5 mL) and then extracted with ethyl acetate (20 mL x 3). The combined organic layer was washed with brine (5 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain Example 1 (15 mg, 6%). 1 H NMR (500 MHz, DMSO-d6) δ 11.68-11.62 (m, 1H), 8.82-8.65 (m, 3H), 8.36-8.34 (m, 1H), 8.13-7.98 (m, 2H), 7.56-7.52 (m, 2H), 7.25-7.16 (m, 1H), 6.74 (s, 1H), 5.53-5.56 (m, 2H), 5.11-5.08 (m, 2H), 4.93-4.82 (m, 3H), 3.93-3.90 (m, 1H), 2.85-2.36 (m, 3H), 2.07-1.79 (m, 3H). LC-MS (M+H) + = 554.3.

[0123] Example 2: (R)-5-amino-N-((5-(2,6-difluorophenyl)pyridine-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinoline-8-yl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Step 1: 5-(2,6-difluorophenyl)picolinealdehyde [ka] 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picoline aldehyde (62 g, 266 mmol) and 1,3-difluoro-2-iodobenzene (95.8 g, 399 mmol) were mixed in dioxane (600 mL), toluene (300 mL), and water (300 mL). Pd(dppf)Cl2 (9.73 g, 13.3 mmol) and K3PO4 (141 g, 665 mmol) were added. The mixture was stirred at 85 °C for 16 hours, cooled to room temperature, and poured into water (1000 mL). The organic layer was separated. The aqueous phase was extracted with ELISA (800 mL x 2). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (PE:Â=50:1~5:1) to obtain the title compound (30g, 51%). LC-MS (M+H) + =220.2.

[0124] Step 2: (R)-N-((5-(2,6-difluorophenyl)pyridine-2-yl)methyl)-5,6,7,8-tetrahydroquinoline-8-amine [ka] To a solution of (R)-5,6,7,8-tetrahydroquinoline-8-amine (1.35 g, 9.12 mmol) in DCM (20 mL), 5-(2,6-difluorophenyl)picoline aldehyde (2.0 g, 9.12 mmol), MeOH (2 mL), and NaBH(OAc)3 (5.80 g, 27.4 mmol) were added. The mixture was stirred at room temperature for 1 hour and quenched with saturated NaHCO3 (50 mL). The organic layer was separated, and the aqueous layer was extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (PE: Depositphotos = 1:0 to 0:1) to obtain the title compound (582 mg, 18%). LC-MS (M+H) + =352.1.

[0125] Step 3: (R)-5-amino-N-((5-(2,6-difluorophenyl)pyridine-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinoline-8-yl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide 5-amino-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid (30 mg, 0.14 mmol) and (R)-N-((5-(2,6-difluorophenyl)pyridine-2-yl)methyl)-5,6,7,8-tetrahydroquinoline-8-amine (48 mg, 0.14 mmol) were dissolved in THF (1 mL), to which DIPEA (53 mg, 0.41 mmol) and BOPCl (52 mg, 0.20 mmol) were added. The mixture was stirred at 25°C for 12 hours. The mixture was diluted with water (5 mL) and extracted with ₹ (5 mL × 3). The combined organic layer was washed with brine (5 mL × 2), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC to obtain Example 2 (13 mg, 17%). 1H NMR (400 MHz, DMSO-d6) 11.71 - 11.61 (m, 1 H), 8.71 - 8.34 (m, 2 H), 7.97 - 7.85 (m, 1 H), 7.58-7.15 (m, 5 H), 6.73-6.21 (m, 1 H), 5.99-5.32 (m, 3 H), 5.25 - 5.11 (m, 2 H), 4.92 - 4.86 (m, 2 H), 4.84 - 3.82 (m, 1 H), 2.92 - 2.66 (m, 3 H), 2.20 - 1.95 (m, 2 H), 1.82 - 1.75 (m, 1 H). LC-MS (M+H) + = 553.0.

[0126] Example 3: 5-amino-N,N-bis(2,6-difluorobenzyl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Step 1: Bis(2,6-difluorobenzyl)amine [ka] To a 15 mL solution of 2,6-difluorobenzaldehyde (142 mg, 1.0 mmol) and (2,6-difluorophenyl)methaneamine (143 mg, 1.0 mmol) in DCM, NaBH(OAc)3 (2 mmol, 422 mg) was added in fractions at 0°C. The mixture was heated to room temperature and stirred for 1 hour. The reaction product was quenched with saturated NaHCO3 (10 mL). The organic layer was separated, and the aqueous layer was extracted with ELISA (30 mL x 2). The combined organic layers were concentrated under reduced pressure to obtain the title compound (256 mg, 95%). LC-MS (M+H) + = 270.1.

[0127] Step 2: 5-amino-N,N-bis(2,6-difluorobenzyl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide 5-amino-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid (100 mg, 0.45 mmol) and bis(2,6-difluorobenzyl)amine (121 mg, 0.45 mmol) were dissolved in THF (4 mL), to which DIPEA (0.4 mL, 2.25 mmol) and BOPCl (171 mg, 0.67 mmol) were added. The mixture was stirred at 25°C for 12 hours. The reaction mixture was diluted with water (5 mL) and then extracted with ₹ (20 mL × 3). The combined organic layer was washed with brine (5 mL × 2), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain the title compound (17 mg, 8%). 1 HNMR (500 MHz, DMSO-d6) δ 11.60 (s, 1H), 7.50 - 7.34 (m, 2H), 7.17 - 6.96 (m, 4H), 6.72 - 6.53 (m, 1H), 5.58 (s, 2H), 5.20 - 5.10 (m, 2H), 4.95 - 4.91 (m, 2H), 4.85 (s, 4H). LC-MS (M+H) + =471.2.

[0128] Example 4: 5-amino-N-((5-(2,6-difluorophenyl)pyridine-2-yl)methyl)-N-((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Step 1: (3R,4R)-3-(((5-(2,6-difluorophenyl)pyridine-2-yl)methyl)amino)tetrahydro-2H-pyran-4-ol [ka] (3R,4R)-3-aminotetrahydro-2H-pyran-4-ol (120 mg, 1.02 mmol) and 5-(2,6-difluorophenyl)picolinealdehyde (224 mg, 1.02 mmol) were dissolved in DCM (10 mL), to which NaBH(OAc)3 (430 mg, 2.03 mmol) was added at 0°C. The mixture was heated to room temperature and stirred for 2 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (PE / siRNA=1 / 1) to obtain the title compound (200 mg, 61%). LCMS (M+H) + = 321.1.

[0129] Step 2: ((5-(2,6-difluorophenyl)pyridine-2-yl)methyl)((3R,4R)-4-hydroxytetrahydro-2H-pyran-3-yl)carbamate tert-butyl [ka] (3R,4R)-3-(((5-(2,6-difluorophenyl)pyridine-2-yl)methyl)amino)tetrahydro-2H-pyran-4-ol (200 mg, 0.62 mmol) was dissolved in DCM (10 mL) and Boc2O (164 mg, 0.75 mmol) and Et3N (188 mg, 1.86 mmol) were added. The mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (PE / Â=2 / 1) to obtain the title compound (230 mg, 88%). LCMS (M+H) + = 421.1.

[0130] Step 3: ((5-(2,6-difluorophenyl)pyridine-2-yl)methyl)((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)carbamate tert-butyl [ka] A mixture of ((5-(2,6-difluorophenyl)pyridine-2-yl)methyl)((3R,4R)-4-hydroxytetrahydro-2H-pyran-3-yl)carbamate tert-butyl (230 mg, 0.55 mmol) and MeI (78 mg, 0.55 mmol) in DMF (10 mL) was mixed with NaH (60%, 29 mg, 0.72 mmol) at 0°C. The mixture was stirred at room temperature under nitrogen for 5 hours. The mixture was diluted with ice water (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layer was washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / ethyl acetate = 2 / 1) to obtain the title compound (230 mg, 96%). LCMS (M+H) + = 435.1.

[0131] Step 4: (3R,4R)-N-((5-(2,6-difluorophenyl)pyridine-2-yl)methyl)-4-methoxytetrahydro-2H-pyran-3-amine hydrochloride [ka] A mixture of ((5-(2,6-difluorophenyl)pyridine-2-yl)methyl)((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)carbamate tert-butyl (230 mg, 0.53 mmol) in HCl (4 M in MeOH, 5 mL) was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to obtain the title compound (180 mg, 92%). LC-MS (M+H) + = 335.1.

[0132] Step 5: 5-amino-N-((5-(2,6-difluorophenyl)pyridine-2-yl)methyl)-N-((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide A mixture of 5-amino-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid (90 mg, 0.40 mmol) in SOCl2 (5 mL) was stirred at 50°C for 3 hours. Volatile substances were removed under vacuum, and the residue was redissolved in DCM (10 mL). (3R,4R)-N-((5-(2,6-difluorophenyl)pyridine-2-yl)methyl)-4-methoxytetrahydro-2H-pyran-3-amine hydrochloride (150 mg, 0.4 mmol) and DIPEA (154 mg, 1.2 mmol) were added to the mixture at 0°C. The mixture was stirred for 1 hour and then diluted with DCM (20 mL). The mixture was sequentially washed with water (10 mL) and brine (10 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM / MeOH = 20 / 1) followed by preparative HPLC to obtain Example 4 (11 mg, 5%). 1 H NMR (500 MHz, DMSO-d6) δ 11.58 (s, 1H), 8.84 - 8.48 (m, 1H), 8.10 - 7.82 (m, 1H), 7.72 - 7.43 (m, 2H), 7.37 - 7.18 (m, 2H), 6.81 - 6.29 (m, 1H), 5.79 - 4.18 (m, 9H), 4.14 - 3.34 (m, 5H), 3.21 - 3.03 (m, 3H), 2.26 - 2.13 (m, 1H), 1.47 - 1.19 (m, 1H). LCMS (M+H) + = 536.4.

[0133] Example 5: (R)-5-amino-N-(2,6-difluorobenzyl)-N-(5,6,7,8-tetrahydroquinoline-8-yl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Step 1: (R)-N-(2,6-difluorobenzyl)-5,6,7,8-tetrahydroquinoline-8-amine [ka] (R)-5,6,7,8-tetrahydroquinoline-8-amine (355 mg, 2.4 mmol) and 2,6-difluorobenzaldehyde (284 mg, 2.0 mmol) were mixed in 10 mL of DCM. NaBH(OAc)3 (848 mg, 4.0 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with 30 mL of DCM and carefully washed with saturated NaHCO3 (30 mL) and brine (30 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM / MeOH = 20 / 1) to obtain the title compound (500 mg, 91%). LC-MS (M+H) + = 275.2.

[0134] Step 2: (R)-5-amino-N-(2,6-difluorobenzyl)-N-(5,6,7,8-tetrahydroquinoline-8-yl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 5 (2 mg, 2%) was prepared from 5-amino-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and (R)-N-(2,6-difluorobenzyl)-5,6,7,8-tetrahydroquinoline-8-amine using the same method as in Example 2, Step 3. 1 H NMR (500 MHz, DMSO-d6) δ 11.61 (s, 1H), 8.33 (s, 1H), 7.50 (s, 1H), 7.30 (s, 1H), 7.16 (s, 1H), 6.98 (s, 2H), 6.59 (s, 1H), 5.52 LC-MS (M+H) + =476.2.

[0135] Example 6: (R)-5-amino-N-(5,6,7,8-tetrahydroquinoline-8-yl)-N-((2',3,6'-trifluoro-[1,1'-biphenyl]-4-yl)methyl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Step 1: 2',3,6'-trifluoro-[1,1'-biphenyl]-4-carbaldehyde [ka] A mixture of 4-bromo-2-fluorobenzaldehyde (609 mg, 3.0 mmol), (2,6-difluorophenyl)boronic acid (948 mg, 6.0 mmol), Pd(dppf)Cl2 (196 mg, 0.3 mmol), and K3PO4 (1.9 g, 9.0 mmol) in dioxane (15 mL) and water (3 mL) was stirred overnight at 100 °C under nitrogen and then cooled to room temperature. The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / ethyl acetate = 10 / 1) to obtain the title compound (520 mg, 73%). LC-MS (M+H) + = 237.1.

[0136] Step 2: (R)-N-((2',3,6'-trifluoro-[1,1'-biphenyl]-4-yl)methyl)-5,6,7,8-tetrahydroquinoline-8-amine [ka] The title compound (282 mg, 76%) was prepared from 2',3,6'-trifluoro-[1,1'-biphenyl]-4-carbaldehyde and (R)-5,6,7,8-tetrahydroquinoline-8-amine by the same method as in Example 5, Step 1. LC-MS (M+H) + = 369.3.

[0137] Step 3: (R)-5-amino-N-(5,6,7,8-tetrahydroquinoline-8-yl)-N-((2',3,6'-trifluoro-[1,1'-biphenyl]-4-yl)methyl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 6 (2 mg, 4%) was prepared from 5-amino-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and (R)-N-((2',3,6'-trifluoro-[1,1'-biphenyl]-4-yl)methyl)-5,6,7,8-tetrahydroquinoline-8-amine using the same method as in Example 2, Step 3. 1 H NMR (500 MHz, DMSO-d6) δ 11.72 - 11.55 (m, 1H), 8.47 - 8.32 (m, 1H), 7.65 - 7.11 (m, 8H), 6.81 - 6.53 (m, 1H), 6.25 - 5.45 (m, 3H), 5.25 - 3.70 (m, 6H), 2.95 - 2.81 (m, 1H), 2.78 - 2.67 (m, 1H), 2.37 - 1.72 (m, 4H). LC-MS (M+H) + = 570.5.

[0138] Example 7: 5-amino-N,N-bis((3-fluoropyridine-2-yl)methyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Step 1: Bis((3-fluoropyridine-2-yl)methyl)amine [ka] The title compound (200 mg, 87%) was prepared from 3-fluoropicoline aldehyde and (3-fluoropyridine-2-yl)methaneamine using the same method as in Example 5, Step 1. LC-MS (M+H) + = 236.2.

[0139] Step 2: 5-amino-N,N-bis((3-fluoropyridine-2-yl)methyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 7 (5 mg, 11%) was prepared from 5-amino-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and bis((3-fluoropyridine-2-yl)methyl)amine using the same method as in Example 2, Step 3. 1 H NMR (500 MHz, DMSO-d6) δ 11.62 (s, 1H), 8.41 (s, 2H), 7.72 (s, 2H), 7.43 (s, 2H), 6.43 (d, J = 2.4 Hz, 1H), 5.52 (s, 2H), 5.35 - 4.76 (m, 8H). LC-MS (M+H) + = 437.4.

[0140] Example 8: 5-amino-N-(2,6-difluorobenzyl)-N-(1-methoxypropan-2-yl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Step 1: N-(2,6-difluorobenzyl)-1-methoxypropane-2-amine [ka] The title compound (150 mg, 49%) was prepared from 2,6-difluorobenzaldehyde and 1-methoxypropan-2-amine using the same method as in Example 5, Step 1. LC-MS (M+H) + = 216.1.

[0141] Step 2: 5-amino-N-(2,6-difluorobenzyl)-N-(1-methoxypropan-2-yl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 8 (4 mg, 7%) was prepared from 5-amino-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and N-(2,6-difluorobenzyl)-1-methoxypropan-2-amine using the same method as in Example 2, Step 3. 1 H NMR (500 MHz, DMSO-d6) δ 11.49 (s, 1H), 8.16 (s, 1H), 7.36 (t, J = 7.4 Hz, 1H), 7.06 (t, J = 8.2 Hz, 2H), 6.53 (d, J = 1.9 Hz, 1H), 5.54 (s, 2H), 5.11 (d, J = 2.7 Hz, 2H), 4.92 (t, J = 2.7 Hz, 2H), 4.84 (s, 1H), 3.56 - 3.49 (m, 1H), 3.15 (s, 3H), 1.19 (d, J = 6.7 Hz, 3H).LC-MS (M+H) + = 417.2.

[0142] Example 9: 5-amino-N-(2,6-difluorobenzyl)-N-(1,3-dimethoxypropan-2-yl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Example 9 (2 mg, 4%) was prepared in the same manner as in Example 2, Step 3. 1 H NMR (500 MHz, DMSO-d6) δ 11.49 (s, 1H), 8.29 (s, 1H), 7.41 - 7.33 (m, 1H), 7.06 (t, J = 8.1 Hz, 2H), 6.62 (d, J = 2.0 Hz, 1H), 5.55 (s, LC-MS (M+H) + = 447.1.

[0143] Example 10: (R)-5-amino-N-((3,5-difluoropyridine-4-yl)methyl)-N-(5,6,7,8-tetrahydroquinoline-8-yl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Example 10 (1 mg, 1%) was prepared in the same manner as in Example 2, Step 3. 1 H NMR (500 MHz, DMSO-d6) δ 11.64 (s, 1H), 8.55 - 8.16 (m, 3H), 7.54 (s, 1H), 7.19 (s, 1H), 6.61 (s, 1H), 5.80 (s, 1H), 5.53 (s, 2H), 5.11 (s, 2H), 4.91 (s, 2H), 4.60 (s, 1H), 4.10 (s, 1H), 2.89 - 2.87 (m, 1H), 2.75 - 2.72 (m, 1H), 2.36 (s, 2H), 2.12 -1.80 (m, 2H).LC-MS (M+H) + = 477.5.

[0144] Example 11: (R)-5-amino-N-((3'-cyano-[3,4'-bipyridine]-6-yl)methyl)-N-(5,6,7,8-tetrahydroquinoline-8-yl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Step 1: 6-Formyl-[3,4'-Bipyridine]-3'-Carbonitrile [ka] The title compound (160 mg, 26%) was prepared from 5-bromopicoline aldehyde and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile using the same method as in Example 6, Step 1. LC-MS (M+H) + = 210.1.

[0145] Step 2: (R)-6-(((5,6,7,8-tetrahydroquinoline-8-yl)amino)methyl)-[3,4'-bipyridine]-3'-carbonitrile [ka] The title compound (88 mg, 64%) was prepared from 6-formyl-[3,4'-bipyridine]-3'-carbonitrile and (R)-5,6,7,8-tetrahydroquinoline-8-amine by the same method as in Example 5, Step 1. LC-MS (M+H) + = 342.2.

[0146] Step 3: (R)-5-amino-N-((3'-cyano-[3,4'-bipyridine]-6-yl)methyl)-N-(5,6,7,8-tetrahydroquinoline-8-yl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 11 (8 mg, 14%) was prepared from 5-amino-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and (R)-6-(((5,6,7,8-tetrahydroquinoline-8-yl)amino)methyl)-[3,4'-bipyridine]-3'-carbonitrile using the same method as in Example 2, Step 3. 1H NMR (500 MHz, DMSO-d6) δ 11.78 - 11.55 (m, 1H), 9.21 - 9.11 (m, 1H), 9.03 - 8.72 (m, 2H), 8.47 - 8.32 (m, 1H), 8.25 - 8.01 (m, 1H), 7.92 - 7.75 (m, 1H), 7.70 - 7.47 (m, 2H), 7.32 - 7.11 (m, 1H), 6.82 - 6.22 (m, 1H), 6.03 - 3.91 (m, 9H), 2.92 - 2.71 (m, 2H), 2.32 - 1.68 (m, 4H). LC-MS (M+H) + = 543.6.

[0147] Example 12: 5-amino-N-(chroman-4-yl)-N-((5-(2,6-difluorophenyl)pyridine-2-yl)methyl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Step 1: N-((5-(2,6-difluorophenyl)pyridine-2-yl)methyl)chroman-4-amine [ka] The title compound (400 mg, 85%) was prepared from chroman-4-amine and 5-(2,6-difluorophenyl)picoline aldehyde by the same method as in Example 5, Step 1. LC-MS (M+H) + = 353.2.

[0148] Step 2: 5-amino-N-(chroman-4-yl)-N-((5-(2,6-difluorophenyl)pyridine-2-yl)methyl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 12 (7 mg, 8%) was prepared from 5-amino-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and N-((5-(2,6-difluorophenyl)pyridine-2-yl)methyl)chroman-4-amine using the same method as in Example 2, Step 3. 1 H NMR (400 MHz, DMSO-d6) δ 11.73 (br s, 1H), 8.67 - 8.56 (m, 1H), 7.91 - 7.88 (m, 1H), 7.57 - 7.49 (m, 2H), 7.29 - 7.05 (m, 4H), 6.97 - 6.36 (m, 3H), 6.11 - 6.01 (m, 1H), 5.55 (br s, 2H), 5.22 - 4.85 (m, 5H), 4.64 - 3.92 (m, 3H), 2.37 - 2.04 (m, 2H). LC-MS (M+H) + = 554.2.

[0149] Example 13: 5-amino-N-(2,6-difluorobenzyl)-N-((5-(2,6-difluorophenyl)pyridine-2-yl)methyl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Step 1: 5-(bis(tert-butoxycarbonyl)amino)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-1,2-dicarboxylic acid 1-(tert-butyl)2-ethyl [ka] To a solution of ethyl 5-amino-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylate (2.0 g, 8.09 mmol) in THF (40 mL), Boc2O (5.3 g, 24.3 mmol), DMAP (99 mg, 0.81 mmol), and Et3N (3.28 g, 16.2 mmol) were added. The mixture was stirred at 45°C for 12 hours and then cooled to room temperature. The mixture was diluted with water (30 mL) and then extracted with toluene (15 mL x 3). The combined organic layer was washed with brine (15 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE:toluene = 1:0~3:1) to obtain the title compound (2.4 g, 54%). LC-MS (M+H) + = 548.4.

[0150] Step 2: 5-((tert-butoxycarbonyl)amino)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid [ka] 5-(bis(tert-butoxycarbonyl)amino)-6,8-dihydro-1H-flu[3,4-d]pyrrolo[3,2-b]pyridine-1,2-dicarboxylic acid 1-(tert-butyl)2-ethyl (2.4 g, 4.38 mmol) was dissolved in THF (20 mL), MeOH (4 mL), and water (4 mL), to which LiOH·H2O (221 mg, 5.26 mmol) was added. The mixture was stirred at 45 °C for 12 hours. The mixture was cooled to room temperature and diluted with water (10 mL). The mixture was washed with ELISA (15 mL x 3). HCl aqueous solution (0.5 M) was carefully added to the aqueous phase until its pH reached 4-5. The solid was collected by filtration to obtain the title compound (0.90 g, 49%). LC-MS (M+H) + = 320.2.

[0151] Step 3: N-(2,6-difluorobenzyl)-1-(5-(2,6-difluorophenyl)pyridine-2-yl)methaneamine [ka] The title compound (260 mg, 55%) was prepared from 5-(2,6-difluorophenyl)picolinealdehyde and (2,6-difluorophenyl)methaneamine by the same method as in Example 5, Step 1. LC-MS (M+H) + = 347.2.

[0152] Step 4: (2-((2,6-difluorobenzyl)((5-(2,6-difluorophenyl)pyridine-2-yl)methyl)carbamoyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-5-yl)carbamate tert-butyl [ka] N-(2,6-difluorobenzyl)-1-(5-(2,6-difluorophenyl)pyridine-2-yl)methaneamine (70 mg, 0.20 mmol) and 5-((tert-butoxycarbonyl)amino)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid (65 mg, 0.20 mmol) were dissolved in THF (3 mL), to which BOPCl (62 mg, 0.24 mmol) and DIPEA (78 mg, 0.61 mmol) were added at 25 °C. The mixture was stirred at 40 °C for 1 hour. The mixture was cooled to room temperature and diluted with water (5 mL). The mixture was extracted with ₹ (5 mL × 4). The combined organic layer was washed with brine (5 mL × 2), dried over Na₂SO₄, filtered, and concentrated under vacuum to obtain the title compound (85 mg, 66%). LC-MS (M+H) + = 648.3.

[0153] Step 5: 5-amino-N-(2,6-difluorobenzyl)-N-((5-(2,6-difluorophenyl)pyridine-2-yl)methyl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide A mixture of (2-((2,6-difluorobenzyl)((5-(2,6-difluorophenyl)pyridine-2-yl)methyl)carbamoyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-5-yl)carbamate tert-butyl (85 mg, 0.13 mmol) in methanolic HCl (3 M, 3 mL) was stirred at 25 °C for 1 hour, and then concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain Example 13 (31 mg, 44%). 1 H NMR (400 MHz, CD3OD) δ 11.67 (s, 1H), 8.60 (br s, 1H), 7.89 (br d, J = 7.9 Hz, 1H), 7.59 - 7.49 (m, 1H), 7.45 (d, J = 8.1 Hz, 1H), 7.40 - 7.32 (m, 1H), 7.31 - 7.23 (m, 2H), 7.09 - 7.00 (m, 2H), 6.65 - 6.26 (m, 1H), 5.55 (s, 2H), 5.13 (br s, 2H), 5.00 (br s, 3H), 4.91 (br s, 3H). LC-MS (M+H) + = 548.2.

[0154] Example 14: 5-amino-N-((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)-N-((2',3,6'-trifluoro-[1,1'-biphenyl]-4-yl)methyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Step 1: (3R,4R)-3-(((2',3,6'-trifluoro-[1,1'-biphenyl]-4-yl)methyl)amino)tetrahydro-2H-pyran-4-ol [ka] The title compound (680 mg, 99%) was prepared from (3R,4R)-3-aminotetrahydro-2H-pyran-4-ol hydrochloride and 2',3,6'-trifluoro-[1,1'-biphenyl]-4-carbaldehyde by the same method as in Example 4, Step 1. LC-MS (M+H) + =338.2.

[0155] Step 2: ((3R,4R)-4-hydroxytetrahydro-2H-pyran-3-yl)((2',3,6'-trifluoro-[1,1'-biphenyl]-4-yl)methyl) tert-butyl carbamate [ka] The title compound (850 mg, 97%) was prepared from (3R,4R)-3-(((2',3,6'-trifluoro-[1,1'-biphenyl]-4-yl)methyl)amino)tetrahydro-2H-pyran-4-ol by the same method as in Step 2 of Example 4. LC-MS (M+H) + =438.3.

[0156] Step 3: ((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)((2',3,6'-trifluoro-[1,1'-biphenyl]-4-yl)methyl) tert-butyl carbamate [ka] The title compound (600 mg, 68%) was prepared from ((3R,4R)-4-hydroxytetrahydro-2H-pyran-3-yl)((2',3,6'-trifluoro-[1,1'-biphenyl]-4-yl)methyl)carbamate tert-butyl by the same method as in Step 3 of Example 4. LC-MS (M+H)+ = 452.3.

[0157] Step 4: (3R,4R)-4-Methoxy-N-((2',3,6'-trifluoro-[1,1'-biphenyl]-4-yl)methyl)tetrahydro-2H-pyran-3-amine hydrochloride [Chemical formula] The title compound (510 mg, 99%) was prepared from tert-butyl ((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)((2’,3,6’-trifluoro-[1,1’-biphenyl]-4-yl)methyl)carbamate by the same method as in Example 4, Step 4. LC-MS (M+H) + =352.2.

[0158] Step 5: tert-Butyl (2-(((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)((2’,3,6’-trifluoro-[1,1’-biphenyl]-4-yl)methyl)carbamoyl)-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-5-yl)carbamate [Chemical formula] The title compound (15 mg, 52%) was prepared from (3R,4R)-4-methoxy-N-((2’,3,6’-trifluoro-[1,1’-biphenyl]-4-yl)methyl)tetrahydro-2H-pyran-3-amine hydrochloride and 5-((tert-butoxycarbonyl)amino)-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid by the same method as in Example 13, Step 4. LC-MS (M+H) + =653.4.

[0159] Step 6: 5-Amino-N-((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)-N-((2’,3,6’-trifluoro-[1,1’-biphenyl]-4-yl)methyl)-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide A mixture of (2-(((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)((2',3,6'-trifluoro-[1,1'-biphenyl]-4-yl)methyl)carbamoyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-5-yl)carbamate tert-butyl (15 mg, 0.020 mmol) in HCl solution of dioxane (4 M, 2 mL) was stirred at room temperature for 1 hour, and then concentrated under vacuum. The residue was purified by preparative HPLC to obtain Example 14 (2 mg, 19%). 1 H NMR (500 MHz, DMSO-d6) δ 11.57 (s, 1H), 7.54-7.45 (m, 2H), 7.38-7.31 (m, 1H), 7.27-7.21 (m, 3H), 6.76 (s, 1H), 5.57 (s, 2H), 5.13 (s, 2H), 4.93 (s, 2H), 4.87-4.76 (m, 1H), 4.75-4.64 (m, 1H), 4.63-4.49 (m, 1H), 4.17-4.04 (m, 1H), 3.86-3.82 (m, 1H), 3.73-3.60 (m, 1H), 3.58-3.50 (m, 1H), 3.41-3.35 (m, 1H), 3.15 (s, 3H), 2.24-2.18 (m, 1H), 1.38-1.27 (m, 1H). LC-MS (M+H) + =553.4.

[0160] Example 15: 5-amino-N-((3',5'-difluoro-[3,4'-bipyridine]-6-yl)methyl)-N-((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Step 1: (3R,4R)-N-((3',5'-difluoro-[3,4'-bipyridine]-6-yl)methyl)-4-methoxytetrahydro-2H-pyran-3-amine [ka] The title compound (150 mg, 85%) was prepared from (3R,4R)-4-methoxytetrahydro-2H-pyran-3-amine and 3',5'-difluoro-[3,4'-bipyridine]-6-carbaldehyde by the same method as in Example 4, Step 1. LC-MS (M+H) + = 336.2.

[0161] Step 2: 5-amino-N-((3',5'-difluoro-[3,4'-bipyridine]-6-yl)methyl)-N-((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 15 (1 mg, 5%) was prepared from 5-amino-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and (3R,4R)-N-((3',5'-difluoro-[3,4'-bipyridine]-6-yl)methyl)-4-methoxytetrahydro-2H-pyran-3-amine using the same method as in Example 2, Step 3. 1 H NMR (500 MHz, DMSO-d6) δ 11.82 - 11.39 (m, 1H), 9.03 - 8.56 (m, 3H), 8.18 - 7.93 (m, 1H), 7.83 - 7.50 (m, 1H), 6.85 - 6.22 (m, 1H), 5.79 - 4.17 (m, 9H), 4.17 - 3.43 (m, 5H), 3.21 - 3.05 (m, 3H), 2.28 - 2.11 (m, 1H), 1.44 - 1.27 (m, 1H). LCMS (M+H) + = 537.4.

[0162] Example 16: 5-amino-N-((5-(2,6-difluorophenyl)pyridine-2-yl)methyl)-N-(1,3-dimethoxypropan-2-yl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Step 1: N-((5-(2,6-Difluorophenyl)pyridin-2-yl)methyl)-1,3-dimethoxypropan-2-amine

Chem.

[0163] Step 2: tert-Butyl (2-(((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)(1,3-dimethoxypropan-2-yl)carbamoyl)-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-5-yl)carbamate

Chem.

[0164] Step 3: 5-amino-N-((5-(2,6-difluorophenyl)pyridine-2-yl)methyl)-N-(1,3-dimethoxypropan-2-yl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 16 (1 mg, 5%) was prepared from (2-(((5-(2,6-difluorophenyl)pyridine-2-yl)methyl)(1,3-dimethoxypropan-2-yl)carbamoyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-5-yl)carbamate tert-butyl by the same method as in Example 14, Step 6. 1H NMR (400 MHz, DMSO-d6) δ 11.52 (s, 1H), 8.59 (brs, 1H), 7.89 (br s, 1H), 7.59 - 7.49 (m, 2H), 7.32 - 7.23 (m, 2H), 6.80 - 6.32 (m, 1H), 5.54 (s, 2H), 5.12 - 4.91 (m, 7H), 3.65 - 3.47 (m, 4H), 3.16 (s, 6H). LC-MS (M+H)+ = 524.2.

[0165] Examples 17 and 18: (S)-5-amino-N-((5-(2,6-difluorophenyl)pyridine-2-yl)methyl)-N-(1-(pyrimidine-2-yl)ethyl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide and (R)-5-amino-N-((5-(2,6-difluorophenyl)pyridine-2-yl)methyl)-N-(1-(pyrimidine-2-yl)ethyl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Step 1: N-((5-(2,6-difluorophenyl)pyridine-2-yl)methyl)-1-(pyrimidine-2-yl)ethane-1-amine [ka] (5-(2,6-difluorophenyl)pyridine-2-yl)methaneamine (0.10 g, 0.45 mmol) and 1-(pyrimidine-2-yl)ethane-1-one (55 mg, 0.45 mmol) were dissolved in DCM (2.7 mL) and MeOH (0.9 mL) to which NaBH(OAc)3 (192 mg, 0.91 mmol) was added. The mixture was stirred at 20°C for 1 hour. Saturated NaHCO3 (10 mL) was added, and the mixture was extracted with DCM (2 mL x 4). The combined organic layer was washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (PE / siRNA = 1 / 0 ~ 0 / 1) to obtain the title compound (70 mg, 47%). LC-MS (M+H) + = 327.3.

[0166] Step 2: (2-(((5-(2,6-difluorophenyl)pyridine-2-yl)methyl)(1-(pyrimidine-2-yl)ethyl)carbamoyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-5-yl)carbamate tert-butyl [ka] N-((5-(2,6-difluorophenyl)pyridine-2-yl)methyl)-1-(pyrimidine-2-yl)ethane-1-amine (70 mg, 0.21 mmol) and 5-((tert-butoxycarbonyl)amino)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid (72 mg, 0.23 mmol) were dissolved in THF (1 mL) and DMF (0.5 mL), respectively. BOPCl (82 mg, 0.32 mmol) and DIPEA (139 mg, 1.07 mmol) were added. The mixture was stirred at 40°C for 1 hour. The mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by silica gel chromatography (PE / Â=3 / 1~0 / 1) to obtain the title compound (50 mg, 37%). LC-MS (M+H) + = 628.3.

[0167] Step 3: (S)-5-amino-N-((5-(2,6-difluorophenyl)pyridine-2-yl)methyl)-N-(1-(pyrimidine-2-yl)ethyl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide and (R)-5-amino-N-((5-(2,6-difluorophenyl)pyridine-2-yl)methyl)-N-(1-(pyrimidine-2-yl)ethyl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide A solution of (2-(((5-(2,6-difluorophenyl)pyridine-2-yl)methyl)(1-(pyrimidine-2-yl)ethyl)carbamoyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-5-yl)carbamate tert-butyl (50 mg, 0.080 mol) in methanolic HCl (4 M, 0.50 mL) was stirred at 20 °C for 12 hours and then concentrated under vacuum. The residue was purified by preparative HPLC and then by preparative SFC to obtain Example 17 (10 mg, 24%) and Example 18 (7 mg, 17%).

[0168] The conditions for the chiral-SFC analysis were as follows: Column: Chiralcel OJ-3, Column size: 4.6 × 50 mm, 3 μm, Mobile phase: A: CO2, B: 14 mM NH3 MeOH solution, Gradient: A:B = 95:5 (0.2 min), A:B = 95:5 to 50:50 (1 min), A:B = 50:50 (1 min), A:B = 50:50 to 95:5 (0.4 min), A:B = 95:5 (0.4 min), Flow rate: 3.4 mL / min, Temperature: 35°C.

[0169] Example 17: Analysis of chiral-SFC tR=1.23 min. 1 H NMR (400 MHz, DMSO-d6) δ 11.74-11.59 (m, 1H), 8.92-8.46 (m, 3H), 8.01-7.22 (m, 6H), 6.81-6.23 (m, 1H), 6.21-5.48 (m, 3H), 5.40-4.52 (m, 6H), 1.78-1.59 (m, 3H). LC-MS (M+H) += 528.2.

[0170] Example 18: Analysis of chiral-SFC tR=1.47 min. 1 H NMR (400 MHz, DMSO-d6) δ 11.75-11.59 (m, 1H), 8.92-8.44 (m, 3H), 8.01-7.22 (m, 6H), 6.81-6.23 (m, 1H), 6.21-5.49 (m, 3H), 5.40-4.52 (m, 6H), 1.78-1.58 (m, 3H). LC-MS (M+H) + = 528.2.

[0171] Examples 19 and 20: (R)-5-amino-N-(3,4-dihydro-2H-pyrano[3,2-b]pyridine-4-yl)-N-((2',3,6'-trifluoro-[1,1'-biphenyl]-4-yl)methyl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide and (S)-5-amino-N-(3,4-dihydro-2H-pyrano[3,2-b]pyridine-4-yl)-N-((2',3,6'-trifluoro-[1,1'-biphenyl]-4-yl)methyl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Step 1: N-((2',3,6'-trifluoro-[1,1'-biphenyl]-4-yl)methyl)-3,4-dihydro-2H-pyrano[3,2-b]pyridine-4-amine [ka] 3,4-Dihydro-2H-pyrano[3,2-b]pyridine-4-amine (330 mg, 2.2 mmol) and 2',3,6'-trifluoro-[1,1'-biphenyl]-4-carbaldehyde (470 mg, 2.0 mmol) were mixed in 20 mL of DCM. NaBH(OAc)3 (848 mg, 4.0 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with 30 mL of DCM, washed with saturated NaHCO3 (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM / MeOH = 20 / 1) to obtain the title compound (620 mg, 83%). LC-MS (M+H) + = 371.4.

[0172] Step 2: (2-((3,4-dihydro-2H-pyrano[3,2-b]pyridine-4-yl)((2',3,6'-trifluoro-[1,1'-biphenyl]-4-yl)methyl)carbamoyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-5-yl) tert-butyl carbamate [ka] The title compound (140 mg, 83%) was prepared from 5-((tert-butoxycarbonyl)amino)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and N-((2',3,6'-trifluoro-[1,1'-biphenyl]-4-yl)methyl)-3,4-dihydro-2H-pyrano[3,2-b]pyridine-4-amine by the same method as in Examples 17 and 18, Step 2. LC-MS (M+H) + = 672.4.

[0173] Step 3: (R)-5-amino-N-(3,4-dihydro-2H-pyrano[3,2-b]pyridine-4-yl)-N-((2',3,6'-trifluoro-[1,1'-biphenyl]-4-yl)methyl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide and (S)-5-amino-N-(3,4-dihydro-2H-pyrano[3,2-b]pyridine-4-yl)-N-((2',3,6'-trifluoro-[1,1'-biphenyl]-4-yl)methyl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide To a solution of (2-((3,4-dihydro-2H-pyrano[3,2-b]pyridine-4-yl)((2',3,6'-trifluoro-[1,1'-biphenyl]-4-yl)methyl)carbamoyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-5-yl)carbamate tert-butyl (140 mg, 0.21 mmol) in DCM (3 mL), a solution of HCl dioxane (4 M, 8 mL) was added, and the mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure. The residue was purified by preparative TLC, followed by chiral preparative HPLC, to obtain Example 19 (19 mg, 16%) and Example 20 (18 mg, 15%).

[0174] The analytical chiral-HPLC conditions were as follows: Column: CHIRALPAK OD-H, Column size: 4.6 × 150 mm, 5 μm, Mobile phase: Hexane:(0.1% diethylamine EtOH solution) = 9:1 (isocratic), Flow rate: 1.0 mL / min, Temperature: 25°C.

[0175] Example 19: Analysis by chiral-HPLC tR=18.65 min. 1 H NMR (500 MHz, DMSO-d6) δ 13.02-12.68 (m, 1H), 8.29-7.04 (m, 9H), 7.01-6.42 (m, 2H), 6.04-3.86 (m, 11H), 2.44-2.10 (m, 2H). LC-MS (M+H) + = 572.4.

[0176] Example 20: Analysis by chiral-HPLC tR=22.16 min. 1 H NMR (500 MHz, DMSO-d6) δ 13.02-12.68 (m, 1H), 8.29-7.04 (m, 9H), 7.01-6.42 (m, 2H), 6.04-3.86 (m, 11H), 2.44-2.10 (m, 2H). LC-MS (M+H) + = 572.4.

[0177] Example 21: (R)-5-amino-N-(4-cyano-2,6-difluorobenzyl)-N-(5,6,7,8-tetrahydroquinoline-8-yl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Step 1: (R)-3,5-difluoro-4-(((5,6,7,8-tetrahydroquinoline-8-yl)amino)methyl)benzonitrile [ka] The title compound (200 mg, 56%) was prepared from (R)-5,6,7,8-tetrahydroquinoline-8-amine and 3,5-difluoro-4-formylbenzonitrile using the same method as in Example 5, Step 1. LC-MS (M+H) + = 300.1.

[0178] Step 2: (R)-(2-((4-cyano-2,6-difluorobenzyl)(5,6,7,8-tetrahydroquinoline-8-yl)carbamoyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-5-yl)carbamate tert-butyl [ka] The title compound (30 mg, 30%) was prepared from 5-((tert-butoxycarbonyl)amino)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and (R)-3,5-difluoro-4-(((5,6,7,8-tetrahydroquinoline-8-yl)amino)methyl)benzonitrile using the same method as in Examples 17 and 18, Step 2. LC-MS (M+H) + = 601.3.

[0179] Step 3: (R)-5-amino-N-(4-cyano-2,6-difluorobenzyl)-N-(5,6,7,8-tetrahydroquinoline-8-yl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 21 (17 mg, 68%) was prepared from (R)-(2-((4-cyano-2,6-difluorobenzyl)(5,6,7,8-tetrahydroquinoline-8-yl)carbamoyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-5-yl)carbamate tert-butyl by the same method as in Example 14, Step 6. 1 H NMR (500 MHz, DMSO-d6) δ 12.21 (s, 1H), 8.33 (s, 1H), 7.82 - 7.61 (m, 2H), 7.53 (s, 1H), 7.19 (s, 1H), 6.89 - 5.62 (m, 3H), 5.31 - 5.05 (m, 2H), 5.05 - 4.80 (m, 2H), 4.71 - 4.44 (m, 1H), 4.31 - 4.08 (m, 1H), 2.97 - 2.66 (m, 2H), 2.44 - 2.23 (m, 2H), 2.11 - 1.92 (m, 1H), 1.83 - 1.63 (m, 1H). LC-MS (M+H) + = 501.3.

[0180] Example 22: 5-amino-N-(4-cyano-2,6-difluorobenzyl)-N-(2,6-difluorobenzyl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Step 1: 4-(((2,6-difluorobenzyl)amino)methyl)-3,5-difluorobenzonitrile [ka] To a mixture of 3,5-difluoro-4-formylbenzonitrile (350 mg, 2.09 mmol) and (2,6-difluorophenyl)methaneamine (300 mg, 2.09 mmol) in DCM (10 mL), NaBH(OAc)3 (889 mg, 4.09 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The mixture was diluted with DCM (30 mL), washed with saturated NaHCO3 (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM / MeOH = 20 / 1) to obtain the title compound (370 mg, 60%). LC-MS (M+H) + = 295.2.

[0181] Step 2: (2-((4-cyano-2,6-difluorobenzyl)(2,6-difluorobenzyl)carbamoyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-5-yl)carbamate tert-butyl [ka] The title compound (50 mg, 93%) was prepared from 5-((tert-butoxycarbonyl)amino)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and 4-(((2,6-difluorobenzyl)amino)methyl)-3,5-difluorobenzonitrile by the same method as in Examples 17 and 18, Step 2. LC-MS (M+H) += 596.3.

[0182] Step 3: 5-amino-N-(4-cyano-2,6-difluorobenzyl)-N-(2,6-difluorobenzyl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide A solution of (2-((4-cyano-2,6-difluorobenzyl)(2,6-difluorobenzyl)carbamoyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-5-yl)carbamate tert-butyl in HCl with dioxane (4M, 2mL) was stirred at room temperature for 3 hours. The mixture was concentrated under vacuum. The residue was purified by preparative HPLC to obtain Example 22 (24 mg, 58%). 1 H NMR (500 MHz, DMSO-d6) δ 11.62 (s, 1H), 7.89 - 7.67 (m, 2H), 7.53 - 7.34 (m, 1H), 7.17 - 6.98 (m, 2H), 6.66 (d, J = 1.7 Hz, 1H), 5.60 (s, 2H), 5.24 - 5.07 (m, 2H), 5.08 - 4.67 (m, 6H). LC-MS (M+H) + =496.3.

[0183] Examples 23 and 24: (R)-5-amino-N-((5-(2,6-difluorophenyl)pyridine-2-yl)methyl)-N-((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)-6-methyl-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide and (S)-5-amino-N-((5-(2,6-difluorophenyl)pyridine-2-yl)methyl)-N-((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)-6-methyl-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Step 1: 2-methyl-4-oxotetrahydrofuran-3-carbonitrile [ka] Methyl glycolate (20.0 g, 0.222 mol) was added at 0°C to a suspension of NaH (60%, 4.44 g, 0.11 mol) in THF (150 mL). The mixture was stirred at 60°C for 30 minutes. A solution of crotononitrile (17.8 g, 0.266 mmol) in THF (50 mL) was added dropwise at 60°C. The mixture was stirred at 70°C for 2 hours. The mixture was cooled to 0°C and acidified with aqueous HCl (1 M) until its pH reached 4-5. The mixture was extracted with HCl (300 mL). The organic layer was washed with water (100 mL) and brine (100 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / HCl = 1 / 1) to obtain the title compound (10.0 g, 36%). 1 H NMR (500 MHz, CDCl3) δ 4.42 - 4.27 (m, 2H), 4.26 - 4.18 (m, 2H), 3.23 - 2.98 (m, 1H), 1.63 - 1.27 (m, 3H).

[0184] Step 2: 4-Cyano-5-methyl-2,5-dihydrofuran-3-yltrifluoromethanesulfonate [ka] To a mixture of 2-methyl-4-oxotetrahydrofuran-3-carbonitride (5.0 g, 40 mmol) and DIPEA (6.7 g, 52 mmol) in DCM (100 mL), Tf2O (13.5 g, 48 mmol) was added dropwise at -78°C, and the mixture was stirred at -78°C for 2 hours. The mixture was diluted with DCM (100 mL), sequentially washed with saturated NaHCO3 (50 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / siRNA=3 / 1) to obtain the title compound (8.5 g, 83%). 1HNMR (500 MHz, CDCl3) δ 5.13-5.06 (m, 1H), 4.94 - 4.76 (m, 2H), 1.49 (d, J = 6.3 Hz, 3H).

[0185] Step 3: 4-((tert-butoxycarbonyl)amino)-5-(4-cyano-5-methyl-2,5-dihydrofuran-3-yl)-1H-pyrrole-2-carboxylate ethyl [ka] To a solution of ethyl 5-bromo-4-((tert-butoxycarbonyl)amino)-1H-pyrrole-2-carboxylate (3.0 g, 9.0 mmol) and BPD (4.6 g, 18.0 mmol) in THF (50 mL), Pd2(dba)3 (0.41 g, 0.45 mmol), KOAc (2.65 g, 27.0 mmol), and XPhos (0.43 g, 0.90 mmol) were added. The mixture was stirred at 75 °C for 3 hours and then cooled to room temperature. The solid was filtered off, and the filtrate was concentrated under vacuum. The crude substance was redissolved in dioxane (100 mL) and water (20 mL), followed by the addition of 4-cyano-5-methyl-2,5-dihydrofuran-3-yltrifluoromethanesulfonate (3.0 g, 11.7 mmol), Pd(dppf)Cl2 (83 mg, 0.58 mmol), and NaHCO3 (1.96 g, 23.4 mmol). The mixture was stirred at 80°C for 5 hours. The mixture was cooled to room temperature and diluted with HCl (100 mL). The mixture was washed with brine (50 mL), and the aqueous layer was back-extracted with HCl (50 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / HCl = 3 / 1) to obtain the title compound (2.0 g, 62%). LC-MS (M+H) + =362.1.

[0186] Step 4: 5-amino-6-methyl-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylate ethyl [ka] 4-((tert-butoxycarbonyl)amino)-5-(4-cyano-5-methyl-2,5-dihydrofuran-3-yl)-1H-pyrrole-2-carboxylate ethyl (2.0 g, 5.5 mmol) was added to a 10 mL solution of dioxane, and the mixture was stirred at room temperature for 5 hours. The mixture was concentrated under reduced pressure, and the crude substance was redissolved in EtOH (60 mL), followed by the addition of K2CO3 (3.44 g, 25 mmol). The mixture was stirred at 70°C for 4 hours, and then cooled to room temperature. The solid was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM / MeOH = 10 / 1) to obtain the title compound (1.0 g, 69%). LC-MS (M+H) + = 262.1.

[0187] Step 5: 5-amino-6-methyl-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid [ka] A mixture of ethyl 5-amino-6-methyl-6,8-dihydro-1H-flu[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylate (1.0 g, 3.8 mmol) and LiOH·H2O (0.32 g, 7.6 mmol) in MeOH (20 mL) and water (10 mL) was stirred at 50°C for 3 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain the title compound (500 mg, 56%). LCMS (M+H) + = 234.1.

[0188] Step 6: (R)-5-amino-N-((5-(2,6-difluorophenyl)pyridine-2-yl)methyl)-N-((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)-6-methyl-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide and (S)-5-amino-N-((5-(2,6-difluorophenyl)pyridine-2-yl)methyl)-N-((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)-6-methyl-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide 5-amino-6-methyl-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid (170 mg, 0.73 mmol), (3R,4R)-N-((5-(2,6-difluorophenyl)pyridine-2-yl)methyl)-4-methoxytetrahydro-2H-pyran-3-amine hydrochloride (270 mg, 0.73 mmol), and DIPEA (471 mg, 3.65 mmol) were mixed in anhydrous DMF (5 mL). HATU (832 mg, 2.19 mmol) was added under nitrogen, and the mixture was stirred at 70°C for 2 hours. The mixture was cooled to room temperature and diluted with ethyl acetate (20 mL). The mixture was washed with water (20 mL) and brine (20 mL). The aqueous layer was back-extracted with ethyl acetate (20 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude substance was purified by preparative HPLC and chiral-SFC to obtain Example 23 (47 mg, 12%) and Example 24 (45 mg, 11%).

[0189] The analytical chiral-HPLC conditions were as follows: Column: CHIRALPAK IE-3, Column size: 4.6 × 50 mm, 3 μm, Mobile phase: (0.1% diethylamine MTBE solution): MeOH:DCM = 3:1:1 (isocratic), Flow rate: 1.0 mL / min, Temperature: 25°C.

[0190] Example 23: Analysis by chiral-HPLC tR=2.26 min. 1H NMR (500 MHz, DMSO-d6) δ 11.92 - 11.42 (m, 1H), 8.90 - 8.46 (m, 1H), 8.06 - 7.80 (m, 1H), 7.76 - 7.46 (m, 2H), 7.40 - 7.14 (m, 2H), 6.85 - 6.24 (m, 1H), 5.88 - 4.72 (m, 7H), 4.61 - 3.35 (m, 6H), 3.20 - 3.10 (m, 3H), 2.24 - 2.14 (m, 1H), 1.41 - 1.29 (m, 4H). LCMS (M+H) + = 550.4.

[0191] Example 24: Analysis by chiral-HPLC tR=2.97 min. 1 H NMR (500 MHz, DMSO-d6) δ 11.90 - 11.46 (m, 1H), 8.82 - 8.48 (m, 1H), 8.03 - 7.76 (m, 1H), 7.74 - 7.46 (m, 2H), 7.38 - 7.19 (m, 2H), 6.85 - 6.26 (m, 1H), 5.81 - 4.70 (m, 7H), 4.67 - 3.61 (m, 4H), 3.59 - 3.35 (m, 2H), 3.20 - 3.06 (m, 3H), 2.27 - 2.15 (m, 1H), 1.43 - 1.27 (m, 4H).LCMS (M+H) + = 550.4.

[0192] Example 25: (R)-5-amino-N-((5-(1-methyl-1H-1,2,4-triazole-5-yl)pyridine-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinoline-8-yl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Step 1: 2-(1,3-dioxolan-2-yl)-5-(1-methyl-1H-1,2,4-triazole-5-yl)pyridine [ka] (6-(1,3-dioxolan-2-yl)pyridine-3-yl)boronic acid (2.0 g, 10.3 mmol) was mixed in dioxane (20 mL), toluene (10 mL), and water (10 mL). 5-bromo-1-methyl-1H-1,2,4-triazole (1.66 g, 10.3 mmol), K3PO4 (6.53 g, 30.8 mmol), and Pd(dppf)Cl2 (751 mg, 1.0 mmol) were added. The mixture was stirred at 80°C for 12 hours and then cooled to room temperature. The solid was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE:Â=5:1~0:1) to obtain the title compound (1.3 g, 55%). LC-MS (M+H) + = 233.3.

[0193] Step 2: 5-(1-methyl-1H-1,2,4-triazol-5-yl)picolinaldehyde [ka] 2-(1,3-dioxolan-2-yl)-5-(1-methyl-1H-1,2,4-triazole-5-yl)pyridine (1.2 g, 5.17 mmol) was mixed in water (6 mL) and dioxane (12 mL). Concentrated HCl (6.5 mL) was added, and the mixture was stirred at 60°C for 3 hours. The mixture was cooled to room temperature and neutralized with saturated NaHCO3 until the pH reached 7-8. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layer was dried over Na2SO4, filtered, and concentrated under vacuum to obtain the title compound (0.60 g, 62%). LC-MS (M+H) + = 189.3.

[0194] Step 3: (R)-N-((5-(1-methyl-1H-1,2,4-triazole-5-yl)pyridine-2-yl)methyl)-5,6,7,8-tetrahydroquinoline-8-amine [ka] The title compound (0.28 g, 25%) was prepared from (R)-5,6,7,8-tetrahydroquinoline-8-amine and 5-(1-methyl-1H-1,2,4-triazole-5-yl)picolinealdehyde by the same method as in Example 5, Step 1. LC-MS (M+H) + = 321.1.

[0195] Step 4: (R)-(2-(((5-(1-methyl-1H-1,2,4-triazole-5-yl)pyridine-2-yl)methyl)(5,6,7,8-tetrahydroquinoline-8-yl)carbamoyl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-5-yl)carbamate tert-butyl [ka] The title compound (30 mg, 32%) was prepared from 5-((tert-butoxycarbonyl)amino)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and (R)-N-((5-(1-methyl-1H-1,2,4-triazole-5-yl)pyridine-2-yl)methyl)-5,6,7,8-tetrahydroquinoline-8-amine by the same method as in Examples 17 and 18, Step 2. LC-MS (M+H) + = 622.1.

[0196] Step 5: (R)-5-amino-N-((5-(1-methyl-1H-1,2,4-triazole-5-yl)pyridine-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinoline-8-yl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 25 (8 mg, 30%) was prepared from (R)-(2-(((5-(1-methyl-1H-1,2,4-triazole-5-yl)pyridine-2-yl)methyl)(5,6,7,8-tetrahydroquinoline-8-yl)carbamoyl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-5-yl)carbamate tert-butyl by the same method as in Example 22, Step 3. 1 H NMR (500 MHz, DMSO-d6) δ 11.75-11.53 (m, 1H), 9.10-8.75 (m, 1H), 8.50-7.90 (m, 6H), 6.81-6.17 (m, 1H), 6.00-4.76 (m, 8H), 4.10-3.87 (m, 4H), 3.05-2.39 (m, 4H), 2.30-1.68 (m, 4H). LC-MS (M+H) + =522.4.

[0197] Example 26: 5-amino-N-((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)-N-((5-(trifluoromethyl)pyridine-2-yl)methyl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Step 1: (3R,4R)-4-Methoxy-N-((5-(trifluoromethyl)pyridine-2-yl)methyl)tetrahydro-2H-pyran-3-amine [ka] The title compound (50 mg, 55%) was prepared from (3R,4R)-4-methoxytetrahydro-2H-pyran-3-amine and 5-(trifluoromethyl)picolinealdehyde by the same method as in Example 4, Step 1. LC-MS (M+H) + = 291.3.

[0198] Step 2: (2-(((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)((5-(trifluoromethyl)pyridine-2-yl)methyl)carbamoyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-5-yl) tert-butyl carbamate [ka] The title compound (60 mg, 59%) was prepared from 5-((tert-butoxycarbonyl)amino)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and (3R,4R)-4-methoxy-N-((5-(trifluoromethyl)pyridine-2-yl)methyl)tetrahydro-2H-pyran-3-amine by the same method as in Examples 17 and 18, Step 2. LC-MS (M+H) + = 592.4.

[0199] Step 3: 5-amino-N-((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)-N-((5-(trifluoromethyl)pyridine-2-yl)methyl)-6,8-dihydro-1H-flu[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 26 (31 mg, 63%) was prepared from (2-(((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)((5-(trifluoromethyl)pyridine-2-yl)methyl)carbamoyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-5-yl)carbamate tert-butyl by the same method as in Example 22, Step 3. 1H NMR (500 MHz, DMSO-d6) δ 11.73 - 11.39 (m, 1H), 9.10 - 8.79 (m, 1H), 8.30 - 8.07 (m, 1H), 7.86 - 7.54 (m, 1H), 6.82 - 6.08 (m, 1H), 5.57 (s, 2H), 5.26 - 4.73 (m, 6H), 4.67 - 3.44 (m, 5H), 3.21 - 3.04 (m, 3H), 2.32 - 2.06 (m, 1H), 1.41 - 1.20 (m, 1H). LC-MS (M+H) + = 492.4.

[0200] Example 27: 5-amino-N-((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)-N-((5-phenylpyridine-2-yl)methyl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Step 1: (3R,4R)-4-Methoxy-N-((5-phenylpyridine-2-yl)methyl)tetrahydro-2H-pyran-3-amine [ka] The title compound (0.050 g, 58%) was prepared from 5-phenylpicoline aldehyde and (3R,4R)-4-methoxytetrahydro-2H-pyran-3-amine by the same method as in Example 4, Step 1. LC-MS (M+H) + = 299.1.

[0201] Step 2: (2-(((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)((5-phenylpyridine-2-yl)methyl)carbamoyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-5-yl)carbamate tert-butyl [ka] The title compound (60 mg, 57%) was prepared from 5-((tert-butoxycarbonyl)amino)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and (3R,4R)-4-methoxy-N-((5-phenylpyridine-2-yl)methyl)tetrahydro-2H-pyran-3-amine by the same method as in Examples 17 and 18, Step 2. LC-MS (M+H) + = 600.2.

[0202] Step 3: 5-amino-N-((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)-N-((5-phenylpyridine-2-yl)methyl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 27 (23 mg, 46%) was prepared from (2-(((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)((5-phenylpyridine-2-yl)methyl)carbamoyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-5-yl)carbamate tert-butyl using the same method as in Example 22, Step 3. 1H NMR (500 MHz, DMSO-d6) δ 11.57 (s, 1H), 8.82 (s, 1H), 8.04 (s, 1H), 7.72 (s, 2H), 7.59 - 7.35 (m, 4H), 6.74 (s, 1H), 5.58-5.51 (m, 2H), 5.13 (s, 2H), 4.93 (s, 3H), 4.77 - 4.55 (m, 1H), 4.05 (s, 1H), 3.84 (d, J = 7.9 Hz, 2H), 3.51 - 3.26 (m, 6H), 2.20 (d, J = 10.1 Hz, 1H), 1.33 (s, 1H). LC-MS (M+H) + = 500.2.

[0203] Example 28: N-([3,4'-bipyridine]-6-ylmethyl)-5-amino-N-((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Step 1: [3,4'-bipyridine]-6-carbaldehyde [ka] The title compound (1.0 g, 100%) was prepared from 5-bromopicoline aldehyde and pyridine-4-ylboronic acid by the same method as in Example 6, Step 1. LC-MS (M+H) + = 185.0.

[0204] Step 2: (3R,4R)-N-([3,4'-bipyridine]-6-ylmethyl)-4-methoxytetrahydro-2H-pyran-3-amine [ka] The title compound (40 mg, 29%) was prepared from [3,4'-bipyridine]-6-carbaldehyde and (3R,4R)-4-methoxytetrahydro-2H-pyran-3-amine using the same method as in Example 4, Step 1. LC-MS (M+H) + = 300.1.

[0205] Step 3: (2-(([3,4'-bipyridine]-6-ylmethyl)((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)carbamoyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-5-yl)carbamate tert-butyl [ka] The title compound (35 mg, 29%) was prepared from 5-((tert-butoxycarbonyl)amino)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and (3R,4R)-N-([3,4'-bipyridine]-6-ylmethyl)-4-methoxytetrahydro-2H-pyran-3-amine by the same method as in Examples 17 and 18, Step 2. LC-MS (M+H) + = 601.2.

[0206] Step 4: N-([3,4'-bipyridine]-6-ylmethyl)-5-amino-N-((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 28 (2 mg, 7%) was prepared from (2-(([3,4'-bipyridine]-6-ylmethyl)((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)carbamoyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-5-yl)carbamate tert-butyl by the same method as in Example 22, Step 3. 1 H NMR (500 MHz, DMSO-d6) δ 11.56 (s, 1H), 9.01 (d, J = 46.7 Hz, 1H), 8.67 (d, J = 5.2 Hz, 2H), 8.17 (s, 1H), 7.79 (s, 2H), 7.65-7.53 (m, 1H), 6.74 (s, 1H), 5.57-5.50 (m, 2H), 5.13 (s, 2H), 4.93 (s, 2H), 4.82 - 4.50 (m, 1H), 4.06 (s, 1H), 3.84 (d, J = 9.7 Hz, 2H), 3.68 (s, 1H), 3.50 (s, 1H), 3.17 (s, 3H), 2.20 (d, J = 10.0 Hz, 1H), 1.34 (s, 1H). LC-MS (M+H) + = 501.2.

[0207] Example 29: N-([3,4'-bipyridine]-6-ylmethyl)-5-amino-N-(2,6-difluorobenzyl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Step 1: 1-([3,4'-bipyridine]-6-yl)-N-(2,6-difluorobenzyl)methaneamine [ka] The title compound (40 mg, 23%) was prepared from [3,4'-bipyridine]-6-carbaldehyde and (2,6-difluorophenyl)methaneamine using the same method as in Example 3, Step 1. LC-MS (M+H) + = 312.1.

[0208] Step 2: (2-(([3,4'-bipyridine]-6-ylmethyl)(2,6-difluorobenzyl)carbamoyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-5-yl)carbamate tert-butyl [ka] The title compound (20 mg, 26%) was prepared from 5-((tert-butoxycarbonyl)amino)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and 1-([3,4'-bipyridine]-6-yl)-N-(2,6-difluorobenzyl)methaneamine by the same method as in Examples 17 and 18, Step 2. LC-MS (M+H) + = 613.2.

[0209] Step 3: N-([3,4'-bipyridine]-6-ylmethyl)-5-amino-N-(2,6-difluorobenzyl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 29 (4 mg, 25%) was prepared from (2-(([3,4'-bipyridine]-6-ylmethyl)(2,6-difluorobenzyl)carbamoyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-5-yl)carbamate tert-butyl using the same method as in Example 22, Step 3. 1 H NMR (500 MHz, DMSO-d6) δ 11.67 (s, 1H), 8.98 (s, 1H), 8.68 (dd, J = 4.6, 1.5 Hz, 2H), 8.20 (d, J = 7.3 Hz, 1H), 7.78 (d, J = 5.9 Hz, 2H), 7.45 (d, J = 8.2 Hz, 1H), 7.44 - 7.32 (m, 1H), 7.05 (t, J = 8.0 Hz, 2H), 6.46 (s, 1H), 5.55 (s, 2H), 5.13 (s, 2H), 5.00 (s, 2H), 4.91 (s,2H).LC-MS (M+H) + = 513.1.

[0210] Example 30: 5-amino-N-((3',5'-difluoro-[3,4'-bipyridine]-6-yl)methyl)-N-(2,6-difluorobenzyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Step 1: 1-(3',5'-difluoro-[3,4'-bipyridine]-6-yl)-N-(2,6-difluorobenzyl)methaneamine [ka] The title compound (130 mg, 75%) was prepared from 3',5'-difluoro-[3,4'-bipyridine]-6-carbaldehyde and (2,6-difluorophenyl)methaneamine using the same method as in Example 3, Step 1. LC-MS (M+H) + = 348.2.

[0211] Step 2: 5-amino-N-((3',5'-difluoro-[3,4'-bipyridine]-6-yl)methyl)-N-(2,6-difluorobenzyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 30 (15 mg, 27%) was prepared from 5-amino-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and 1-(3',5'-difluoro-[3,4'-bipyridine]-6-yl)-N-(2,6-difluorobenzyl)methaneamine using the same method as in Example 2, Step 3. 1 H NMR (500 MHz, DMSO-d6) δ 11.72 (s, 1H), 8.78 - 8.62 (m, 3H), 8.05 - 7.95 (m, 1H), 7.55 - 7.30 (m, 2H), 7.04 (t, J = 8.0 Hz, 2H), 6.52 (s, 1H), 5.85 - 4.75 (m, 10H). LC-MS (M+H) + = 549.3.

[0212] Example 31: 5-amino-N-(2,6-dichlorobenzyl)-N-((3',5'-difluoro-[3,4'-bipyridine]-6-yl)methyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Step 1: N-(2,6-dichlorobenzyl)-1-(3',5'-difluoro-[3,4'-bipyridine]-6-yl)methaneamine [ka] The title compound (140 mg, 74%) was prepared from 3',5'-difluoro-[3,4'-bipyridine]-6-carbaldehyde and (2,6-dichlorophenyl)methaneamine by the same method as in Example 5, Step 1. LC-MS (M+H) + = 380.1

[0213] Step 2: 5-amino-N-(2,6-dichlorobenzyl)-N-((3',5'-difluoro-[3,4'-bipyridine]-6-yl)methyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 31 (14 mg, 24%) was prepared from 5-amino-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and N-(2,6-dichlorobenzyl)-1-(3',5'-difluoro-[3,4'-bipyridine]-6-yl)methaneamine using the same method as in Example 2, Step 3. 1 H NMR (500 MHz, DMSO-d6) δ 11.69 (s, 1H), 8.72 - 8.53 (m, 3H), 7.94 (d, J = 8.0 Hz, 1H), 7.51 - 7.35 (m, 3H), 7.28 (t, J = 8.0 Hz, 1H), 6.52 (s, 1H), 5.56 (s, 2H), 5.47 - 4.62(m, 8H). LC-MS (M+H) + = 581.3.

[0214] Example 32: 5-amino-N-((5-cyanopyridine-2-yl)methyl)-N-(2,6-difluorobenzyl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Step 1: 6-(((2,6-difluorobenzyl)amino)methyl)nicotinonitrile [ka] The title compound (260 mg, 100%) was prepared from (2,6-difluorophenyl)methaneamine and 6-formylnicotinonitrile using the same method as in Example 3, Step 1. LC-MS (M+H) + = 260.2.

[0215] Step 2: 5-Amino-N-((5-cyanopyridin-2-yl)methyl)-N-(2,6-difluorobenzyl)-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 32 (8 mg, 9%) was prepared from 6-(((2,6-difluorobenzyl)amino)methyl)nicotinonitrile and 5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid in the same manner as in Example 2, Step 3. 1 H NMR (500 MHz, DMSO-d6) δ 11.64 (s, 1H), 8.95 (s, 1H), 8.27 (d, J = 7.2 Hz, 1H), 7.51 (d, J = 7.8 Hz, 1H), 7.40 - 7.30 (m, 1H), 7.13 - 6.96 (m, 2H), 6.87 - 6.11 (m, 1H), 5.55 (s, 2H), 5.27 - 4.71 (m, 8H). LC-MS (M+H) + = 461.4.

[0216] Example 33: 5-Amino-N-(cyclopropylmethyl)-N-(2,6-difluorobenzyl)-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide

Chemical formula

Chemical formula

[0217] Step 2: 5-amino-N-(cyclopropylmethyl)-N-(2,6-difluorobenzyl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 33 (9 mg, 16%) was prepared from 5-amino-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and 1-cyclopropyl-N-(2,6-difluorobenzyl)methaneamine using the same method as in Example 2, Step 3. 1H NMR (500 MHz, DMSO-d6) δ 11.75-11.47 (m, 1H), 7.51-7.36 (m, 1H), 7.21-7.00 (m, 2H), 6.71-6.57 (m, 1H), 5.74-5.47 (m, 2H), 5.25-4.84 (m, 6H), 3.57-3.39 (m, 2H), 1.11-0.97 (m, 1H), 0.60-0.33 (m, 2H), 0.27-0.03 (m, 2H). LC-MS (M+H) + =399.3.

[0218] Example 34: 5-amino-N-((3-fluoro-5-(trifluoromethyl)pyridine-2-yl)methyl)-N-((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Step 1: (3R,4R)-N-((3-fluoro-5-(trifluoromethyl)pyridine-2-yl)methyl)-4-methoxytetrahydro-2H-pyran-3-amine [ka] Triethylamine (575 mg, 5.7 mmol) was added to a mixture of 3-fluoro-5-(trifluoromethyl)picoline aldehyde (1.0 g, 5.18 mmol) and (3R,4R)-4-methoxytetrahydro-2H-pyran-3-amine (747 mg, 5.7 mmol) in 50 mL of distilled mineral water (DCM), and the mixture was stirred at room temperature for 10 minutes. NaBH(OAc)3 (2.2 g, 10.36 mmol) was added, and the mixture was stirred at room temperature for a further 2 hours. The mixture was quenched with saturated NaHCO3, diluted in 40 mL of DCM, sequentially washed with water (40 mL) and brine (40 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain the title compound (1.3 g, 82%). LC-MS (M+H) + =309.2.

[0219] Step 2: (2-(((3-fluoro-5-(trifluoromethyl)pyridine-2-yl)methyl)((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)carbamoyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-5-yl)carbamate tert-butyl [ka] The title compound (1.5 g, 58%) was prepared from 5-((tert-butoxycarbonyl)amino)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and (3R,4R)-N-((3-fluoro-5-(trifluoromethyl)pyridine-2-yl)methyl)-4-methoxytetrahydro-2H-pyran-3-amine by the same method as in Step 4 of Example 13. LC-MS (M+H) + =610.3.

[0220] Step 3: 5-amino-N-((3-fluoro-5-(trifluoromethyl)pyridine-2-yl)methyl)-N-((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 34 (970 mg, 77%) was prepared from (2-(((3-fluoro-5-(trifluoromethyl)pyridine-2-yl)methyl)((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)carbamoyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-5-yl)carbamate tert-butyl by the same method as in Example 14, Step 6. 1 H NMR (400 MHz, DMSO-d6) δ 11.48 (s, 1H), 8.76 (s, 1H), 8.27 (s, 1H), 6.65 (s, 1H), 5.55 (s, 2H), 5.31 - 4.98 (m, 3H), 4.89 (s, 2H), 4.76 - 4.64 (m, 1H), 4.60 - 4.68 (m, 1H), 4.19 - 4.02 (m, 1H), 3.89 - 3.69 (m, 2H), 3.55 - 3.44 (m, 1H), 3.38 - 3.35 (m, 1H), 3.34 (s, 3H), 2.25 - 2.11 (m, 1H), 1.43 - 1.30 (m, 1H). LC-MS (M+H)+ =510.3.

[0221] Example 35: (R)-5-amino-N-((3-fluoro-5-(trifluoromethyl)pyridine-2-yl)methyl)-N-(1-(pyrimidine-2-yl)ethyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Step 1: (R)-N-((3-fluoro-5-(trifluoromethyl)pyridine-2-yl)methyl)-1-(pyrimidine-2-yl)ethane-1-amine [ka] 3-Fluoro-5-(trifluoromethyl)picolinealdehyde (100 mg, 0.52 mmol) and (R)-1-(pyrimidine-2-yl)ethane-1-amine dihydrochloride (122 mg, 0.62 mmol) were mixed in DCM (2 mL) and MeOH (0.2 mL) to which NaBH(OAc)3 (220 mg, 1.04 mmol) was added. The mixture was stirred at 25°C for 1 hour, and then quenched with a mixture of saturated NaHCO3 (5 mL) and water (5 mL). The mixture was extracted with RINKAN (5 mL x 3). The combined organic layer was washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound (100 mg, 64%). LC-MS (M+H) + =301.1.

[0222] Step 2: (R)-(2-(((3-fluoro-5-(trifluoromethyl)pyridine-2-yl)methyl)(1-(pyrimidine-2-yl)ethyl)carbamoyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-5-yl)carbamate tert-butyl [ka] (R)-N-((3-fluoro-5-(trifluoromethyl)pyridine-2-yl)methyl)-1-(pyrimidine-2-yl)ethane-1-amine (100 mg, 0.33 mmol) and 5-((tert-butoxycarbonyl)amino)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid (106 mg, 0.33 mmol) were mixed in THF (5 mL), to which BOPCl (170 mg, 0.67 mmol) and DIPEA (129 mg, 1.0 mmol) were added. The mixture was stirred at 40°C for 1 hour and cooled to room temperature. The mixture was diluted with water (15 mL) and extracted with ELISA (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound (100 mg, 50%). LC-MS (M+H-Boc) +=502.3.

[0223] Step 3: (R)-5-amino-N-((3-fluoro-5-(trifluoromethyl)pyridine-2-yl)methyl)-N-(1-(pyrimidine-2-yl)ethyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide (R)-(2-(((3-fluoro-5-(trifluoromethyl)pyridine-2-yl)methyl)(1-(pyrimidine-2-yl)ethyl)carbamoyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-5-yl)carbamate tert-butyl (100 mg, 0.167 mmol) was dissolved in MeOH (1 mL) and HCl (4 M in MeOH, 1 mL, 4.0 mmol) was added. The mixture was stirred at 40°C for 1 hour and cooled to room temperature. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain Example 35 (15 mg, 18%). 1 H NMR (400 MHz, DMSO-d6) δ 11.69 - 11.47 (m, 1H), 8.98 - 8.53 (m, 3H), 8.42 - 8.05 (m, 1H), 7.62 - 7.17 (m, 1H), 6.77 - 6.20 (m, 1H), 6.20 - 5.63 (m, 1H), 5.63 - 5.18 (m, 3H), 5.18 - 4.98 (m, 3H), 4.95 - 4.61 (m, 3H), 1.86 - 1.34 (m, 3H). LC-MS (M+H) + =502.1.

[0224] Example 36: 5-amino-N-((5-cyclopropylpyridine-2-yl)methyl)-N-((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Step 1: 5-Cyclopropylpicolinealdehyde [ka] A mixture of 5-bromopicoline aldehyde (1.0 g, 5.38 mmol), K3PO4 (2.28 g, 10.8 mmol), Pd(OAc)2 (120 mg, 0.54 mmol), and SPhos (440 mg, 1.08 mmol) in toluene (15 mL) and water (1.5 mL) was mixed with cyclopropylboronic acid (550 mg, 6.46 mmol). The mixture was stirred at 100 °C under nitrogen for 3 hours and then cooled to room temperature. The mixture was diluted with RINKAN (100 mL), sequentially washed with water (40 mL) and brine (40 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain the title compound (450 mg, 57%). LC-MS (M+H) + =148.2.

[0225] Step 2: (3R,4R)-N-((5-cyclopropylpyridine-2-yl)methyl)-4-methoxytetrahydro-2H-pyran-3-amine [ka] The title compound (280 mg, 87%) was prepared from 5-cyclopropyl picoline aldehyde and (3R,4R)-4-methoxytetrahydro-2H-pyran-3-amine by the same method as in Example 34, Step 1. LC-MS (M+H) + =263.3.

[0226] Step 3: (2-(((5-cyclopropylpyridine-2-yl)methyl)((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)carbamoyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-5-yl)carbamate tert-butyl [ka] The title compound (90 mg, 42%) was prepared from 5-((tert-butoxycarbonyl)amino)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and (3R,4R)-N-((5-cyclopropylpyridine-2-yl)methyl)-4-methoxytetrahydro-2H-pyran-3-amine by the same method as in Step 4 of Example 13. LC-MS (M+H) + =564.4.

[0227] Step 4: 5-amino-N-((5-cyclopropylpyridine-2-yl)methyl)-N-((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 36 (43 mg, 58%) was prepared from (2-(((5-cyclopropylpyridine-2-yl)methyl)((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)carbamoyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-5-yl)carbamate tert-butyl by the same method as in Example 14, Step 6. 1 H NMR (400 MHz, DMSO-d6) δ 11.51 (s, 1H), 8.30 (s, 1H), 7.34 - 7.23 (m, 2H), 6.66 (s, 1H), 5.53 (s, 2H), 5.10 (s, 2H), 5.01 - 4.75 (m, 4H), 4.61 - 4.45 (m, 1H), 3.98 - 3.91 (m, 1H), 3.84 - 3.70 (m, 2H), 3.65 - 3.56 (m, 1H), 3.44 - 3.35 (m, 1H), 3.11 (s, 3H), 2.14 (s, 1H), 1.91 (s, 1H), 1.29 (s, 1H), 0.95 (s, 2H), 0.68 (s, 2H). LC-MS (M+H) + =464.3.

[0228] Example 37: 5-amino-N-(2,6-difluorobenzyl)-N-((6-(trifluoromethyl)pyridazin-3-yl)methyl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Step 1: 6-(trifluoromethyl)pyridazine-3-carbaldehyde [ka] To a solution of ethyl 6-(trifluoromethyl)pyridazine-3-carboxylate (920 mg, 4.18 mmol) in DCM (10 mL), DIBAL-H (5.57 mL, 8.36 mmol) was added under nitrogen at -78°C. The mixture was stirred at -78°C for 3 hours. The mixture was poured into a saturated NH4Cl solution (100 mL) and then extracted with DCM (100 mL x 2). The combined organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound (350 mg, 48%). LC-MS (M+H) + =177.1.

[0229] Step 2: N-(2,6-difluorobenzyl)-1-(6-(trifluoromethyl)pyridazin-3-yl)methaneamine [ka] The title compound (38 mg, 35%) was prepared from 6-(trifluoromethyl)pyridazine-3-carbaldehyde and (2,6-difluorophenyl)methaneamine using the same method as in Example 5, Step 1. LC-MS (M+H) + = 304.3.

[0230] Step 3: 5-amino-N-(2,6-difluorobenzyl)-N-((6-(trifluoromethyl)pyridazin-3-yl)methyl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 37 (18 mg, 28%) was prepared from 5-amino-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and N-(2,6-difluorobenzyl)-1-(6-(trifluoromethyl)pyridazin-3-yl)methaneamine using the same method as in Example 2, Step 3. 1 H NMR (500 MHz, DMSO-d6) δ 11.66 (s, 1H), 8.32-8.06 (m, 1H), 8.01-7.76 (m, 1H), 7.42-7.23 (m, 1H), 7.14-6.92 (m, 2H), 6.80-6.26 (m, 1H), 5.74-5.47 (m, 2H), 5.40-4.65 (m, 8H). LC-MS (M+H) + =505.2.

[0231] Example 38: (R)-5-amino-N-((3-fluoropyridine-2-yl)methyl)-6-methyl-N-((5-(trifluoromethyl)pyridine-2-yl)methyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Step 1: (S)-5-amino-6-methyl-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylate ethyl and (R)-5-amino-6-methyl-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylate ethyl [ka] To a solution of 4-((tert-butoxycarbonyl)amino)-5-(4-cyano-5-methyl-2,5-dihydrofuran-3-yl)-1H-pyrrole-2-carboxylate ethyl (20 g, 55 mmol) in dioxane (100 mL), a solution of HCl in dioxane (100 mL, 4 M) was added, and the mixture was stirred at room temperature for 5 hours. The mixture was concentrated under reduced pressure. The crude substance was redissolved in EtOH (200 mL), followed by the addition of K2CO3 (27.6 g, 200 mmol). The mixture was stirred at 70 °C for 4 hours, and then cooled to room temperature. The solid was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM:MeOH = 10:1) to obtain a racemic mixture (5.0 g). The substances were separated by SFC to obtain (S)-5-amino-6-methyl-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylate ethyl (2.25 g, 16%) and (R)-5-amino-6-methyl-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylate ethyl (2.34 g, 16%).

[0232] The analytical chiral-SFC conditions are as follows: Column: CHIRALPAK IC-3, Column size: 3.0 × 100 mm, 3 μm, Mobile phase: 10 μM methanol solution of NH3:CO2, 1:9 to 1:1 for 2 minutes, 1:1 for 1 minute, Flow rate: 2.0 mL / min, Temperature: 35°C, Back pressure: 1500 psi.

[0233] (S)-5-amino-6-methyl-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylate ethyl: Analysis by SFC tR=2.01 min. LC-MS (M+H) + = 262.1.

[0234] (R)-5-amino-6-methyl-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylate ethyl: Analysis by SFC tR=2.36 min. LC-MS (M+H) + = 262.1.

[0235] Step 2: (R)-5-amino-6-methyl-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid [ka] (R)-5-amino-6-methyl-6,8-dihydro-1H-flu[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylate ethyl (1.5 g, 5.7 mmol) and LiOH·H2O (0.32 g, 7.6 mmol) were mixed in MeOH (20 mL) and water (10 mL) and stirred at 50°C for 3 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain the title compound (1.2 g, 90%). LC-MS (M+H) + = 234.1.

[0236] Step 3: 1-(3-fluoropyridine-2-yl)-N-((5-(trifluoromethyl)pyridine-2-yl)methyl)methaneamine [ka] The title compound (100 mg, 60%) was prepared from 5-(trifluoromethyl)picolinealdehyde and (3-fluoropyridine-2-yl)methaneamine by the same method as in Example 5, Step 1. LC-MS (M+H) + = 286.2.

[0237] Step 4: (R)-5-amino-N-((3-fluoropyridine-2-yl)methyl)-6-methyl-N-((5-(trifluoromethyl)pyridine-2-yl)methyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 38 (18 mg, 43%) was prepared from 1-(3-fluoropyridine-2-yl)-N-((5-(trifluoromethyl)pyridine-2-yl)methyl)methaneamine and (R)-5-amino-6-methyl-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid using the same method as in Example 2, Step 3.1 H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H),9.1 -8.75 (m, 1H), 8.5-8.1 (m, 2H), 7.8-7.56 (m, 2H), 7.42 (s, 1H), 6.6-6.1 (m, 1H), 5.44 (s, 2H), 5.37 - 4.69 (m, 7H), 1.32 (d, J = 6.1 Hz, 3H). LC-MS (M+H) + = 501.1.

[0238] Examples 39 and 40: (R)-5-amino-N-methyl-N-(7-(trifluoromethyl)isochroman-4-yl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide and (S)-5-amino-N-methyl-N-(7-(trifluoromethyl)isochroman-4-yl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Step 1: 2-((allyloxy)methyl)-1-bromo-4-(trifluoromethyl)benzene [ka] (2-bromo-5-(trifluoromethyl)phenyl)methanol (5.0 g, 19.6 mmol) was dissolved in THF (100 mL) and NaH (60%, 941 mg, 23.5 mmol) was added over 1 hour at 0°C. Allyl bromide (3.08 g, 25.5 mmol) was added dropwise at 0°C. The mixture was stirred at room temperature for 11 hours. The mixture was diluted with water (100 mL). The mixture was extracted with ethyl acetate (100 mL x 2). The combined organic layer was washed with brine (50 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / Â=1 / 0~10 / 1) to obtain the title compound (8.0 g, 69%). 1H NMR (400 MHz, DMSO-d6) δ 7.84 (d, J = 8.0 Hz, 1H), 7.76 (s, 1H), 7.58 (d, J = 8.0 Hz, 1H), 6.04 - 5.88 (m, 1H), 5.37 - 5.28 (m, 1H), 5.23 - 5.16 (m, 1H), 4.55 (s, 2H), 4.16 - 4.07 (m, 2H).

[0239] Step 2: 4-methylene-7-(trifluoromethyl)isochromane [ka] A mixture of 2-((allyloxy)methyl)-1-bromo-4-(trifluoromethyl)benzene (8.0 g, 27.1 mmol), Pd(OAc)2 (913 mg, 4.07 mmol), Cs2CO3 (10.6 g, 32.5 mmol), and PPh3 (3.20 g, 12.2 mmol) in DMF (80 mL) was degassed, purged three times with nitrogen, and stirred at 90°C for 12 hours. The mixture was cooled to room temperature and diluted with water (100 mL). The mixture was extracted with RINKAN (100 mL x 2). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / RINKAN = 1 / 0 to 5 / 1) to obtain the title compound (5.0 g, 86%). 1 H NMR (400 MHz, DMSO-d6) δ 7.97 (d, J = 8.4 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.52 (s, 1H), 5.87 - 5.83 (m, 1H), 5.24 - 5.18 (m, 1H), 4.80 (s, 2H), 4.41(s, 2H).

[0240] Step 3: 7-(trifluoromethyl)isochroman-4-one [ka] To a solution of 4-methylene-7-(trifluoromethyl)isochroman (4.9 g, 22.9 mmol) in dioxane (100 mL) and water (20 mL), potassium osmium(VI) dihydrate (843 mg, 2.29 mmol), 2,6-lutidine (4.90 g, 45.8 mmol), and sodium periodate (19.6 g, 91.5 mmol) were added. The mixture was stirred at 25°C for 2 hours. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / ethyl acetate = 1 / 0 to 5 / 1) to obtain the title compound (3.0 g, 61%). 1 H NMR (400 MHz, DMSO-d6) δ 8.13 - 8.06 (m, 1H), 7.93 - 7.78 (m, 2H), 4.99 (s, 2H), 4.44 (s, 2H).

[0241] Step 4: 7-(trifluoromethyl)isochroman-4-oneoxime [ka] To a solution of 7-(trifluoromethyl)isochroman-4-one (500 mg, 2.32 mmol) in MeOH (10 mL), hydroxylamine hydrochloride (804 mg, 11.6 mmol) and pyridine (5.4 mL) were added. The mixture was stirred at 65 °C for 1 hour and then cooled to room temperature. The mixture was concentrated under reduced pressure and diluted with water (10 mL). HCl aqueous solution (1 M) was added until the pH reached 5. The mixture was extracted with ethyl acetate (10 mL x 3). The combined organic layer was washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / ethyl acetate = 1 / 0 to 3 / 1) to obtain the title compound (500 mg, 94%). 1H NMR (400 MHz, DMSO-d6) δ 11.76 (s, 1H), 8.07 - 8.00 (m, 1H), 7.68 - 7.62 (m, 2H), 4.77 - 4.68 (m, 4H).

[0242] Step 5: 7-(trifluoromethyl)isochroman-4-amine [ka] Raney-Ni (371 mg) was added to a solution of 7-(trifluoromethyl)isochroman-4-one oxime (500 mg, 2.16 mmol) in MeOH (10 mL) under nitrogen. The suspension was degassed and purged three times with hydrogen. The mixture was stirred at 40°C for 1 hour under hydrogen (30 psi) and then cooled to room temperature. The solid was filtered off and the filtrate was concentrated under reduced pressure to obtain the title compound (400 mg, 85%). LC-MS (M+H) + = 218.1.

[0243] Step 6: (7-(trifluoromethyl)isochroman-4-yl)carbamate tert-butyl [ka] To a solution of 7-(trifluoromethyl)isochroman-4-amine (350 mg, 1.61 mmol) in THF (4 mL), Boc2O (352 mg, 1.61 mmol) and DIPEA (417 mg, 3.22 mmol) were added. The mixture was stirred at room temperature for 1 hour, then diluted with water (10 mL). The mixture was extracted with ethyl acetate (5 mL x 3). The combined organic layer was washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / ethyl acetate = 1 / 0 to 10 / 1) to obtain the title compound (400 mg, 78%). LC-MS (M+H-tBu) + = 262.0.

[0244] Step 7: (7-(trifluoromethyl)isochroman-4-yl)carbamate tert-butylmethyl [ka] A solution of tert-butyl (7-(trifluoromethyl)isochroman-4-yl)carbamate (350 mg, 1.10 mmol) in THF (5 mL) was added dropwise to a suspension of NaH (60%, 49 mg, 1.21 mmol) in THF (5 mL) at 0°C. The resulting mixture was stirred for 10 minutes, and MeI (172 mg, 1.21 mmol) was added dropwise at 0°C. The mixture was warmed to room temperature and stirred for 12 hours. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layer was washed with brine (5 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / ethyl acetate = 1 / 0 to 10 / 1) to obtain the title compound (300 mg, 82%). LC-MS (M+H-tBu) + = 276.2.

[0245] Step 8: N-methyl-7-(trifluoromethyl)isochroman-4-amine hydrochloride [ka] To a solution of tert-butylmethyl (7-(trifluoromethyl)isochroman-4-yl)carbamate (300 mg, 0.91 mmol) in MeOH (3 mL), HCl (4 M in MeOH, 3 mL) was added. The mixture was stirred at room temperature for 12 hours. The mixture was concentrated under reduced pressure to obtain the title compound (200 mg, 82%). LC-MS (M+H) + = 232.2.

[0246] Step 9: (2-(methyl(7-(trifluoromethyl)isochroman-4-yl)carbamoyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-5-yl)carbamate tert-butyl [ka] N-methyl-7-(trifluoromethyl)isochroman-4-amine hydrochloride (200 mg, 0.75 mmol) and 5-((tert-butoxycarbonyl)amino)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid (276 mg, 0.87 mmol) were dissolved in THF (5 mL), to which DIPEA (559 mg, 4.33 mmol) and BOPCl (440 mg, 1.73 mmol) were added. The mixture was stirred at room temperature for 1 hour, then diluted with water (5 mL). The mixture was extracted with ₹ (5.0 mL × 3). The combined organic layer was washed with brine (5.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound (300 mg, 75%). LC-MS (M+H) + = 533.1.

[0247] Step 10: (R)-5-amino-N-methyl-N-(7-(trifluoromethyl)isochroman-4-yl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide and (S)-5-amino-N-methyl-N-(7-(trifluoromethyl)isochroman-4-yl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide (2-(methyl(7-(trifluoromethyl)isochroman-4-yl)carbamoyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-5-yl)carbamate tert-butyl (300 mg, 0.56 mmol) was dissolved in MeOH (4 mL), to which HCl (4 M in MeOH, 4 mL) was added. The mixture was stirred at 25°C for 1 hour and concentrated under reduced pressure. The residue was purified by preparative HPLC and further separated by SFC to obtain Example 39 (21 mg, 9%) and Example 40 (20 mg, 8%).

[0248] The analytical chiral-SFC conditions are as follows: Column: CHIRALPAK AD-3, Column size: 4.6 × 50 mm, 3 μm, Mobile phase: 14 mM NH3 methanol solution:CO2 (1:1, isocratic), Flow rate: 4.0 mL / min, Temperature: 35°C, Back pressure: 1800 psi.

[0249] Example 39: Analysis SFC tR = 1.11 min. 1 H NMR (400 MHz, DMSO-d6) δ 11.86 - 11.51 (m, 1H), 7.69 - 7.62 (m, 1H), 7.61 (s, 1H), 7.53 - 7.35 (m, 1H), 6.84 - 6.45 (m, 1H), 5.96 - 5.65 (m, 1H), 5.59 (s, 2H), 5.25 - 5.10 (m, 2H), 4.99 - 4.84 (m, 3H), 4.75 (d, J = 15.4 Hz, 1H), 4.27 - 3.99 (m, 2H), 3.18 - 2.58 (m, 3H). LC-MS (M+H) + = 433.1.

[0250] Example 40: Analysis SFC tR = 2.14 mins. 1 H NMR (400 MHz, DMSO-d6) δ 11.88 - 11.51 (m, 1H), 7.69 - 7.62 (m, 1H), 7.61 (s, 1H), 7.53 - 7.35 (m, 1H), 6.85 - 6.45 (m, 1H), 5.97 - 5.67 (m, 1H), 5.59 (s, 2H), 5.23 - 5.09 (m, 2H), 4.99 - 4.84 (m, 3H), 4.75 (d, J = 15.4 Hz, 1H), 4.27 - 3.99 (m, 2H), 3.17 - 2.59 (m, 3H). LC-MS (M+H) + = 433.1.

[0251] Example 41: (R)-5-amino-N-((5-bromo-3-fluoropyridine-2-yl)methyl)-N-(1-(pyrimidine-2-yl)ethyl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Step 1: (R)-N-((5-bromo-3-fluoropyridine-2-yl)methyl)-1-(pyrimidine-2-yl)ethane-1-amine [ka] The title compound (90 mg, 59%) was prepared from 5-bromo-3-fluoropicolinaldehyde and (R)-1-(pyrimidine-2-yl)ethane-1-amine dihydrochloride by the same method as in Example 35, Step 1. LC-MS (M+H) + =311.1.

[0252] Step 2: (R)-(2-(((5-bromo-3-fluoropyridine-2-yl)methyl)(1-(pyrimidine-2-yl)ethyl)carbamoyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-5-yl)carbamate tert-butyl [ka] The title compound (90 mg, 57%) was prepared from 5-((tert-butoxycarbonyl)amino)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and (R)-N-((5-bromo-3-fluoropyridine-2-yl)methyl)-1-(pyrimidine-2-yl)ethane-1-amine by the same method as in Step 2 of Example 35. LC-MS (M+H) + =612.2.

[0253] Step 3: (R)-5-amino-N-((5-bromo-3-fluoropyridine-2-yl)methyl)-N-(1-(pyrimidine-2-yl)ethyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 41 (30 mg, 40%) was prepared from (R)-(2-(((5-bromo-3-fluoropyridine-2-yl)methyl)(1-(pyrimidine-2-yl)ethyl)carbamoyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-5-yl)carbamate tert-butyl by the same method as in Example 35, Step 3. 1 H NMR (400 MHz, DMSO-d6) δ 11.35 (s, 1H), 8.76 - 8.75 (m, 2H), 8.42 (s, 1H), 8.01 - 7.98 (m, 1H), 7.34 - 7.38 (m, 1H), 6.55 (s, 1H), 5.97 - 5.87 (m, 1H), 5.29 (s, 2H), 5.14 - 5.04 (m, 3H), 4.93 - 4.78 (m, 3H), 1.66 (d, 3H). LC-MS (M+H) + =512.2.

[0254] Example 42: 5-amino-N-((3-fluoro-5-(trifluoromethyl)pyridine-2-yl)methyl)-N-(pyrimidine-2-ylmethyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Step 1: 1-(3-fluoro-5-(trifluoromethyl)pyridine-2-yl)-N-(pyrimidine-2-ylmethyl)methanamine [ka] The title compound (45 mg, 17%) was prepared from pyrimidine-2-ylmethaneamine and 3-fluoro-5-(trifluoromethyl)picolinealdehyde by the same method as in Example 3, Step 1. LC-MS (M+H) + = 287.0.

[0255] Step 2: (2-(((3-fluoro-5-(trifluoromethyl)pyridine-2-yl)methyl)(pyrimidine-2-ylmethyl)carbamoyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-5-yl)carbamate tert-butyl [ka] The title compound (60 mg, 58%) was prepared from 5-((tert-butoxycarbonyl)amino)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and 1-(3-fluoro-5-(trifluoromethyl)pyridine-2-yl)-N-(pyrimidine-2-ylmethyl)methaneamine by the same method as in Examples 17 and 18, Step 2. LC-MS (M+H) + = 588.1.

[0256] Step 3: 5-amino-N-((3-fluoro-5-(trifluoromethyl)pyridine-2-yl)methyl)-N-(pyrimidine-2-ylmethyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 42 (30 mg, 35%) was prepared from (2-(((3-fluoro-5-(trifluoromethyl)pyridine-2-yl)methyl)(pyrimidine-2-ylmethyl)carbamoyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-5-yl)carbamate tert-butyl by the same method as in Example 22, Step 3. 1H NMR (400 MHz, DMSO-d6) δ 11.59 (s, 1H), 8.87-8.78 (m, 3H), 8.28 (d, J = 9.4 Hz, 1H), 7.48 (s, 1H), 6.33 (s, 1H), 5.54 (s, 2H), 5.38-5.52 (m, 2H), 5.08 (s, 4H), 4.88 (s, 2H). LC-MS (M+H) + = 488.1.

[0257] Example 43: 5-amino-N-(4-cyano-2,6-difluorobenzyl)-N-((3-fluoropyridine-2-yl)methyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Step 1: 3,5-difluoro-4-((((3-fluoropyridine-2-yl)methyl)amino)methyl)benzonitrile [ka] The title compound (70 mg, 25%) was prepared from (3-fluoropyridine-2-yl)methaneamine hydrochloride and 3,5-difluoro-4-formylbenzonitrile using the same method as in Example 3, Step 1. LC-MS (M+H) + = 278.2.

[0258] Step 2: (2-((4-cyano-2,6-difluorobenzyl)((3-fluoropyridine-2-yl)methyl)carbamoyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-5-yl)carbamate tert-butyl [ka] The title compound (35 mg, 24%) was prepared from 5-((tert-butoxycarbonyl)amino)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and 3,5-difluoro-4-((((3-fluoropyridine-2-yl)methyl)amino)methyl)benzonitrile by the same method as in Examples 17 and 18, Step 2. LC-MS (M+H) + = 579.3.

[0259] Step 3: 5-amino-N-(4-cyano-2,6-difluorobenzyl)-N-((3-fluoropyridine-2-yl)methyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 43 (8 mg, 27%) was prepared from (2-((4-cyano-2,6-difluorobenzyl)((3-fluoropyridine-2-yl)methyl)carbamoyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-5-yl)carbamate tert-butyl by the same method as in Example 22, Step 3. 1 H NMR (400 MHz, DMSO) δ 11.61 (s, 1H), 8.36 - 8.35 (m, 1H), 7.75 - 7.69 (m, 3H), 7.43 - 7.38 (m, 1H), 6.42 (s, 1H), 5.54 (s, 2H), 5.25 - 4.99 (m, 4H), 4.97 - 4.78 (m, 4H). LC-MS (M+H) + = 479.2.

[0260] Example 44: (R)-5-amino-N-((3-fluoro-5-(trifluoromethyl)pyridine-2-yl)methyl)-N-(1-methoxypropan-2-yl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Step 1: 5-Bromo-4-((tert-butoxycarbonyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carboxylate ethyl [ka] To a solution of ethyl 5-bromo-4-((tert-butoxycarbonyl)amino)-1H-pyrrole-2-carboxylate (320 g, 960 mmol) in DMF (4000 mL), K2CO3 (332 g, 2.40 mol) and SEMCl (400 g, 2.40 mol) were added. The mixture was stirred at 45 °C for 12 hours and cooled to room temperature. Most of the DMF was removed under reduced pressure. Water (1500 mL) was added, and the mixture was extracted with HCl (800 mL × 3). The combined organic layer was washed with brine (500 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE:HCl = 1:0~5:1) to obtain the title compound (310 g, 70%). LC-MS (M+Na) + = 485.2.

[0261] Step 2: 4-((tert-butoxycarbonyl)amino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carboxylate ethyl [ka] To a mixture of ethyl 5-bromo-4-((tert-butoxycarbonyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carboxylate (276 g, 596 mmol) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (152 g, 1.19 mol) in dioxane (450 mL), allyl palladium chloride dimer (13.1 g, 35.7 mmol), triethylamine (301 g, 2.98 mol), and XPhos (56.8 g, 119 mmol) were added. The mixture was stirred under nitrogen at 80°C for 12 hours. The mixture was cooled to room temperature, and the solid was filtered off. The filtrate was concentrated under reduced pressure to obtain the title compound (300 g, crude). This substance was used directly in Example 44, Step 3. LC-MS (M+Na) + = 533.3.

[0262] Step 3: 5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylate ethyl [ka] To a solution of 4-((tert-butoxycarbonyl)amino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carboxylate ethyl (300 g, crude) and 4-cyano-2,5-dihydrofuran-3-yltrifluoromethanesulfonate (214 g, 881 mmol) in dioxane (3900 mL) and water (780 mL), K2CO3 (244 g, 1.76 mol) and Pd(dppf)Cl2·CH2Cl2 (24.0 g, 29.4 mmol) were added. The mixture was stirred under nitrogen at 80°C for 12 hours. The mixture was cooled to room temperature, and most of the dioxane was removed under reduced pressure. The remainder was diluted with water (1500 mL) and extracted with ethyl acetate (500 mL x 3). The combined organic layer was washed with brine (500 mL x 2), dried on Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE:ethyl acetate = 1:0 to 0:1) to obtain the title compound (100 g, 44%) in two steps. 1 H NMR (400 MHz, DMSO-d6) δ 6.99 (s, 1H), 5.87 (s, 2H), 5.76 (s, 2H), 5.37 - 5.32 (m, 2H), 4.97 - 4.90 (m, 2H), 4.31 (q, J = 7.0 Hz, 2H), 3.39 (t, J = 7.8 Hz, 2H), 1.32 (t, J = 7.0 Hz, 3H), 0.76 (t, J = 7.8 Hz, 2H), -0.12 (s, 9H). LC-MS (M+H) + = 378.2.

[0263] Step 4: 5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid [ka] 5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-flu[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylate ethyl (65 g, 172 mmol) was dissolved in MeOH (150 mL), THF (450 mL), and water (150 mL), to which LiOH·H2O (14.5 g, 344 mmol) was added. The mixture was stirred at 45 °C for 12 hours. Most of the organic solvent was removed under reduced pressure, and the remainder was diluted with water (200 mL). The mixture was washed with MTBE (100 mL x 3). HCl aqueous solution (1 M) was added to the aqueous phase until its pH reached 2-3. The solid was collected by filtration and then triturated with MTBE (500 mL) for 1 hour. The solid was collected by filtration and dried under vacuum to obtain the title compound (49.4 g, 82%). 1 ¹H NMR (400 MHz, DMSO-d6) δ 6.95 (s, 1H), 5.94 (br s, 2H), 5.80 (s, 2H), 5.36 - 5.32 (m, 2H), 4.96 - 4.91 (m, 2H), 3.40 (t, J=8.0 Hz, 2H), 0.76 (t, J=8.0 Hz, 2H), -0.12 (s, 9H); (-COOH is not clear). LC-MS (M+H) + = 350.2.

[0264] Step 5: (R)-N-((3-fluoro-5-(trifluoromethyl)pyridine-2-yl)methyl)-1-methoxypropan-2-amine [ka] To a solution of (R)-1-methoxypropan-2-amine (691 mg, 7.7 mmol) in DCM (30 mL), 3-fluoro-5-(trifluoromethyl)picoline aldehyde (1.5 g, 7.7 mmol) and NaBH(OAc)3 (3.29 g, 15.5 mmol) were added. The mixture was stirred at room temperature for 2 hours. The mixture was carefully added to an aqueous solution of NaHCO3 (100 mL, saturated) and extracted with DCM (100 mL). The organic layer was separated, washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM:MeOH = 20:1) to obtain the title compound (1.9 g, 91%). LC-MS (M+H) + =267.3.

[0265] Step 6: (R)-5-amino-N-((3-fluoro-5-(trifluoromethyl)pyridine-2-yl)methyl)-N-(1-methoxypropan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] (R)-N-((3-fluoro-5-(trifluoromethyl)pyridine-2-yl)methyl)-1-methoxypropan-2-amine (1.75 g, 6.6 mmol) was dissolved in THF (30 mL) and 5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid (2.3 g, 6.6 mmol), BOPCl (2.5 g, 9.9 mmol), and DIPEA (2.54 g, 19.7 mmol) were added. The mixture was stirred at 60 °C for 16 hours and then cooled to room temperature. The mixture was poured into water (100 mL) and extracted with RINKAN (100 mL x 2). The combined organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM:MeOH = 20:1) to obtain the title compound (3.0 g, 76%). LC-MS (M+H)+ =598.1.

[0266] Step 7: (R)-5-amino-N-((3-fluoro-5-(trifluoromethyl)pyridine-2-yl)methyl)-N-(1-methoxypropan-2-yl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide (R)-5-amino-N-((3-fluoro-5-(trifluoromethyl)pyridine-2-yl)methyl)-N-(1-methoxypropan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide (3.0 g, 5.0 mmol) was dissolved in DCM (15 mL) and TFA (15 mL) was added. The mixture was stirred at room temperature for 3 hours and then concentrated under reduced pressure. MeOH (30 mL) and aqueous ammonia solution (28%, 3 mL) were added and the mixture was stirred at room temperature for 3 hours. The mixture was poured into water (100 mL) and then extracted with ELISA (100 × 2 mL). The combined organic layer was washed with brine (100 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM:MeOH = 10:1) to obtain Example 44 (1.8 g, 77%). 1 H NMR (400 MHz, DMSO-d6) δ 11.47 (s, 1H), 8.99-8.60 (m, 1H), 8.29-8.27 (m, 1H), 6.84-6.09 (m,1H), 5.79-5.38 (m, 2H), 5.29-4.37 (m, 7H), 3.68-3.51 (m, 1H), 3.49-3.37 (m, 1H), 3.29-2.95 (m,3H), 1.51-0.83 (m, 3H). LC-MS (M+H) + = 468.3.

[0267] Example 45: (R)-5-amino-N-((5-bromopyridine-2-yl)methyl)-N-(1-methoxypropan-2-yl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Step 1: (R)-N-((5-bromopyridine-2-yl)methyl)-1-methoxypropane-2-amine [ka] The title compound (130 mg, 94%) was prepared from (R)-1-methoxypropan-2-amine and 5-bromopicolinealdehyde by the same method as in Example 44, Step 5. LC-MS (M+H) + = 259.1.

[0268] Step 2: (R)-(2-(((5-bromopyridine-2-yl)methyl)(1-methoxypropan-2-yl)carbamoyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-5-yl)carbamate tert-butyl [ka] The title compound (174 mg, 73%) was prepared from 5-((tert-butoxycarbonyl)amino)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and (R)-N-((5-bromopyridine-2-yl)methyl)-1-methoxypropan-2-amine by the same method as in Examples 17 and 18, Step 2. LC-MS (M+H) + = 560.2.

[0269] Step 3: (R)-5-amino-N-((5-bromopyridine-2-yl)methyl)-N-(1-methoxypropan-2-yl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 45 (27 mg, 17%) was prepared from (R)-(2-(((5-bromopyridine-2-yl)methyl)(1-methoxypropan-2-yl)carbamoyl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-5-yl)carbamate tert-butyl by the same method as in Example 22, Step 3. 1 H NMR (400 MHz, DMSO-d6) δ 11.52 (s, 1H), 8.65 (s, 1H), 8.01 (d, J = 6.8 Hz, 1H), 7.28 - 7.49 (m, 1H), 6.07 - 6.82 (m, 1H), 5.54 (s, LC-MS (M+H) + = 460.1.

[0270] Example 46: (R)-5-amino-N-(4-cyano-2,6-difluorobenzyl)-N-(1-methoxypropan-2-yl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Step 1: (R)-3,5-difluoro-4-(((1-methoxypropan-2-yl)amino)methyl)benzonitrile [ka] The title compound (140 mg, 97%) was prepared from (R)-1-methoxypropan-2-amine and 3,5-difluoro-4-formylbenzonitrile using the same method as in Example 44, Step 5. LC-MS (M+H) + = 241.2.

[0271] Step 2: (R)-(2-((4-cyano-2,6-difluorobenzyl)(1-methoxypropan-2-yl)carbamoyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-5-yl) tert-butyl carbamate [ka] The title compound (33 mg, 15%) was prepared from 5-((tert-butoxycarbonyl)amino)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and (R)-3,5-difluoro-4-(((1-methoxypropan-2-yl)amino)methyl)benzonitrile by the same method as in Examples 17 and 18, Step 2. LC-MS (M+H) + = 542.2.

[0272] Step 3: (R)-5-amino-N-(4-cyano-2,6-difluorobenzyl)-N-(1-methoxypropan-2-yl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 46 (4 mg, 15%) was prepared from (R)-(2-((4-cyano-2,6-difluorobenzyl)(1-methoxypropan-2-yl)carbamoyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-5-yl)carbamate tert-butyl by the same method as in Example 22, Step 3. 1 H NMR (400 MHz, DMSO-d6) δ 11.44 - 11.58 (m, 1H), 7.68 - 7.83 (m, 2H). 6.58 - 6.50 (m, 1H), 5.57 (s, 2H) 5.10 (s, 2H), 4.91 (s, 2H), 4.51 - 4.85 (m, 3H) 3.60 - 3.49 (m, 1H), 3.36 - 3.40 (m, 1H), 3.16 (s, 3H) 1.27 (d, J= 6.5 Hz, 3H). LC-MS (M+H) + = 442.1.

[0273] Example 47: 5-amino-N-((3-fluoropyridine-2-yl)methyl)-N-(2,4,6-trifluorobenzyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Step 1: 1-(3-fluoropyridine-2-yl)-N-(2,4,6-trifluorobenzyl)methaneamine [ka] The title compound (180 mg, 67%) was prepared from 2,4,6-trifluorobenzaldehyde and (3-fluoropyridine-2-yl)methaneamine using the same method as in Example 3, Step 1. LC-MS (M+H) + = 271.1.

[0274] Step 2: (2-(((3-fluoropyridine-2-yl)methyl)(2,4,6-trifluorobenzyl)carbamoyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-5-yl)carbamate tert-butyl [ka] The title compound (60 mg, 42%) was prepared from 5-((tert-butoxycarbonyl)amino)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and 1-(3-fluoropyridine-2-yl)-N-(2,4,6-trifluorobenzyl)methaneamine by the same method as in Examples 17 and 18, Step 2. LC-MS (M+H) + = 572.3.

[0275] Step 3: 5-amino-N-((3-fluoropyridine-2-yl)methyl)-N-(2,4,6-trifluorobenzyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 47 (26 mg, 50%) was prepared from (2-(((3-fluoropyridine-2-yl)methyl)(2,4,6-trifluorobenzyl)carbamoyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-5-yl)carbamate tert-butyl by the same method as in Example 22, Step 3. 1 H NMR (400 MHz, DMSO-d6) δ 11.61 (s, 1H), 8.36 (d, J = 4.4 Hz, 1H), 7.70 (t, J = 9.3 Hz, 1H), 7.39 (dt, J = 8.5, 4.4 Hz, 1H), 7.12 (t, J = LC-MS (M+H) + = 472.2.

[0276] Example 48: (R)-5-amino-N-((5-cyclopropylpyridine-2-yl)methyl)-N-(1-(pyrimidine-2-yl)ethyl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Step 1: (R)-N-((5-cyclopropylpyridine-2-yl)methyl)-1-(pyrimidine-2-yl)ethane-1-amine [ka] The title compound (60 mg, 35%) was prepared from 5-cyclopropyl picoline aldehyde and (R)-1-(pyrimidine-2-yl)ethane-1-amine dihydrochloride by the same method as in Example 3, Step 1. LC-MS (M+H) + = 255.3.

[0277] Step 2: (R)-(2-(((5-cyclopropylpyridine-2-yl)methyl)(1-(pyrimidine-2-yl)ethyl)carbamoyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-5-yl)carbamate tert-butyl [ka] The title compound (60 mg, 45%) was prepared from 5-((tert-butoxycarbonyl)amino)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and (R)-N-((5-cyclopropylpyridine-2-yl)methyl)-1-(pyrimidine-2-yl)ethane-1-amine by the same method as in Step 4 of Example 13. LC-MS (M+H) + = 556.4.

[0278] Step 3: (R)-5-amino-N-((5-cyclopropylpyridine-2-yl)methyl)-N-(1-(pyrimidine-2-yl)ethyl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 48 (20 mg, 40%) was prepared from (R)-(2-(((5-cyclopropylpyridine-2-yl)methyl)(1-(pyrimidine-2-yl)ethyl)carbamoyl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-5-yl)carbamate tert-butyl by the same method as in Example 14, Step 6. 1H NMR (400 MHz, DMSO-d6) δ 11.42 (s, 1H), 8.74 - 8.73 (m, 2H), 8.30 (s, 1H), 7.36 - 7.31 (m, 2H), 7.25 - 7.21 (m, 1H), 6.50 (s, 1H), 5.82 (brs, 1H), 5.25 (s, 2H), 5.12 (s, 2H),5.05 - 4.97 (m, 1H), 4.91 (s, 2H), 4.79 - 4.68 (m, 1H), 1.97 - 1.89 (m, 1H), 1.61 (d, J = ?? Hz, 3H), 0.99 - 0.93 (m, 2H), 0.71 - 0.67 (m, 2H). LC-MS (M+H) + =456.3.

[0279] Example 49: (R)-5-amino-N-((5-bromo-3-fluoropyridine-2-yl)methyl)-N-(1-methoxypropan-2-yl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Step 1: (R)-N-((5-bromo-3-fluoropyridine-2-yl)methyl)-1-methoxypropane-2-amine [ka] The title compound (231 mg, 57%) was prepared from (R)-1-methoxypropan-2-amine and 5-bromo-3-fluoropicoline aldehyde by the same method as in Example 44, Step 5. LC-MS (M+H) + = 277.1.

[0280] Step 2: (R)-5-amino-N-((5-bromo-3-fluoropyridine-2-yl)methyl)-N-(1-methoxypropan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] The title compound (234 mg, 43%) was prepared from 5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and (R)-N-((5-bromo-3-fluoropyridine-2-yl)methyl)-1-methoxypropan-2-amine by the same method as in Example 44, Step 6. LC-MS (M+H) + = 608.1.

[0281] Step 3: (R)-5-amino-N-((5-bromo-3-fluoropyridine-2-yl)methyl)-N-(1-methoxypropan-2-yl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 49 (54 mg, 18%) was prepared from (R)-5-amino-N-((5-bromo-3-fluoropyridine-2-yl)methyl)-N-(1-methoxypropan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide by the same method as in Example 44, Step 7. 1 H NMR (400 MHz, DMSO-d6) δ 11.55 (s, 1H), 8.53 (s, 1H), 8.15 (d, J = 10.0 Hz, 1H), 6.75 - 6.23 (m, 1H), 5.82 - 5.54 (m, 2H), 5.11 (s, LC-MS (M+H) + = 478.2.

[0282] Example 50: (R)-5-amino-N-((5-bromopyridine-2-yl)methyl)-N-((3-fluoropyridine-2-yl)methyl)-6-methyl-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Step 1: 1-(5-bromopyridine-2-yl)-N-((3-fluoropyridine-2-yl)methyl)methanamine [ka] The title compound (100 mg, 65%) was prepared from 5-bromopicoline aldehyde and (3-fluoropyridine-2-yl)methaneamine using the same method as in Example 5, Step 1. LC-MS (M+H) + = 296.2.

[0283] Step 2: (R)-5-amino-N-((5-bromopyridine-2-yl)methyl)-N-((3-fluoropyridine-2-yl)methyl)-6-methyl-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 50 (52 mg, 60%) was prepared from 1-(5-bromopyridine-2-yl)-N-((3-fluoropyridine-2-yl)methyl)methaneamine and (R)-5-amino-6-methyl-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid using the same method as in Example 2, Step 3. 1 H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1H), 8.8-8.53 (m, 1H), 8.34 (brs, 1H), 8.00 (brs, 1H), 7.67 (brs, 1H), 7.38 (brs, 2H), 6.5-6.1 (m, 1H), 5.40 (s, 2H), 5.32 - 4.56 (m, 7H), 1.28 (d, J = 6.1 Hz, 3H). LC-MS (M+H) + = 511.4.

[0284] Example 51: (R)-5-amino-N-((5-iodopyridine-2-yl)methyl)-N-(1-(pyrimidine-2-yl)ethyl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Step 1: 5-iodopicolinaldehyde [ka] The title compound (136 mg, 77%) was prepared from methyl 5-iodopicolinate using the same method as in Example 37, Step 1. LC-MS (M+H) + = 233.9.

[0285] Step 2: (R)-N-((5-iodopyridine-2-yl)methyl)-1-(pyrimidine-2-yl)ethane-1-amine [ka] The title compound (84 mg, 67%) was prepared from 5-iodopicoline aldehyde and (R)-1-(pyrimidine-2-yl)ethane-1-amine dihydrochloride by the same method as in Example 34, Step 1. LC-MS (M+H) + = 341.3.

[0286] Step 3: (R)-5-amino-N-((5-iodopyridine-2-yl)methyl)-N-(1-(pyrimidine-2-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] The title compound (80 mg, 48%) was prepared from 5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and (R)-N-((5-iodopyridine-2-yl)methyl)-1-(pyrimidine-2-yl)ethane-1-amine by the same method as in Example 44, Step 6. LC-MS (M+H) + = 672.3.

[0287] Step 4: (R)-5-amino-N-((5-iodopyridine-2-yl)methyl)-N-(1-(pyrimidine-2-yl)ethyl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 51 (20 mg, 31%) was prepared from (R)-5-amino-N-((5-iodopyridine-2-yl)methyl)-N-(1-(pyrimidine-2-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide by the same method as in Example 44, Step 7. 1 H NMR (400 MHz, DMSO-d6) δ: 11.63 (s, 1H), 8.98 - 8.46 (m, 3H), 8.25 - 7.95 (m, 1H), 7.55 - 7.00 (m, 2H), 6.30 - 6.05 (m, 1H), 5.71 - 4.42 (m, 9H), 1.76 - 1.48 (m, 3H). LC-MS (M+H) + = 542.2.

[0288] Example 52: (R)-5-amino-N-((5-cyclopropyl-3-fluoropyridine-2-yl)methyl)-N-(1-(pyrimidine-2-yl)ethyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Step 1: (R)-N-((5-cyclopropyl-3-fluoropyridine-2-yl)methyl)-1-(pyrimidine-2-yl)ethane-1-amine [ka] To a solution of 5-cyclopropyl-3-fluoropicoline aldehyde (84 mg, 0.51 mmol) in DCM (3 mL), (R)-1-(pyrimidine-2-yl)ethane-1-amine dihydrochloride (100 mg, 0.51 mmol), triethylamine (103 mg, 1.02 mmol), and NaBH(OAc)3 (217 mg, 1.02 mmol) were added. The mixture was stirred at room temperature for 3 hours. The mixture was carefully added to saturated NaHCO3 (50 mL) and then extracted with DCM (50 mL). The organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 20:1) to obtain the title compound (61 mg, 44%). LC-MS (M+H) + =273.4.

[0289] Step 2: (R)-5-amino-N-((5-cyclopropyl-3-fluoropyridine-2-yl)methyl)-N-(1-(pyrimidine-2-yl)ethyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 52 (27 mg, 25%) was prepared from 5-amino-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and (R)-N-((5-cyclopropyl-3-fluoropyridine-2-yl)methyl)-1-(pyrimidine-2-yl)ethane-1-amine using the same method as in Example 2, Step 3. 1H NMR (500 MHz, DMSO) δ 11.71-11.39 (m, 1H), 9.02-8.58 (m, 2H), 8.46-7.86 (m, 1H), 7.61-7.08 (m, 2H), 6.74-6.23 (m, 1H), 6.19-4.36 (m, 9H), 2.12-1.85 (m, 1H), 1.85-1.43 (m, 3H), 1.05-0.89 (m, 2H), 0.89-0.64 (m, 2H). LC-MS (M+H) + =474.4.

[0290] Example 53: (R)-5-amino-N-((5-cyclopropylpyrazine-2-yl)methyl)-N-(1-methoxypropan-2-yl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Step 1: 5-Cyclopropylpyrazine-2-carbaldehyde [ka] The title compound (0.60 g, 29%) was prepared from 5-chloropyrazine-2-carbaldehyde and cyclopropylboronic acid by the same method as in Example 36, Step 1. LC-MS (M+H) + =149.1.

[0291] Step 2: (R)-N-((5-cyclopropylpyrazine-2-yl)methyl)-1-methoxypropane-2-amine [ka] The title compound (190 mg, 85%) was prepared from (R)-1-methoxypropan-2-amine and 5-cyclopropylpyrazine-2-carbaldehyde by the same method as in Example 44, Step 5. LC-MS (M+H) + =222.2.

[0292] Step 3: (R)-5-amino-N-((5-cyclopropylpyrazine-2-yl)methyl)-N-(1-methoxypropan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] The title compound (234 mg, 43%) was prepared from 5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and (R)-N-((5-cyclopropylpyrazine-2-yl)methyl)-1-methoxypropan-2-amine by the same method as in Example 44, Step 6. LC-MS (M+H) + =553.4.

[0293] Step 4: (R)-5-amino-N-((5-cyclopropylpyrazine-2-yl)methyl)-N-(1-methoxypropan-2-yl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 53 (25 mg, 30%) was prepared from (R)-5-amino-N-((5-cyclopropylpyrazine-2-yl)methyl)-N-(1-methoxypropan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide by the same method as in Example 44, Step 7. 1H NMR (400 MHz, DMSO-d6) δ 11.48 (s, 1H), 8.54 (s, 1H), 8.46 (s, 1H), 6.75 - 6.44 (m, 1H), 5.52 (s, 2H), 5.12 (s, 2H), 5.01 - 4.59 (m, 5H), 3.50 (t, J = 9.3 Hz, 1H), 3.39 - 3.34 (m, 1H), 3.12 (s, 3H), 2.22 - 2.13 (m, 1H), 1.31-1.11 (m, 3H), 1.04 - 0.98 (m, 2H), 0.94 - 0.87 (m, 2H).LC-MS (M+H) + = 423.2.

[0294] Examples 54 and 55: (S)-5-amino-N-ethyl-N-(7-(trifluoromethyl)isochroman-4-yl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide and (R)-5-amino-N-ethyl-N-(7-(trifluoromethyl)isochroman-4-yl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Step 1: (7-(trifluoromethyl)isochroman-4-yl)carbamate tert-butylethyl [ka] The title compound (0.50 g, 92%) was prepared from tert-butyl (7-(trifluoromethyl)isochroman-4-yl)carbamate and EtI by the same method as in Examples 39 and 40, Step 7. LCMS (M+H-tBu) + = 290.1.

[0295] Step 2: N-ethyl-7-(trifluoromethyl)isochroman-4-amine hydrochloride [ka] The title compound (0.20 g, 62%) was prepared from tert-butylethyl (7-(trifluoromethyl)isochroman-4-yl)carbamate by the same method as in Examples 39 and 40, Step 8. LC-MS (M+H) + = 246.1.

[0296] Step 3: (2-(ethyl(7-(trifluoromethyl)isochroman-4-yl)carbamoyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-5-yl)carbamate tert-butyl [ka] The title compound (0.40 g, 90%) was prepared from 5-((tert-butoxycarbonyl)amino)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and N-ethyl-7-(trifluoromethyl)isochroman-4-amine hydrochloride by the same method as in Examples 39 and 40, Step 9. LC-MS (M+H) + = 547.2.

[0297] Step 4: (S)-5-amino-N-ethyl-N-(7-(trifluoromethyl)isochroman-4-yl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide and (R)-5-amino-N-ethyl-N-(7-(trifluoromethyl)isochroman-4-yl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Examples 54 (22 mg, 14%) and 55 (23 mg, 14%) were prepared from (2-(ethyl(7-(trifluoromethyl)isochroman-4-yl)carbamoyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-5-yl)carbamate tert-butyl and N-ethyl-7-(trifluoromethyl)isochroman-4-amine hydrochloride in the same manner as in Examples 39 and 40 and Step 10.

[0298] The analytical chiral-SFC conditions were as follows: Column: CHIRALPAK AD-3, Column size: 4.6 × 50 mm, 3 μm, Mobile phase: (ethanol containing 0.2% 7M methanolic NH3): CO2, 1:19 for 0.2 min, 1:19 to 1:1 for 1.0 min, 1:1 for 1 min, 1:1 to 1:19 for 0.4 min, Flow rate: 3.4 mL / min, Temperature: 35°C, Back pressure: 1800 psi.

[0299] Example 54: Analysis SFC tR = 1.70 min. 1 H NMR (400 MHz, DMSO-d6) δ 11.68 - 11.52 (m, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.58 (s, 1H), 7.44 (d, J = 7.6 Hz, 1H), 6.62 (s, 1H), 5.61 (s, 1H), 5.56 (s, 2H), 5.14 (s, 2H), 4.93 (d, J = 3.2 Hz, 2H), 4.90 (s, 1H), 4.81 - 4.73 (m, 1H), 4.10 - 4.21 (m, 2H), 3.72 (brs, 1H), 3.56 - 3.33 (m, 1H), 1.02 - 1.17 (m, 3H). LC-MS (M+H) + = 447.2.

[0300] Example 55: Analysis SFC tR = 2.14 mins. 1 H NMR (400 MHz, DMSO-d6) δ 11.68 - 11.52 (m, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.58 (s, 1H), 7.44 (d, J = 7.6 Hz, 1H), 6.62 (s, 1H), 5.61 (s, 1H), 5.56 (s, 2H), 5.14 (s, 2H), 4.93 (d, J = 3.2 Hz, 2H), 4.90 (s, 1H), 4.81 - 4.73 (m, 1H), 4.10 - 4.21 (m, 2H), 3.72 (brs, 1H), 3.56 - 3.33 (m, 1H), 1.02 - 1.17 (m, 3H). LC-MS (M+H)+ = 447.2.

[0301] Example 56: (R)-5-amino-N-((5-cyclopropyl-3-fluoropyridine-2-yl)methyl)-N-(1-methoxypropan-2-yl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Step 1: (R)-N-((5-cyclopropyl-3-fluoropyridine-2-yl)methyl)-1-methoxypropane-2-amine [ka] The title compound (110 mg, 51%) was prepared from (R)-1-methoxypropan-2-amine and 5-cyclopropyl-3-fluoropicoline aldehyde by the same method as in Example 44, Step 5. LC-MS (M+H) + = 239.1.

[0302] Step 2: (R)-(2-(((5-cyclopropyl-3-fluoropyridine-2-yl)methyl)(1-methoxypropan-2-yl)carbamoyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-5-yl)carbamate tert-butyl [ka] The title compound (100 mg, 40%) was prepared from 5-((tert-butoxycarbonyl)amino)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and (R)-N-((5-cyclopropyl-3-fluoropyridine-2-yl)methyl)-1-methoxypropan-2-amine by the same method as in Step 4 of Example 13. LC-MS (M+H) + = 540.1.

[0303] Step 3: (R)-5-amino-N-((5-cyclopropyl-3-fluoropyridine-2-yl)methyl)-N-(1-methoxypropan-2-yl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 56 (30 mg, 37%) was prepared from (R)-(2-(((5-cyclopropyl-3-fluoropyridine-2-yl)methyl)(1-methoxypropan-2-yl)carbamoyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-5-yl)carbamate tert-butyl by the same method as in Example 14, Step 5. 1H NMR (400 MHz, DMSO-d6) δ 11.47 (s, 1H), 8.23 ​​(s, 1H), 7.33 (d, J = 11.6 Hz, 1H), 6.61 - 6.27 (m, 1H), 5.50 (s, 2H), 5.10 (br s, 2H), 5.05 - 4.41 (m, 5H), 3.56 (dd, J = 7.4, 9.8 Hz, 1H), 3.37 (dd, J = 5.4, 10.0 Hz, 1H), 3.17 (s, 3H), 2.03 - 1.94 (m, 1H), 1.07 - 1.27 (m, 3H), 1.05 - 0.96 (m, 2H), 0.77 (d, J = 4.9 Hz, 2H). LC-MS (M+H) + = 440.2.

[0304] Examples 57, 58, 59, and 60: 5-amino-N-methyl-N-((1R,4R)-1-methyl-7-(trifluoromethyl)isochroman-4-yl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide and 5-amino-N-methyl-N-((1S,4R)-1-methyl-7-(trifluoromethyl)isochroman-4-yl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Lysine-2-carboxamide and 5-amino-N-methyl-N-((1S,4S)-1-methyl-7-(trifluoromethyl)isochroman-4-yl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide and 5-amino-N-methyl-N-((1R,4S)-1-methyl-7-(trifluoromethyl)isochroman-4-yl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Step 1: 1-(2-bromo-5-(trifluoromethyl)phenyl)ethane-1-ol [ka] To a solution of 2-bromo-5-(trifluoromethyl)benzaldehyde (15.0 g, 59.3 mmol) in THF (150 mL), MeMgBr (3 M in Et2O, 19.8 mL, 59.3 mmol) was added at 0°C, and the mixture was stirred at 0°C for 1 hour. The mixture was quenched with saturated NH4Cl (100 mL) and extracted with Depositphotos (80 mL x 3). The combined organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / Depositphotos = 1 / 0 to 5 / 1) to obtain the title compound (12.0 g, yield 75%). 1H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 2.0 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.39 (dd, J = 8.4, 2.0 Hz, 1H), 5.32-5.23 (m, 1H), 2.03 (s, 1H), 1.51 (d, J = 6.4 Hz, 3H).

[0305] Step 2: 2-(1-(allyloxy)ethyl)-1-bromo-4-(trifluoromethyl)benzene [ka] The title compound (9.7 g, 70%) was prepared from 1-(2-bromo-5-(trifluoromethyl)phenyl)ethane-1-ol and allyl bromide by the same method as in Example 40, Step 1. 1 H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 2.0 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.39 (dd, J = 8.4, 2.0 Hz, 1H), 5.98-5.85 (m, 1H), 5.33-5.17 (m, 2H), 4.93-4.85 (m, 1H), 3.97-3.77 (m, 2H), 1.44 (d, J = 6.4 Hz, 3H).

[0306] Step 3: 1-Methyl-4-methylene-7-(trifluoromethyl)isochromane [ka] The title compound (4.6 g, 64%) was prepared from 2-(1-(allyloxy)ethyl)-1-bromo-4-(trifluoromethyl)benzene by the same method as in Example 40, Step 2. LC-MS (M+H) + = 229.1.

[0307] Step 4: 1-Methyl-7-(trifluoromethyl)isochroman-4-one [ka] The title compound (3.3 g, 71%) was prepared from 1-methyl-4-methylene-7-(trifluoromethyl)isochromane by the same method as in Example 40, Step 3. 1 H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.53 (s, 1H), 5.03-4.94 (m, 1H), 4.57, 4.35 (ABq, J = 17.2 Hz, 2H), 1.71 (d, J = 6.8 Hz, 3H). LC-MS (M+H) + = 231.2.

[0308] Step 5: 1-Methyl-7-(trifluoromethyl)isochroman-4-oneoxime [ka] The title compound (0.75 g, 70%) was prepared from 1-methyl-7-(trifluoromethyl)isochroman-4-one in the same manner as in Example 40, Step 4. 1 H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 8.4 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.44 (s, 1H), 5.13, 4.64 (ABq, J = 17.0 Hz, 2H), 4.73 (q, J = 6.5 Hz, 1H), 1.65 (d, J = 6.4 Hz, 3H). LC-MS (M+H) + = 246.2.

[0309] Step 6: 1-Methyl-7-(trifluoromethyl)isochroman-4-amine [ka] The title compound (0.26 g, 79%) was prepared from 1-methyl-7-(trifluoromethyl)isochroman-4-one oxime by the same method as in Example 40, Step 5. LC-MS (M+H) + = 232.1.

[0310] Step 7: (1-methyl-7-(trifluoromethyl)isochroman-4-yl) tert-butyl carbamate [ka] The title compound (0.30 g, 87%) was prepared from 1-methyl-7-(trifluoromethyl)isochroman-4-amine by the same method as in Example 40, Step 6. LCMS (M+H-tBu) + = 276.2.

[0311] Step 8: (1-methyl-7-(trifluoromethyl)isochroman-4-yl)carbamate tert-butylmethyl [ka] The title compound (0.30 g, 87%) was prepared from tert-butyl (1-methyl-7-(trifluoromethyl)isochroman-4-yl)carbamate by the same method as in Example 40, Step 7. LCMS (M+H-tBu) + = 290.2.

[0312] Step 9: N,1-dimethyl-7-(trifluoromethyl)isochroman-4-amine hydrochloride [ka] The title compound (0.20 g, 94%) was prepared from tert-butylmethyl (1-methyl-7-(trifluoromethyl)isochroman-4-yl)carbamate by the same method as in Step 8 of Example 40. LC-MS (M+H) + = 246.1.

[0313] Step 10: (2-(methyl(1-methyl-7-(trifluoromethyl)isochroman-4-yl)carbamoyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-5-yl)carbamate tert-butyl [ka] The title compound (0.15 g, 51%) was prepared from 5-((tert-butoxycarbonyl)amino)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and N,1-dimethyl-7-(trifluoromethyl)isochroman-4-amine hydrochloride by the same method as in Example 40, Step 9. LC-MS (M+H) + = 547.4.

[0314] Step 11: 5-amino-N-methyl-N-((1R,4R)-1-methyl-7-(trifluoromethyl)isochroman-4-yl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide and 5-amino-N-methyl-N-((1S,4R)-1-methyl-7-(trifluoromethyl)isochroman-4-yl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Thamide and 5-amino-N-methyl-N-((1S,4S)-1-methyl-7-(trifluoromethyl)isochroman-4-yl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide and 5-amino-N-methyl-N-((1R,4S)-1-methyl-7-(trifluoromethyl)isochroman-4-yl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Examples 57 (3 mg, 2%), 58 (13 mg, 8%), 59 (9 mg, 6%), and 60 (5 mg, 3%) were prepared from tert-butyl (2-(methyl(1-methyl-7-(trifluoromethyl)isochroman-4-yl)carbamoyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-5-yl)carbamate using the same method as in Example 40 and Step 10, and the isomers were separated by chiral SFC.

[0315] Analytical chiral-SFC conditions 1: Column: CHIRALPAK AD-3, Column size: 4.6 × 50 mm, 3 μm, Mobile phase: (ethanol containing 0.2% 7M methanolic NH3): CO2 (1:1, isocratic), Flow rate: 4 mL / min, Temperature: 35°C, Back pressure: 1800 psi.

[0316] Analytical chiral-SFC conditions 2: Column: CHIRALPAK OJ-3, Column size: 4.6 × 50 mm, 3 μm, Mobile phase: Mobile phase: (ethanol containing 0.2% 7M methanolic NH3): CO2, 1:19 for 0.2 min, 1:19 to 1:1 for 1.0 min, 1:1 for 1 min, 1:1 to 1:19 for 0.4 min, Flow rate: 3.4 mL / min, Temperature: 35°C, Back pressure: 1800 psi.

[0317] Example 57: Analytical SFC (Condition 1) tR = 0.64 min. 1H NMR (400 MHz, DMSO-d6) δ 11.68 (s, 1H), 7.76 - 7.61 (m, 2H), 7.45 (d, J = 8.0 Hz, 1H), 6.90 - 6.60 (m, 1H), 5.99 - 5.78 (m, 1H), 5.64 (br s, 2H), 5.22 (s, 2H), 5.10 - 4.92 (m, 3H), 4.36 - 4.17 (m, 1H), 4.08 - 3.93 (m, 1H), 3.24 - 2.76 (m, 3H), 1.57 (d, J = 6.0 Hz, 3H).LC-MS (M+H) + = 447.2.

[0318] Example 58: Analysis of SFC (Condition 2) tR=1.18 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 11.93 (s, 1H), 7.71 - 7.65 (m, 2H), 7.55 - 7.42 (m, 1H), 6.80 - 6.62 (m, 1H), 6.38 - 6.05 (m, 2H), 5.85 - 5.60 (m, 1H), 5.20 (br s, 2H), 4.95 (s, 2H), 4.86 - 4.78 (m, 1H), 4.29 - 4.17 (m, 1H), 4.13 - 4.02 (m, 1H), 3.17 - 2.76 (m, 3H), 1.59 (d, J = 6.4 Hz, 3H). LC-MS (M+H) + = 447.2.

[0319] Example 59: Analysis of SFC (Condition 2) tR=1.38 minutes. 1H NMR (400 MHz, DMSO-d6) δ 12.50 (s, 1H), 7.74 - 7.61 (m, 2H), 7.58 - 7.17 (m, 3H), 6.92 - 6.63 (m, 1H), 5.90 - 5.54 (m, 1H), 5.26 (s, 2H), 4.99 (s, 3H), 4.30 - 4.14 (m, 1H), 4.03 - 3.89 (m, 1H), 3.07 - 2.68 (m, 2H), 2.75 - 2.68 (m, 1H), 1.51 (d, J = 5.6 Hz, 3H). LC-MS (M+H) + = 447.2.

[0320] Example 60: Analysis of SFC (Condition 1) tR=1.32 minutes. 1H NMR (400 MHz, DMSO-d6) δ 11.69 (s, 1H), 7.71-7.64 (m, 2H), 7.48 (s, 1H), 6.72 (s, 1H), 5.89-5.60 (m, 3H), 5.21-5.13 (m, 2H), 4.98-4.90 (m, 2H), 4.86-4.78 (m, 1H), 4.30-4.01 (m, 2H), 3.19-2.80 (m, 3H), 1.59 (d, J = 6.8 Hz, 3H). LC-MS (M+H) + = 447.2.

[0321] Examples 61 and 62: (S)-5-amino-N-((5-bromo-3-fluoropyridine-2-yl)methyl)-N-(1-(pyrazine-2-yl)ethyl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide and (R)-5-amino-N-((5-bromo-3-fluoropyridine-2-yl)methyl)-N-(1-(pyrazine-2-yl)ethyl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Step 1: N-((5-bromo-3-fluoropyridine-2-yl)methyl)-1-(pyrazine-2-yl)ethane-1-amine [ka] The title compound (90 mg, 40%) was prepared from (5-bromo-3-fluoropyridine-2-yl)methaneamine and 1-(pyrazine-2-yl)ethane-1-one using the same method as in Examples 17 and 18, Step 1. LC-MS (M+H) + = 311.0.

[0322] Step 2: (2-(((5-bromo-3-fluoropyridine-2-yl)methyl)(1-(pyrazine-2-yl)ethyl)carbamoyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-5-yl)carbamate tert-butyl [ka] The title compound (120 mg, 76%) was prepared from 5-((tert-butoxycarbonyl)amino)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and N-((5-bromo-3-fluoropyridine-2-yl)methyl)-1-(pyrazine-2-yl)ethane-1-amine by the same method as in Examples 17 and 18, Step 2. LC-MS (M+H) + = 612.2.

[0323] Step 3: (S)-5-amino-N-((5-bromo-3-fluoropyridine-2-yl)methyl)-N-(1-(pyrazine-2-yl)ethyl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide and (R)-5-amino-N-((5-bromo-3-fluoropyridine-2-yl)methyl)-N-(1-(pyrazine-2-yl)ethyl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Examples 61 (4 mg, 4%) and 62 (2 mg, 2%) were prepared from (2-(((5-bromo-3-fluoropyridine-2-yl)methyl)(1-(pyrazine-2-yl)ethyl)carbamoyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-5-yl)carbamate tert-butyl using the same method as in Examples 17 and 18 and Step 3, and the enantiomers were separated by chiral SFC.

[0324] The analytical chiral-SFC conditions are as follows: Column: CHIRALPAK IG-3, Column size: 4.6 × 50 mm, 3 μm, Mobile phase: 14 mM NH3 in isopropanol solution: CO2 (3:2, isocratic), Flow rate: 4 mL / min, Temperature: 35°C, Back pressure: 1800 psi.

[0325] Example 61: Analysis SFC tR = 1.28 min. 1 H NMR (400 MHz, DMSO-d6) δ 11.55 (br s, 1H) 8.73 (s, 1H) 8.58-8.48 (m, 2H) 8.45 (s, 1H), 8.11 (d, J=9.5 Hz, 1H) 6.40 (br s, 1H) 5.90 (br s, 1H) 5.51 (s, 2H), 4.77 - 5.22 (m, 6H), 1.73 - 1.57 (m, 3H). LCMS (M+H) + = 512.0.

[0326] Example 62: Analysis SFC tR = 2.17 mins. 1 H NMR (400 MHz, DMSO-d6) δ 11.55 (br s, 1H) 8.73 (s, 1H) 8.58-8.48 (m, 2H) 8.45 (s, 1H), 8.11 (d, J=9.5 Hz, 1H) 6.40 (br s, 1H) 5.90 (br s, 1H) 5.51 (s, 2H), 4.79 - 5.22 (m, 6H), 1.73 - 1.57 (m, 3H). LCMS (M+H) + = 512.0.

[0327] Examples 63 and 64: (S)-5-amino-N-(7-bromoisochroman-4-yl)-N-methyl-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide and (R)-5-amino-N-(7-bromoisochroman-4-yl)-N-methyl-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Step 1: 7-Bromoisochroman-4-ol [ka] To a mixture of 7-bromoisochroman-4-one (500 mg, 2.2 mmol) in MeOH (20 mL), NaBH4 (91 mg, 2.4 mmol) was added at 0°C, and the mixture was stirred at room temperature for 30 minutes. The mixture was diluted with water (10 mL), and the MeOH was evaporated under reduced pressure. The mixture was extracted with ethyl acetate (20 mL). The organic layer was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated to obtain the title compound (500 mg, 99%). LC-MS (M+H) + = 229.1.

[0328] Step 2: 7-bromo-4-chloroisochromane [ka] A mixture of 7-bromoisochroman-4-ol (500 mg, 2.2 mmol) and SOCl2 (524 mg, 4.4 mmol) in THF (15 mL) was stirred at 60°C for 2 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / Â=20 / 1) to obtain the title compound (300 mg, 55%). LC-MS (M+H) + = 247.1.

[0329] Step 3: 7-Bromo-N-methylisochroman-4-amine [ka] A mixture of 7-bromo-4-chloroisochroman (150 mg, 0.6 mmol), methylamine hydrochloride (122 mg, 1.8 mmol), K2CO3 (248 mg, 1.8 mmol), and KI (298.8 mg, 1.8 mmol) in DMAC (10 mL) was stirred at 100 °C for 15 hours and then cooled to room temperature. The mixture was diluted with  (20 mL), then sequentially washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM / MeOH = 20 / 1) to obtain the title compound (80 mg, 55%). LC-MS (M+H) + = 242.1.

[0330] Step 4: 5-amino-N-(7-bromoisochroman-4-yl)-N-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] The title compound (110 mg, 58%) was prepared from 5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-flu[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and 7-bromo-N-methylisochroman-4-amine by the same method as in Example 44, Step 6. LC-MS (M+H) + = 573.2.

[0331] Step 5: (S)-5-amino-N-(7-bromoisochroman-4-yl)-N-methyl-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide and (R)-5-amino-N-(7-bromoisochroman-4-yl)-N-methyl-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Examples 63 (20 mg, 24%) and 64 (31 mg, 37%) were prepared from 5-amino-N-(7-bromoisochroman-4-yl)-N-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide using the same method as in Example 44, Step 7, and the enantiomers were separated by chiral SFC.

[0332] The analytical chiral-SFC conditions are as follows: Column: CHIRALPAK AS-H, Column size: 20 × 250 mm, 5 μm, Mobile phase: (MeOH solution of 0.1% Et2NH): CO2 (1:2, isocratic), Flow rate: 40 mL / min, Temperature: 35 °C, Back pressure: 1450 psi.

[0333] Example 63: Analysis SFC tR = 7.00 min. 1 H NMR (400 MHz, DMSO-d6) δ 11.59 (s, 1H), 7.58 - 7.36 (m, 2H), 7.31 - 7.05 (m, 1H), 6.95 - 6.55 (m, 1H), 5.84 - 5.36 (m, 3H), 5.30 - 5.02 (m, 2H), 5.00 - 4.55 (m, 4H), 4.20 - 3.84 (m, 2H), 3.17 - 2.68 (m, 3H). LCMS (M+H) + = 443.2.

[0334] Example 64: Analysis SFC tR = 8.07 mins. 1 H NMR (400 MHz, DMSO-d6) δ 11.59 (s, 1H), 7.58 - 7.36 (m, 2H), 7.31 - 7.05 (m, 1H), 6.95 - 6.55 (m, 1H), 5.84 - 5.36 (m, 3H), 5.30 - 5.02 (m, 2H), 5.00 - 4.55 (m, 4H), 4.20 - 3.84 (m, 2H), 3.17 - 2.68 (m, 3H). LCMS (M+H) + = 443.2.

[0335] Example 65: 5-amino-N-cyclopentyl-N-((5-cyclopropyl-3-fluoropyridine-2-yl)methyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Step 1: N-((5-cyclopropyl-3-fluoropyridine-2-yl)methyl)cyclopentanamine [ka] The title compound (60 mg, 85%) was prepared from 5-cyclopropyl-3-fluoropicoline aldehyde and cyclopentanamine using the same method as in Example 5, Step 1. LC-MS (M+H) + = 235.2.

[0336] Step 2: 5-Amino-N-cyclopentyl-N-((5-cyclopropyl-3-fluoropyridine-2-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] The title compound (120 mg, 83%) was prepared from 5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and N-((5-cyclopropyl-3-fluoropyridine-2-yl)methyl)cyclopentanamine by the same method as in Example 44, Step 6. LC-MS (M+H) + = 566.4.

[0337] Step 3: 5-amino-N-cyclopentyl-N-((5-cyclopropyl-3-fluoropyridine-2-yl)methyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 65 (62 mg, 67%) was prepared from 5-amino-N-cyclopentyl-N-((5-cyclopropyl-3-fluoropyridine-2-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide using the same method as in Example 44, Step 7. 1 H NMR (400 MHz, DMSO-d6) δ 11.49 (s, 1H), 8.22 (s, 1H), 7.33 (d, J=11.6, 1H), 6.38 (s, 1H), 5.51 (s, 2H), 5.09 (s, 2H), 4.98 - 4.65 LC-MS (M+H) + = 436.4.

[0338] Example 66: 5-amino-N-((5-cyclopropyl-3-fluoropyridine-2-yl)methyl)-N-isopropyl-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Step 1: N-((5-cyclopropyl-3-fluoropyridine-2-yl)methyl)propan-2-amine [ka] NaBH(OAc)3 (154 mg, 0.73 mmol) was added to a solution of 5-cyclopropyl-3-fluoropicoline aldehyde (60 mg, 0.36 mmol) and isopropylamine (32 mg, 0.54 mmol) in DCM (5 mL). The mixture was stirred at room temperature for 2 hours and then slowly added to saturated NaHCO3 (10 mL). The mixture was extracted with  (10 mL). The organic layer was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM:MeOH = 10:1) to obtain the title compound (57 mg, 75%). 1 H NMR (400 MHz, DMSO-d6) δ 8.32 - 8.15 (m, 1H), 7.28 (dd, J = 11.3, 1.6 Hz, 1H), 3.77 (d, J = 1.8 Hz, 2H), 2.69 (septet, J = 6.2 Hz, 1H), 2.05 (br s, 1H), 2.02 - 1.91 (m, 1H), 1.11 - 0.91 (m, 8H), 0.88 - 0.69 (m, 2H). LC-MS (M+H) + = 209.1.

[0339] Step 2: 5-Amino-N-((5-Cyclopropyl-3-Fluoropyridine-2-yl)methyl)-N-Isopropyl-1-((2-(Trimethylsilyl)ethoxy)methyl)-6,8-Dihydro-1H-Fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] To a solution of N-((5-cyclopropyl-3-fluoropyridine-2-yl)methyl)propan-2-amine (57 mg, 0.27 mmol) in THF (5 mL), 5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid (80 mg, 0.23 mmol), BOPCl (88 mg, 0.35 mmol), and DIPEA (148 mg, 1.15 mmol) were added. The mixture was stirred at 70°C for 2 hours and then cooled to room temperature. The mixture was poured into water (20 mL) and extracted with RINKAN (10 × 2 mL). The combined organic layer was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM:MeOH = 20:1) to obtain the title compound (60 mg, 41%). LC-MS (M+H) + =540.3.

[0340] Step 3: 5-amino-N-((5-cyclopropyl-3-fluoropyridine-2-yl)methyl)-N-isopropyl-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide 5-amino-N-((5-cyclopropyl-3-fluoropyridine-2-yl)methyl)-N-isopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide (60 mg, 0.11 mmol) was dissolved in DCM (1 mL) and TFA (1 mL) was added. The mixture was stirred at room temperature for 3 hours and then concentrated under reduced pressure. The residue was redissolved in MeOH (1 mL) and K2CO3 (46 mg, 0.33 mmol) was added. The mixture was stirred at 40°C for 1 hour and then cooled to room temperature. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain Example 66 (28 mg, 61%). 1H NMR (400 MHz, DMSO-d6) δ 11.47 (s, 1H), 8.23 ​​(s, 1H), 7.33 (d, J = 11.7 Hz, 1H), 6.64 - 6.17 (m, 1H), 5.58 - 5.41 (m, 2H), 5.17 - 5.06 (m, 2H), 4.95 - 4.49 (m, 5H), 2.07 - 1.91 (m, 1H), 1.36 - 1.08 (m, 6H), 1.07 - 0.94 (m, 2H), 0.83 - 0.73 (m, 2H). LC-MS (M+H) + = 410.4.

[0341] Example 67: (R)-5-amino-N-(sec-butyl)-N-((5-cyclopropyl-3-fluoropyridine-2-yl)methyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Step 1: (R)-N-((5-cyclopropyl-3-fluoropyridine-2-yl)methyl)butan-2-amine [ka] The title compound (118 mg, 73%) was prepared from 5-cyclopropyl-3-fluoropicolinaldehyde and (R)-butane-2-amine hydrochloride by the same method as in Example 66, Step 1. LC-MS (M+H) + = 223.2.

[0342] Step 2: (R)-5-amino-N-(sec-butyl)-N-((5-cyclopropyl-3-fluoropyridine-2-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] The title compound (145 mg, 61%) was prepared from 5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and (R)-N-((5-cyclopropyl-3-fluoropyridine-2-yl)methyl)butan-2-amine by the same method as in Example 66, Step 2. LC-MS (M+H) + = 554.3.

[0343] Step 3: (R)-5-amino-N-(sec-butyl)-N-((5-cyclopropyl-3-fluoropyridine-2-yl)methyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 67 (24 mg, 22%) was prepared from (R)-5-amino-N-(sec-butyl)-N-((5-cyclopropyl-3-fluoropyridine-2-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide by the same method as in Example 66, Step 3. 1 H NMR (400 MHz, DMSO-d6) δ: 11.48 (s, 1H), 8.22 (s, 1H), 7.32 (d, J = 11.4 Hz, 1H), 6.42 (s, 1H), 5.51 (s, 2H), 5.10 (s, 2H), 4.98 - 4.35 (m, 5H), 2.02 - 1.92 (m, 1H), 1.75 -1.40 (m, 2H), 1.30 - 1.05 (m, 3H), 1.05 - 0.95 (m, 2H), 0.85 - 0.73 (m, 5H). LC-MS (M+H) + = 424.4.

[0344] Example 68: (R)-5-amino-N,6-dimethyl-N-((S)-7-(trifluoromethyl)isochroman-4-yl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Step 1: (S)-(7-(trifluoromethyl)isochroman-4-yl)carbamate tert-butyl [ka] The racemic mixture of (7-(trifluoromethyl)isochroman-4-yl)carbamate tert-butyl (13.0 g, 41.0 mmol) was separated by SFC to obtain the title compound (5.0 g, 38%).

[0345] The analytical chiral-SFC conditions were as follows: Column: CHIRALPAK IC-3, Column size: 4.6 × 100 mm, 3 μm, Mobile phase: 14 mM methanol solution of NH3:CO2, 1:9 for 0.2 min, 1:9 to 1:1 for 2.2 min, 1:1 for 1 min, Flow rate: 3.4 mL / min, Temperature: 35°C, Back pressure: 2000 psi.

[0346] (S)-(7-(trifluoromethyl)isochroman-4-yl)carbamate tert-butyl: Analysis SFC tR=1.18 min. 1H NMR (400 MHz, DMSO-d6) δ 7.59 (d, J = 8.0 Hz, 1H), 7.60-7.44 (m, 1H), 7.35 (d, J = 8.0 Hz, 1H), 4.82-4.64 (m, 3H), 3.93 (dd, J = 5.2, 11.0 Hz, 1H), 3.63 (dd, J = 7.6, 11.0 Hz, 1H), 1.43 (s, 9H). LC-MS (M+Ht-Bu) + = 262.0.

[0347] (R)-(7-(trifluoromethyl)isochroman-4-yl)carbamate tert-butyl: Analysis SFC tR=0.66 min.

[0348] Step 2: (S)-(7-(trifluoromethyl)isochroman-4-yl)carbamate tert-butylmethyl [ka] The title compound (1.5 g, 72%) was prepared from (S)-(7-(trifluoromethyl)isochroman-4-yl)carbamate tert-butyl by the same method as in Examples 39 and 40, Step 7. LCMS (M+H-tBu) + = 276.1.

[0349] Step 3: (S)-N-methyl-7-(trifluoromethyl)isochroman-4-amine hydrochloride [ka] The title compound (1.4 g, 100%) was prepared from tert-butylmethyl (S)-(7-(trifluoromethyl)isochroman-4-yl)carbamate by the same method as in Examples 39 and 40, Step 8. LC-MS (M+H) + = 232.0.

[0350] Step 4: (R)-5-amino-N,6-dimethyl-N-((S)-7-(trifluoromethyl)isochroman-4-yl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 68 (46 mg, 21%) was prepared from (S)-N-methyl-7-(trifluoromethyl)isochroman-4-amine hydrochloride and (R)-5-amino-6-methyl-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid using the same method as in Example 2, Step 3. 1H NMR (400 MHz, DMSO-d6) δ 11.61 (s, 1H), 7.74 - 7.38 (m, 3H), 6.72 (brs, 1H), 5.80 (s, 1H), 5.50 (s, 2H), 5.37 - 5.30 (m, 1H), 5.17 (dd, J = 13.9, 3.4 Hz, 1H), 5.06 (d, J = 13.8 Hz, 1H), 4.91 (d, J = 15.6 Hz, 1H), 4.74 (d, J = 15.6 Hz, 1H), 4.10 (s, 2H), 3.06 (brs, 3H), 1.36 (d, J = 6.1 Hz, 3H). LC-MS (M+H) + = 447.4.

[0351] Example 69: 5-amino-N-cyclobutyl-N-((5-cyclopropyl-3-fluoropyridine-2-yl)methyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Step 1: N-((5-cyclopropyl-3-fluoropyridine-2-yl)methyl)cyclobutanamine [ka] The title compound (20 mg, 15%) was prepared from 5-cyclopropyl-3-fluoropicoline aldehyde and cyclobutylamine using the same method as in Example 66, Step 1. LC-MS (M+H) + = 221.2.

[0352] Step 2: 5-amino-N-cyclobutyl-N-((5-cyclopropyl-3-fluoropyridine-2-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] The title compound (20 mg, 40%) was prepared from N-((5-cyclopropyl-3-fluoropyridine-2-yl)methyl)cyclobutanamine and 5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid by the same method as in Example 66, Step 2. LC-MS (M+H) + = 552.3.

[0353] Step 3: 5-amino-N-cyclobutyl-N-((5-cyclopropyl-3-fluoropyridine-2-yl)methyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 69 (3 mg, 22%) was prepared from 5-amino-N-cyclobutyl-N-((5-cyclopropyl-3-fluoropyridine-2-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide using the same method as in Example 66, Step 3. 1 H NMR (400 MHz, DMSO-d6) δ 11.51 (s, 1H), 8.20 (s, 1H), 7.33 (d, J = 11.6 Hz, 1H), 6.42 (s, 1H), 5.54 (s, 2H), 5.20 - 5.07 (m, 2H), 5.00 - 4.66 (m, 5H), 2.24 - 2.04 (m, 4H), 2.02 - 1.92 (m, 1H), 1.65 - 1.47 (m, 2H), 1.06 - 0.95 (m, 2H), 0.81 - 0.72 (m, 2H). LC-MS (M+H) + = 422.4.

[0354] Example 70: (R)-5-amino-N-((5-cyclopropyl-3-fluoropyridine-2-yl)methyl)-N-(3-methylbutan-2-yl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Step 1: (R)-N-((5-cyclopropyl-3-fluoropyridine-2-yl)methyl)-3-methylbutan-2-amine [ka] The title compound (110 mg, 77%) was prepared from 5-cyclopropyl-3-fluoropicoline aldehyde and (R)-3-methylbutan-2-amine by the same method as in Example 66, Step 1. LC-MS (M+H) + = 237.0.

[0355] Step 2: (R)-5-amino-N-((5-cyclopropyl-3-fluoropyridine-2-yl)methyl)-N-(3-methylbutan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] The title compound (40 mg, 33%) was prepared from (R)-N-((5-cyclopropyl-3-fluoropyridine-2-yl)methyl)-3-methylbutan-2-amine and 5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid by the same method as in Example 66, Step 2. LC-MS (M+H) + = 568.3.

[0356] Step 3: (R)-5-amino-N-((5-cyclopropyl-3-fluoropyridine-2-yl)methyl)-N-(3-methylbutan-2-yl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 70 (31 mg, 100%) was prepared from (R)-5-amino-N-((5-cyclopropyl-3-fluoropyridine-2-yl)methyl)-N-(3-methylbutan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide by the same method as in Example 66, Step 3. 1 H NMR (400 MHz, DMSO-d6) δ 11.46 (s, 1H), 8.21 (s, 1H), 7.30 (d, J = 11.1 Hz, 1H), 6.58 - 6.34 (m, 1H), 5.50 (s, 2H), 5.20 - 3.87 (m, 7H), 2.06 - 1.86 (m, 2H), 1.45 - 0.94 (m, 5H), 0.91 - 0.73 (m, 8H). LC-MS (M+H) + = 438.4.

[0357] Examples 71 and 72: (R)-5-amino-N-((R)-7-bromoisochroman-4-yl)-N,6-dimethyl-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide and (R)-5-amino-N-((S)-7-bromoisochroman-4-yl)-N,6-dimethyl-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Examples 71 (47 mg, 35%) and 72 (43 mg, 32%) were prepared from (R)-5-amino-6-methyl-6,8-dihydro-1H-flu[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and 7-bromo-N-methylisochroman-4-amine using the same method as in Examples 124 and 125 and Step 2, and the diastereomers were separated by chiral HPLC.

[0358] The analytical chiral-HPLC conditions were as follows: Column: YMC Cellulose-C, Column size: 4.6 × 250 mm, 5 μm, Mobile phase: (0.1% 2.0 M methanoly NH3 EtOH solution): Hexane (1:1, isocratic), Flow rate: 1.0 mL / min, Temperature: 25 °C.

[0359] Example 71: Analysis by chiral-HPLC tR=7.07 min. 1 H NMR (400 MHz, DMSO-d6) δ 11.59 (s, 1H), 7.56-7.36 (m, 2H), 7.29-7.08 (m, 1H), 6.70 (s, 1H), 5.70 (s, 1H), 5.49 (s, 2H), 5.4-5.29 (m, 1H), 5.22-5.02 (m, 2H), 4.90-4.57 (m, 2H), 4.65 (d, J = 15.4 Hz, 1H), 4.06 (s, 2H), 3.16 - 2.66 (m, 3H), 1.36 (d, J = 6.1 Hz, 3H).LCMS (M+H) + = 457.2.

[0360] Example 72: Analysis by chiral-HPLC tR=8.84 min. 1 H NMR (400 MHz, DMSO-d6) δ 11.59 (s, 1H), 7.56-7.36 (m, 2H), 7.29-7.08 (m, 1H), 6.70 (s, 1H), 5.70 (s, 1H), 5.49 (s, 2H), 5.4-5.29 (m, 1H), 5.22-5.02 (m, 2H), 4.90-4.57 (m, 2H), 4.65 (d, J = 15.4 Hz, 1H), 4.06 (s, 2H), 3.16 - 2.66 (m, 3H), 1.36 (d, J = 6.1 Hz, 3H).LCMS (M+H) + = 457.2.

[0361] Examples 73 and 74: (S)-5-amino-N-(7-chloroisochroman-4-yl)-N-ethyl-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide and (R)-5-amino-N-(7-chloroisochroman-4-yl)-N-ethyl-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Step 1: Methyl 2-(bromomethyl)-4-chlorobenzoate [ka] To a solution of methyl 4-chloro-2-methylbenzoate (5.0 g, 27.1 mmol) in CCl4 (100 mL), NBS (5.3 g, 29.7 mmol) and AIBN (2.2 g, 13.5 mmol) were added. The mixture was stirred overnight at 80°C under nitrogen. The mixture was cooled to room temperature, diluted with DCM (100 mL), and washed with water (80 mL) and brine (60 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (PE:Â=50:1) to obtain the title compound (6.3 g, 88%). LC-MS (M+H) + =263.1.

[0362] Step 2: 4-Chloro-2-((2-Methoxy-2-oxoethoxy)methyl benzoate [ka] To a mixture of methyl 2-hydroxyacetate (4.3 g, 47.9 mmol) in DMF (100 mL), NaH (60%, 1.92 g, 47.9 mmol) was added at 0°C. The mixture was stirred at room temperature for 30 minutes and then cooled to 0°C. A solution of methyl 2-(bromomethyl)-4-chlorobenzoate (6.3 g, 23.9 mmol) in DMF (10 mL) was added, and the mixture was stirred at 0°C for 10 minutes. Saturated NH4Cl (40 mL) was added dropwise, and the mixture was then fractionated between water (100 mL) and HCl (150 mL). The organic layer was washed with brine (2 × 60 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (PE:HCl = 4:1) to obtain the title compound (3.8 g, 58%). LC-MS (M + Na) + =295.1.

[0363] Step 3: 2-((carboxymethoxy)methyl)-4-chlorobenzoic acid [ka] A solution of 4-chloro-2-((2-methoxy-2-oxoethoxy)methyl)benzoate (3.8 g, 13.97 mmol) in EtOH (20 mL) was mixed with a solution of NaOH (2.5 g, 62.5 mmol) in water (14 mL). The mixture was stirred at room temperature for 1 hour. The pH of the mixture was adjusted to 3-4 with hydrochloric acid (1 M). The mixture was extracted with DCM (80 mL). The organic layer was washed with brine (60 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain the title compound (3.3 g, 97%). LC-MS (M+H) + = 245.1.

[0364] Step 4: 7-chloro-4-oxoisochroman-3-carboxylic acid anhydride [ka] KOAc (6.1 g, 62.2 mmol) was added to a mixture of 2-((carboxymethoxy)methyl)-4-chlorobenzoic acid (3.3 g, 13.5 mmol) in Ac2O (60 mL). The mixture was stirred at 140 °C for 3 hours. The mixture was cooled to room temperature and fractionated between ice water (100 mL) and ethyl acetate (120 mL). The aqueous phase was extracted with ethyl acetate (50 mL). The combined organic layers were washed with brine (60 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain the title compound (2.2 g, 61%).

[0365] Step 5: 7-Chloroisochroman-4-one [ka] A solution of 7-chloro-4-oxoisochroman-3-carboxylic acid anhydride (2.2 g, 8.21 mmol) in EtOH (60 mL) was mixed with a solution of NaOH (1.64 g, 41.0 mmol) in water (20 mL). The mixture was stirred at room temperature for 15 minutes and then fractionated between HCl (150 mL) and brine (70 mL). The organic layer was dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (PE:HCl = 10:1) to obtain the title compound (1.3 g, 87%). LC-MS (M+H) + =183.1.

[0366] Step 6: 7-chloroisochroman-4-ol [ka] To a solution of 7-chloroisochroman-4-one (1.0 g, 5.49 mmol) in EtOH (25 mL), NaBH4 (208 mg, 5.49 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Saturated NH4Cl (30 mL) was added while stirring, and the mixture was sequentially extracted with EA (80 + 50 mL). The combined organic layer was washed with brine (60 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain the title compound (950 mg, 94%). LC-MS (M+H) + =185.1.

[0367] Step 7: 4,7-Dichloroisochromane [ka] To a mixture of 7-chloroisochroman-4-ol (950 mg, 5.16 mmol) in THF (15 mL), SOCl2 (1.96 g, 16.5 mmol) was added dropwise, and the mixture was stirred at 80°C for 30 minutes. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was redissolved in  (50 mL) and sequentially washed with saturated NaHCO3 (30 mL) and brine (20 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum to obtain the title compound (810 mg, 78%). LC-MS (M+H) + =203.1.

[0368] Step 8: 7-Chloro-N-ethylisochroman-4-amine [ka] To a mixture of 4,7-dichloroisochromane (404 mg, 2.0 mmol) in DMA (10 mL), ethylamine hydrochloride (492 mg, 6.0 mmol), K2CO3 (1.1 g, 7.97 mmol), and KI (400 mg, 2.41 mmol) were added. The mixture was stirred overnight at 100°C. The mixture was cooled to room temperature and diluted with SiO2 (50 mL), and sequentially washed with water (20 mL) and brine (20 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative TLC (PE:SiO2 = 1:1) to obtain the title compound (100 mg, 24%). LC-MS (M+H) + =212.3.

[0369] Step 9: 5-amino-N-(7-chloroisochroman-4-yl)-N-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] 5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid (166 mg, 0.47 mmol) and 7-chloro-N-ethylisochroman-4-amine (100 mg, 0.47 mmol) were mixed in THF (10 mL) and DIPEA (303 mg, 3.0 mmol) and BOPCl (203 mg, 0.80 mmol) were added. The mixture was stirred at 60°C for 2 hours. The mixture was diluted with  (50 mL) and washed sequentially with water (20 mL) and brine (20 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (MeOH:DCM = 1:15) to obtain the title compound (160 mg, 62%). LC-MS (M+H) + = 543.3.

[0370] Step 10: (S)-5-amino-N-(7-chloroisochroman-4-yl)-N-ethyl-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide and (R)-5-amino-N-(7-chloroisochroman-4-yl)-N-ethyl-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide A mixture of 5-amino-N-(7-chloroisochroman-4-yl)-N-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide (160 mg, 0.29 mmol) in TFA (5 mL) was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure. Methanol ammonia (7.0 M, 10 mL) was added to the residue, and the mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC and further purified by SFC to obtain Example 73 (27 mg, 22%) and Example 74 (28 mg, 23%).

[0371] The analytical chiral-SFC conditions were as follows: Column: CHIRALPAK IH, Column size: 4.6 × 100 mm, 5 μm, Mobile phase: 0.2% diethylamine MeOH solution: CO2, 1:9 to 4:6 for 3 minutes, 4:6 for 2 minutes, 4:6 to 1:9 for 0.1 minutes, 1:9 for 1.9 minutes, Flow rate: 2.0 mL / min, Temperature: 35°C, Back pressure: 1500 psi.

[0372] Example 73: Analysis SFC tR = 3.82 mins. 1 H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1H), 7.32 (d, J = 12.0 Hz, 1H), 7.28 (s, 1H), 7.23 (d, J = 12.0 Hz, 1H), 6.59 (s, 1H), 6.66 - 6.55 (m, 1H), 5.53 (s, 2H), 5.14 (s, 2H), 4.92 (s, 2H), 4.83 (d, J = 15.6 Hz, 1H), 4.66 (d, J = 15.6 Hz, 1H), 4.12 (s, 2H), 3.31 - 3.30 (m, 2H), 1.11 - 1.01 (m, 3H). LCMS (M+H) + = 413.4.

[0373] Example 74: Analysis of SFC tR = 4.09 mins. 1 H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1H), 7.32 (d, J = 12.0 Hz, 1H), 7.28 (s, 1H), 7.23 (d, J = 12.0 Hz, 1H), 6.59 (s, 1H), 6.66 - 6.55 (m, 1H), 5.53 (s, 2H), 5.14 (s, 2H), 4.92 (s, 2H), 4.83 (d, J = 15.6 Hz, 1H), 4.66 (d, J = 15.6 Hz, 1H), 4.12 (s, 2H), 3.31 - 3.30 (m, 2H), 1.11 - 1.01 (m, 3H). LCMS (M+H) + = 413.3.

[0374] Examples 75 and 76: (S)-5-amino-N-(5,7-difluoroisochroman-4-yl)-N-ethyl-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide and (R)-5-amino-N-(5,7-difluoroisochroman-4-yl)-N-ethyl-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Step 1: (2-bromo-3,5-difluorophenyl)methanol [ka] 2-Bromo-3,5-difluorobenzaldehyde (5.0 g, 22.6 mmol) was dissolved in MeOH (50 mL) and NaBH4 (942 mg, 24.9 mmol) was added under nitrogen at 0°C. The mixture was stirred at 25°C for 0.5 hours. Saturated NH4Cl (10 mL) was added to the reaction mixture at 0°C, and the mixture was stirred at 25°C for 1 hour. The mixture was extracted with Depositphotos (2 × 100 mL). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / Depositphotos = 1 / 0 to 5 / 1) to obtain the title compound (4.8 g, 95%). LCMS (M + Na) + = 246.0.

[0375] Step 2: 1-((allyloxy)methyl)-2-bromo-3,5-difluorobenzene [ka] To a solution of (2-bromo-3,5-difluorophenyl)methanol (4.0 g, 17.9 mmol) in THF (40 mL), allyl bromide (2.82 g, 23.3 mmol) and NaH (60%, 861 mg, 21.5 mmol) were added under nitrogen at 0°C. The mixture was stirred at 25°C for 2 hours. The mixture was poured into ice water (100 mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic layer was washed with brine (50 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / ethyl acetate = 1 / 0 to 5 / 1) to obtain the title compound (4.3 g, 91%). 1 H NMR (400 MHz, CD3OD) δ 7.20-7.12 (m, 1H), 7.09-7.00 (m, 1H), 6.06-5.92 (m, 1H), 5.35 (dd, J = 17.2, 1.6 Hz, 1H), 5.23 (d, J = 10.4 Hz, 1H), 4.58 (s, 2H), 4.14 (d, J = 5.6 Hz, 2H).

[0376] Step 3: 5,7-difluoro-4-methyleneisochromane [ka] To a solution of 1-(allyloxymethyl)-2-bromo-3,5-difluorobenzene (4.5 g, 17.1 mmol) in DMF (90 mL), Cs2CO3 (6.69 g, 20.5 mmol), PPh3 (1.08 g, 4.11 mmol), and Pd(OAc)2 (307 mg, 1.37 mmol) were added. The container was degassed and purged three times with N2. The mixture was stirred under nitrogen at 90°C for 16 hours. The mixture was cooled to room temperature and diluted with water (100 mL). The mixture was extracted with HCl (2 × 100 mL). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / HCl = 1 / 0 to 5 / 1) to obtain the title compound (1.5 g, 48%). 1H NMR (400 MHz, CD3OD) δ 6.92-6.82 (m, 1H), 6.80-6.73 (m, 1H), 5.82 (s, 1H), 5.28 (d, J = 4.4 Hz, 1H), 4.78 (s, 2H), 4.39-4.35 (m, 2H).

[0377] Step 4: 5,7-difluoroisochroman-4-one [ka] To a mixture of 5,7-difluoro-4-methylene-isochroman (1.5 g, 8.23 ​​mmol) in dioxane (20 mL) and water (4 mL), potassium osmium(VI) dihydrate (303 mg, 823 μmol), 2,6-lutidine (1.76 g, 16.47 mmol), and sodium periodate (7.04 g, 32.9 mmol) were added under nitrogen at 25°C. The mixture was stirred at 25°C for 2 hours. The mixture was quenched with saturated Na₂S₂O₃ (5 mL), diluted with water (100 mL), and extracted with toluene (3 × 100 mL). The combined organic layer was washed with brine (50 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / toluene = 1 / 0 to 5 / 1) to obtain the title compound (1.0 g, 66%). 1 H NMR (400 MHz, CD3OD) δ 7.10-6.96 (m, 2H), 5.88 (s, 2H), 4.29 (s, 2H).

[0378] Step 5: 5,7-difluoroisochroman-4-oneoxime [ka] The title compound (0.92 g, 85%) was prepared from 5,7-difluoroisochroman-4-one using the same method as in Examples 39 and 40, Step 4. LC-MS (M+H) + = 200.2.

[0379] Step 6: 5,7-Difluoroisochroman-4-amine [ka] The title compound (822 mg, 96%) was prepared from 5,7-difluoroisochroman-4-one oxime by the same method as in Examples 39 and 40, Step 5. LC-MS (M+H) + = 186.1.

[0380] Step 7: (5,7-difluoroisochroman-4-yl)carbamate tert-butyl [ka] The title compound (820 mg, 65%) was prepared from 5,7-difluoroisochroman-4-amine by the same method as in Examples 39 and 40, Step 6. LCMS (M+H-tBu) + = 230.1.

[0381] Step 8: (5,7-difluoroisochroman-4-yl)(ethyl)carbamate tert-butyl [ka] The title compound (100 mg, 91%) was prepared from tert-butyl (5,7-difluoroisochroman-4-yl)carbamate and EtI by the same method as in Examples 39 and 40, Step 7. LCMS (M+H-tBu) + = 258.1.

[0382] Step 9: N-ethyl-5,7-difluoroisochroman-4-amine hydrochloride [ka] The title compound (125 mg, 100%) was prepared from tert-butyl (5,7-difluoroisochroman-4-yl)(ethyl)carbamate by the same method as in Example 39 and Example 40, Step 8. LC-MS (M+H)+ = 214.1.

[0383] Step 10: 5-amino-N-(5,7-difluoroisochroman-4-yl)-N-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] The title compound (260 mg, 100%) was prepared from N-ethyl-5,7-difluoroisochroman-4-amine hydrochloride and 5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-flu[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid by the same method as in Examples 73 and 74, Step 9. LC-MS (M+H) + = 545.3.

[0384] Step 11: (R)-5-amino-N-(5,7-difluoroisochroman-4-yl)-N-ethyl-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide and (S)-5-amino-N-(5,7-difluoroisochroman-4-yl)-N-ethyl-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Examples 75 (14 mg, 7%) and 76 (13 mg, 6%) were prepared from 5-amino-N-(5,7-difluoroisochroman-4-yl)-N-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide using the same method as in Examples 73 and 74 and step 10, and the enantiomers were separated by chiral SFC.

[0385] The analytical chiral-SFC conditions were as follows: Column: ChiralPak IH, Column size: 4.6 × 100 mm, 3 μm, Mobile phase: (Isopropanol containing 0.2% 7M methanolic NH3): CO21, 1:9 for 0.2 min, 1:9 to 1:1 for 2.4 min, 1:1 for 1 min, 1:1 to 1:9 for 0.6 min, Flow rate: 3.4 mL / min, Temperature: 35°C, Back pressure: 2000 psi.

[0386] Example 75: Analysis of SFC tR = 2.10 mins. 1 H NMR (400 MHz, DMSO-d6) δ 11.55 (s, 1H), 7.15 (t, J = 8.8 Hz, 1H), 7.00 (d, J = 8.8 Hz, 1H), 6.55 (s, 1H), 5.68 (s, 1H), 5.54 (s, 2H), 5.15 (d, J = 2.4 Hz, 2H), 4.96 - 4.88 (m, 3H), 4.63 (d, J = 15.6 Hz, 1H), 4.36 - 3.94 (m, 4H), 0.98 (t, J = 6.8 Hz, 3H). LC-MS (M+H) + = 415.1.

[0387] Example 76: Analysis SFC tR = 2.54 mins. 1 H NMR (400 MHz, DMSO-d6) δ 11.55 (s, 1H), 7.15 (t, J = 8.8 Hz, 1H), 7.00 (d, J = 8.8 Hz, 1H), 6.55 (s, 1H), 5.68 (s, 1H), 5.54 (s, 2H), 5.15 (d, J = 2.4 Hz, 2H), 4.96 - 4.88 (m, 3H), 4.63 (d, J = 15.6 Hz, 1H), 4.36 - 3.94 (m, 4H), 0.98 (t, J = 6.8 Hz, 3H). LC-MS (M+H) + = 415.1.

[0388] Example 77: (S)-5-amino-N-ethyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Step 1: (S)-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)carbamate tert-butyl [ka] The title compound (300 mg, 99%) was prepared from (S)-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine hydrochloride by the same method as in Example 39 and Example 40, Step 6. LC-MS (M+Na) + = 326.1.

[0389] Step 2: (S)-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)carbamate tert-butylethyl [ka] The title compound (240 mg, 73%) was prepared from (S)-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)carbamate tert-butyl and EtI by the same method as in Examples 39 and 40, Step 7. LC-MS (M+H-tBu) + = 276.1.

[0390] Step 3: (S)-N-ethyl-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine [ka] (S)-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)carbamate tert-butylethyl (240 mg, 0.72 mmol) was mixed with HCl (4.0 M in dioxane, 5 mL) and stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure. The residue was fractionated between saturated NaHCO3 (50 mL) and ethyl acetate (40 mL). The aqueous layer was sequentially extracted with ethyl acetate (2 × 40 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound (120 mg, 79%). LC-MS (M+H) + = 232.1.

[0391] Step 4: (S)-5-amino-N-ethyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] The title compound (250 mg, 86%) was prepared from (S)-N-ethyl-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine and 5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-flu[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid by the same method as in Examples 73 and 74 and Step 9. LC-MS (M+H) + = 563.4.

[0392] Step 5: (S)-5-amino-N-ethyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 77 (103 mg, 60%) was prepared from (S)-5-amino-N-ethyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide by the same method as in Example 66, Step 3. 1 H NMR (400 MHz, DMSO-d6) δ 11.57 (s, 1H), 7.55 (d, J = 7.6, 1H), 7.38 - 7.11 (m, 2H), 6.60 (d, J = 2.0 Hz, 1H), 6.12 (s, 1H), 5.58 (s, LC-MS (M+H) + = 433.3.

[0393] Examples 78, 79, 80, and 81: 5-amino-N-((1S,4R)-7-bromo-1-methylisochroman-4-yl)-N-methyl-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide and 5-amino-N-((1R,4R)-7-bromo-1-methylisochroman-4-yl)-N-methyl-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Lysine-2-carboxamide and 5-amino-N-((1S,4S)-7-bromo-1-methylisochroman-4-yl)-N-methyl-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide and 5-amino-N-((1R,4S)-7-bromo-1-methylisochroman-4-yl)-N-methyl-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Step 1: 1-(5-bromo-2-iodophenyl)ethane-1-ol [ka] The title compound (22 g, 84%) was prepared from 5-bromo-2-iodobenzaldehyde and MeMgBr in the same manner as in Examples 57, 58, 59, and 60, and in Step 1. 1 H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 1.6 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.11 (dd, J = 8.4, 2.4 Hz, 1H), 5.01 (q, J = 6.4 Hz, 1H), 1.99 (br s, 1H), 1.46 (d, J = 6.4 Hz, 3H).

[0394] Step 2: 2-(1-(allyloxy)ethyl)-4-bromo-1-iodobenzene [ka] The title compound (19 g, 77%) was prepared from 1-(5-bromo-2-iodophenyl)ethane-1-ol and allyl bromide by the same method as in Examples 39 and 40 and Step 1. 1 H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 2.4 Hz, 1H), 7.11 (dd, J = 8.4, 2.8 Hz, 1H), 5.98-5.85 (m, 1H), 5.28-5.17 (m, 2H), 4.62 (q, J = 6.4 Hz, 1H), 3.97-3.88 (m, 1H), 3.86-3.77 (m, 1H), 1.39 (d, J = 6.4 Hz, 3H).

[0395] Step 3: 7-Bromo-1-methyl-4-methyleneisochromane [ka] The title compound (2.6 g, 21%) was prepared from 2-(1-(allyloxy)ethyl)-4-bromo-1-iodobenzene by the same method as in Examples 39 and 40, Step 2. 1 H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 8.4 Hz, 1H), 7.37 (dd, J = 8.0, 1.2 Hz, 1H), 7.29-7.26 (m, 1H), 5.59 (s, 1H), 5.04 (s, 1H), 4.84 (q, J = 6.4 Hz, 1H), 4.54, 4.35 (ABq, J = 13.2 Hz, 2H), 1.56 (d, J = 6.8 Hz, 3H).

[0396] Step 4: 7-Bromo-1-methylisochroman-4-one [ka] The title compound (2.2 g, 83%) was prepared from 7-bromo-1-methyl-4-methyleneisochromane by the same method as in Example 39 and Example 40, Step 3. 1 H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.43 (s, 1H), 4.91 (q, J = 6.4 Hz, 1H), 4.51, 4.29 (ABq, J = 17.2 Hz, 2H), 1.66 (d, J = 6.8 Hz, 3H). LC-MS (M+H) + = 241.0.

[0397] Step 5: 7-bromo-1-methylisochroman-4-ol [ka] 7-Bromo-1-methylisochroman-4-one (2.2 g, 9.13 mmol) was dissolved in MeOH (30 mL) and NaBH4 (449 mg, 11.9 mmol) was added at 0°C. The mixture was stirred at 25°C for 1 hour. The reaction mixture was quenched with saturated NH4Cl (10 mL) and extracted with ELISA (3 × 30 mL). The combined organic layer was washed with brine (40 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / ELISA = 100 / 1~5 / 1) to obtain the title compound (1.9 g, 86%). LC-MS (M+H-H2O) + = 225.0.

[0398] Step 6: 4-azido-7-bromo-1-methylisochromane [ka] DPPA (2.31 g, 8.39 mmol) was added to a toluene (17 mL) solution of 7-bromo-1-methylisochroman-4-ol at 0°C. A toluene (4 mL) solution of DBU (1.60 g, 10.5 mmol) was added dropwise. The mixture was stirred at 25°C for 12 hours. The mixture was diluted with water (30 mL) and extracted with HCl (3 × 30 mL). The combined organic layers were washed with brine (40 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel chromatography (PE / HCl = 1 / 0~10 / 1) to obtain the title compound (1.4 g, 75%). LC-MS (M+H-N₂) + = 240.0.

[0399] Step 7: 7-Bromo-1-methylisochroman-4-amine [ka] To a solution of 4-azido-7-bromo-1-methylisochromane (1.4 g, 5.22 mmol) in THF (15 mL), solutions of PPh3 (2.74 g, 10.44 mmol) and KOH (732 mg, 13.0 mmol) in aqueous solution (3 mL) were added. The mixture was stirred at 50°C for 1 hour and at 25°C for 12 hours. The pH of the mixture was adjusted to approximately 2 with hydrochloric acid (2 M), and the mixture was washed with SiO2 (3 × 10 mL). The pH of the aqueous layer was adjusted to approximately 11 with saturated KOH solution, and the mixture was then extracted with SiO2 (3 × 40 mL). The combined organic layer was washed with brine (40 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude title compound (0.9 g, 71%). LC-MS (M+H) + = 242.0.

[0400] Step 8: (7-bromo-1-methylisochroman-4-yl)carbamate tert-butyl [ka] The title compound (1.2 g, 94%) was prepared from 7-bromo-1-methylisochroman-4-amine by the same method as in Example 39 and Example 40, Step 6. LCMS (M+H-tBu) + = 286.1.

[0401] Step 9: (7-bromo-1-methylisochroman-4-yl)(methyl)carbamate tert-butyl [ka] The title compound (900 mg, 72%) was prepared from tert-butyl (7-bromo-1-methylisochroman-4-yl)carbamate and MeI by the same method as in Examples 39 and 40, Step 7. LCMS (M+H-tBu) + = 300.0.

[0402] Step 10: 7-Bromo-N,1-dimethylisochroman-4-amine hydrochloride [ka] The title compound (650 mg, 88%) was prepared from (7-bromo-1-methylisochroman-4-yl)(methyl)carbamate tert-butyl by the same method as in Example 39 and Example 40, Step 8. LC-MS (M+H) + = 256.1.

[0403] Step 11: 5-amino-N-(7-bromo-1-methylisochroman-4-yl)-N-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] The title compound (0.6 g, 40%) was prepared from 5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and 7-bromo-N,1-dimethylisochroman-4-amine hydrochloride by the same method as in Examples 73 and 74 and Step 9. LC-MS (M+H) + = 587.3.

[0404] Step 12: 5-amino-N-((1S,4R)-7-bromo-1-methylisochroman-4-yl)-N-methyl-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide and 5-amino-N-((1R,4R)-7-bromo-1-methylisochroman-4-yl)-N-methyl-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Thamide and 5-amino-N-((1S,4S)-7-bromo-1-methylisochroman-4-yl)-N-methyl-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide and 5-amino-N-((1R,4S)-7-bromo-1-methylisochroman-4-yl)-N-methyl-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Examples 78 (66 mg, 14%), 79 (16 mg, 3%), 80 (21 mg, 4%), and 81 (73 mg, 16%) were prepared from 5-amino-N-(7-bromo-1-methylisochroman-4-yl)-N-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide using the same method as in Examples 73 and 74 and step 10, and the isomers were separated by chiral SFC.

[0405] The analytical chiral-SFC conditions were as follows: Column: CHIRALPAK OJ-3, Column size: 4.6 × 50 mm, 3 μm, Mobile phase: (ethanol containing 0.2% 7M methanolic NH3): CO2, 1:19 for 0.2 min, 1:19 to 1:1 for 1.0 min, 1:1 for 1 min, 1:1 to 1:19 for 0.4 min, 1:19 for 0.4 min, Flow rate: 3.4 mL / min, Temperature: 35°C, Back pressure: 1800 psi.

[0406] Example 78: Analysis of SFC tR = 1.45 min. 1 H NMR (400 MHz, DMSO-d6) δ 11.57 (br s, 1H), 7.58 - 7.43 (m, 2H), 7.27 - 7.09 (m, 1H), 6.69 (br s, 1H), 5.71 - 5.50 (m, 3H), 5.15 (s, 2H), 4.93 (s, 2H), 4.73 (q, J = 6.2 Hz, 1H), 4.27 - 4.11 (m, 1H), 4.08 - 3.97 (m, 1H), 3.19 - 2.71 (m, 3H), 1.54 (d, J = 6.4 Hz, 3H).LC-MS (M+H) + = 457.0.

[0407] Example 79: Analysis SFC tR = 1.52 mins. 1H NMR (400 MHz, DMSO-d6) δ 11.60 (br s, 1H), 7.53 - 7.42 (m, 2H), 7.11 (d, J = 8.4 Hz, 1H), 6.74 (br s, 1H), 5.85 - 5.66 (m, 1H), 5.57 (s, 2H), 5.15 (s, 2H), 4.97 - 4.86 (m, 3H), 4.30 - 4.07 (m, 1H), 3.96 - 3.77 (m, 1H), 3.09 - 2.62 (m, 3H), 1.46 (d, J = 6.4 Hz, 3H). LC-MS(M+H) + = 457.0.

[0408] Example 80: Analysis of SFC tR=1.87 points. 1 H NMR (400 MHz, DMSO-d6) δ 11.60 (br s, 1H), 7.54 - 7.40 (m, 2H), 7.11 (d, J = 8.4 Hz, 1H), 6.74 (br s, 1H), 5.85 - 5.66 (m, 1H), 5.57 (s, 2H), 5.15 (s, 2H), 4.98 - 4.85 (m, 3H), 4.30 - 4.07 (m, 1H), 3.96 - 3.77 (m, 1H), 3.09 - 2.63 (m, 3H), 1.46 (d, J = 6.4 Hz, 3H). LC-MS(M+H) + = 457.0.

[0409] Example 81: Analysis of SFC tR=2.23 points. 1H NMR (400 MHz, DMSO-d6) δ 11.57 (br s, 1H), 7.58 - 7.43 (m, 2H), 7.27 - 7.09 (m, 1H), 6.69 (br s, 1H), 5.71 - 5.50 (m, 3H), 5.15 (s, 2H), 4.93 (s, 2H), 4.73 (q, J = 6.2 Hz, 1H), 4.27 - 4.11 (m, 1H), 4.08 - 3.97 (m, 1H), 3.19 - 2.71 (m, 3H), 1.54 (d, J = 6.4 Hz, 3H).LC-MS (M+H) + = 457.0.

[0410] Example 82: (S)-5-amino-N-(5-fluoro-7-(trifluoromethyl)isochroman-4-yl)-N-methyl-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Step 1: 2-Bromo-6-fluoro-4-(trifluoromethyl)aniline [ka] 2-Fluoro-4-(trifluoromethyl)aniline (25 g, 140 mmol) was dissolved in DMF (200 mL) and NBS (26.1 g, 146.6 mmol) was added at 0°C. The mixture was stirred at 25°C for 12 hours. The mixture was diluted with water (500 mL) and then extracted with ethyl acetate (3 × 150 mL). The combined organic layer was washed with brine (3 × 150 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / siRNA = 1 / 0 to 10 / 1) to obtain the title compound (29 g, 80%). 1 H NMR (DMSO-d6, 400 MHz) δ 7.57 (s, 1H), 7.48 (dd, J = 11.2, 0.8 Hz, 1H), 6.11 (s, 2H). LC-MS (M+H) += 257.9.

[0411] Step 2: Methyl 2-amino-3-fluoro-5-(trifluoromethyl)benzoate [ka] A mixture of 2-bromo-6-fluoro-4-(trifluoromethyl)aniline (29 g, 112.4 mmol), PdCl2 (1.99 g, 11.2 mmol), BINAP (14.0 g, 22.5 mmol), and Et3N (22.8 g, 224.8 mmol) in MeOH (200 mL) was degassed and purged three times with CO. The mixture was stirred under CO at 80°C for 24 hours. The solid was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / siRNA = 1 / 0 to 10 / 1) to obtain the title compound (15 g, 56%). 1 H NMR (DMSO-d6, 400 MHz) δ 7.80 (s, 1H), 7.63 (dd, J = 11.5, 1.9 Hz, 1H), 7.18 (br s, 2H), 3.84 (s, 3H). LC-MS (M+H) + = 238.0.

[0412] Step 3: Methyl 2-bromo-3-fluoro-5-(trifluoromethyl)benzoate [ka] To a solution of methyl 2-amino-3-fluoro-5-(trifluoromethyl)benzoate (15 g, 63.3 mmol) in MeCN (100 mL), CuBr2 (18.4 g, 82.2 mmol) was added, and the mixture was stirred at 25°C for 1 hour. Tert-butyl nitrite (7.83 g, 75.9 mmol) was added, and the mixture was stirred at 25°C for 4 hours. The mixture was diluted with water (100 mL) and extracted with toluene (100 mL x 2). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / toluene = 1 / 0 to 100 / 1) to obtain the title compound (12.5 g, 66%). 1 H NMR (DMSO-d6, 400 MHz) δ 8.10 (d, J = 8.5 Hz, 1H), 7.96 (s, 1H), 3.91 (s, 3H).

[0413] Step 4: (2-bromo-3-fluoro-5-(trifluoromethyl)phenyl) methanol [ka] A solution of methyl 2-bromo-3-fluoro-5-(trifluoromethyl)benzoate (12.5 g, 41.5 mmol) in THF (120 mL) was added to a solution of LiBH4 in THF (2.0 M, 83.0 mL, 166 mmol) at 0°C. The mixture was stirred under nitrogen at 20°C for 3 hours. The mixture was quenched with saturated NH4Cl (150 mL) and then extracted with Depositphotos (3 × 150 mL). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / Depositphotos = 1 / 0 to 10 / 1) to obtain the title compound (10.5 g, 93%). 1 H NMR (DMSO-d6, 400 MHz) δ 7.77 (d, J = 8.4 Hz, 1H), 7.66 (s, 1H), 5.80 (t, J = 5.6 Hz, 1H), 4.59 (d, J = 5.4 Hz, 2H).

[0414] Step 5: 1-((allyloxy)methyl)-2-bromo-3-fluoro-5-(trifluoromethyl)benzene [ka] (2-bromo-3-fluoro-5-(trifluoromethyl)phenyl)methanol (10.5 g, 38.5 mmol) was dissolved in DMF (100 mL) and allyl bromide (9.31 g, 76.9 mmol) and NaH (60%, 3.08 g, 76.9 mmol) were added at 0°C. The mixture was stirred under nitrogen at 25°C for 12 hours. The mixture was poured into ice water (100 mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic layer was washed with brine (50 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / ethyl acetate = 1 / 0 to 10 / 1) to obtain the title compound (10.5 g, 87%). 1 H NMR (DMSO-d6, 400 MHz) δ 7.82 (dd, J = 8.5, 1.5 Hz, 1H), 7.63 (s, 1H), 6.00 - 5.93 (m, 1H), 5.35-5.30 (m, 1H), 5.23 - 5.20 (m, 1H), 4.60 (s, 2H), 4.13 (td, J = 5.5, 1.4 Hz, 2H).

[0415] Step 6: 5-fluoro-4-methylene-7-(trifluoromethyl)isochromane [ka] To a solution of 1-((allyloxy)methyl)-2-bromo-3-fluoro-5-(trifluoromethyl)benzene (1.0 g, 3.19 mmol) in DMF (100 mL), PPh3 (377 mg, 1.44 mmol), Pd(OAc)2 (143 mg, 639 μmol), and Cs2CO3 (1.25 g, 3.83 mmol) were added. The mixture was stirred under nitrogen at 90°C for 12 hours. The mixture was cooled to room temperature and diluted with water (100 mL). The mixture was extracted with HCl (2 × 100 mL). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / HCl = 1 / 0 to 10 / 1) to obtain the title compound (0.44 g, 59%). 1 H NMR (CDCl3, 400 MHz) δ 7.24 (d, J = 11.6 Hz, 1H), 7.12 (s, 1H), 6.06 (s, 1H), 5.42 (d, J = 3.0 Hz, 1H), 4.85 (s, 2H), 4.42 (s, 2H).

[0416] Step 7: 5-Fluoro-7-(trifluoromethyl)isochroman-4-one [ka] To a solution of 5-fluoro-4-methylene-7-(trifluoromethyl)isochroman (5.7 g, 24.6 mmol) in dioxane (150 mL) and water (30 mL), potassium osmium(VI) dihydrate (905 mg, 2.46 mmol), sodium periodate (21.0 g, 98.2 mmol), and 2,6-lutidine (5.26 g, 49.1 mmol) were added. The mixture was stirred under nitrogen at 25°C for 2 hours. The mixture was quenched with saturated Na₂S₂O₃ (20 mL), diluted with water (50 mL), and extracted with Depositphotos (3 × 50 mL). The combined organic layer was washed with brine (50 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / Depositphotos = 1 / 0 to 5 / 1) to obtain the title compound (4.4 g, 77%). 1H NMR (DMSO-d6, 400 MHz) δ 7.77 (d, J = 10.9 Hz, 1H), 7.72 (s, 1H), 4.97 (s, 2H), 4.37 (s, 2H).

[0417] Step 8: (R)-5-fluoro-7-(trifluoromethyl)isochroman-4-ol [ka] To a mixture of 5-fluoro-7-(trifluoromethyl)isochroman-4-one (4.4 g, 18.8 mmol) in a formic acid-Et3N complex (5:2, 20 mL), [(S,S)-N-(2-amino-1,2-diphenylethyl)-p-toluenesulfonamide]chloro(p-cymene)ruthenium(II) (599 mg, 940 μmol) was added under hydrogen. The mixture was stirred at 0°C for 2 hours, then slowly heated to 25°C and stirred for 12 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layer was washed with brine (40 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / ethyl acetate = 30 / 1 to 4 / 1) to obtain the title compound (4.1 g, 92%). 1 H NMR (CDCl3, 400 MHz) δ 7.18 (d, J = 10.0 Hz, 1H), 7.05 (s, 1H), 4.82 - 4.73 (m, 2H), 4.60 (d, J = 15.6 Hz, 1H), 4.15 (dd, J = 12.4, 2.0 Hz, 1H), 3.75 (dd, J = 12.4, 2.4 Hz, 1H), 2.53 (br s, 1H).

[0418] Step 9: (S)-N-(5-fluoro-7-(trifluoromethyl)isochroman-4-yl)-N-methyl-2-nitrobenzenesulfonamide [ka] (R)-5-fluoro-7-(trifluoromethyl)isochroman-4-ol (1.0 g, 4.23 mmol) and N-methyl-2-nitrobenzenesulfonamide (1.01 g, 4.66 mmol) were dissolved in THF (16 mL), to which PPh3 (1.22 g, 4.66 mmol) and DIAD (941.85 mg, 4.66 mmol) were added at 0°C. The mixture was stirred at 25°C for 1 hour. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layer was washed with brine (40 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / ethyl acetate = 5 / 1 to 1 / 1) to obtain the title compound (1.8 g, 98%). LC-MS (M + Na) + = 457.1.

[0419] Step 10: (S)-5-fluoro-N-methyl-7-(trifluoromethyl)isochroman-4-amine [ka] (S)-N-(5-fluoro-7-(trifluoromethyl)isochroman-4-yl)-N-methyl-2-nitrobenzenesulfonamide (6.3 g, 14.5 mmol) was dissolved in THF (63 mL) and DMF (6.3 mL). Lithium hydroxide monohydrate (3.0 g, 72.5 mmol) and dodecane-1-thiol (14.7 g, 72.5 mmol) were added at 0°C. The mixture was stirred at 25°C for 12 hours. The pH of the mixture was adjusted to approximately 2 with hydrochloric acid (2 M), and the mixture was washed with ELISA (3 × 50 mL). The pH of the aqueous layer was adjusted to approximately 13 with aqueous NaOH solution (2 M), and the mixture was extracted with ELISA (3 × 50 mL). The combined organic layer was washed with brine (70 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the title compound (1.1 g, 30%). LC-MS (M+H) + = 250.2.

[0420] Step 11: (S)-5-amino-N-(5-fluoro-7-(trifluoromethyl)isochroman-4-yl)-N-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] (S)-5-fluoro-N-methyl-7-(trifluoromethyl)isochroman-4-amine (0.30 g, 1.20 mmol) and 5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid (463 mg, 1.32 mmol) were dissolved in THF (10 mL), to which BOPCl (398 mg, 1.56 mmol) and DIPEA (467 mg, 3.61 mmol) were added. The mixture was stirred at 40 °C for 2 hours and cooled to room temperature. The mixture was diluted with water (30 mL) and extracted with RINKAN (3 × 30 mL). The combined organic layer was washed with brine (40 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the title compound (0.55 g, 79%). LC-MS (M+H) + = 581.3.

[0421] Step 12: (S)-5-amino-N-(5-fluoro-7-(trifluoromethyl)isochroman-4-yl)-N-methyl-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide A solution of (S)-5-amino-N-(5-fluoro-7-(trifluoromethyl)isochroman-4-yl)-N-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-fluoro[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide (0.55 g, 0.95 mmol) in TFA (4 mL) was stirred at 40°C for 0.5 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. Methanolic ammonia (7.0 M, 4 mL) was added to the residue, and the mixture was stirred at 25°C for 0.5 hours. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain Example 82 (390 mg, 91%). 1 H NMR (400 MHz, DMSO-d6) δ 11.58 (br s, 1H), 7.61 (d, J = 9.2 Hz, 1H), 7.55 (s, 1H), 6.75-6.50 (m, 1H), 5.83 (br s, 1H), 5.58 (s, 2H), 5.22 - 5.10 (m, 2H), 5.05 - 4.91 (m, 3H), 4.72 (d, J = 15.6 Hz, 1H), 4.24 - 3.99 (m, 2H), 3.19 - 2.69 (m, 3H). LC-MS (M+H) + = 451.0.

[0422] Example 83: (R)-5-amino-N,6-dimethyl-N-((1R,4S)-1-methyl-7-(trifluoromethyl)isochroman-4-yl)-6,8-dihydro-1H-fl[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide [ka] Step 1: (R)-1-(2-bromo-5-(trifluoromethyl)phenyl)ethane-1-ol [ka] To a mixture of 1-(2-bromo-5-(trifluoromethyl)phenyl)ethane-1-one (11.2 g, 41.9 mmol) in a formic acid-Et3N complex (5:2, 11 mL), [(R,R)-N-(2-amino-1,2-diphenylethyl)-p-toluenesulfonamide]chloro(p-cymene)ruthenium(II) (1.33 g, 2.1 mmol) was added under hydrogen at -18 °C. The mixture was stirred at 0 °C for 2 hours and at room temperature for 12 hours. The mixture was fractionated between saturated NaHCO3 (150 mL) and ethyl acetate (250 mL). The organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE:ethyl acetate = 20:1) to obtain the title compound (10.5 g, 93%). LC-MS (M+H) + = 269.1.

[0423] Step 2: (R)-2-(1-(allyloxy)ethyl)-1-bromo-4-(trifluoromethyl)benzene [ka] (R)-1-(2-bromo-5-(trifluoromethyl)phenyl)ethane-1-ol (10.0 g, 37.2 mmol) was dissolved in DMF (100 mL) and NaH (60%, 1.78 g, 44.6 mmol) was added under nitrogen at 0°C. After 30 minutes, allyl bromide (5.85 g, 48.3 mol) was added, and the mixture was stirred at 25°C for 3 hours. The reaction mixture was poured into water (150 mL) and then extracted with ethyl acetate (2 × 200 mL). The combined organic layer was washed with brine (2 × 100 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (PE:ethyl acetate = 20:1) to obtain the title compound (10.4 g, 90%). 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 1.1 Hz, 1H), 7.64 (d, J = 8.3 Hz, 1H), 7.38 (dd, J = 8.2, 1.6 Hz, 1H), 6.00 - 5.84 (m, 1H), 5.32 - 5.23 (m, 1H), 5.19 (d, J = 10.4 Hz, 1H), 4.88 (q, J = 6.4 Hz, 1H), 3.92 (dd, J = 12.6, 5.3 Hz, 1H), 3.85 (dd, J = 12.6, 5.9 Hz, 1H), 1.43 (d, J = 6.4 Hz, 3H).LC-MS (M+H) + =309.1.

[0424] Step 3: (R)-1-methyl-4-methylene-7-(trifluoromethyl)isochromane [ka] To a solution of (R)-2-(1-(allyloxy)ethyl)-1-bromo-4-(trifluoromethyl)benzene (10.4 g, 33.7 mmol) in DMF (250 mL), Pd(OAc)2 (1.13 g, 5.1 mol), Cs2CO3 (13.2 g, 40.4 mol), and PPh3 (5.3 g, 20.2 mol) were added. The mixed solution was stirred at 100 °C under nitrogen for 16 hours and then cooled to room temperature. The mixture was poured into water (300 mL) and then extracted with HCl (2 × 400 mL). The combined organic layer was washed with brine (3 × 300 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel chromatography (PE:HCl = 30:1) to obtain the title compound (5.7 g, 74%). 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 8.2 Hz...

Claims

1. Compound of formula (I): 【Chemistry 631】 or its N-oxide, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, or deuterated analog thereof, wherein in the formula, L is a single bond or -C(R) ８ R ９ ) - and R １ and R ２ are each independently selected from hydrogen, -C １～８ alkyl, -C ３ ~C ８ cycloalkyl, -C ３ ~C １２ cycloalkenyl, a 3- to 12-member heterocyclyl, -C ６ ~C １２ aryl and a 5- to 12-member heteroaryl, and each of the -C １～８ alkyl, -C ３ ~C ８ cycloalkyl, a 3- to 12-member heterocyclyl, -C ６ ~C １２ aryl and a 5- to 12-member heteroaryl is optionally substituted with at least one substituent R １ａ or R １ and R ２ However, together with the nitrogen atom to which they are bonded, they form a 3- to 8-membered unsaturated or saturated ring, the ring containing 0 to 3 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the ring having at least one substituent R １ａ It is arbitrarily replaced with, R １ａ However, hydrogen, halogen, deuterium, and -C are independent of each other. １～８ Alkyl, -C ３ ~C ８ Cycloalkyl, -C ３ ~C １２ Cycloalkenyl, 3-12 membered heterocyclyl, -C ６ ~C １２ Aryl, 5-12 member heteroaryl, -OR １ｂ , -SO ２ R １ｂ , -SO ２ NR １ｂ R １ｃ , -COR １ｂ , -CO ２ R １ｂ , -CONR １ｂ R １ｃ , -NR １ｂ R １ｃ , -NR １ｂ COR １ｃ , -NR １ｂ CO ２ R １ｃ , -NR １ｂ SO ２ R １ｃ , oxo, or -CN, and the -C １～８ Alkyl, -C ３ ~C ８ Cycloalkyl, -C ３ ~C １２ Cycloalkenyl, 3-12 membered heterocyclyl, -C ６ ~C １２ Each of the aryl and 5- to 12-membered heteroaryl has at least one substituent R １ｄ It can be arbitrarily replaced with, or Two R １ａ However, together with the atom(s) to which they are bonded, they form a 3- to 8-membered unsaturated or saturated ring, the ring contains 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the ring has at least one substituent R １ｄ It is arbitrarily replaced with, R １ｂ and R １ｃ However, hydrogen, -C １～８ Alkyl, -C ３ ~C ８ Cycloalkyl, 3-12 membered heterocyclyl, -C ６ ~C １２ Each is independently selected from aryls and 5- to 12-membered heteroaryls, and the -C １～８ Alkyl, -C ３ ~C ８ Cycloalkyl, 3-12 membered heterocyclyl, -C ６ ~C １２ Each of the aryl and 5- to 12-membered heteroaryl has at least one substituent R １ｅ It is arbitrarily replaced with, R １ｄ and R １ｅ each independently is hydrogen, halogen, -C １～８ alkyl, -C ３ to -C ８ cycloalkyl, -C ３ to -C １２ cycloalkenyl, 3- to 12-membered heterocyclyl, -C ６ to -C １２ aryl, 5- to 12-membered heteroaryl, -OR １ｆ , -SO ２ R １ｆ , -SO ２ NR １ｆ R １ｇ , -COR １ｆ , -CO ２ R １ｆ , -CONR １ｆ R １ｇ , -NR １ｆ R １ｇ , -NR １ｆ COR １ｇ , -NR １ｆ CO ２ R １ｇ , -NR １ｆ SO ２ R １ｇ , oxo, or -CN, wherein each of said -C １～８ alkyl, -C ３ to -C ８ cycloalkyl, -C ３ to -C １２ cycloalkenyl, 3- to 12-membered heterocyclyl, -C ６ to -C １２ aryl and 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R １ｈ , R １ｆ and R １ｇ However, hydrogen, -C １～８ Alkyl, -C ３ ~C ８ Cycloalkyl, 3-12 membered heterocyclyl, -C ６ ~C １２ Each is independently selected from aryls and 5- to 12-membered heteroaryls, and the -C １～８ Alkyl, -C ３ ~C ８ Cycloalkyl, 3-12 membered heterocyclyl, -C ６ ~C １２ Each of the aryl and 5- to 12-membered heteroaryl has at least one substituent R １ｉ It is arbitrarily replaced with, R １ｈ and R １ｉ However, each is independently hydrogen, halogen, and -C １～８ Alkyl, -C ３ ~C ８ Cycloalkyl, -C ３ ~C １２ Cycloalkenyl, 3-12 membered heterocyclyl, -C ６ ~C １２ Aryl, 5-12 member heteroaryl, -OR １ｊ , -SO ２ R １ｊ , -SO ２ NR １ｊ R １ｋ , -COR １ｊ , -CO ２ R １ｊ , -CONR １ｊ R １ｋ , -NR １ｊ R １ｋ , -NR １ｊ COR １ｋ , -NR １ｊ CO ２ R １ｋ , -NR １ｊ SO ２ R １ｋ , oxo, or -CN, and the -C １～８ Alkyl, -C ３ ~C ８ Cycloalkyl, -C ３ ~C １２ Cycloalkenyl, 3-12 membered heterocyclyl, -C ６ ~C １２ Each of the aryl and 5- to 12-membered heteroaryl groups is a halogen, -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 Aryl, 5-12 member heteroaryl, -CN, -OH, -NH ２ Alternatively, it may be optionally substituted with at least one substituent selected from the group consisting of oxos. R １ｊ and R １ｋ However, hydrogen, -C １～８ Alkyl, -C ３ ~C ８ Cycloalkyl, 3-12 membered heterocyclyl, -C ６ ~C １２ Each is independently selected from aryls and 5- to 12-membered heteroaryls, and the -C １～８ Alkyl, -C ３ ~C ８ Cycloalkyl, 3-12 membered heterocyclyl, -C ６ ~C １２ Each of the aryl and 5- to 12-membered heteroaryl groups is a halogen, -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 Aryl, 5-12 member heteroaryl, -CN, -OH, -NH ２ Alternatively, it may be optionally substituted with at least one substituent selected from the group consisting of oxos. R ３ However, hydrogen, halogen, -C １～８ Alkyl, -C ３ ~C ８ Cycloalkyl, -CN, -OH, or -NH ２ Selected from, the above-C １～８ Alkyl and -C ３ ~C ８ Each of the cycloalkyl groups is a halogen, -C １～８ Alkoxy, -C １～８ Alkyl, -C ３ ~C ８ Optionally substituted with at least one substituent selected from the group consisting of cycloalkyl and 3- to 8-membered heterocyclyl groups, R ４ , R ５ , R ６ , R ７ , R ８ and R ９ However, hydrogen, halogen, -C １～８ Alkyl or -C ３ ~C ８ Each is independently selected from cycloalkyl groups, and the -C １～８ Alkyl and -C ３ ~C ８ Each of the cycloalkyl groups is a halogen, -C １～８ Alkoxy, -C １～８ Alkyl, -C ３ ~C ８ Cycloalkyl, 3-8 membered heterocyclyl, C ６ ~C １２ Aryl, 5-12 member heteroaryl, oxo, -CN, -OR ４ａ , -SO ２ R ４ａ , -SO ２ NR ４ａ R ４ｂ , -COR ４ａ , -CO ２ R ４ａ , -CONR ４ａ R ４ｂ , -NR ４ａ R ４ｂ , -NR ４ａ COR ４ｂ , -NR ４ａ CO ２ R ４ｂ , or -NR ４ａ SO ２ R ４ｂ It is optionally substituted with at least one substituent selected from the group consisting of the following: R ４ａ and R ４ｂ However, each independently produces hydrogen and -C １～８ Alkyl, C ３ ~C ８ Cycloalkyl, 3-8 membered heterocyclyl, -C ６ ~C １２ The aryl or 5- to 12-membered heteroaryl, and the -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 groups contains at least one 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 The compound, or its N-oxide, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, or deuterated analog, optionally substituted with an aryl or a 5- to 12-membered heteroaryl.

2. The compound is of formula (IIa) or (IIb): 【Chemical 632】 The compound according to claim 1, which is the same as or its N-oxide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analog thereof.

3. The compound is of formula (IIc) or (IId): 【Chemical Formula 633】 The compound according to claim 2, which is the same as or its N-oxide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analog thereof.

4. The compound is of formula (IIe), (IIf), (IIg), or (IIh): 【Transformation 634】 The compound according to claim 3, which is the same as or its N-oxide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analog thereof.

5. The aforementioned compound is of formula (IIIa): 【Chemical 635】 The compound according to claim 1, which is the same as or its N-oxide, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, or deuterated analog, wherein n1 is 0, 1, 2, or 3.

6. The compound according to claim 5, wherein n1 is 1 or 2.

7. The compound according to claim 6, wherein n1 is 1.

8. The aforementioned compound is of formula (IIIb): 【Chemical Formula 636】 The compound according to any one of claims 5 to 7, which is the same as or its N-oxide, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, or deuterated analog.

9. The aforementioned compound is of formula (IIIc): 【Chemical Formula 637】 The compound according to any one of claims 5 to 8, which is the same as or its N-oxide, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, or deuterated analog.

10. The compound is of formula (IIId), (IIIe), (IIIf), or (IIIg): 【Chemical 638】 The compound according to any one of claims 5 to 9, which is the same as or its N-oxide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analog thereof.

11. The compound is of formula (IIIh), (IIIi), (IIIj), or (IIIk): 【Chemistry 639】 The compound according to any one of claims 5 to 10, which is the same as or its N-oxide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analog thereof.

12. The compound is of the formula (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (IVg), or (IVh): 【Chemical 640】 The compound according to claim 1, which is a compound thereof, its N-oxide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analog thereof, wherein n2 is 0, 1, 2, or 3.

13. The compound according to claim 12, wherein n2 is 0, 1, or 2.

14. The aforementioned compound is of the formula (IVi), (IVj), (IVk), (IVl), (IVm), (IVn), (IVo), (IVp), (IVq), (IVr), (IVs), (IVt), (IVu), or (IVv): 【Chemistry 641-1】 【Chemistry 641-2】 The compound according to claim 12 or 13, which is the same as or its N-oxide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analog thereof.

15. The aforementioned compound is of formula (Va): 【Chemistry 642】 or its N-oxide, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, or deuterated analog, in which, n3 is 0, 1, 2, 3 or 4, The compound according to claim 1, wherein each occurrence of X is independently N or CH.

16. The compound according to claim 15, wherein n3 is 1, 2, or 3.

17. The compound according to claim 15 or 16, wherein 0, one or two occurrences of X are N, and the remainder are CH.

18. The compound is of the formula (Vb), (Vc), (Vd), (Ve), or (Vf): 【Chemistry 643】 The compound according to claim 16, which is the same as or its N-oxide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analog thereof.

19. The compound according to any one of claims 15 to 18, wherein n3 is 1 or 2.

20. The compound according to claim 19, wherein n3 is 1.

21. The aforementioned compound is of the formula (Vg), (Vh), (Vi), (Vj), (Vk), (Vl), (Vm), (Vn), or (Vo): 【Chemical Formula 644】 The compound according to any one of claims 15 to 20, which is the same as or its N-oxide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analog thereof.

22. The aforementioned compound is of the formula (Vp), (Vq), (Vr), (Vs), (Vt), (Vu), (Vv), (Vw), (Vx), (Vy), or (Vz): 【Chemistry 645】 The compound according to claim 21, which is the same as or its N-oxide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analog thereof.

23. Compound of formula (VI): 【Chemical Formula 646】 or its N-oxide, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, or deuterated analog thereof, wherein in the formula, R １ and R ２ However, hydrogen, -C １～８ Alkyl, -C ３ ~C ８ Cycloalkyl, -C ３ ~C １２ Cycloalkenyl, 3-12 membered heterocyclyl, -C ６ ~C １２ Each is independently selected from aryls and 5- to 12-membered heteroaryls, and the -C １～８ Alkyl, -C ３ ~C ８ Cycloalkyl, 3-12 membered heterocyclyl, -C ６ ~C １２ Each of the aryl and 5- to 12-membered heteroaryl has at least one substituent R １ａ It can be arbitrarily replaced with, or R １ and R ２ However, together with the nitrogen atom to which they are bonded, they form a 3- to 8-membered unsaturated or saturated ring, the ring containing 0 to 3 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the ring having at least one substituent R １ａ It is arbitrarily replaced with, R １ａ However, hydrogen, halogen, deuterium, and -C are independent of each other. １～８ Alkyl, -C ３ ~C ８ Cycloalkyl, -C ３ ~C １２ Cycloalkenyl, 3-12 membered heterocyclyl, -C ６ ~C １２ Aryl, 5-12 member heteroaryl, -OR １ｂ , -SO ２ R １ｂ , -SO ２ NR １ｂ R １ｃ , -COR １ｂ , -CO ２ R １ｂ , -CONR １ｂ R １ｃ , -NR １ｂ R １ｃ , -NR １ｂ COR １ｃ , -NR １ｂ CO ２ R １ｃ , -NR １ｂ SO ２ R １ｃ , oxo, or -CN, and the -C １～８ Alkyl, -C ３ ~C ８ Cycloalkyl, -C ３ ~C １２ Cycloalkenyl, 3-12 membered heterocyclyl, -C ６ ~C １２ Each of the aryl and 5- to 12-membered heteroaryl has at least one substituent R １ｄ It can be arbitrarily replaced with, or Two R １ａ However, together with the atom(s) to which they are bonded, they form a 3- to 8-membered unsaturated or saturated ring, the ring contains 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the ring has at least one substituent R １ｄ It is arbitrarily replaced with, R １ｂ and R １ｃ However, hydrogen, -C １～８ Alkyl, -C ３ ~C ８ Cycloalkyl, 3-12 membered heterocyclyl, -C ６ ~C １２ Each is independently selected from aryls and 5- to 12-membered heteroaryls, and the -C １～８ Alkyl, -C ３ ~C ８ Cycloalkyl, 3-12 membered heterocyclyl, -C ６ ~C １２ Each of the aryl and 5- to 12-membered heteroaryl has at least one substituent R １ｅ It is arbitrarily replaced with, R １ｄ and R １ｅ However, each is independently hydrogen, halogen, and -C １～８ Alkyl, -C ３ ~C ８ Cycloalkyl, -C ３ ~C １２ Cycloalkenyl, 3-12 membered heterocyclyl, -C ６ ~C １２ Aryl, 5-12 member heteroaryl, -OR １ｆ , -SO ２ R １ｆ , -SO ２ NR １ｆ R １ｇ , -COR １ｆ , -CO ２ R １ｆ , -CONR １ｆ R １ｇ , -NR １ｆ R １ｇ , -NR １ｆ COR １ｇ , -NR １ｆ CO ２ R １ｇ , -NR １ｆ SO ２ R １ｇ , oxo, or -CN, and the -C １～８ Alkyl, -C ３ ~C ８ Cycloalkyl, -C ３ ~C １２ Cycloalkenyl, 3-12 membered heterocyclyl, -C ６ ~C １２ Each of the aryl and 5- to 12-membered heteroaryl has at least one substituent R １ｈ It is arbitrarily replaced with, R １ｆ and R １ｇ However, hydrogen, -C １～８ Alkyl, -C ３ ~C ８ Cycloalkyl, 3-12 membered heterocyclyl, -C ６ ~C １２ Each is independently selected from aryls and 5- to 12-membered heteroaryls, and the -C １～８ Alkyl, -C ３ ~C ８ Cycloalkyl, 3-12 membered heterocyclyl, -C ６ ~C １２ Each of the aryl and 5- to 12-membered heteroaryl has at least one substituent R １ｉ It is arbitrarily replaced with, R １ｈ and R １ｉ However, each is independently hydrogen, halogen, and -C １～８ Alkyl, -C ３ ~C ８ Cycloalkyl, -C ３ ~C １２ Cycloalkenyl, 3-12 membered heterocyclyl, -C ６ ~C １２ Aryl, 5-12 member heteroaryl, -OR １ｊ , -SO ２ R １ｊ , -SO ２ NR １ｊ R １ｋ , -COR １ｊ , -CO ２ R １ｊ , -CONR １ｊ R １ｋ , -NR １ｊ R １ｋ , -NR １ｊ COR １ｋ , -NR １ｊ CO ２ R １ｋ , -NR １ｊ SO ２ R １ｋ , oxo, or -CN, and the -C １～８ Alkyl, -C ３ ~C ８ Cycloalkyl, -C ３ ~C １２ Cycloalkenyl, 3-12 membered heterocyclyl, -C ６ ~C １２ Each of the aryl and 5- to 12-membered heteroaryl groups is a halogen, -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 Aryl, 5-12 member heteroaryl, -CN, -OH, -NH ２ Alternatively, it may be optionally substituted with at least one substituent selected from the group consisting of oxos. R １ｊ and R １ｋ However, hydrogen, -C １～８ Alkyl, -C ３ ~C ８ Cycloalkyl, 3-12 membered heterocyclyl, -C ６ ~C １２ Each is independently selected from aryls and 5- to 12-membered heteroaryls, and the -C １～８ Alkyl, -C ３ ~C ８ Cycloalkyl, 3-12 membered heterocyclyl, -C ６ ~C １２ Each of the aryl and 5- to 12-membered heteroaryl groups is a halogen, -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 Aryl, 5-12 member heteroaryl, -CN, -OH, -NH ２ Alternatively, it may be optionally substituted with at least one substituent selected from the group consisting of oxos. R ６ and R ７ The compound, or its N-oxide, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, or deuterated analog, each independently selected from hydrogen or methyl.

24. The aforementioned compound is of formula (VIIa): 【Chemical Formula 647】 or its N-oxide, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, or deuterated analog, in which, n4 is 0, 1, 2, 3 or 4, The compound according to claim 23, wherein each occurrence of Y is independently N or CH.

25. The compound according to claim 24, wherein n4 is 0, 1, 2, or 3.

26. The compound according to claim 25, wherein n4 is 1, 2, or 3.

27. The compound according to any one of claims 24 to 26, wherein 0, one or two occurrences of Y are N and the remainder are CH.

28. The compound is of formula (VIIb), (VIIC), (VIID), (VIIe), or (VIIF): 【Chemical 648】 The compound according to any one of claims 25 to 27, which is the same as or its N-oxide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analog thereof.

29. The compound according to any one of claims 25 to 28, wherein n4 is 1 or 2.

30. The compound according to claim 29, wherein n4 is 1.

31. The aforementioned compound is of formula (VIIg), (VIIh), (VII), (VIIj), (VIIk), (VIIl), (VIIm), (VIIn), (VIIo), (VIIp), or (VIIq): 【Chemical Formula 649】 The compound according to any one of claims 23 to 30, which is the same as or its N-oxide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analog thereof.

32. The aforementioned compound is of formula (VIIIa): 【Chemical 650】 or its N-oxide, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, or deuterated analog, in which, n5 is 0, 1, 2, 3 or 4, Z １ and Z ２ However, O or CH ２ Each is independently selected from, Z ３ and Z ４ The compound according to claim 23, wherein N or CH is independently selected.

33. The compound has the formula (VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIg), (VIII h), (VIIIi), (VIIIj), (VIIIk), (VIIIl), (VIIIm), (VIIIn) or (VIIIo): 【Chemical 651-1】 【Chemistry 651-2】 The compound according to claim 32, which is the same as or its N-oxide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analog thereof.

34. The compound according to claim 32 or 33, wherein n5 is 1, 2, or 3.

35. The compound according to claim 34, wherein n5 is 1 or 2.

36. R １ and R ２ However, hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C ３ ~C １２ Each of the following is independently selected from cycloalkenyls, 3-12 membered heterocyclyls, phenyls, and 5-12 membered heteroaryls, and each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-12 membered heterocyclyls, phenyls, and 5-12 membered heteroaryls has at least one substituent R １ａ It can be arbitrarily replaced with, or R １ and R ２ However, together with the nitrogen atoms bonded to them, they form a 3, 4, 5, 6, 7, or 8-membered unsaturated or saturated ring, wherein the ring contains 0, 1, 2, or 3 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the ring has at least one substituent R １ａ It is arbitrarily replaced with, R １ａ However, independently, hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C ３ ~C １２ Cycloalkenyl, 3-12 member heterocyclyl, phenyl, 5-12 member heteroaryl, -OR １ｂ , -SO ２ R １ｂ , -SO ２ NR １ｂ R １ｃ , -COR １ｂ , -CO ２ R １ｂ , -CONR １ｂ R １ｃ , -NR １ｂ R １ｃ , -NR １ｂ COR １ｃ , -NR １ｂ CO ２ R １ｃ , -NR １ｂ SO ２ R １ｃ , oxo, or -CN, and the aforementioned methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C ３ ~C １２ Each of the cycloalkenyl, 3- to 12-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl has at least one substituent R １ｄ It can be arbitrarily replaced with, or Two R １ａ However, together with the atom(s) to which they are bonded, they form a 3, 4, 5, 6, 7, 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 has at least one substituent R １ｄ It is arbitrarily replaced with, R １ｂ and R １ｃ However, each of the following is independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-12 member heterocyclyl, phenyl, or 5-12 member heteroaryl, and each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-12 member heterocyclyl, phenyl, or 5-12 member heteroaryl has at least one substituent R １ｅ It is arbitrarily replaced with, R １ｄ and R １ｅ However, each independently consists of hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and -C. ３ ~C １２ Cycloalkenyl, 3-12 member heterocyclyl, phenyl, 5-12 member heteroaryl, -OR １ｆ , -SO ２ R １ｆ , -SO ２ NR １ｆ R １ｇ , -COR １ｆ , -CO ２ R １ｆ , -CONR １ｆ R １ｇ , -NR １ｆ R １ｇ , -NR １ｆ COR １ｇ , -NR １ｆ CO ２ R １ｇ , -NR １ｆ SO ２ R １ｇ , oxo, or -CN, and the aforementioned methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C ３ ~C １２ Each of the cycloalkenyl, 3- to 12-membered heterocyclyl, phenyl, and 5- to 12-membered heteroaryl has at least one substituent R １ｈ It is arbitrarily replaced with, R １ｆ and R １ｇ However, each of the following is independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-12 member heterocyclyl, phenyl, or 5-12 member heteroaryl, and each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-12 member heterocyclyl, phenyl, or 5-12 member heteroaryl has at least one substituent R １ｉ It is arbitrarily replaced with, R １ｈ and R １ｉ However, each independently consists of hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and -C. ３ ~C １２ Cycloalkenyl, 3-12 member heterocyclyl, phenyl, 5-12 member heteroaryl, -OR １ｊ , -SO ２ R １ｊ , -SO ２ NR １ｊ R １ｋ , -COR １ｊ , -CO ２ R １ｊ , -CONR １ｊ R １ｋ , -NR １ｊ R １ｋ , -NR １ｊ COR １ｋ , -NR １ｊ CO ２ R １ｋ , -NR １ｊ SO ２ R １ｋ , oxo, or -CN, and the aforementioned methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C ３ ~C １２ Each of the cycloalkenyl, 3-12 membered heterocyclyl, phenyl, and 5-12 membered heteroaryl has at least one substituent -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, or -C ２～８ Alkenyl, -C ２～８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, 5-12 membered heteroaryl, -CN, -OH, -NH ２ Alternatively, it may be optionally replaced with an oxo. R １ｊ and R １ｋ However, each is independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-12 member heterocyclyl, phenyl, and 5-12 member heteroaryl. Each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-12 member heterocyclyl, phenyl, and 5-12 member heteroaryl compounds has at least one substituent -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C ２～８ Alkenyl, -C ２～８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, 5-12 membered heteroaryl, -CN, -OH, -NH ２ The compound according to any one of claims 1 to 35, or optionally substituted with an oxo.

37. R １ and R ２ However, each is independently selected from hydrogen, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, chromanil, isochromanil, dihydropyranopyridinyl, pyrimidinil, tetrahydro-2H-pyranil, pyridadinil, pyrazinil, dihydrophlopyridinil, tetrahydronaphthalenyl, benzo[d]thiazolyl, triazolyl, pyridinil, quinolinil, isoquinolinil, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranil, tetrahydroquinolinil, tetrahydronaphthyl, dihydrophlopyridinil, or tetrahydrophlopyridinil. Each of the above-mentioned methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, chromanil, isochromanil, dihydropyranopyridinyl, pyrimidinil, tetrahydro-2H-pyranil, pyridadinil, pyrazinil, dihydrophlopyridinil, tetrahydronaphthalenyl, benzo[d]thiazolyl, triazolyl, pyridinil, quinolinil, isoquinolinil, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranil, tetrahydroquinolinil, tetrahydronaphthyl, dihydrophlopyridinil, or tetrahydrophlopyridinil has at least one substituent R １ａ It can be arbitrarily replaced with, or R １ and R ２ However, together with the nitrogen atoms bonded to them, they form a 3, 4, 5, 6, 7, or 8-membered unsaturated or saturated ring, wherein the ring contains 0, 1, 2, or 3 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the ring has at least one substituent R １ａ It is arbitrarily replaced with, R １ａ However, independently, hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, chromanil, isochromanil, dihydropyranopyridinyl, pyrimidinyl, tetrahydro-2H-pyranil, pyridadinyl, pyrazinyl, dihydrophlopyridinyl, tetrahydronaphthalenyl, benzo[d]thiazolyl, triazolyl, pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranil, tetrahydroquinolinyl, tetrahydronaphthyl, tetrahydrophlopyridinyl, -OR １ｂ , -SO ２ R １ｂ , -SO ２ NR １ｂ R １ｃ , -COR １ｂ , -CO ２ R １ｂ , -CONR １ｂ R １ｃ , -NR １ｂ R １ｃ , -NR １ｂ COR １ｃ , -NR １ｂ CO ２ R １ｃ , -NR １ｂ SO ２ R １ｃ Each of the following is a substituent R: , oxo, or -CN, and each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, chromanil, isochromanil, dihydropyranopyridinyl, pyrimidinil, tetrahydro-2H-pyranil, pyridadinil, pyrazinil, dihydrophlopyridinil, tetrahydronaphthalenyl, benzo[d]thiazolyl, triazolyl, pyridinil, quinolinil, isoquinolinil, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranil, tetrahydroquinolinil, tetrahydronaphthyl, dihydrophlopyridinil, or tetrahydrophlopyridinil has at least one substituent R １ｄ It can be arbitrarily replaced with, or Two R １ａ However, together with the atom(s) to which they are bonded, they form a 3, 4, 5, or 6-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 has at least one substituent R １ｄ It is arbitrarily replaced with, R １ｂ and R １ｃ However, each is independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, chromanil, isochromanil, dihydropyranopyridinyl, pyrimidinyl, tetrahydro-2H-pyranil, pyridadinyl, pyrazinyl, dihydrophlopyridinyl, tetrahydronaphthalenyl, benzo[d]thiazolyl, triazolyl, pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranil, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrophlopyridinyl, or tetrahydrophlopyridinyl. Each of the above methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, chromanil, isochromanil, dihydropyranopyridinyl, pyrimidinyl, tetrahydro-2H-pyranil, pyridadinyl, pyrazinyl, dihydrophlopyridinyl, tetrahydronaphthalenyl, benzo[d]thiazolyl, triazolyl, pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranil, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrophlopyridinyl, or tetrahydrophlopyridinyl has at least one substituent R １ｅ It is arbitrarily replaced with, R １ｄ and R １ｅ However, each independently consists of hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, chromanil, isochromanil, dihydropyranopyridinyl, pyrimidinil, tetrahydro-2H-pyranil, pyridadinil, pyrazinil, dihydrophlopyridinil, tetrahydronaphthalenyl, benzo[d]thiazolyl, triazolyl, pyridinil, quinolinil, isoquinolinil, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranil, tetrahydroquinolinil, tetrahydronaphthyl, dihydrophlopyridinil, tetrahydrophlopyridinil, -OR １ｆ , -SO ２ R １ｆ , -COR １ｆ , -CO ２ R １ｆ , -CONR １ｆ R １ｇ , -NR １ｆ R １ｇ , -NR １ｆ COR １ｇ , -NR １ｆ CO ２ R １ｇ Each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, chromanil, isochromanil, dihydropyranopyridinyl, pyrimidinil, tetrahydro-2H-pyranil, pyridadinil, pyrazinil, dihydrophlopyridinil, tetrahydronaphthalenyl, benzo[d]thiazolyl, triazolyl, pyridinil, quinolinil, isoquinolinil, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranil, tetrahydroquinolinil, tetrahydronaphthyl, dihydrophlopyridinil, or tetrahydrophlopyridinil has at least one substituent R １ｈ It is arbitrarily replaced with, R １ｆ and R １ｇ However, each is independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, chromanil, isochromanil, dihydropyranopyridinyl, pyrimidinyl, tetrahydro-2H-pyranil, pyridadinyl, pyrazinyl, dihydrophlopyridinyl, tetrahydronaphthalenyl, benzo[d]thiazolyl, triazolyl, pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranil, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrophlopyridinyl, or tetrahydrophlopyridinyl. Each of the above methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, chromanil, isochromanil, dihydropyranopyridinyl, pyrimidinyl, tetrahydro-2H-pyranil, pyridadinyl, pyrazinyl, dihydrophlopyridinyl, tetrahydronaphthalenyl, benzo[d]thiazolyl, triazolyl, pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranil, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrophlopyridinyl, or tetrahydrophlopyridinyl has at least one substituent R １ｉ It is arbitrarily replaced with, R １ｈ and R １ｉ However, each independently consists of hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, chromanil, isochromanil, dihydropyranopyridinyl, pyrimidinyl, tetrahydro-2H-pyranil, pyridadinyl, pyrazinyl, dihydrophlopyridinyl, tetrahydronaphthalenyl, benzo[d]thiazolyl, triazolyl, pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranil, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrophlopyridinyl, tetrahydrophlopyridinyl, -OR １ｊ , -COR １ｊ , -CO ２ R １ｊ , -CONR １ｊ R １ｋ , -NR １ｊ R １ｋ , -NR １ｊ COR １ｋ , -NR １ｊ CO ２ R １ｋ , oxo, or -CN, and the aforementioned methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, chromanil, isochromanil, dihydropyranopyridinyl, pyrimidinil, tetrahydro-2H-pyranil, pyridadinil, pyrazinil, dihydrophlopyridinil, tetrahydronaphthalenyl, benzo[d]thiazolyl, triazolyl, py Each of the following compounds may have at least one substituent: -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, or -C. ２～８ Alkenyl, -C ２～８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrophlopyridinyl, tetrahydrophlopyridinyl, -CN, -OH, -NH ２ Alternatively, it may be optionally replaced with an oxo. R １ｊ and R １ｋ However, each is independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, chromanil, isochromanil, dihydropyranopyridinyl, pyrimidinyl, tetrahydro-2H-pyranil, pyridadinyl, pyrazinyl, dihydrophlopyridinyl, tetrahydronaphthalenyl, benzo[d]thiazolyl, triazolyl, pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranil, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrophlopyridinyl, or tetrahydrophlopyridinyl, and the above methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclo Robutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, chromanil, isochromanil, dihydropyranopyridinyl, pyrimidinyl, tetrahydro-2H-pyranil, pyridadinyl, pyrazinyl, dihydrophlopyridinyl, tetrahydronaphthalenyl, benzo[d]thiazolyl, triazolyl, pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranil, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrophlopyridinyl, or tetrahydrophlopyridinyl each have at least one substituent -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C ２～８ Alkenyl, -C ２～８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrophlopyridinyl, tetrahydrophlopyridinyl, -CN, -OH, -NH ２ The compound according to any one of claims 1 to 36, or optionally substituted with an oxo.

38. R １ and R ２ However, each is independently selected from hydrogen, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, chromanil, isochromanil, dihydropyranopyridinyl, pyrimidinil, tetrahydro-2H-pyranil, pyridadinil, pyrazinil, dihydrophlopyridinil, tetrahydronaphthalenyl, benzo[d]thiazolyl, triazolyl, pyridinil, quinolinil, isoquinolinil, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranil, tetrahydroquinolinil, tetrahydronaphthyl, dihydrophlopyridinil, or tetrahydrophlopyridinil. Each of the above-mentioned methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, chromanil, isochromanil, dihydropyranopyridinyl, pyrimidinil, tetrahydro-2H-pyranil, pyridadinil, pyrazinil, dihydrophlopyridinil, tetrahydronaphthalenyl, benzo[d]thiazolyl, triazolyl, pyridinil, quinolinil, isoquinolinil, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranil, tetrahydroquinolinil, tetrahydronaphthyl, dihydrophlopyridinil, or tetrahydrophlopyridinil has at least one substituent R １ａ It can be arbitrarily replaced with, or R １ and R ２ However, together with the nitrogen atoms bonded to them, they form a 3, 4, 5, 6, 7, or 8-membered unsaturated or saturated ring, wherein the ring contains 0, 1, 2, or 3 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the ring has at least one substituent R １ａ It is arbitrarily replaced with, R １ａ However, independently, hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, chromanil, isochromanil, dihydropyranopyridinyl, pyrimidinil, tetrahydro-2H-pyranil, pyridadinil, pyrazinil, dihydrophlopyridinil, tetrahydronaphthalenyl, benzo[d]thiazolyl, triazolyl, pyridinil, quinolinil, isoquinolinil, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranil, tetrahydroquinolinil, tetrahydronaphthyl, dihydrophlopyridinil, tetrahydrophlopyridinil, -OR １ｂ or -CN, and each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, chromanil, isochromanil, dihydropyranopyridinyl, pyrimidinil, tetrahydro-2H-pyranil, pyridadinil, pyrazinil, dihydrophlopyridinil, tetrahydronaphthalenyl, benzo[d]thiazolyl, triazolyl, pyridinil, quinolinil, isoquinolinil, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranil, tetrahydroquinolinil, tetrahydronaphthyl, dihydrophlopyridinil, or tetrahydrophlopyridinil has at least one substituent R １ｄ It can be arbitrarily replaced with, or Two R １ａ However, together with the atom(s) to which they are bonded, they form a 3, 4, 5, or 6-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 has at least one substituent R １ｄ It is arbitrarily replaced with, R １ｂ However, each is independently hydrogen, methyl, ethyl, propyl, cyclopropyl, or cyclobutyl. R １ｄ However, each independently consists of hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, chromanil, isochromanil, dihydropyranopyridinyl, pyrimidinil, tetrahydro-2H-pyranil, pyridadinil, pyrazinil, dihydrophlopyridinil, tetrahydronaphthalenyl, benzo[d]thiazolyl, triazolyl, pyridinil, quinolinil, isoquinolinil, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranil, tetrahydroquinolinil, tetrahydronaphthyl, dihydrophlopyridinil, tetrahydrophlopyridinil, -OR １ｆ , -NR １ｆ R １ｇ , -NR １ｆ COR １ｇ , oxo, -SO ２ R １ｆ or -CN, and each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, chromanil, isochromanil, dihydropyranopyridinyl, pyrimidinil, tetrahydro-2H-pyranil, pyridadinil, pyrazinil, dihydrophlopyridinil, tetrahydronaphthalenyl, benzo[d]thiazolyl, triazolyl, pyridinil, quinolinil, isoquinolinil, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranil, tetrahydroquinolinil, tetrahydronaphthyl, dihydrophlopyridinil, or tetrahydrophlopyridinil has at least one substituent R １ｈ It is arbitrarily replaced with, R １ｆ and R １ｇ However, each is independently selected from hydrogen, methyl, ethyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, chromanil, isochromanil, dihydropyranopyridinyl, pyrimidinil, tetrahydro-2H-pyranil, pyridadinil, pyrazinil, dihydrophlopyridinil, tetrahydronaphthalenyl, benzo[d]thiazolyl, triazolyl, pyridinil, quinolinil, isoquinolinil, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranil, tetrahydroquinolinil, tetrahydronaphthyl, dihydrophlopyridinil, or tetrahydrophlopyridinil, and the above M Each of the following compounds has at least one substituent R: tyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, chromanil, isochromanil, dihydropyranopyridinyl, pyrimidinil, tetrahydro-2H-pyranil, pyridadinil, pyrazinil, dihydrophlopyridinil, tetrahydronaphthalenyl, benzo[d]thiazolyl, triazolyl, pyridinil, quinolinil, isoquinolinil, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranil, tetrahydroquinolinil, tetrahydronaphthyl, dihydrophlopyridinil, or tetrahydrophlopyridinil. １ｉ It is arbitrarily replaced with, R １ｈ and R １ｉ The compound according to claim 37, wherein each is independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, chromanil, isochromanil, dihydropyranopyridinyl, pyrimidinyl, tetrahydro-2H-pyranil, pyridadinyl, pyrazinyl, dihydrophlopyridinyl, tetrahydronaphthalenyl, benzo[d]thiazolyl, triazolyl, pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranil, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrophlopyridinyl, tetrahydrophlopyridinyl, -OH, or -CN.

39. R １ and R ２ However, hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, chromanil, isochromanil, dihydropyranopyridinyl, pyrimidinil, tetrahydro-2H-pyranil, pyridadinil, pyrazinil, dihydrophlopyridinil, tetrahydronaphthalenyl, benzo[d]thiazolyl, pyridinil, quinolinil, isoquinolinil, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranil, tetrahydroquinolinil, tetrahydronaphthyl, dihydrophlopyridinyl or tetrahydrophlopyridinyl Each of the following is independently selected from nyl, and each of the methyl, ethyl, propyl, phenyl, chromanil, isochromanil, dihydropyranopyridinil, pyrimidinil, tetrahydro-2H-pyranil, pyridadinil, pyrazinil, dihydrophlopyridinil, tetrahydronaphthalenyl, benzo[d]thiazolyl, pyridinil, quinolinil, isoquinolinil, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranil, tetrahydroquinolinil, tetrahydronaphthyl, dihydrophlopyridinil, or tetrahydrophlopyridinil has at least one substituent R １ａ It can be arbitrarily replaced with, or R １ and R ２ However, together with the nitrogen atom to which they are bonded, they form a six-membered unsaturated or saturated ring, and the ring has at least one substituent R １ａ It is arbitrarily replaced with, R １ａ However, independently, hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrimidinyl, pyridadinyl, pyrazinyl, dihydroflopyridinyl, benzo[d]thiazolyl, pyridinyl, quinolinyl, isoquinolinyl, thiazolyl, -OR １ｂ or -CN, where each of the methyl, ethyl, propyl, phenyl, pyrimidinyl, pyridadinyl, pyrazinyl, dihydrophlopyridinyl, benzo[d]thiazolyl, pyridinyl, quinolinyl, isoquinolinyl, or thiazolyl has at least one substituent R １ｄ It is arbitrarily replaced with, R １ｂ However, each is independently hydrogen, methyl, ethyl, propyl, cyclopropyl, or cyclobutyl. R １ｄ However, each independently contains hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, phenyl, pyrimidinyl, tetrahydro-2H-pyranyl, pyridadinyl, pyrazinyl, triazolyl, pyridinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydroflopyridinyl, tetrahydroflopyridinyl, -OR １ｆ , -SO ２ R １ｆ or -CN, and each of the methyl, ethyl, propyl, butyl, phenyl, pyrimidinyl, tetrahydro-2H-pyranyl, pyridadinyl, pyrazinyl, triazolyl, pyridinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrophlopyridinyl, or tetrahydrophlopyridinyl has at least one substituent R １ｈ It is arbitrarily replaced with, R １ｆ each of the following is independently selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or phenyl, and each of the methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or phenyl has at least one substituent R １ｉ It is arbitrarily replaced with, R １ｈ and R １ｉ The compound according to claim 38, wherein each is independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -OH, or -CN.

40. R １ and R ２ However, -C １～８ Alkyl, -C ３ ~C ８ Cycloalkyl, -C ３ ~C １２ A cycloalkenyl and a 3- to 12-membered heterocyclyl are independently selected, and the -C １～８ Alkyl, -C ３ ~C ８ Cycloalkyl, -C ３ ~C １２ Each of the cycloalkenyl and the 3- to 12-membered heterocyclyl has at least one substituent R １ａ It can be arbitrarily replaced with, or R １ and R ２ However, together with the nitrogen atom to which they are bonded, they form a 3- to 8-membered unsaturated or saturated ring, the ring containing 0 to 3 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the ring having at least one substituent R １ａ It is arbitrarily replaced with, R １ａ However, hydrogen, halogen, deuterium, and -C are independent of each other. １～８ Alkyl, -C ３ ~C ８ Cycloalkyl, -C ６ ~C １２ Aryl, 5-12 member heteroaryl, -OR １ｂ Alternatively, -CN, and the aforementioned -C １～８ Alkyl, -C ３ ~C ８ Cycloalkyl, -C ６ ~C １２ Each of the aryl and 5- to 12-membered heteroaryl has at least one substituent R １ｄ It can be arbitrarily replaced with, or Two R １ａ However, together with the atom(s) to which they are bonded, they form a 3- to 8-membered unsaturated or saturated ring, the ring contains 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the ring has at least one substituent R １ｄ It is arbitrarily replaced with, R １ｂ However, hydrogen, -C １～８ Each alkyl is independently selected, and the -C １～８ Alkyl has at least one substituent R １ｅ It is arbitrarily replaced with, R １ｄ and R １ｅ However, each is independently hydrogen, halogen, and -C １～８ Alkyl, -C ３ ~C ８ Cycloalkyl, -C ６ ~C １２ Aryl, 5-12 member heteroaryl, -OR １ｆ , -SO ２ R １ｆ or -CN, and the -C １～８ Alkyl, -C ６ ~C １２ Each of the aryl and 5- to 12-membered heteroaryl has at least one substituent R １ｈ It is arbitrarily replaced with, R １ｆ However, hydrogen, -C １～８ Alkyl and -C ３ ~C ８ Each is independently selected from cycloalkyl groups, and the -C １～８ Alkyl and -C ３ ~C ８ Each cycloalkyl group has at least one substituent R １ｉ It is arbitrarily replaced with, R １ｈ and R １ｉ However, each is independently hydrogen, halogen, and -C １～８ A compound according to any one of claims 1 to 35, wherein it is alkyl or -CN.

41. R １ and R ２ Each of the above is independently selected from methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, chromanil, isochromanil, pyridinyl, quinolinil, isoquinolinil, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranil, tetrahydroquinolinil, tetrahydronaphthyl, dihydropyridinyl, or tetrahydropyridinyl, and each of the above methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, chromanil, isochromanil, pyridinyl, quinolinil, isoquinolinil, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranil, tetrahydroquinolinil, tetrahydronaphthyl, dihydropyridinyl, or tetrahydropyridinyl has at least one substituent R １ａ It can be arbitrarily replaced with, or R １ and R ２ However, together with the nitrogen atoms bonded to them, they form a 3, 4, 5, 6, 7, or 8-membered unsaturated or saturated ring, wherein the ring contains 0, 1, 2, or 3 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the ring has at least one substituent R １ａ It is arbitrarily replaced with, R １ａ However, independently, hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridinyl, pyrimidinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrophlopyridinyl, tetrahydrophlopyridinyl, -OR １ｂ Alternatively, -CN, and each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridinyl, pyrimidinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrophlopyridinyl, or tetrahydrophlopyridinyl has at least one substituent R １ｄ It can be arbitrarily replaced with, or Two R １ａ However, together with the atom(s) to which they are bonded, they form a 3, 4, 5, or 6-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 has at least one substituent R １ｄ It is arbitrarily replaced with, R １ｂ However, each of the following is independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and octyl, and each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and octyl has at least one substituent R １ｅ It is arbitrarily replaced with, R １ｄ and R １ｅ However, each independently consists of hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrophlopyridinyl, tetrahydrophlopyridinyl, -OR １ｆ , -SO ２ R １ｆ or -CN, where each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, phenyl, pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrophlopyridinyl, or tetrahydrophlopyridinyl has at least one substituent R １ｈ It is arbitrarily replaced with, R １ｆ each of the following is independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, and each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl has at least one substituent R １ｉ It is arbitrarily replaced with, R １ｈ and R １ｉ The compound according to claim 40, wherein each is independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, or -CN.

42. R １ and R ２ However, -Me, -Et, -Pr, -Bu, pentyl, -CF ３ ien-CH ２ CF ３ , 【Chemical 652-1】 【Chemical 652-2】 【Chemistry 652-3】 They are either selected independently from each other, or R １ and R ２ However, along with the nitrogen atoms to which they are bonded, 【Chemical 653】 A compound according to any one of claims 1 to 41, which forms a compound.

43. The compound according to any one of claims 1, 5 to 10, 12, 13, 15 to 21, and 36 to 42, wherein L is a single bond.

44. R １ａ However, hydrogen, methyl, ethyl, propyl, halo, methyl substituted with one or more halos, C ３～５ A cycloalkyl group, or one independently selected from -CN, or two R groups bonded to the same atom. １ａ However, C ３～５ A compound according to any one of claims 1 to 41 and 43, which forms a cycloalkyl group.

45. R １ａ However, hydrogen, methyl, ethyl, -F, -Cl, -Br, -I, -CF ３ A cyclopropyl or -CN molecule, independently selected from the same atom, or two R atoms bonded to the same atom. １ａ The compound according to claim 44, wherein it forms a cyclopropyl group.

46. R １ｄ However, hydrogen, halo, C １～４ Alkyl, C substituted with one or more halos １～４ C substituted with alkyl and -OH groups １～４ Alkyl, -O-C １～４ Alkyl, -O-C substituted with one or more halos １～４ C optionally substituted with alkyl or fluoro groups ３～５ Cycloalkyl, -SO ２ -C １～４ A compound according to any one of claims 1 to 41 and 43 to 45, independently selected from alkyl or -CN.

47. R １ｄ However, hydrogen, -F, -Br, -Cl, -I, methyl, ethyl, propyl, butyl, -CF ３ Hydroxypropyl, Methoxy, Trifluoromethoxy, Cyclopropyl, Fluorocyclopropyl, Cyclobutyl, -SO ２ CH ３ The compound according to claim 46, which is independently selected from , or -CN.

48. R ２ However, C １～８ A compound according to any one of claims 1 to 47, wherein it is alkyl.

49. R ２ The compound according to claim 48, wherein the compound is methyl, ethyl, propyl, or butyl.

50. R ３ However, hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -CN, -OH or -NH ２ A compound selected from any one of claims 1, 2, 5-22, and 36-49.

51. R ３ The compound according to claim 50, wherein the selected element is hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -CN, or -OH.

52. R ３ The compound according to claim 51, wherein hydrogen, -F, -Cl, methyl, ethyl, propyl, and butyl are selected.

53. R ３ The compound according to claim 52, wherein is hydrogen.

54. R ４ , R ５ , R ６ , R ７ , R ８ and R ９ However, each is independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, and each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl is -F, -Cl, -Br, -I, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, 5-12 membered heteroaryl, oxo, -CN, -OR ４ａ , -SO ２ R ４ａ , -SO ２ NR ４ａ R ４ｂ , -COR ４ａ , -CO ２ R ４ａ , -CONR ４ａ R ４ｂ , -NR ４ａ R ４ｂ , -NR ４ａ COR ４ｂ , -NR ４ａ CO ２ R ４ｂ , or -NR ４ａ SO ２ R ４ｂ Optionally substituted with at least one substituent selected from, R ４ａ and R ４ｂ Each of these is independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 member heterocyclyl, phenyl, or 5-12 member heteroaryl, and each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 member heterocyclyl, phenyl, or 5-12 member heteroaryl is at least one -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 The compound according to any one of claims 1 to 3 and 5 to 53, which is optionally substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl.

55. R ４ , R ５ , R ６ , R ７ , R ８ and R ９ The compound according to claim 54, wherein each is independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

56. R ４ , R ５ , R ６ , R ７ , R ８ and R ９ The compound according to claim 55, wherein each is independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, cyclopropyl, or cyclobutyl.

57. R ４ , R ５ , R ６ , R ７ , R ８ and R ９ The compound according to claim 56, wherein each of the following is independently selected: hydrogen, -F, -Cl, -Br, -I, or methyl.

58. R ４ , R ５ , R ６ , R ７ , R ８ and R ９ The compound according to claim 57, wherein hydrogen or methyl is independently selected.

59. The aforementioned compound is of formula (VIIIp): 【Chemical 654】 The following: R １ａ ' is independently selected from hydrogen, methyl, or ethyl, R １ａ Is '' hydrogen, or R １ａ 'and R １ａ '' along with the atoms to which they are bonded, C ３～５ Forming a cycloalkyl group, The compound according to any one of claims 1, 32, and 36-58, wherein n5' is 0, 1, or 2.

60. R １ａ However, halo, methyl, C substituted with one or more halos ３～５ Selected independently from cycloalkyl or -CN, R ２ However, C １～８ It is alkyl, R ６ However, it is hydrogen or methyl, R ７ The compound according to claim 59, wherein is hydrogen.

61. R １ａ is -F, -Cl, -Br, -I, -CF ３ The compound according to claim 59 or 60, independently selected from cyclopropyl or -CN.

62. (i) R １ａ ' is methyl or (iii)R １ａ 'and R １ａ The compound according to any one of claims 59 to 63, wherein the atoms form a cyclopropyl group together with the atoms to which they are bonded.

63. R ２ The compound according to any one of claims 59 to 62, wherein is methyl.

64. R ６ The compound according to any one of claims 59 to 63, wherein is hydrogen.

65. The aforementioned compound is of formula (VIIr): 【Chemical 655】 The substance thereof, or its N-oxide, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, or deuterated analog thereof, wherein Y' is N or C (R １ｄ The compound according to any one of claims 1, 24, and 36 to 58.

66. R １ａ However, it is hydrogen or methyl, R １ｄ However, C is optionally substituted with hydrogen, halo, methyl or fluoro, or methyl or fluoro. ３～５ Selected independently from cycloalkyl or -CN, R ２ However, C １～８ It is alkyl, R ６ However, it is hydrogen or methyl, R ７ The compound according to claim 65, wherein is hydrogen.

67. R １ｄ However, hydrogen, -F, -Br, -I, -CF ３ The compound according to claim 65 or 66, independently selected from cyclopropyl, fluorocyclopropyl, cyclobutyl, or -CN.

68. The compound according to any one of claims 65 to 67, wherein Y' is N.

69. Y' is C(R １ｄ The compound according to any one of claims 65 to 68.

70. A compound, or its N-oxide, or a pharmaceutically acceptable salt thereof, or its stereoisomer, or its tautomer, or its deuterated analog, 【Chemistry 656-1】 【Chemistry 656-2】 【Chemistry 656-3】 【Chemistry 656-4】 【Chemistry 656-5】 【Transformation 656-6】 【Transformation 656-7】 【Transformation 656-8】 【Chemistry 656-9】 【Chemistry 656-10】 【Chemistry 656-11】 【Chemistry 656-12】 【Chemistry 656-13】 【Chemistry 656-14】 【Chemistry 656-15】 【Chemistry 656-16】 【Chemistry 656-17】 【Chemistry 656-18】 【Chemistry 656-19】 【Chemistry 656-20】 【Chemistry 656-21】 【Chemistry 656-22】 【Chemistry 656-23】 【Chemistry 656-24】 【Chemistry 656-25】 【Chemistry 656-26】 A compound selected from the above, or its N-oxide, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a deuterated analog thereof.

71. A pharmaceutical composition comprising a compound according to any one of claims 1 to 70, or its N-oxide, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a deuterated analog thereof, and a pharmaceutically acceptable excipient.

72. A method for inhibiting PRMT5 activity, comprising administering an effective amount of a compound according to any one of claims 1 to 70, or its N-oxide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analog thereof, to a subject requiring such action.

73. A method for treating a disease regulated by PRMT5, comprising administering an effective amount of a compound according to any one of claims 1 to 70, or its N-oxide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analog thereof, to a subject in need thereof.

74. A method for treating cancer, comprising administering an effective amount of a compound according to any one of claims 1 to 70, or its N-oxide, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a deuterated analog thereof, to a subject in need thereof.

75. The method according to claim 73, wherein the disease is cancer.

76. The method according to claim 74 or 75, wherein the cancer comprises a methylthioadenosine phosphorylase (MTAP)-null solid tumor.

77. The method according to any one of claims 74 to 76, wherein the cancer is lung cancer, bladder cancer, melanoma, pancreatic cancer, esophageal cancer, gastric adenocarcinoma, breast cancer, or glioblastoma.

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