5-amino-6,8-dihydro-1h-furo[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide derivatives

Abstract

The present disclosure provides 5-amino-6,8-dihydro-lH-furo[3,4-d]pyrrolo[3,2-b]pyridine-2- carboxamide derivatives for use in treating various diseases, including cancer, in patients carrying MTAP DEL The use of compounds that selectively inhibit the activity of PRMT5 in concert with MTA in mutated tumors, for example, for the treatment of various diseases, including cancer, and pharmaceutical compositions comprising these compounds.

Description

[0001] This application is a divisional application of patent application No. 202480022921.X, filed on March 27, 2024, entitled "5-amino-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide derivative as an MTA-synergistic PRMT5 inhibitor". Technical Field

[0002] This disclosure provides a 5-amino-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide derivative, the use of which, for example, in the presence of MTAP-carrying compounds. DEL Selective inhibition of PRMT5 activity in mutated tumors in synergy with methionine (MTA), and pharmaceutical compositions containing these compounds. Background Technology

[0003] Epigenetic modification is a process that alters genetic output by changing the original DNA sequence. Epigenetic modification plays a crucial role in multiple dimensions, including gene expression and regulation, protein production, 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 PMTs (protein methyltransferases) are key participants in epigenetic modification, consisting of two subfamilies: PKMTs (protein lysine methyltransferases) and PRMTs (protein arginine methyltransferases). Copeland, RA, et al., Oncogene [Oncogenes] 2012. 32 (8): pp. 939-46 PMT is associated with a variety of human diseases and is considered a potential therapeutic target. Copeland, RA, et al., Oncogene, 2012, 32(8): 939-46 ].

[0004] As its name suggests, PRMT catalyzes the methylation of arginine residues in proteins. Besides its primary function of methylating histone tails, PRMT also targets other cellular proteins, such as NAB2p, FOXO1, PABP1, and SmD1. Bedford, M. T. et al., Molecular Cell, 2005, 18(3): 263-72 Based on the products, the nine mammalian PRMTs can be divided into three subtypes: Type I (PRMT1, PRMT2, PRMT3, PRMT4, PRMT6, and PRMT8) catalyze the formation of aDMA (asymmetric dimethyl arginine); Type II (PRMT5 and PRMT9) catalyze the formation of sDMA (symmetric dimethyl arginine); and Type III (PRMT7) catalyzes the formation of MMA (monomethyl arginine). Yang, Y., et al., Nature Reviews Cancer [from [Juvenile Cancer Review], 2012, 13(1): pp. 37-50Furthermore, type I / II PRMTs can also catalyze MMA formation, serving as intermediates for aDMA and sDMA. PRMTs contain a pocket that interacts with its cofactor SAM (S-adenosylmethionine) and an adjacent pocket that interacts with arginine residues on the protein—the SAM pocket and substrate pocket. The methylation process involves the transfer of an activated methyl group from the cofactor SAM to a guanidino group on the arginine residue. N 2-type mechanism 。 [ Bedford, MT et al., Molecular Cell, 2005, 18(3): 263-72 The byproduct of this process is SAH (S-adenosine-L-homocysteine).

[0005] The overall arginine level in cells is approximately 1500:3:2:1 (Arg:aDMA:MMA:sDMA), and PRMT5 accounts for the vast majority of sDMA formation. Dhar, S., et al., Scientific Reports, 2013, 3: 1311 Compared to PRMT1 (the major type I PRMT that functions independently in cells), PRMT5 binds to MEP50 (methylbody protein 50) to form a heterocomplex, which is typically elevated in cancer cells and is associated with poorer patient survival. Gao, G., et al., Nucleic Acids Research, 2019, 47 (10): 5038-48. PRMT5 promotes tumorigenesis through multiple mechanisms. PRMT5 is a potent repressor of many genes; when PRMT5 methylates histone H2a and H4 on Arg3 and histone H3 on Arg8, it inhibits the transcription of genes involved in differentiation, transformation, cell cycle progression, and tumor suppression. Karkhanis, V., et al., Trends in Biochemical Sciences [Scientific Trends], 2011, 36 (12): 633-41 In addition to its epigenetic role, PRMT5 can also regulate RNA-binding proteins, such as splicing factors. For example, a reproducible event was observed in PRMT5 knockout mice in which exon 6 skipping of MDM4 (mouse two-microsome 4) occurred, and p53 was released to upregulate the p53 pathway. Gerhart, SV, et al. Scientific Reports, 2018, 8: 9711 Furthermore, PRMT5 can be directly applied to p53[]. Jansson, M., et al., Nature Cell Biology, 2008, 10 (12): 1431- 9 pages ]、EGFR [ Hsu, J.-M., et al., Nature Cell Biology, 2011, 13 (2): Pages 174-81 ]、PI3K [ Wei, T.-YW, et al., Cellular Signaling. 2014, 26 (12): Pages 2940-50 Methylation of PRMT5 directly affects key proliferation pathways. Therefore, PRMT5 has great potential to become a relevant clinical target.

[0006] On the other hand, PRMT5 is an essential gene in normal tissues, and systemic inhibition of PRMT5 can lead to serious consequences, particularly hematologic toxicity. Ahnert, JR, et al., Journal of Clinical Oncology [Journal of Oncology], 2021, 39 (15-Supplement): Page 3019Therefore, a strategy of selectively blocking PRMT5 activity in tumor cells is essential for safer therapies.

[0007] Homozygous deletion of the tumor suppressor CDKN2A (cyclin-dependent kinase inhibitor 2A) occurs in approximately 15% of all tumor types. Interestingly, this mutation often involves co-deletion of immediately adjacent genes present in 9p21, including genes encoding MTAP (methionine phosphorylase). Firestone, RS et al., Journal of American Chemical Society (ACS) Journal, 2017, 139 (39): No. 13754-60 [Page]. Due to MTAP deficiency, the MTAP substrate MTA (methionine) accumulates. MTA is structurally related to SAM and is a weak ligand / inhibitor of PRMT5, occupying the same pocket as SAM. The formation of the MTA-PRMT5 complex provides an opportunity for further inhibition of PRMT5 by forming a tertiary complex. In this way, a correlation between MTAP empty state and PRMT5 dependence can be established through MTA concentration levels to provide precise oncology therapy.

[0008] Currently, most clinically-developed PRMT5 inhibitors cannot distinguish between normal and cancer cells. These inhibitors are based on either a SAM / MTA competition mechanism (JNJ64619178, PF06939999, PRT543, and PRT811) or a non-MTA synergistic mechanism (GSK3326595). Therefore, the medical need for effective and selective MTA-synergistic PRMT5 inhibitors remains unmet and persists. Summary of the Invention

[0009] One object of the present invention is to provide a PRMT5 inhibitory compound, its preparation method and use.

[0010] Aspect 1. A compound having formula (I): (I), Or its N-oxide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analogue, wherein: L is a single bond or -C(R) 8 R 9 )-; R 1 and R 2 Each is independently selected from hydrogen and -C 1-8 Alkyl, -C3-C8 cycloalkyl, -C3-C 12 Cycloalkenyl, 3- to 12-membered heterocyclic groups, -C6-C 12 aryl and 5- to 12-membered heteroaryl, wherein the -C 1-8 Alkyl, -C3-C8 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C12 Each of the aryl and 5- to 12-membered heteroaryl groups is optionally substituent R. 1a Replace; or R 1 and R 2 Together with the nitrogen atoms to which they are attached, they form 3- to 8-membered unsaturated or saturated rings, the rings containing 0-3 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the rings are optionally substituents R. 1a replace; R 1a Independently, it is hydrogen, halogen, deuterium, -C 1-8 Alkyl, -C3-C8 cycloalkyl, -C3-C 12 Cycloalkenyl, 3- to 12-membered heterocyclic groups, -C6-C 12 Aryl, 5- to 12-membered 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, wherein the -C 1-8 Alkyl, -C3-C8 cycloalkyl, -C3-C 12 Cycloalkenyl, 3- to 12-membered heterocyclic groups, -C6-C 12 Each of the aryl and 5- to 12-membered heteroaryl groups is optionally substituent R. 1d Replace; or Two Rs 1a Together with one or more atoms to which they are attached, they form 3- to 8-membered unsaturated or saturated rings, the rings comprising 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the rings optionally being substituents R. 1d replace; R 1b and R 1c Each is independently selected from hydrogen and -C 1-8 Alkyl, -C3-C8 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 aryl and 5- to 12-membered heteroaryl, wherein the -C 1-8Alkyl, -C3-C8 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 Each of the aryl and 5- to 12-membered heteroaryl groups is optionally substituent R. 1e replace; R 1d and R 1e Each is independently hydrogen, halogen, -C 1-8 Alkyl, -C3-C8 cycloalkyl, -C3-C 12 Cycloalkenyl, 3- to 12-membered heterocyclic groups, -C6-C 12 Aryl, 5- to 12-membered 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, wherein the -C 1-8 Alkyl, -C3-C8 cycloalkyl, -C3-C 12 Cycloalkenyl, 3- to 12-membered heterocyclic groups, -C6-C 12 Each of the aryl and 5- to 12-membered heteroaryl groups is optionally substituent R. 1h replace; R 1f and R 1g Each is independently selected from hydrogen and -C 1-8 Alkyl, -C3-C8 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 aryl and 5- to 12-membered heteroaryl, wherein the -C 1-8 Alkyl, -C3-C8 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 Each of the aryl and 5- to 12-membered heteroaryl groups is optionally substituent R. 1i replace; R 1h and R 1i Each is independently hydrogen, halogen, -C 1-8 Alkyl, -C3-C8 cycloalkyl, -C3-C 12 Cycloalkenyl, 3- to 12-membered heterocyclic groups, -C6-C 12Aryl, 5- to 12-membered 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, wherein the -C 1-8 Alkyl, -C3-C8 cycloalkyl, -C3-C 12 Cycloalkenyl, 3- to 12-membered heterocyclic groups, -C6-C 12 Each of the aryl and 5- to 12-membered heteroaryl groups is optionally substituted with at least one substituent selected from the group consisting of: halogen, -C 1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 alkenyl, -C 2-8 Alkyne group, -C3-C8 cycloalkyl group, 3- to 8-membered heterocyclic group, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, -CN, -OH, -NH2 or oxo; R 1j and R 1k Each is independently selected from hydrogen and -C 1-8 Alkyl, -C3-C8 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 aryl and 5- to 12-membered heteroaryl, wherein the -C 1-8 Alkyl, -C3-C8 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 Each of the aryl and 5- to 12-membered heteroaryl groups is optionally substituted with at least one substituent selected from the group consisting of: halogen, -C 1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 alkenyl, -C 2-8 Alkyne group, -C3-C8 cycloalkyl group, 3- to 8-membered heterocyclic group, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, -CN, -OH, -NH2 or oxo; R 3 Selected from hydrogen, halogens, -C 1-8Alkyl, -C3-C8 cycloalkyl, -CN, -OH, or -NH2, wherein the -C 1-8 Each of the alkyl and -C3-C8 cycloalkyl groups is optionally substituted with at least one substituent selected from the group consisting of: halogen, -C 1-8 Alkoxy, -C 1-8 Alkyl groups, -C3-C8 cycloalkyl groups, and 3- to 8-membered heterocyclic groups; R 4 R 5 R 6 R 7 R 8 and R 9 Each is independently selected from hydrogen, halogen, -C 1-8 Alkyl or -C3-C8 cycloalkyl, wherein the -C 1-8 Each of the alkyl and -C3-C8 cycloalkyl groups is optionally substituted with at least one substituent selected from the group consisting of: halogen, -C 1-8 Alkoxy, -C 1-8 Alkyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic groups, C6-C 12 Aryl, 5- to 12-membered 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 ; R 4a and R 4b Each is independently hydrogen, -C 1-8 Alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic groups, -C6-C 12 aryl, or 5- to 12-membered heteroaryl; the -C 1-8 Alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic groups, -C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted by at least one of the following substituents: halogen, -OH, -C. 1-8 Alkyl, -C 1-8 Alkoxy, C 1-8 Alkoxy-C 1-8Alkyl-, -C 2-8 alkenyl, -C 2-8 Alkyne group, -C3-C8 cycloalkyl group, 3- to 8-membered heterocyclic group, -C6-C 12 Aryl, or 5 to 12-membered heteroaryl.

[0011] In one embodiment, R 1 and R 2 Each is independently selected from -C 1-8 Alkyl, -C3-C8 cycloalkyl, -C3-C 12 Cycloalkenyl and 3- to 12-membered heterocyclic groups, wherein the -C 1-8 Alkyl, -C3-C8 cycloalkyl, -C3-C 12 Each of the cycloalkenyl and 3- to 12-membered heterocyclic groups is optionally substituent R. 1a Replace. R 1a As previously defined.

[0012] In one embodiment, R 1 and R 2 Each is independently selected from -C 1-8 Alkyl, wherein the -C 1-8 The alkyl group is optionally substituent for at least one R group. 1a Replace. R 1a As previously defined. Preferably, R 1 and R 2 Each is independently selected from -C 1-4 Alkyl, wherein the -C 1-8 The alkyl group is optionally substituent for at least one R group. 1a Replace. R 1a As previously defined. More preferably, R 1 and R 2 Each is independently selected from methyl, ethyl, and propyl (isopropyl or n-propyl), wherein each of the methyl, ethyl, and propyl (isopropyl or n-propyl) groups is optionally substituent R. 1a Replace. R 1a As previously defined. In one embodiment, R 1 The methyl, ethyl, propyl (isopropyl or n-propyl), and butyl (n-butyl, sec-butyl, isobutyl, or tert-butyl) groups are optionally substituents R. 1a Replace, R 1a As previously defined. In one embodiment, R 1aIt is phenyl, pyrimidinyl, tetrahydro-2H-pyranyl, pyrazinyl, pyrazinyl, triazolyl (preferably 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl), pyridinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, dihydrofuranopyridinyl, or tetrahydrofuranopyridinyl; each of the phenyl, pyrimidinyl, tetrahydro-2H-pyranyl, pyrazinyl, pyrazinyl, triazolyl (preferably 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl), pyridinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, dihydrofuranopyridinyl, or tetrahydrofuranopyridinyl is optionally substituent R. 1d Replace, R 1d As previously defined. In one embodiment, R 1 yes 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 yes , , , or .

[0013] In one embodiment, R 1 yes Y is N or CH; preferably, the zeroth, one, or two occurrences of Y are N, and the rest are CH; more preferably, the zeroth or one occurrence of Y is N, and the rest are CH; R 1a Is it hydrogen or C? 1-8 Alkyl; preferably, R 1a It is hydrogen, methyl, ethyl, propyl (isopropyl or n-propyl), or butyl (n-butyl, sec-butyl, isobutyl, or tert-butyl); more preferably, R 1a It is hydrogen, methyl, ethyl, or propyl (isopropyl or n-propyl); R 1d The C-terminus is independently selected from halogenated, methyl groups substituted with one or more halogenated groups, or C-terminus optionally substituted with fluorine. 3-5 cycloalkyl, or -CN; preferably, R 1d Independently selected from -F, -Br, -I, -CF3, cyclopropyl, fluorocyclopropyl, cyclobutyl, or -CN; n4 is 0, 1, 2, 3, or 4; preferably, n4 is 1, 2, or 3. In another embodiment, R 1 yes , , , or .

[0014] In one embodiment, R 1 and R 2Each of the following groups is independently selected from methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, chromium, isochorium, dihydropyranopyridyl (preferably 5,8-dihydro-6H-pyrano[3,4-b]pyridyl, 3,4-dihydro-2H-pyrano[3,2-b]pyridyl or 7,8-dihydro-5H-pyrano[4,3-b]pyridyl), pyrimidinyl, tetrahydro-2H-pyranyl, pyridazinyl, dihydrofuranopyridyl (preferably...) The methyl group is 2,3-dihydrofurano[2,3-b]pyridyl, tetrahydronaphthalenyl (preferably 1,2,3,4-tetrahydronaphthalenyl), benzo[d]thiazolyl, pyridyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl, or tetrahydrofuranopyridyl, wherein the methyl group is... Ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, chromanyl, isochromyl, dihydropyranopyridyl (preferably 5,8-dihydro-6H-pyrano[3,4-b]pyridyl, 3,4-dihydro-2H-pyrano[3,2-b]pyridyl or 7,8-dihydro-5H-pyrano[4,3-b]pyridyl), pyrimidinyl, tetrahydro-2H-pyranyl, pyrazinyl, dihydrofuranopyridyl (preferably 2,3-dihydrofuranopyridyl) Each of the following groups is optionally substituent R: [2,3-b]pyridyl, tetrahydronaphthalenyl (preferably 1,2,3,4-tetrahydronaphthalenyl), benzo[d]thiazolyl, pyridyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl, or tetrahydrofuranopyridyl. 1a Replace. R 1a As previously defined.

[0015] In one embodiment, R 1 It is a 3- to 12-membered heterocyclic group, wherein the 3- to 12-membered heterocyclic group is optionally substituent R. 1a Replace, R 1a As previously defined. Preferably, R 1 It is a 6- to 10-membered heterocyclic group, wherein the 6- to 10-membered heterocyclic group is optionally substituent R. 1a Replace, R 1aAs previously defined. In one embodiment, R 1 It is a 3- to 12-membered heterocyclic group, wherein the 3- to 12-membered heterocyclic group is optionally substituent R. 1a Replace; and R 2 It is -C 1-8 Alkyl groups, which are further divided into 3- to 12-membered heterocyclic groups, -C6-C 12 Aryl, 5- to 12-membered heteroaryl substitution, and the 3- to 12-membered heterocyclic group, -C6-C 12 Each of the aryl and 5- to 12-membered heteroaryl groups is optionally substituent R. 1d Replacement. Preferably, R 2 It is -C 1-4 The alkyl group is further substituted with a 5- to 10-membered heterocyclic group, a phenyl group, or a 5- to 6-membered heteroaryl group, and each of the 5- to 10-membered heterocyclic group, the phenyl group, and the 5- to 6-membered heteroaryl group is optionally substituted with at least one substituent R. 1d replace.

[0016] In one embodiment, R 1 It is a 3- to 12-membered heterocyclic group, wherein the 3- to 12-membered heterocyclic group is optionally substituent R. 1a Replace, R 1a As previously defined. In one embodiment, R 1 It is a tetrahydropyranyl group, which is optionally substituent by at least one R group. 1a Replace, R 1a As previously defined. Preferably, R 1a It is -C 1-8 Alkoxy, more preferably, R 1a It is methoxy or ethoxy. In one embodiment, R 1 yes R 1b It is -C 1-8 Alkyl, preferably, R 1b It is methyl or ethyl.

[0017] In one embodiment, R 1 It is a 3- to 12-membered heterocyclic group; preferably, R 1 It is a tetrahydroquinolinyl group, which is optionally substituent for at least one R group. 1a Replace, R 1a As previously defined. In one embodiment, R 1a It is H. In one embodiment, R 1 yes or .

[0018] In one embodiment, R 1It is a 3- to 12-membered heterocyclic group; preferably, R 1 It is a chromatid or a heterochromatid, each of which is optionally substituent R. 1a Replace, R 1a As previously defined. In one embodiment, R 1a It is H. In one embodiment, R 1a It is -F, -CH3, or -CF3. In one embodiment, R 1 yes or .

[0019] In one embodiment, R 1 yes R 1a Independently selected from methyl, ethyl, propyl, halogenated, methyl groups substituted with one or more halogens, C 3-5 cycloalkyl or -CN, or two R 1a Attached to the same atom to form C 3-5 cycloalkyl; preferably, R 1a It is hydrogen, methyl, ethyl, -F, -Cl, -Br, -I, -CF3, cyclopropyl, or -CN, or two Rs. 1a Attached to the same atom to form a cyclopropyl group; 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; even more preferably, n5 is 1, 2 or 3.

[0020] R 1a It can be of Partial or of One or more substituent groups on a portion.

[0021] In one embodiment, R 1 The group is benzyl, pyridylmethyl, pyridazinylmethyl, pyrimidinylmethyl, pyrazinylmethyl, 1-pyridylethyl, 1-pyridazinylethyl, 1-pyrimidinylethyl, or 1-pyrazinylethyl, wherein each of the benzyl, pyridylmethyl, pyridazinylmethyl, pyrimidinylmethyl, pyrazinylmethyl, 1-pyridylethyl, 1-pyridazinylethyl, 1-pyrimidinylethyl, or 1-pyrazinylethyl is optionally substituent R. 1d Replace, R 1d As previously defined. In one embodiment, R 1dEach of the following is 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, pyridazinyl, pyrazinyl, triazolyl (preferably 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl), pyridinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl, tetrahydrofuranopyridyl, -OR 1f -SO2R 1f or -CN, wherein each of the methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl, or tert-butyl), phenyl, pyrimidinyl, tetrahydro-2H-pyranyl, pyridazinyl, pyrazinyl, triazolyl (preferably 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl), pyridinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl, or tetrahydrofuranopyridyl is optionally substituent R. 1h Replace; R 1f Each of the following is independently selected from hydrogen, methyl, ethyl, propyl (isopropyl or n-propyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or phenyl, wherein each of the methyl, ethyl, propyl (isopropyl or n-propyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or phenyl groups is optionally substituent R. 1i Replace; R 1h and R 1i Each can be 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.

[0022] In one embodiment, R 2 It is C 1-8 Alkyl group. In one embodiment, R 2 It is methyl, ethyl, propyl (isopropyl or n-propyl), or butyl (n-butyl, sec-butyl, isobutyl, or tert-butyl). In one embodiment, R 2 It is methyl, ethyl, or propyl (isopropyl or n-propyl). In one embodiment, R 2 It is a methyl group.

[0023] Aspect 2. The compound as described in aspect 1, wherein the compound has formula (IIa) or (IIb):

[0024] Preferably, the compound has formula (IIc) or (IId):

[0025] Or preferably, the compound has the formula (IIe), (IIIf), (IIg), or (IIh):

[0026] Where R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 and R 9 It is as defined in aspect 1.

[0027] Aspect 3. The compound as described in aspect 1, wherein the compound has formula (IIIa): (IIIa); Preferably, the compound has the formula (IIIb): (IIIb); More preferably, the compound has formula (IIIc): (IIIc); Even more preferably, the compound has the formula (IIId), (IIIe), (IIIf), or (IIIg):

[0028] Even more preferably, the compound has the formula (IIIh), (IIIi), (IIIj), or (IIIk):

[0029] Wherein, n1 is 0, 1, 2 or 3; preferably, n1 is 1 or 2; more preferably, n1 is 1; R 1a R 1b R 2 R 3 R 4 R 5 R 6 R 7 L is as defined in aspect 1.

[0030] Aspect 4. The compound as described in aspect 1, wherein the compound has the formula (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (IVg), or (IVh): (IVa); (IVb); (IVc); (IVd); (IVe); (IVf); (IVh); Preferably, the compound has the formula (IVVi), (IVj), (IVk), (IVl), (IVm), (IVn), (IVo), (IVp), (IVq), (IVr), (IVs), (IVt), (IVu), or (IVv):

[0031] Wherein, 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 L is as defined in aspect 1.

[0032] R 1a It is possible , , , , , or It can be replaced at any position (that satisfies the price theory).

[0033] Aspect 5. The compound as described in aspect 1, wherein the compound has the formula (Va): (Va), Wherein, n3 is 0, 1, 2, 3 or 4; preferably, n3 is 1, 2 or 3; Each occurrence of X is independently N or CH; preferably, the zeroth, one, or twoth 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 are as defined in aspect 1; Preferably, the compound has the formula (Vb), (Vc), (Vd), (Ve), or (Vf):

[0034] Wherein, n3 is 0, 1, 2 or 3; preferably, n3 is 1 or 2; more preferably, n3 is 1; R 1a R 1d R 2 R 3 R 4 R 5 R 6 R 7 And L are as defined in aspect 1; More preferably, the compound has the formula (Vg), (Vh), (Vi), (Vj), (Vk), (Vl), (Vm), (Vn), or (Vo):

[0035] Even more preferably, the compound has the formula (Vp), (Vq), (Vr), (Vs), (Vt), (Vu), (Vv), (Vw), (Vx), (Vy), or (Vz):

[0036] Among them, R 1a R 1d R 2 R 3 R 4 R 5 R 6 R 7 L is as defined in aspect 1.

[0037] Aspect 6. A compound having formula (VI), (VI) Or its N-oxide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analogue, wherein: R 1 and R 2 Each is independently selected from hydrogen and -C 1-8 Alkyl, -C3-C8 cycloalkyl, -C3-C 12 Cycloalkenyl, 3- to 12-membered heterocyclic groups, -C6-C 12 aryl and 5- to 12-membered heteroaryl, wherein the -C 1-8 Alkyl, -C3-C8 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 Each of the aryl and 5- to 12-membered heteroaryl groups is optionally substituent R. 1a Replace; or R 1 and R 2 Together with the nitrogen atoms to which they are attached, they form 3- to 8-membered unsaturated or saturated rings, the rings containing 0-3 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the rings are optionally substituents R. 1a replace; R 1a Independently, it is hydrogen, halogen, deuterium, -C 1-8 Alkyl, -C3-C8 cycloalkyl, -C3-C 12 Cycloalkenyl, 3- to 12-membered heterocyclic groups, -C6-C 12 Aryl, 5- to 12-membered 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, wherein the -C 1-8 Alkyl, -C3-C8 cycloalkyl, -C3-C 12 Cycloalkenyl, 3- to 12-membered heterocyclic groups, -C6-C 12 Each of the aryl and 5- to 12-membered heteroaryl groups is optionally substituent R. 1d Replace; or Two Rs 1aTogether with one or more atoms to which they are attached, they form 3- to 8-membered unsaturated or saturated rings, the rings comprising 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the rings optionally being substituents R. 1d replace; R 1b and R 1c Each is independently selected from hydrogen and -C 1-8 Alkyl, -C3-C8 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 aryl and 5- to 12-membered heteroaryl, wherein the -C 1-8 Alkyl, -C3-C8 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 Each of the aryl and 5- to 12-membered heteroaryl groups is optionally substituent R. 1e replace; R 1d and R 1e Each is independently hydrogen, halogen, -C 1-8 Alkyl, -C3-C8 cycloalkyl, -C3-C 12 Cycloalkenyl, 3- to 12-membered heterocyclic groups, -C6-C 12 Aryl, 5- to 12-membered 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, wherein the -C 1-8 Alkyl, -C3-C8 cycloalkyl, -C3-C 12 Cycloalkenyl, 3- to 12-membered heterocyclic groups, -C6-C 12 Each of the aryl and 5- to 12-membered heteroaryl groups is optionally substituent R. 1h replace; R 1f and R 1g Each is independently selected from hydrogen and -C 1-8 Alkyl, -C3-C8 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 aryl and 5- to 12-membered heteroaryl, wherein the -C 1-8Alkyl, -C3-C8 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 Each of the aryl and 5- to 12-membered heteroaryl groups is optionally substituent R. 1i replace; R 1h and R 1i Each is independently hydrogen, halogen, -C 1-8 Alkyl, -C3-C8 cycloalkyl, -C3-C 12 Cycloalkenyl, 3- to 12-membered heterocyclic groups, -C6-C 12 Aryl, 5- to 12-membered 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, wherein the -C 1-8 Alkyl, -C3-C8 cycloalkyl, -C3-C 12 Cycloalkenyl, 3- to 12-membered heterocyclic groups, -C6-C 12 Each of the aryl and 5- to 12-membered heteroaryl groups is optionally substituted with at least one substituent selected from the group consisting of: halogen, -C 1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 alkenyl, -C 2-8 Alkyne group, -C3-C8 cycloalkyl group, 3- to 8-membered heterocyclic group, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, -CN, -OH, -NH2 or oxo; R 1j and R 1k Each is independently selected from hydrogen and -C 1-8 Alkyl, -C3-C8 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 aryl and 5- to 12-membered heteroaryl, wherein the -C 1-8 Alkyl, -C3-C8 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 Each of the aryl and 5- to 12-membered heteroaryl groups is optionally substituted with at least one substituent selected from the group consisting of: halogen, -C1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 alkenyl, -C 2-8 Alkyne group, -C3-C8 cycloalkyl group, 3- to 8-membered heterocyclic group, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, -CN, -OH, -NH2 or oxo; R 6 and R 7 Each is independently selected from hydrogen or methyl.

[0038] Aspect 7. The compound as described in aspect 6, wherein the compound is of formula (VIIa): (VIIa), Wherein, n4 is 0, 1, 2, 3 or 4; preferably, n4 is 1, 2 or 3; Each occurrence of Y is independently N or CH; preferably, the zeroth, one, or twoth occurrences of Y are N, and the rest are CH; R 1a R 1d R 2 R 6 and R 7 It is as defined in aspect 6; Preferably, the compound is of formula (VIIb), (VIIc), (VIId), (VIIe), or (VIIf):

[0039] Wherein, n4 is 0, 1, 2 or 3; preferably, n4 is 1 or 2; more preferably, n4 is 1; R 1a R 1d R 2 R 6 and R 7 It is as defined in aspect 6; Even more preferably, the compound is of formula (VIIg), (VIIh), (VIIi), (VIIj), (VIIk), (VIIl), (VIIm), (VIIn), (VIIo), (VIIp), or (VIIq):

[0040] Among them, R 1a R 1d R 2 R 6 and R 7 It is as defined in aspect 6.

[0041] Aspect 8. The compound as described in aspect 6, wherein the compound is of formula (VIIIa): (VIIIa), Wherein, n5 is 0, 1, 2, 3 or 4; preferably, n5 is 1, 2 or 3; Z 1 and Z 2 Each is independently selected from O or CH2; Z 3 and Z 4 Each is independently selected from N or CH; R 1a R 6 and R 7 It is 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):

[0042] Wherein, n5 is 0, 1, 2 or 3; preferably, n5 is 1 or 2; R 1a R 1d R 2 R 6 and R 7 It is as defined in aspect 6; R 1a It is possible , , , , , , or It can be replaced at any position (that satisfies the price theory).

[0043] Aspect 9. The compound as described in any of the preceding aspects, wherein R 1 and R 2 Each 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, -C3-C 12Cycloalkenyl, 3- to 12-membered heterocyclic, phenyl, and 5- to 12-membered heteroaryl, wherein 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- to 12-membered heterocyclic, phenyl, and 5- to 12-membered heteroaryl groups is optionally substituent R. 1a Replace; or R 1 and R 2 Together with the nitrogen atoms to which they are attached, they form 3-, 4-, 5-, 6-, 7-, or 8-membered unsaturated or saturated rings, said rings containing 0, 1, 2, or 3 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur, and said rings are optionally substituents R. 1a replace; R 1a Independently, it is 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- to 12-membered heterocyclic, phenyl, 5- to 12-membered 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 Oxygenated or -CN, wherein 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, -C3-C 12 Each of the cycloalkenyl, 3- to 12-membered heterocyclic, phenyl, or 5- to 12-membered heteroaryl groups is optionally substituent R. 1d Replace; or Two Rs 1aTogether with one or more atoms to which they are attached, they form 3-, 4-, 5-, 6-, 7-, or 8-membered unsaturated or saturated rings, said rings comprising 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and said rings optionally being substituents R. 1d replace; R 1b and R 1c Each of the following groups 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- to 12-membered heterocyclic groups, phenyl, or 5- to 12-membered heteroaryl groups, wherein 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- to 12-membered heterocyclic groups, phenyl, or 5- to 12-membered heteroaryl groups is optionally substituent R. 1e replace; R 1d and R 1e Each of the following can be 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- to 12-membered heterocyclic, phenyl, 5- to 12-membered 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 Oxygenated or -CN, wherein 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, -C3-C 12 Each of the cycloalkenyl, 3- to 12-membered heterocyclic, phenyl, and 5- to 12-membered heteroaryl groups is optionally substituent R. 1hreplace; R 1f and R 1g Each of the following groups 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- to 12-membered heterocyclic groups, phenyl, or 5- to 12-membered heteroaryl groups, wherein 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- to 12-membered heterocyclic groups, phenyl, or 5- to 12-membered heteroaryl groups is optionally substituent R. 1i replace; R 1h and R 1i Each of the following can be 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- to 12-membered heterocyclic, phenyl, 5- to 12-membered 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 Oxygenated or -CN, wherein 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, -C3-C 12 Each of the cycloalkenyl, 3- to 12-membered heterocyclic, phenyl, and 5- to 12-membered heteroaryl groups is optionally substituted by at least one of the following substituents: -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, octyloxy, -C 2-8alkenyl, -C 2-8 Alkyne, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic groups, phenyl, 5- to 12-membered heteroaryl, -CN, -OH, -NH2 or oxo; R 1j and R 1k Each is independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 12-membered heterocyclic groups, phenyl, and 5- to 12-membered heteroaryl groups. Each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 12-membered heterocyclic groups, phenyl, and 5- to 12-membered heteroaryl groups is optionally substituted by at least one of the following substituents: -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, -C 2-8 alkenyl, -C 2-8 Alkyne, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic groups, phenyl, 5- to 12-membered heteroaryl, -CN, -OH, -NH2 or oxo.

[0044] Aspect 10. The compound as described in any of the preceding aspects, wherein R 1 and R 2Each is independently selected from hydrogen, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, chromium, isochorium, dihydropyranopyridyl (preferably 5,8-dihydro-6H-pyrano[3,4-b]pyridyl, 3,4-dihydro-2H-pyrano[3,2-b]pyridyl or 7,8-dihydro-5H-pyrano[4,3-b]pyridyl), pyrimidinyl, tetrahydro-2H-pyranyl, pyrazinyl, dihydrofuranopyridyl (preferably 2,3-dihydrofurano[2 ...pyridyl), pyrimidinyl, pyrimidinyl, dihydrofurano [b]pyridyl), tetrahydronaphthalenyl (preferably 1,2,3,4-tetrahydronaphthalenyl), benzo[d]thiazolyl, triazolyl (preferably 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl), pyridyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl or tetrahydrofuranopyridyl, wherein the methyl alkyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, chromium, isochorium, dihydropyranopyridyl (preferably 5,8-dihydro-6H-pyrano[3,4-b]pyridyl, 3,4-dihydro-2H-pyrano[3,2-b]pyridyl or 7,8-dihydro-5H-pyrano[4,3-b]pyridyl), pyrimidinyl, tetrahydro-2H-pyranyl, pyrazinyl, pyrazinyl, dihydrofuranopyridyl (preferably 2,3-dihydrofurano[2,3-b]pyridyl), tetrahydro Each of the following groups is optionally substituent R: naphthyl (preferably 1,2,3,4-tetrahydronaphthalenyl), benzo[d]thiazolyl, triazolyl (preferably 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl), pyridyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl, or tetrahydrofuranopyridyl. 1a Replace; or R 1 and R 2 Together with the nitrogen atoms to which they are attached, they form 3-, 4-, 5-, 6-, 7-, or 8-membered unsaturated or saturated rings, said rings containing 0, 1, 2, or 3 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur; said rings are optionally substituents R. 1a replace; R 1a Independently, it is 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, chromanyl, isochoryl, dihydropyranopyridyl (preferably, 5,8-dihydro-6H-pyrano[3,4-b]pyridyl, 3,4-dihydro-2H-pyrano[3,2-b]pyridyl or 7,8-dihydro-5H-pyrano[4,3-b]pyridyl), pyrimidinyl, tetrahydro-2H-pyranyl, pyrazinyl, pyrazinyl, dihydrofuranopyridyl (preferably) The following are listed: 2,3-dihydrofurano[2,3-b]pyridyl), tetrahydronaphthalenyl (preferably 1,2,3,4-tetrahydronaphthalenyl), benzo[d]thiazolyl, triazolyl (preferably 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl), pyridyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, tetrahydrofuranopyridyl-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 1cOxylated or -CN, wherein the methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, chromium, isochorium, dihydropyranopyridyl (preferably 5,8-dihydro-6H-pyrano[3,4-b]pyridyl, 3,4-dihydro-2H-pyrano[3,2-b]pyridyl or 7,8-dihydro-5H-pyrano[4,3-b]pyridyl), pyrimidinyl, tetrahydro-2H-pyranyl, pyrazinyl, dihydrofuranopyridyl (preferably 2,3-dihydrofurano[2,3- b]pyridyl), tetrahydronaphthalenyl (preferably 1,2,3,4-tetrahydronaphthalenyl), benzo[d]thiazolyl, triazolyl (preferably 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl), pyridyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl, or tetrahydrofuranopyridyl, each optionally being substituent R 1d Replace; or Two Rs 1a Together with one or more atoms to which they are attached, they form ternary, quaternary, quinary, or hexaternary unsaturated or saturated rings, said rings containing 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said rings are optionally substituents R. 1d replace; R 1b and R 1cEach 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, phenyl, chromium, isochorium, dihydropyranopyridyl (preferably 5,8-dihydro-6H-pyrano[3,4-b]pyridyl, 3,4-dihydro-2H-pyrano[3,2-b]pyridyl or 7,8-dihydro-5H-pyrano[4,3-b]pyridyl), pyrimidinyl, tetrahydro-2H-pyranyl, pyrazinyl, pyrazinyl, dihydrofuranopyridyl (preferably 2,3... -dihydrofurano[2,3-b]pyridyl), tetrahydronaphthalenyl (preferably 1,2,3,4-tetrahydronaphthalenyl), benzo[d]thiazolyl, triazolyl (preferably 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl), pyridyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl or tetrahydrofuranopyridyl, wherein the methyl alkyl, 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, chromanyl, isochoryl, dihydropyranopyridyl (preferably 5,8-dihydro-6H-pyrano[3,4-b]pyridyl, 3,4-dihydro-2H-pyrano[3,2-b]pyridyl or 7,8-dihydro-5H-pyrano[4,3-b]pyridyl), pyrimidinyl, tetrahydro-2H-pyranyl, pyrazinyl, pyrazinyl, dihydrofuranopyridyl (preferably 2,3-dihydrofurano[2,3-b]pyridyl), pyrimidinyl, tetrahydro-2H-pyranyl, pyridazinyl, dihydrofuranopyridyl (preferably 2,3-dihydrofurano[2,3-b]pyridyl), pyrimidinyl, tetrahydro-2H-pyranyl, pyraz ...ridazinyl, dihydrofuranopyridyl (preferably 2 [b]pyridyl), tetrahydronaphthalenyl (preferably 1,2,3,4-tetrahydronaphthalenyl), benzo[d]thiazolyl, triazolyl (preferably 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl), pyridyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl, or tetrahydrofuranopyridyl, each optionally being substituent R. 1e replace; R 1d and R 1eEach of the following 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, chromium, isochorium, dihydropyranopyridyl (preferably 5,8-dihydro-6H-pyrano[3,4-b]pyridyl, 3,4-dihydro-2H-pyrano[3,2-b]pyridyl or 7,8-dihydro-5H-pyrano[4,3-b]pyridyl), pyrimidinyl, tetrahydro-2H-pyranyl, pyrazinyl, dihydrofuranopyridyl (preferably 2, 3-Dihydrofurano[2,3-b]pyridyl), tetrahydronaphthalenyl (preferably 1,2,3,4-tetrahydronaphthalenyl), benzo[d]thiazolyl, triazolyl (preferably 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl), pyridyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl, tetrahydrofuranopyridyl, -OR 1f -SO2R 1f -COR 1f -CO2R 1f -CONR 1f R 1g -NR 1f R 1g -NR 1f COR 1g -NR 1f CO2R 1gOxylated or -CN, wherein the methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, chromium, isochorium, dihydropyranopyridyl (preferably 5,8-dihydro-6H-pyrano[3,4-b]pyridyl, 3,4-dihydro-2H-pyrano[3,2-b]pyridyl or 7,8-dihydro-5H-pyrano[4,3-b]pyridyl), pyrimidinyl, tetrahydro-2H-pyranyl, pyrazinyl, dihydrofuranopyridyl (preferably 2,3-dihydrofurano[2,3- b]pyridyl), tetrahydronaphthalenyl (preferably 1,2,3,4-tetrahydronaphthalenyl), benzo[d]thiazolyl, triazolyl (preferably 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl), pyridyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl, or tetrahydrofuranopyridyl, each optionally being substituent R 1h replace; R 1f and R 1gEach 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, phenyl, chromium, isochorium, dihydropyranopyridyl (preferably 5,8-dihydro-6H-pyrano[3,4-b]pyridyl, 3,4-dihydro-2H-pyrano[3,2-b]pyridyl or 7,8-dihydro-5H-pyrano[4,3-b]pyridyl), pyrimidinyl, tetrahydro-2H-pyranyl, pyrazinyl, pyrazinyl, dihydrofuranopyridyl (preferably 2,3... -dihydrofurano[2,3-b]pyridyl), tetrahydronaphthalenyl (preferably 1,2,3,4-tetrahydronaphthalenyl), benzo[d]thiazolyl, triazolyl (preferably 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl), pyridyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl or tetrahydrofuranopyridyl, wherein the methyl alkyl, 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, chromanyl, isochoryl, dihydropyranopyridyl (preferably 5,8-dihydro-6H-pyrano[3,4-b]pyridyl, 3,4-dihydro-2H-pyrano[3,2-b]pyridyl or 7,8-dihydro-5H-pyrano[4,3-b]pyridyl), pyrimidinyl, tetrahydro-2H-pyranyl, pyrazinyl, pyrazinyl, dihydrofuranopyridyl (preferably 2,3-dihydrofurano[2,3-b]pyridyl), pyrimidinyl, tetrahydro-2H-pyranyl, pyridazinyl, dihydrofuranopyridyl (preferably 2,3-dihydrofurano[2,3-b]pyridyl), pyrimidinyl, tetrahydro-2H-pyranyl, pyraz ...ridazinyl, dihydrofuranopyridyl (preferably 2 [b]pyridyl), tetrahydronaphthalenyl (preferably 1,2,3,4-tetrahydronaphthalenyl), benzo[d]thiazolyl, triazolyl (preferably 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl), pyridyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl, or tetrahydrofuranopyridyl, each optionally being substituent R. 1i replace; R 1h and R 1iEach of the following 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, chromium, isochorium, dihydropyranopyridyl (preferably 5,8-dihydro-6H-pyrano[3,4-b]pyridyl, 3,4-dihydro-2H-pyrano[3,2-b]pyridyl or 7,8-dihydro-5H-pyrano[4,3-b]pyridyl), pyrimidinyl, tetrahydro-2H-pyranyl, pyrazinyl, pyrazinyl, dihydrofuranopyridyl (Preferably, 2,3-dihydrofurano[2,3-b]pyridyl), tetrahydronaphthalenyl (preferably, 1,2,3,4-tetrahydronaphthalenyl), benzo[d]thiazolyl, triazolyl (preferably, 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl), pyridyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl, tetrahydrofuranopyridyl, -OR 1j -COR 1j -CO2R 1j -CONR 1j R 1k -NR 1j R 1k -NR 1j COR 1k -NR 1j CO2R 1kOxylated or -CN, wherein 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, phenyl, chromium, isochorium, dihydropyranopyridyl (preferably 5,8-dihydro-6H-pyrano[3,4-b]pyridyl, 3,4-dihydro-2H-pyrano[3,2-b]pyridyl or 7,8-dihydro-5H-pyrano[4,3-b]pyridyl), pyrimidinyl, tetrahydro-2H-pyranyl, pyrazinyl, pyrazinyl, dihydrofuranopyridyl (preferably 2,3-dihydrofurano[2,3-b]pyridyl), tetrahydronaphthalenyl (preferably 1,2, Each of 3,4-tetrahydronaphthalenyl, benzo[d]thiazolyl, triazolyl (preferably 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl), pyridyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl, or tetrahydrofuranopyridyl is optionally substituted by at least one of the following substituents: -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, octyloxy, -C 2-8 alkenyl, -C 2-8 Alkyne, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, pyridyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl, tetrahydrofuranopyridyl, -CN, -OH, -NH2 or oxo; R 1j and R 1kEach of the following groups is independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, chromanyl, isochoryl, dihydropyranopyridyl (preferably 5,8-dihydro-6H-pyrano[3,4-b]pyridyl, 3,4-dihydro-2H-pyrano[3,2-b]pyridyl or 7,8-dihydro-5H-pyrano[4,3-b]pyridyl), pyrimidinyl, tetrahydro-2H-pyranyl, pyrazinyl, pyrazinyl, dihydrofuranopyridyl (preferably 2,3-dihydrofurano[2,3-b]pyridyl), tetrahydronaphthyl (tetrahydr Onaphthalenyl (preferably 1,2,3,4-tetrahydronaphthalenyl), benzo[d]thiazolyl, triazolyl (preferably 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl), pyridyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl or tetrahydrofuranopyridyl, wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Cycloheptyl, cyclooctyl, phenyl, chromanyl, isochoryl, dihydropyranopyridyl (preferably 5,8-dihydro-6H-pyrano[3,4-b]pyridyl, 3,4-dihydro-2H-pyrano[3,2-b]pyridyl or 7,8-dihydro-5H-pyrano[4,3-b]pyridyl), pyrimidinyl, tetrahydro-2H-pyranyl, pyrazinyl, pyrazinyl, dihydrofuranopyridyl (preferably 2,3-dihydrofurano[2,3-b]pyridyl), tetrahydronaphthalenyl (preferably 1,2,3,4-tetrahydronaphthalenyl). lenyl), benzo[d]thiazolyl, triazolyl (preferably 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl), pyridyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl or tetrahydrofuranopyridyl, each optionally substituted by at least one of the following substituents: -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, -C 2-8 alkenyl, -C 2-8Alkyne, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, pyridyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl, tetrahydrofuranopyridyl, -CN, -OH, -NH2 or oxo; Preferably, R 1 and R 2Each is independently selected from hydrogen, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, chromium, isochorium, dihydropyranopyridyl (preferably 5,8-dihydro-6H-pyrano[3,4-b]pyridyl, 3,4-dihydro-2H-pyrano[3,2-b]pyridyl or 7,8-dihydro-5H-pyrano[4,3-b]pyridyl), pyrimidinyl, tetrahydro-2H-pyranyl, pyrazinyl, dihydrofuranopyridyl (preferably 2,3-dihydrofurano[2 ...pyridyl), pyrimidinyl, pyrimidinyl, dihydrofurano [b]pyridyl), tetrahydronaphthalenyl (preferably 1,2,3,4-tetrahydronaphthalenyl), benzo[d]thiazolyl, triazolyl (preferably 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl), pyridyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl or tetrahydrofuranopyridyl, wherein the methyl alkyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, chromium, isochorium, dihydropyranopyridyl (preferably 5,8-dihydro-6H-pyrano[3,4-b]pyridyl, 3,4-dihydro-2H-pyrano[3,2-b]pyridyl or 7,8-dihydro-5H-pyrano[4,3-b]pyridyl), pyrimidinyl, tetrahydro-2H-pyranyl, pyrazinyl, pyrazinyl, dihydrofuranopyridyl (preferably 2,3-dihydrofurano[2,3-b]pyridyl), tetrahydro Each of the following groups is optionally substituent R: naphthyl (preferably 1,2,3,4-tetrahydronaphthalenyl), benzo[d]thiazolyl, triazolyl (preferably 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl), pyridyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl, or tetrahydrofuranopyridyl. 1a Replace; or R 1 and R 2 Together with the nitrogen atoms to which they are attached, they form 3-, 4-, 5-, 6-, 7-, or 8-membered unsaturated or saturated rings, said rings containing 0, 1, 2, or 3 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur; said rings are optionally substituents R. 1a replace; R 1a Independently, it is 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, chromanyl, isochoryl, dihydropyranopyridyl (preferably 5,8-dihydro-6H-pyrano[3,4-b]pyridyl, 3,4-dihydro-2H-pyrano[3,2-b]pyridyl, or 7,8-dihydro-5H-pyrano[4,3-b]pyridyl), pyrimidinyl, tetrahydro-2H-pyranyl, pyrazinyl, pyrazinyl, dihydrofuranopyridyl (preferably 2,3-dihydrofurano[2,3-b]pyridyl) Pyridyl), tetrahydronaphthalenyl (preferably 1,2,3,4-tetrahydronaphthalenyl), benzo[d]thiazolyl, triazolyl (preferably 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl), pyridyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl (preferably 2,3-dihydrofurano[2,3-b]pyridyl), tetrahydrofuranopyridyl, -OR 1b Or -CN, wherein the methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, chromium, isochorium, dihydropyranopyridyl (preferably, 5,8-dihydro-6H-pyrano[3,4-b]pyridyl, 3,4-dihydro-2H-pyrano[3,2-b]pyridyl or 7,8-dihydro-5H-pyrano[4,3-b]pyridyl), pyrimidinyl, tetrahydro-2H-pyranyl, pyrazinyl, pyrazinyl, dihydrofuranopyridyl (preferably, 2,3-dihydrofurano[2,3-b) Each of the following groups is optionally substituent R: pyridyl, tetrahydronaphthalenyl (preferably 1,2,3,4-tetrahydronaphthalenyl), benzo[d]thiazolyl, triazolyl (preferably 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl), pyridyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl, or tetrahydrofuranopyridyl, and is optionally substituent R. 1d Replace; or Two Rs 1aTogether with one or more atoms to which they are attached, they form ternary, quaternary, quinary, or hexaternary unsaturated or saturated rings, said rings containing 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said rings are optionally substituents R. 1d replace; R 1b Each can be independently hydrogen, methyl, ethyl, propyl (isopropyl or n-propyl), cyclopropyl or cyclobutyl; R 1d Each of the following 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, chromium, isochorium, dihydropyranopyridyl (preferably 5,8-dihydro-6H-pyrano[3,4-b]pyridyl, 3,4-dihydro-2H-pyrano[3,2-b]pyridyl or 7,8-dihydro-5H-pyrano[4,3-b]pyridyl), pyrimidinyl, tetrahydro-2H-pyranyl, pyrazinyl, dihydrofuranopyridyl (preferably 2, 3-Dihydrofurano[2,3-b]pyridyl), tetrahydronaphthalenyl (preferably 1,2,3,4-tetrahydronaphthalenyl), benzo[d]thiazolyl, triazolyl (preferably 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl), pyridyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl, tetrahydrofuranopyridyl, -OR 1f -NR 1f R 1g -NR 1f COR 1g , oxo, -SO2R 1fOr -CN, wherein the methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, chromium, isochorium, dihydropyranopyridyl (preferably, 5,8-dihydro-6H-pyrano[3,4-b]pyridyl, 3,4-dihydro-2H-pyrano[3,2-b]pyridyl or 7,8-dihydro-5H-pyrano[4,3-b]pyridyl), pyrimidinyl, tetrahydro-2H-pyranyl, pyrazinyl, pyrazinyl, dihydrofuranopyridyl (preferably, 2,3-dihydrofurano[2,3-b) Each of the following groups is optionally substituent R: pyridyl, tetrahydronaphthalenyl (preferably 1,2,3,4-tetrahydronaphthalenyl), benzo[d]thiazolyl, triazolyl (preferably 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl), pyridyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl, or tetrahydrofuranopyridyl, and is optionally substituent R. 1h replace; R 1f and R 1gEach is independently selected from hydrogen, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, chromium, isochorium, dihydropyranopyridyl (preferably 5,8-dihydro-6H-pyrano[3,4-b]pyridyl, 3,4-dihydro-2H-pyrano[3,2-b]pyridyl or 7,8-dihydro-5H-pyrano[4,3-b]pyridyl), pyrimidinyl, tetrahydro-2H-pyranyl, pyrazinyl, pyrazinyl, dihydrofuranopyridyl (preferably 2,3-dihydrofurano[...]...) [2,3-b]pyridyl), tetrahydronaphthalenyl (preferably 1,2,3,4-tetrahydronaphthalenyl), benzo[d]thiazolyl, triazolyl (preferably 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl), pyridyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl or tetrahydrofuranopyridyl, wherein the methyl alkyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, chromanyl, isochromyl, dihydropyranopyridyl (preferably 5,8-dihydro-6H-pyrano[3,4-b]pyridyl, 3,4-dihydro-2H-pyrano[3,2-b]pyridyl or 7,8-dihydro-5H-pyrano[4,3-b]pyridyl), pyrimidinyl, tetrahydro-2H-pyranyl, pyrazinyl, pyrazinyl, dihydrofuranopyridyl (preferably 2,3-dihydrofurano[2,3-b]pyridyl) Each of the following groups is optionally substituent R: tetrahydronaphthalenyl (preferably 1,2,3,4-tetrahydronaphthalenyl), benzo[d]thiazolyl, triazolyl (preferably 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl), pyridyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl, or tetrahydrofuranopyridyl. 1i replace; R 1h and R 1iEach of the following 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, chromanyl, isochoryl, dihydropyranopyridyl (preferably 5,8-dihydro-6H-pyrano[3,4-b]pyridyl, 3,4-dihydro-2H-pyrano[3,2-b]pyridyl or 7,8-dihydro-5H-pyrano[4,3-b]pyridyl), pyrimidinyl, tetrahydro-2H-pyranyl, pyrazinyl, dihydrofuranopyridyl (preferably 2,3-dihydro-2H-pyranyl), pyrimidinyl, tetrahydro-2H-pyranyl, pyrazinyl, dihydrofuranopyridyl (preferably 2,3-dihydro-2H-pyranyl), pyrimidinyl, tetrahydro-2H-pyranyl, pyrazinyl, dihydrofuranopyridyl (preferably 2,3-dihydro-2H-pyranyl), pyridinyl, tetrahydro-2H-pyranyl, pyrazinyl, dihydrofuranopyridyl (preferably 2,3-dihydro-2H-pyranyl), pyrimidinyl, tetrahydro-2H-pyranyl, pyridaz ... The following compounds are used: [2,3-b]pyridyl, tetrahydronaphthalenyl (preferably 1,2,3,4-tetrahydronaphthalenyl), benzo[d]thiazolyl, triazolyl (preferably 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl), pyridyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl, tetrahydrofuranopyridyl, -OH or -CN; More preferably, R 1 and R 2Each is independently selected from hydrogen, methyl, ethyl, propyl (isopropyl or n-propyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, chromium, isochorium, dihydropyranopyridyl (preferably 5,8-dihydro-6H-pyrano[3,4-b]pyridyl, 3,4-dihydro-2H-pyrano[3,2-b]pyridyl or 7,8-dihydro-5H-pyrano[4,3-b]pyridyl), pyrimidinyl, tetrahydro-2H-pyranyl, pyrazinyl, dihydrofuranopyridyl (preferably 2... ,3-dihydrofurano[2,3-b]pyridyl), tetrahydronaphthalenyl (preferably 1,2,3,4-tetrahydronaphthalenyl), benzo[d]thiazolyl, pyridyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl or tetrahydrofuranopyridyl The compound is a pyridyl group, wherein the methyl, ethyl, propyl (isopropyl or n-propyl), phenyl, chromium, isochorium, dihydropyranopyridyl (preferably 5,8-dihydro-6H-pyrano[3,4-b]pyridyl, 3,4-dihydro-2H-pyrano[3,2-b]pyridine, or 7,8-dihydro-5H-pyrano[4,3-b]pyridyl), pyrimidinyl, tetrahydro-2H-pyranyl, pyridazinyl, pyrazinyl, or dihydrofuranopyridyl (preferably 2,3-dihydrofurano[2,3-b]pyridyl). Each of the following groups is optionally substituent R: tetrahydronaphthalenyl (preferably 1,2,3,4-tetrahydronaphthalenyl), benzo[d]thiazolyl, pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl, or tetrahydrofuranopyridyl. 1a Replace; or R 1 and R 2 Together with the nitrogen atoms to which they are attached, they form a 6-membered unsaturated or saturated ring, which is optionally substituent R. 1a replace; R 1a Independently, it is hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (isopropyl or n-propyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrimidinyl, pyridazinyl, pyrazinyl, dihydrofuranopyridyl (preferably 2,3-dihydrofurano[2,3-b]pyridyl), benzo[d]thiazolyl, pyridyl, quinolinyl, isoquinolinyl, thiazolyl, -OR 1bor -CN, wherein each of the methyl, ethyl, propyl (isopropyl or n-propyl), phenyl, pyrimidinyl, pyridazinyl, pyrazinyl, dihydrofuranopyridinyl (preferably 2,3-dihydrofurano[2,3-b]pyridinyl), benzo[d]thiazolyl, pyridinyl, quinolinyl, isoquinolinyl, or thiazolyl groups is optionally substituent R. 1d replace; R 1b Each can be independently hydrogen, methyl, ethyl, propyl (isopropyl or n-propyl), cyclopropyl or cyclobutyl; R 1d Each of the following is 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, pyridazinyl, pyrazinyl, triazolyl (preferably 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl), pyridinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl, tetrahydrofuranopyridyl, -OR 1f -SO2R 1f or -CN, wherein each of the methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl, or tert-butyl), phenyl, pyrimidinyl, tetrahydro-2H-pyranyl, pyridazinyl, pyrazinyl, triazolyl (preferably 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl), pyridinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl, or tetrahydrofuranopyridyl is optionally substituent R. 1h replace; R 1f Each of the following is independently selected from hydrogen, methyl, ethyl, propyl (isopropyl or n-propyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or phenyl, wherein each of the methyl, ethyl, propyl (isopropyl or n-propyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or phenyl groups is optionally substituent R. 1i replace; R 1h and R 1i Each can be 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.

[0045] Aspect 11. The compound as described in any of the preceding aspects, wherein R 1and R 2 Each is independently selected from -C 1-8 Alkyl, -C3-C8 cycloalkyl, -C3-C 12 Cycloalkenyl and 3- to 12-membered heterocyclic groups, wherein the -C 1-8 Alkyl, -C3-C8 cycloalkyl, -C3-C 12 Each of the cycloalkenyl and 3- to 12-membered heterocyclic groups is optionally substituent R. 1a Replace; or R 1 and R 2 Together with the nitrogen atoms to which they are attached, they form 3- to 8-membered unsaturated or saturated rings, the rings containing 0-3 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the rings are optionally substituents R. 1a replace; R 1a Independently, it is hydrogen, halogen, deuterium, -C 1-8 Alkyl, -C3-C8 cycloalkyl, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, -OR 1b Or -CN, where -C 1-8 Alkyl, -C3-C8 cycloalkyl, -C6-C 12 Each of the aryl and 5- to 12-membered heteroaryl groups is optionally substituent R. 1d Replace; or Two Rs 1a Together with one or more atoms to which they are attached, they form 3- to 8-membered unsaturated or saturated rings, the rings comprising 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the rings optionally being substituents R. 1d replace; R 1b Each is independently selected from hydrogen and -C 1-8 Alkyl, wherein the -C 1-8 The alkyl group is optionally substituent for at least one R group. 1e replace; R 1d and R 1e Each is independently hydrogen, halogen, -C 1-8 Alkyl, -C3-C8 cycloalkyl, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, -OR 1f -SO2R 1f Or -CN, where -C 1-8 Alkyl, -C6-C 12 Each of the aryl and 5- to 12-membered heteroaryl groups is optionally substituent R. 1h replace; R1f Each is independently selected from hydrogen and -C 1-8 Alkyl and -C3-C8 cycloalkyl, wherein the -C 1-8 Each of the alkyl and -C3-C8 cycloalkyl groups is optionally substituent R. 1i replace; R 1h and R 1i Each is independently hydrogen, halogen, -C 1-8 Alkyl or -CN; Preferably, R 1 and R 2 Each of the following is independently selected from methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl, or tert-butyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, chromium, isochorium, pyridyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl, or tetrahydrofuranopyridyl, wherein the methyl group is... Each of the following groups is optionally substituent R: ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, chromanyl, isochoryl, pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl, or tetrahydrofuranopyridyl. 1a Replace; or R 1 and R 2 Together with the nitrogen atoms to which they are attached, they form 3-, 4-, 5-, 6-, 7-, or 8-membered unsaturated or saturated rings, said rings containing 0, 1, 2, or 3 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur; said rings are optionally substituents R. 1a replace; R 1a Independently, it is 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, pyridyl, pyrimidinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl (preferably 2,3-dihydrofurano[2,3-b]pyridyl), tetrahydrofuranopyridyl-OR 1bOr -CN, wherein 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, pyridyl, pyrimidinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl, or tetrahydrofuranopyridyl is optionally substituent R. 1d Replace; or Two Rs 1a Together with one or more atoms to which they are attached, they form ternary, quaternary, quinary, or hexaternary unsaturated or saturated rings, said rings containing 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said rings are optionally substituents R. 1d replace; R 1b Each of the following groups 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, wherein each of the methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl, or tert-butyl), pentyl, hexyl, heptyl, and octyl groups is optionally substituent R. 1e replace; R 1d and R 1e Each of the following can be 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, dihydrofuranopyridyl, tetrahydrofuranopyridyl, -OR 1f -SO2R 1f or -CN, wherein each of the methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl, or tert-butyl), pentyl, hexyl, phenyl, pyridyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl, or tetrahydrofuranopyridyl is optionally substituent R. 1h replace; R 1fEach of the following groups 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, wherein 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, or cyclooctyl groups is optionally substituent R. 1i replace; R 1h and R 1i Each can be 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.

[0046] Aspect 12. The compound as described in any of the preceding aspects, wherein R 1 and R 2 Each is independently selected from -Me, -Et, -Pr (-nPr or -isoPr), -Bu ( , , , or ), pentyl ( , , , , , , , , , or -CF3, -CH2CF3, ( or ), ( , , or ), ( , , or ), ( or ), ( or ), ( , , or ), ( , , or ), ( or ), ( or ), ( or ), ( or ), ( or ), ( or ), ( or ), ( or ), ( or ), ( , , or ), ( or ), ( or ), ( , , or ), ( , , or ), ( , , or ), ( , , or ), ( , , or ), ( , , or ), ( , , or ), ( , , or ), ( , , or ), ( , , or ), ( , , or ), , , , , , , ( or ), , , , , , , , , , , , , , , , , , , , , , , , ( or ), , , , , , , , , , , , , , , , , , , , , , , , , , ( or ), , ( or ), , , , , , , , ( or ), , ( or ), , , , , , , , , , ( or ), ( or ), ( or ), , , , , , , , , , , , , , , , , , , , ( or ), ( or ), , , , , ( or ), , ( or ), ( or ), ( or ), ( or ), ( or ), ( , , or ), ( or ), ( or ), ( or ), ( or ), ( or ), ( or ), ( or ), ( or ), ( , ), , , , , , , , , , , , , , , ( or ), ( or ), ( or ), , , ( or ), ( or ), ( , ), ( , ), ( , ), ( or ), , ( or )or ( or );or R 1 and R 2 Together with the nitrogen atoms to which they are attached, they form , ( , , or ), ( , , or ), ( , , or ).

[0047] Aspect 13. The compound as described in any of the preceding aspects, wherein L is a single bond.

[0048] Aspect 13'. The compound as described in any of the preceding aspects, wherein R 1a Independently selected from hydrogen, methyl, ethyl, propyl, halogenated, methyl groups substituted with one or more halogens, C 3-5 cycloalkyl or -CN, or two R 1a Attached to the same atom to form C 3-5 cycloalkyl; preferably, R 1a Independently selected from hydrogen, methyl, ethyl, -F, -Cl, -Br, -I, -CF3, cyclopropyl, or -CN, or two Rs. 1a It attaches to the same atom to form a cyclopropyl group.

[0049] Aspect 13". The compound as described in any of the preceding aspects, wherein R 1d Independently selected from hydrogen, halogenated, C 1-4 Alkyl groups, C substituted with one or more halogens 1-4 Alkyl groups, C groups substituted with -OH 1-4 Alkyl, -OC 1-4 Alkyl groups, -OC groups substituted with one or more halogens 1-4 Alkyl groups, C groups optionally substituted with fluorine 3-5 cycloalkyl, -SO2-C 1-4 Alkyl or -CN; preferably, R 1d Selected from hydrogen, -F, -Br, -Cl, -I, methyl, ethyl, propyl, butyl, -CF3, hydroxypropyl, methoxy, trifluoromethoxy, cyclopropyl, fluorocyclopropyl, cyclobutyl, -SO2CH3, or -CN.

[0050] Aspect 13'''. The compound as described in any of the preceding aspects, wherein R 2 It is C 1-8 Alkyl; preferably, R 2 It is methyl, ethyl, propyl (isopropyl or n-propyl) or butyl (n-butyl, sec-butyl, isobutyl or tert-butyl); more preferably, R 2 It is methyl, ethyl, or propyl (isopropyl or n-propyl); more preferably, R 2 It is a methyl group.

[0051] Aspect 14. The compound as described in any of the preceding aspects, wherein R 3Selected 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, wherein 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 optionally substituted by at least one substituent selected from the following: -F, -Cl, -Br, -I, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptaoxy, octoxy, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl, or tert-butyl), pentyl, hexyl, heptayl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or a 3- to 8-membered heterocyclic group; Preferably, R 3 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; More preferably, R 3 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; Even more preferably, R 3 Selected from hydrogen, -F, -Cl, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl); Even more preferably, R 3 Selected from hydrogen.

[0052] Aspect 15. The compound as described in any of the preceding aspects, wherein R 4 R 5 R 6 R 7 R 8 and R 9Each 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, wherein 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, or cyclooctyl groups are selected from the following: Each of these groups is optionally substituted with at least one of the following substituents: -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- to 8-membered heterocyclic group, phenyl, 5- to 12-membered 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 ; R 4a and R 4b Each of the following 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- to 8-membered heterocyclic group, phenyl, or 5- to 12-membered heteroaryl; wherein the methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl, or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl Each of the following groups is optionally substituted by at least one of the following substituents: yl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic, phenyl, or 5- to 12-membered heteroaryl: -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, octyloxy, C 1-8Alkoxy-C 1-8 Alkyl-, -C 2-8 alkenyl, -C 2-8 Alkyne, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic groups, phenyl or 5- to 12-membered heteroaryl groups; Preferably, R 4 R 5 R 6 R 7 R 8 and R 9 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; More preferably, R 4 R 5 R 6 R 7 R 8 and R 9 Each is independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (isopropyl or n-propyl), cyclopropyl, and cyclobutyl; Even more preferably, R 4 R 5 R 6 R 7 R 8 and R 9 Each is independently selected from hydrogen, -F, -Cl, -Br, -I, and methyl.

[0053] Aspect 15'. A compound having the formula (VIIIp):

[0054] Or its N-oxide, or its pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analogue, or its N-oxide, or its pharmaceutically acceptable salt, or its stereoisomer, or its tautomer, or its deuterated analogue, wherein: R 1a 'Independently selected from hydrogen, methyl, or ethyl; R 1a '' is hydrogen; or R 1a 'and R 1a Together with the atoms to which they are attached, they form C 3-5 cycloalkyl; n5' is 0, 1, or 2; and R 1a R 2 R 6 and R7 As specified in any of the foregoing aspects.

[0055] In one embodiment: R 1a Independently selected from halogenated, methyl groups substituted by one or more halogenations, C 3-5 Cycloalkyl or -CN; preferably -F, -Cl, -Br, -I, -CF3, cyclopropyl or -CN; R 2 It is C 1-8 Alkyl; preferably, methyl; R 6 It is hydrogen or methyl; preferably, hydrogen; and R 7 It is hydrogen.

[0056] Aspect 15”. A compound having formula (VIIr): (VIIr), Or its N-oxide, or its pharmaceutically acceptable salt, or its stereoisomer, or its tautomer, or its deuterated analogue, wherein Y' is N or C(R) 1d ), and R 1a R 1d R 2 R 6 and R 7 As defined in any of the foregoing aspects.

[0057] In one embodiment: R 1a It is hydrogen or methyl; R 1d Independently selected from hydrogen, halogenated, methyl groups substituted with one or more halogenated groups, and C groups optionally substituted with fluorine. 3-5 Cycloalkyl, or -CN; preferably, hydrogen, -F, -Br, -I, -CF3, cyclopropyl, fluorocyclopropyl, cyclobutyl, or -CN; R 2 It is C 1-8 Alkyl; preferably, methyl, ethyl or propyl; R 6 It is hydrogen or methyl; and R 7 It is hydrogen.

[0058] In one embodiment, Y' is N. In another embodiment, Y' is C(R). 1d ).

[0059] Aspect 16. The compound as described in any of the preceding aspects, wherein the compound is selected from:

[0060] Aspect 17. A pharmaceutical composition comprising a compound as described in any one of Aspects 1-16, or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, a stereoisomer, a tautomer thereof, or a deuterated analog thereof, and a pharmaceutically acceptable excipient.

[0061] In one embodiment, the pharmaceutical composition is used as described herein, for example, in any of aspects 18-22.

[0062] Aspect 18. A method for reducing or inhibiting PRMT5 activity, the method comprising administering to a subject in need an effective amount of a compound as described in any one of Aspects 1-16, or its N-oxide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analogue, including compounds having formula (I) or any specific compound exemplified herein.

[0063] Aspect 19. A method of treating a disease regulated by PRMT5, the method comprising administering to a subject in need an effective amount of a compound, such as any one of Aspects 1-16, or its N-oxide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analogue, including compounds having formula (I) or any particular compound exemplified herein.

[0064] Aspect 20. Use of any compound of any one of Aspects 1-16, or its N-oxide, or pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analog thereof, in the preparation of a medicament for treating diseases regulated by PRMT5.

[0065] Aspect 21. The method as described in aspect 19 or the use as described in aspect 20, wherein the disease is cancer.

[0066] Aspect 22. The method as described in aspect 19 or the use as described in aspect 20, wherein the disease is an MTAP-empty solid tumor, including lung cancer, bladder cancer, melanoma, pancreatic cancer, esophageal cancer, gastric adenocarcinoma, breast cancer, and glioblastoma. Detailed Implementation

[0067] The following terms have indicative meanings throughout the specification: Unless otherwise defined elsewhere in this document, all other technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this invention pertains.

[0068] The following terms have indicative meanings throughout the specification: As used herein, including the appended claims, unless the context clearly indicates otherwise, the singular forms of words such as “a / an” and “the” include their corresponding plural referents.

[0069] Unless the context clearly indicates otherwise, the term “or” means the term “and / or” and is used interchangeably with the term “and / or”.

[0070] The term "alkyl" includes a hydrocarbon group selected from straight-chain and branched saturated hydrocarbon groups, comprising 1 to 18, for example, 1 to 12, further for example, 1 to 10, even further for example, 1 to 8, or 1 to 6, or 1 to 4 carbon atoms. Alkyl groups comprising 1 to 6 carbon atoms (i.e., C...) 1-6Examples 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 sec-butyl (“s-Bu”), 1,1-dimethylethyl or tert-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. Unless otherwise defined, "C" 1-8 "alkyl" includes hydrocarbon groups selected from straight-chain and branched saturated hydrocarbon groups, which contain from 1 to 8 carbon atoms, "C 1-8 "Alkyl" also includes hydrocarbon groups selected from straight-chain and branched saturated hydrocarbon groups, which contain 1 to 6 carbon atoms (C64-C64). 1-6 Alkyl groups or 1 to 4 carbon atoms (C 1-4 alkyl).

[0071] The term "propyl" includes 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr").

[0072] The term “butyl” includes 1-butyl or n-butyl (“n-Bu”), 2-methyl-1-propyl or isobutyl (“i-Bu”), 1-methylpropyl or sec-butyl (“s-Bu”), and 1,1-dimethylethyl or tert-butyl (“t-Bu”).

[0073] 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" further includes... , ( or ), , , ( or ), , and .

[0074] 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.

[0075] The term "alkylene" refers to a divalent alkyl group formed by removing two hydrogen atoms from an alkane. Alkylenes include, but are not limited to, methylene, ethylene, and propylene.

[0076] The term "halogen" includes fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0077] The term “H” or “hydrogen” disclosed in this article includes hydrogen and the non-radioactive isotope deuterium.

[0078] The term "alkenyl" includes a hydrocarbon group selected from straight-chain and branched hydrocarbon groups, which contains at least one C=C double bond and 2 to 18, for example, 2 to 8, and more specifically, 2 to 6 carbon atoms. Alkenyl groups (e.g., C...) 2-6 Examples of alkenyl groups include, but are not limited to, ethenyl (or vinyl), propenyl, propenyl, 2-propenyl, 2-methylpropenyl, butenyl, butenyl, butenyl, 3-propenyl, butenyl, 1,3-dienyl, 2-methylbutenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, and 1,3-dienyl groups.

[0079] The term "alkenyl" refers to a divalent alkenyl group formed by removing two hydrogens from an olefin. Alkenyl groups include, but are not limited to, vinylidene and buteneyl groups.

[0080] The term "alkynyl" includes a hydrocarbon group selected from straight-chain and branched hydrocarbon groups, which contains at least one C≡C triple bond and 2 to 18, for example, 2 to 8, and more specifically, 2 to 6 carbon atoms. The alkynyl group (e.g., C...) 2-6 Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl (propynyl), 1-butynyl, 2-butynyl and 3-butynyl groups.

[0081] The term "alkenylyl" refers to a divalent alkynyl group formed by removing two hydrogens from an alkyne. Alkenylyl groups include, but are not limited to, ethynylylene.

[0082] The term "cycloalkyl" includes hydrocarbon groups selected from saturated cyclic hydrocarbon groups, which contain monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups (including fused, bridged, or spirocycloalkyl).

[0083] For example, the cycloalkyl group can contain 3 to 12, such as 3 to 10, further such as 3 to 8, further such as 3 to 6, 3 to 5, or 3 to 4 carbon atoms. Even further, for example, the cycloalkyl group can be selected from monocyclic groups containing 3 to 12, such as 3 to 10, further such as 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., C16, C26, C36, C46, ​​C56, C6 ... 3-8 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In a preferred embodiment, the cycloalkyl group is a monocyclic ring (abbreviated as C16) containing 3 to 6 carbon atoms. 3-6 Cycloalkyl groups, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of bicyclic cycloalkyl groups include those having 7 to 12 ring atoms, having a fused bicyclic arrangement (selected from the [4,4], [4,5], [5,5], [5,6], and [6,6] ring systems) or having a bridged bicyclic arrangement (selected from bicyclic [2.2.1]heptane, bicyclic [2.2.2]octane, and bicyclic [3.2.2]nonane). Further examples of bicyclic cycloalkyl groups include those having a bicyclic arrangement (selected from the [5,6] and [6,6] ring systems).

[0084] The term "spirocycloalkyl" includes cyclic structures containing carbon atoms and formed by at least two rings sharing one atom.

[0085] The term “fused cycloalkyl” includes bicyclic cycloalkyl groups as defined herein, which are saturated and formed by two or more rings sharing two adjacent atoms.

[0086] The term "bridged cycloalkyl" includes a cyclic structure containing carbon atoms and formed by two rings sharing two non-adjacent atoms. The term "7- to 10-membered bridged cycloalkyl" includes a cyclic structure containing 7 to 12 carbon atoms and formed by two rings sharing two non-adjacent atoms.

[0087] Examples of fused cycloalkyl, fused cycloalkenyl, or fused cycloalkynyl groups include, but are not limited to, 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, naphthane, and benzo3- to 8-membered cycloalkyl, benzoC 4-6 Cycloalkenyl, 2,3-dihydro-1H-indenyl, 1H-indenyl, 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl, etc. Preferred embodiments are 8- to 9-membered fused rings, referring to the cyclic structures containing 8 to 9 ring atoms in the above examples.

[0088] The term "aryl" used alone or in combination with other terms includes groups selected from the following: 5- and 6-membered carbon-ring aromatic rings, such as phenyl; Bicyclic systems (such as 7- to 12-membered bicyclic systems), wherein at least one ring is a carbocyclic ring and an aromatic ring, such as naphthyl and indeneyl; and, Tricyclic systems (such as decacyclic to 15-membered tricyclic systems) in which at least one ring is a carbocyclic ring and an aromatic ring, such as a fluorene ring.

[0089] The terms "aromatic ring" and "aryl" are used interchangeably throughout the disclosure herein. In some embodiments, the monocyclic or bicyclic aromatic ring has 5 to 10 cyclic carbon atoms (i.e., C10). 5-10 Aryl). Examples of monocyclic or bicyclic aromatic hydrocarbon rings include, but are not limited to, phenyl, naphth-1-yl, naphth-2-yl, anthraceneyl, phenanthrene, etc. In some embodiments, the aromatic hydrocarbon ring is a naphthyl ring (naphth-1-yl or naphth-2-yl) or a phenyl ring. In some embodiments, the aromatic hydrocarbon ring is a phenyl ring.

[0090] In particular, the term "bicyclic fused aryl" includes a bicyclic aryl ring as defined herein. A typical bicyclic fused aryl is naphthalene.

[0091] The term "heteroaryl" includes groups 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., from 1 to 4, or in some embodiments from 1 to 3, or in some embodiments from 1 to 2 heteroatoms), wherein the remaining ring atoms are carbon; A 7- to 12-membered bicyclic ring comprising at least one heteroatom selected from N, O, and S (e.g., from 1 to 4, or in some embodiments from 1 to 3, or in other embodiments 1 or 2 heteroatoms), wherein the remaining ring atoms are carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring; and The 11- to 14-membered tricyclic rings contain at least one heteroatom selected from N, O, and S (e.g., from 1 to 4, or from 1 to 3 in some embodiments, or 1 or 2 heteroatoms in other embodiments), wherein the remaining ring atoms are carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring.

[0092] When the total number of S and O atoms in a heteroaryl group exceeds 1, those heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in a heteroaryl group does not exceed 2. In some embodiments, the total number of S and O atoms in an aromatic heterocycle does not exceed 1. When a heteroaryl group contains more than one heteroatom ring member, these heteroatoms can be the same or different. The nitrogen atom in the ring of a heteroaryl group can be oxidized to form an N-oxide.

[0093] Specifically, the term "bicyclic fused heteroaryl" includes 7- to 12-membered, preferably 7- to 10-membered, and more preferably 9- or 10-membered fused bicyclic heteroaryl rings as defined herein. Typically, bicyclic fused heteroaryl groups are 5 / 5, 5 / 6, 6 / 6, or 6 / 7 bicyclic rings. The group can be attached to the remainder of the molecule via either ring.

[0094] "Heterocyclic group", "heterocyclic" or "heterocyclic" are interchangeable and include non-aromatic heterocyclic groups (which contain one or more heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring members, wherein the remaining ring members are carbon), including monocyclic, fused, bridging, and spirocyclic groups, i.e. containing monocyclic heterocyclic groups, bridging heterocyclic groups, spirocyclic groups, and fused heterocyclic groups.

[0095] The term "at least one substituent" disclosed herein includes, for example, 1 to 4, such as 1 to 3, further such as 1 or 2 substituents, provided that valence theory is satisfied. For example, "at least one substituent F" disclosed herein includes 1 to 4, such as 1 to 3, further such as 1 or 2 substituents F.

[0096] The term "divalent" refers to a linking group capable of forming covalent bonds with two other moieties. For example, "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 heterocyclic group," or "divalent heteroaryl group" should be understood in a similar manner.

[0097] The compounds disclosed herein may contain asymmetric centers and therefore may exist as enantiomers. "Enantiomer" refers to two stereoisomers of a compound that are non-overlapping mirror images of each other. When the compounds disclosed herein have two or more asymmetric centers, they may also exist as diastereomers. Enantiomers and diastereomers belong to a broader category of stereoisomers. This is intended to include all possible stereoisomers, such as substantially pure, separated enantiomers, their racemic mixtures, and mixtures of diastereomers. This is intended to include all stereoisomers of the compounds disclosed herein and / or their pharmaceutically acceptable salts. Unless otherwise specifically stated, reference to one isomer applies to any possible isomer. Whenever the composition of an isomer is not specified, all possible isomers are included.

[0098] When the compounds disclosed herein contain olefinic double bonds, such double bonds are intended to include E and Z geometric isomers unless otherwise stated.

[0099] When the compounds disclosed herein contain a disubstituted ring system, the substituents found on such a ring system can be formed in cis and trans arrangements. A cis arrangement means that both substituents are located above the two substituent positions on the carbon atom, while a trans arrangement means that they are located on opposite sides. For example, a disubstituted ring system can be a cyclohexyl ring or a cyclobutyl ring.

[0100] Separating reaction products from each other and / or from starting materials can be advantageous. The desired products of each step or series of steps are separated and / or purified (hereinafter referred to as separation) to the desired homogeneity using common techniques in the art. Typically, such separation involves multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve many methods, including, 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 techniques for small-scale thin-layer and rapid chromatography. Those skilled in the art can select and apply the technique most likely to achieve the desired separation.

[0101] "Diarrhetinic isomers" refer to stereoisomers of compounds having two or more chiral centers that are not mirror images of each other. Mixtures of diastereomers can be separated into their individual diastereomers based on their physicochemical differences using methods known to those skilled in the art, such as chromatography and / or fractional crystallization. Enantiomers can be separated by reacting the enantiomer mixture with a suitable optically active compound (e.g., a chiral auxiliary, such as a chiral alcohol or Mosher's acid chloride) to convert the enantiomer mixture into a diastereomer mixture, separating these diastereomers, and converting (e.g., hydrolyzing) the individual diastereomers into their respective pure enantiomers. Enantiomers can also be separated using a chiral HPLC column.

[0102] A single stereoisomer (e.g., a substantially pure enantiomer) can be obtained by resolving a racemic mixture using an optically active resolving agent to form a diastereomer. Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. Stereochemistry of organic compounds New York: John Wiley & Sons, Inc. [New York: John Wiley & Sons Publishing Company], 1994; Lochmuller, CH et al. Chromatographic resolution of enantiomers: Selective review [Separation by method: a selective review]." J. Chromatogr. [Journal of Chromatography], 113(3) (1975): (Pages 283-302). Racemic mixtures of the chiral compounds of the present invention can be separated and isolated by any suitable method comprising: (1) forming ionic diastereomeric salts with the chiral compounds and separating them by fractional crystallization or other methods; (2) forming diastereomeric compounds with chiral derivatizing agents, separating these diastereomeric compounds and converting them to pure stereoisomers; and (3) directly separating substantially pure or enriched stereoisomers under chiral conditions. See also: Wainer, Irving W. (ed.) Drug Stereochemistry: Analytical Methods and Pharmacology. [Analytical Methods and Pharmacology] New York: Marcel Dekker, Inc. [New York: Marcel Dekker, Inc.], 1993.

[0103] Some of the compounds disclosed herein can have different hydrogen attachment sites, referred to as tautomers. For example, compounds containing a carbonyl -CH2C(O)- group (ketone form) can undergo tautomerism to form a hydroxyl -CH=C(OH)- group (enol form). Where applicable, both ketone and enol forms, as well as mixtures thereof, are also intended to be included.

[0104] A "prodrug" is a derivative of an active agent that needs to be converted in vivo to release the active agent. In some embodiments, this conversion is an enzymatic conversion. Prodrugs are often (though not essential) pharmacologically inactive until they are converted into the active agent.

[0105] "Pharmaceutically acceptable salts" refer to those salts that, to the extent of reasonable medical judgment, are suitable for contact with tissues of humans and lower animals without undue toxicity, irritation, allergic reactions, etc., and in proportion to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compounds disclosed herein, or separately by reacting a free base functional group with a suitable organic acid, or separately by reacting an acidic group with a suitable base. This term also includes salts of stereoisomers (e.g., enantiomers and / or diastereomers), tautomers, and prodrugs of the compounds of the present invention.

[0106] Furthermore, if the compounds disclosed herein are obtained as acid addition salts, the free base can be obtained by alkalizing the solution of the acid salt. Conversely, if the product is a free base, the addition salt (such as a pharmaceutically acceptable addition salt) can be produced by following the conventional procedure for preparing acid addition salts from base compounds, by dissolving the free base in a suitable organic solvent and treating the solution with acid. Those skilled in the art will recognize various synthetic methods that can be used to prepare non-toxic, pharmaceutically acceptable addition salts without excessive experimentation.

[0107] The terms “administration” and “administering” as used herein, when applied to animals, humans, experimental subjects, cells, tissues, organs, or biological fluids, mean contact between an exogenous pharmaceutical, therapeutic, or diagnostic agent or composition and an animal, human, subject, cell, tissue, organ, or biological fluid. Cellular treatment encompasses contact between a reagent and a cell, as well as contact between a reagent and a fluid, wherein the fluid contacts the cell. The terms “administration” and “administering” also mean, for example, in vitro and ex vivo treatment of cells by means of a reagent, diagnostic agent, conjugated compound, or another cell. The term “subject” as used herein includes any biological entity, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, and rabbit), and most preferably a human.

[0108] The term "effective amount" or "therapeutic effective amount" refers to the amount of an active ingredient (e.g., a compound) sufficient to affect the treatment of a disease, disorder, or symptom when administered to a subject to treat at least one clinical symptom of such disease, disorder, or symptom. The term "therapeutic effective amount" can vary depending on the compound, the disease, disorder, and / or the symptom of the disease or disorder, the severity of the disease, disorder, and / or the age of the subject being treated, and / or the weight of the subject being treated. The appropriate amount in any given situation will be obvious to those skilled in the art or can be determined by routine experiments. In some embodiments, "therapeutic effective amount" is the amount of at least one compound disclosed herein and / or at least one of its stereoisomers, tautomers, or prodrugs, and / or at least one pharmaceutically acceptable salt thereof, as defined herein, that effectively "treats" a subject's disease or disorder. In the case of combination therapies, the term "therapeutic effective amount" refers to the total amount of the combination of substances used to effectively treat a disease, disorder, or symptom.

[0109] The term “disease” refers to any illness, discomfort, ailment, symptom, or indication and is interchangeable with the terms “disorder” or “symptom”.

[0110] Throughout this specification and the appended claims, unless the context otherwise requires, the term "comprise" and variations such as "comprises" and "comprising" are intended to specify the presence of the following feature but do not exclude the presence or addition of one or more other features. When used herein, the term "comprise" may be replaced by the terms "containing," "including," or sometimes "having."

[0111] Throughout this specification and the appended claims, the term "C" is used. n-m The indicator includes the range of endpoints, where n and m are integers, and indicates the number of carbons. Examples include C. 1-8 C 1-6 wait.

[0112] Unless otherwise stated, the descriptions herein of one or more substituents bonded to a cyclic group (e.g., aryl, heteroaryl, cycloalkyl, fused cyclic group, spirocyclic group) via inter-ring bonds are intended to show that one or more substituents may be bonded to the cyclic group at any ring position in any ring of the cyclic group (e.g., any ring in a fused cyclic group), provided that such substitution yields a stable compound.

[0113] Unless otherwise defined elsewhere in this document, all other technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this invention pertains.

[0114] Example Universal synthesis The compounds disclosed herein (including their salts) can be prepared using known organic synthesis techniques and can be synthesized according to any of the many possible synthetic pathways.

[0115] The reactions for preparing the compounds disclosed herein can be carried out in suitable solvents that can be readily selected by those skilled in the art of organic synthesis. Suitable solvents are substantially unreactive with the starting materials, intermediates, or products at temperatures ranging from the solvent's boiling point. A given reaction can be carried out in one solvent or a mixture of solvents.

[0116] The selection of appropriate protecting groups can be readily determined by those skilled in the art. In the synthetic scheme, some protecting / deprotecting steps are not shown and can be incorporated before, after, or between any step. The protecting groups shown in the synthetic scheme may or may not be used depending on the reaction conditions. The order of the reactions can be varied to provide similar results.

[0117] The reaction can be monitored using any suitable method known in the art (e.g., NMR, UV, HPLC, LC-MS, and TLC). Compounds can be purified by a variety of methods, including preparative HPLC and silica gel chromatography. Unless otherwise specified, preparative HPLC uses a buffered acetonitrile / water system, and silica gel chromatography (including column chromatography and preparative TLC) uses a PE / EtOAc or DCM / MeOH system as the mobile phase. NMR spectra are recorded using a Bruker or Varian instrument with a preset pulse sequence.

[0118] Option I For example, a compound having formula (I) can be formed as shown in scheme I. Compound (i) and compound (ii) can be coupled together by transition metal-catalyzed coupling to give compound (iii). Compound (iii) can be deprotected to give compound (iv). Compound (iv) can be intramolecularly cyclized to give compound (v). Compound (v) can be saponified to give compound (vi). Compound (vi) can be coupled with compound (vii) to give compound (viii) [i.e., formula (I)].

[0119] Option II For example, a compound having formula (I) can be formed as shown in scheme II. Compound (i) can be dehydrated and cyclized to give compound (ii). Compound (ii) can be saponified to give compound (iii). Compound (iii) can be coupled with compound (iv) to give compound (v) [i.e., formula (I)].

[0120] Option III For example, a compound having formula (I) can be formed as shown in scheme III. Compound (i) can be halogenated to give compound (ii). Compound (ii) can be reacted with compound (iii) via an enamine-Heck reaction to give compound (iv). Compound (iv) can be amination to give compound (v). Compound (v) can be saponified to give compound (vi). Compound (vi) can be coupled with compound (vii) to give compound (viii) [i.e., formula (I)].

[0121] Option IV For example, a compound having formula (I) can be formed as shown in scheme IV. Compound (i) can be amination, for example via a metal-catalyzed coupling reaction, to give compound (ii). Compound (ii) can be halogenated to give compound (iii). Compound (iii) and compound (iv) can be coupled together by transition metal-catalyzed coupling to give compound (v). Compound (v) can be deprotected to give compound (vi). Compound (vi) can be intramolecularly cyclized to give compound (vii). Compound (vii) can be saponified to give compound (viii). Compound (viii) can be coupled with compound (ix), followed by optional deprotection, to give compound (x) [i.e., formula (I)].

[0122] Option V For example, a compound having formula (I) can be formed as shown in scheme V. Compound (i) can be condensed with compound (ii) to give compound (iii). Compound (iii) can be amination, for example via a metal-catalyzed coupling reaction, to give compound (iv). Compound (iv) can be deprotected to give compound (v). Compound (v) can be intramolecularly cyclized to give compound (vi). Compound (vi) can be saponified to give compound (vii). Compound (vii) can be coupled with compound (viii), followed by optional deprotection, to give compound (ix) [i.e., formula (I)].

[0123] Solution VI For example, a compound having formula (I) can be formed as shown in scheme VI. Compound (i) can be condensed with compound (ii) to give compound (iii). Compound (iii) can be deprotected to give compound (iv). Compound (iv) can be intramolecularly cyclized to give compound (v). Compound (v) can be saponified to give compound (vi). Compound (vi) can be coupled with compound (vii), followed by optional deprotection, to give compound (viii) [i.e., formula (I)].

[0124] abbreviation

[0125] Example 1: (R)-5-amino-N-((3',5'-difluoro-[3,4'-bipyridin]-6-yl)methyl)-N-(5,6,7,8-tetrahydroquinolin-8-yl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Step 1: 3',5'-Difluoro-[3,4'-Bipyridine]-6-carboxaldehyde At 20 °C, 5-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)pyridinecarboxaldehyde (1.64 g, 7.05 mmol), K3PO4 (2.25 g, 10.6 mmol), and Pd(dppf)Cl2 (258 mg, 0.35 mmol) were added 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). The mixture was stirred at 85 °C for 3 h. 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:EtOAc = 1:0 to 1:1) to give the title compound (0.70 g, 90%). LC-MS (M+H) + = 221.2.

[0126] Step 2: (R)-N-((3',5'-difluoro-[3,4'-bipyridine]-6-yl)methyl)-5,6,7,8-tetrahydroquinoline-8- amine 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-carboxaldehyde (0.65 g, 2.95 mmol) were added. The mixture was stirred at 20 °C for 1 h and then poured into saturated NaHCO3 (50 mL). The mixture 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 preparative HPLC to give the title compound (216 mg, 21%). LC-MS (M+H) + = 353.2.

[0127] Step 3: Ethyl 4-amino-1H-pyrrole-2-carboxylate Pd / C (10%, 5.2 g, 4.89 mmol) was added to a solution of ethyl 4-nitro-1H-pyrrole-2-carboxylate (9.0 g, 48.9 mmol) in MeOH (100 mL). The mixture was stirred at 25 °C for 12 h under hydrogen (15 psi). The mixture was filtered through a short diatomaceous earth pad. The filtrate was concentrated under vacuum to give the title compound (7 g, 93%). LCMS (M+H) + =155.2.

[0128] Step 4: 4-((tert-butoxycarbonyl)amino)-1H-pyrrole-2-carboxylic acid ethyl ester Boc₂O (14.9 g, 68.1 mmol) and Et₃N (13.8 g, 136 mmol) were added to a solution of ethyl 4-amino-1H-pyrrole-2-carboxylate (7.0 g, 45.4 mmol) in DCM (80 mL). The mixture was stirred at 25 °C for 1 h. The mixture was diluted with water (100 mL) and then extracted with DCM (50 mL x 3). The combined organic layers were 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:EtOAc = 1:0 to 1:1) to give the title compound (8.0 g, 69%). LCMS (M+Ht-Bu) + = 199.2.

[0129] Step 5: 5-Bromo-4-((tert-butoxycarbonyl)amino)-1H-pyrrole-2-carboxylic acid ethyl ester NBS (4.90 g, 27.5 mmol) was added to a solution of ethyl 4-((tert-butoxycarbonyl)amino)-1H-pyrrole-2-carboxylate (7.0 g, 27.5 mmol) in DCM (35 mL). The mixture was stirred at 25 °C for 2 h. The mixture was diluted with water (50 mL) and then extracted with DCM (30 mL x 3). The combined organic layers were 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:EtOAc = 5:1) to give the title compound (6.0 g, 65%). LCMS (M+H-tBu) + = 277.1.

[0130] Step 6: 4-Cyano-2,5-dihydrofuran-3-yltrifluoromethanesulfonate DIPEA (14.0 g, 108 mmol) and Tf₂O (25.4 g, 90.0 mmol) were added to a solution of 4-oxotetrahydrofuran-3-carboxynitrile (10.0 g, 90.0 mmol) in DCM (100 mL) at -78 °C, and the mixture was stirred at -78 °C for 1 h. The reaction mixture was diluted with water (100 mL), heated to room temperature, and then extracted with DCM (50 mL x 3). The combined organic layers were 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:EtOAc = 1:0 to 3:1) to give the title compound (10.0 g, 46%). 1 H NMR (400MHz, CDCl3) δ 4.95-4.60 (m, 4H).

[0131] Step 7: 4-((tert-butoxycarbonyl)amino)-5-(4-cyano-2,5-dihydrofuran-3-yl)-1H-pyrrole-2- Ethyl formate and 5-amino-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid ethyl ester and 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 to a solution of ethyl 5-bromo-4-((tert-butoxycarbonyl)amino)-1H-pyrrole-2-carboxylate (13.0 g, 39.0 mmol) and BPD (19.8 g, 78.0 mmol) in THF (200 mL). The mixture was stirred at 75 °C for 3 h and cooled to room temperature. The solid was filtered off and the filtrate was concentrated under vacuum. The crude product was redissolved in dioxane (150 mL) and water (30 mL), followed by the addition of 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). The mixture was degassed and purged three times with nitrogen, and then stirred at 80 °C for 12 h. The mixture was cooled to room temperature, diluted with water (400 mL), and extracted with EtOAc (300 mL × 3). The combined organic layers were washed with brine (100 mL x 2), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (PE / EtOAc = 1 / 0 to 3 / 1) to give the following compounds: 4-((tert-butoxycarbonyl)amino)-5-(4-cyano-2,5-dihydrofuran-3-yl)-1H-pyrrole-2-carboxylic acid ethyl ester (7.0 g, 52%). LCMS (M+H- t -Bu) + = 292.1.

[0132] 5-Amino-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid ethyl ester (2.0 g, 21%). LCMS (M+H) + = 248.2.

[0133] Step 8: 5-Amino-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid methyl ester At 25 °C, HCl (3 M, 10 mL) in MeOH was added to ethyl 4-((tert-butoxycarbonyl)amino)-5-(4-cyano-2,5-dihydrofuran-3-yl)-1H-pyrrole-2-carboxylate (0.70 g, 2.02 mmol) and stirred for 1 h. 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 h, 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 / EtOAc = 2 / 1 to 3 / 1, then EtOAc / MeOH = 5 / 1) to give 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.

[0134] Step 9: 5-Amino-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid LiOH was added to a solution of methyl 5-amino-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid (0.40 g, 1.72 mmol) in THF (4 mL), MeOH (0.8 mL), and water (0.8 mL). .H2O (108 mg, 2.57 mmol). The mixture was stirred at 45 °C for 4 h and then cooled to room temperature. The mixture was diluted with H2O (10 mL) and then washed with EtOAc (15 mL x 3). The aqueous phase was lyophilized to give the residue. The residue was purified by preparative HPLC to give the title compound (80 mg, 21%). LCMS (M+H) + = 220.1.

[0135] Step 10: (R)-5-amino-N-((3',5'-difluoro-[3,4'-bipyridin]-6-yl)methyl)-N-(5,6,7,8- Tetrahydroquinolino-8-yl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide DIPEA (0.25 mL, 1.35 mmol) and HATU (171 mg, 0.45 mmol) were added to a solution of 5-amino-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid (100 mg, 0.45 mmol) and (R)-N-((3',5'-difluoro-[3,4'-bipyridin]-6-yl)methyl)-5,6,7,8-tetrahydroquinoline-8-amine (158 mg, 0.45 mmol) in DMF (2 mL). The mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with water (5 mL) and then extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (5 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 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.

[0136] Example 2: (R)-5-amino-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinolin-8-yl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridin-2-carboxamide Step 1: 5-(2,6-difluorophenyl)pyridinecarboxaldehyde Pd(dppf)Cl2 (9.73 g, 13.3 mmol) and K3PO4 (141 g, 665 mmol) were added to a mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)pyridinecarboxaldehyde (62 g, 266 mmol) and 1,3-difluoro-2-iodobenzene (95.8 g, 399 mmol) in dioxane (600 mL), toluene (300 mL), and water (300 mL). The mixture was stirred at 85 °C for 16 h, cooled to room temperature, and poured into water (1000 mL). The organic layers were separated. The aqueous phase was extracted with EtOAc (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:EtOAc = 50:1 to 5:1) to give the title compound (30 g, 51%). LC-MS (M+H) + =220.2.

[0137] Step 2: (R)-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinoline-8-amine 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)pyridinecarboxaldehyde (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 h and quenched with saturated NaHCO3 (50 mL). The organic layers were 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:EtOAc = 1:0 to 0:1) to give the title compound (582 mg, 18%). LC-MS (M+H) + =352.1.

[0138] Step 3: (R)-5-amino-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-N-(5,6,7,8-tetrahydro)Quinolino-8-yl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide DIPEA (53 mg, 0.41 mmol) and BOPCl (52 mg, 0.20 mmol) were added to a solution of 5-amino-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid (30 mg, 0.14 mmol) and (R)-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinoline-8-amine (48 mg, 0.14 mmol) in THF (1 mL). The mixture was stirred at 25 °C for 12 h. The mixture was diluted with water (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine (5 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give Example 2 (13 mg, 17%). 1 H 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.

[0139] Example 3: 5-amino-N,N-bis(2,6-difluorobenzyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Step 1: Bis(2,6-difluorobenzyl)amine At 0 °C, NaBH(OAc)3 (2 mmol, 422 mg) was added fractionally to a solution of 2,6-difluorobenzaldehyde (142 mg, 1.0 mmol) and (2,6-difluorophenyl)methylamine (143 mg, 1.0 mmol) in DCM (15 mL). The mixture was heated to room temperature and stirred for 1 h. The reaction was quenched by saturated NaHCO3 (10 mL). The organic layers were separated, and the aqueous layer was extracted with EtOAc (30 mL x 2). The combined organic layers were concentrated under reduced pressure to give the title compound (256 mg, 95%). LC-MS (M+H) + = 270.1.

[0140] Step 2: 5-Amino-N,N-bis(2,6-difluorobenzyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3, [2-b]pyridine-2-carboxamide DIPEA (0.4 mL, 2.25 mmol) and BOPCl (171 mg, 0.67 mmol) were added to a solution of 5-amino-6,8-dihydro-1H-furano[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) in THF (4 mL). The mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with water (5 mL) and then extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (5 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 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.

[0141] Example 4: 5-amino-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-N-((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridin-2-carboxamide Step 1: (3R,4R)-3-(((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)amino)tetrahydro-2H-pyran- 4-ol At 0 °C, NaBH(OAc)3 (430 mg, 2.03 mmol) was added to a solution of (3R,4R)-3-aminotetrahydro-2H-pyran-4-ol (120 mg, 1.02 mmol) and 5-(2,6-difluorophenyl)pyridinecarboxaldehyde (224 mg, 1.02 mmol) in DCM (10 mL). The mixture was heated to room temperature and stirred for 2 h. The mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (PE / EtOAc = 1 / 1) to give the title compound (200 mg, 61%). LCMS (M+H) + = 321.1.

[0142] Step 2: ((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)((3R,4R)-4-hydroxytetrahydro-2H-pyran-3- tert-butyl carbamate Add Boc₂O (164 mg, 0.75 mmol) and Et₃N (188 mg, 1.86 mmol) to a solution of (3R,4R)-3-(((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)amino)tetrahydro-2H-pyran-4-ol (200 mg, 0.62 mmol) in DCM (10 mL). Stir the mixture overnight at room temperature. Concentrate the mixture under reduced pressure, and purify the residue by silica gel chromatography (PE / EtOAc = 2 / 1) to give the title compound (230 mg, 88%). LCMS (M+H) + = 421.1.

[0143] Step 3: ((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)((3R,4R)-4-methoxytetrahydro-2H-pyran- 3-yl)tert-butyl carbamate At 0 °C, NaH (60%, 29 mg, 0.72 mmol) was added to a mixture of ((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)((3R,4R)-4-hydroxytetrahydro-2H-pyran-3-yl)carbamate tert-butyl ester (230 mg, 0.55 mmol) and MeI (78 mg, 0.55 mmol) in DMF (10 mL). The mixture was stirred at room temperature under nitrogen for 5 h. The mixture was diluted with ice water (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / EtOAc = 2 / 1) to give the title compound (230 mg, 96%). LCMS (M+H) + = 435.1.

[0144] Step 4: (3R,4R)-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-4-methoxytetrahydro-2H-pyridyl 3-Aminohydrochloride A mixture of ((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)carbamate tert-butyl ester (230 mg, 0.53 mmol) in HCl (4 M in MeOH, 5 mL) was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure to give the title compound (180 mg, 92%). LCMS (M+H) + =335.1.

[0145] Step 5: 5-Amino-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-N-((3R,4R)-4-methoxy Tetrahydro-2H-pyran-3-yl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide A mixture of 5-amino-6,8-dihydro-1H-furano[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 h. Volatile substances were removed under vacuum, and the residue was redissolved in DCM (10 mL). At 0 °C, (3R,4R)-N-((5-(2,6-difluorophenyl)pyridin-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. The mixture was stirred for 1 h and then diluted with DCM (20 mL). The mixture was washed successively 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) and then by preparative HPLC to give Example 4 (11 mg, 5%). 1 H NMR (500 MHz, DMSO- d6 ) δ11.58 (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.

[0146] Example 5: (R)-5-amino-N-(2,6-difluorobenzyl)-N-(5,6,7,8-tetrahydroquinolin-8-yl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Step 1: (R)-N-(2,6-difluorobenzyl)-5,6,7,8-tetrahydroquinoline-8-amine To a mixture of (R)-5,6,7,8-tetrahydroquinoline-8-amine (355 mg, 2.4 mmol) and 2,6-difluorobenzaldehyde (284 mg, 2.0 mmol) in DCM (10 mL), NaBH(OAc)3 (848 mg, 4.0 mmol) was added and the mixture was stirred at room temperature for 2 h. The mixture was diluted with DCM (30 mL) 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 give the title compound (500 mg, 91%). LC-MS (M+H) + = 275.2.

[0147] Step 2: (R)-5-amino-N-(2,6-difluorobenzyl)-N-(5,6,7,8-tetrahydroquinolin-8-yl)-6,8-dihydro- 1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 5 (2 mg, 2%) was prepared from 5-amino-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and (R)-N-(2,6-difluorobenzyl)-5,6,7,8-tetrahydroquinoline-8-amine in a manner similar to that in Example 2 and 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 (s, 2H), 5.23 –5.04 (m, 2H), 4.91 (s, 2H), 4.74 (s, 1H), 2.79 – 2.64 (m, 3H), 2.24 -1.71 (m, 3H). LC-MS(M+H) + =476.2.

[0148] Example 6: (R)-5-amino-N-(5,6,7,8-tetrahydroquinolin-8-yl)-N-((2',3,6'-trifluoro-[1,1'-biphenyl]-4-yl)methyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Step 1: 2',3,6'-Trifluoro-[1,1'-Biphenyl]-4-carboxaldehyde 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 and then cooled to room temperature under nitrogen atmosphere at 100 °C. The mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc = 10 / 1) to give the title compound (520 mg, 73%). LC-MS (M+H) + = 237.1.

[0149] Step 2: (R)-N-((2',3,6'-trifluoro-[1,1'-biphenyl]-4-yl)methyl)-5,6,7,8-tetrahydroquinoline- 8-amine The title compound (282 mg, 76%) was prepared from 2',3,6'-trifluoro-[1,1'-biphenyl]-4-carboxaldehyde and (R)-5,6,7,8-tetrahydroquinoline-8-amine in a manner similar to that in Example 5, Step 1. LC-MS (M+H) + = 369.3.

[0150] Step 3: (R)-5-amino-N-(5,6,7,8-tetrahydroquinolin-8-yl)-N-((2',3,6'-trifluoro-[1,1'-bi) [Phenyl]-4-yl)methyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 6 (2 mg, 4%) was prepared from 5-amino-6,8-dihydro-1H-furano[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 in a manner similar to that in Example 2 and 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.

[0151] Example 7: 5-Amino-N,N-bis((3-fluoropyridin-2-yl)methyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Step 1: Bis((3-fluoropyridin-2-yl)methyl)amine The title compound (200 mg, 87%) was prepared from 3-fluoropyridinecarboxaldehyde and (3-fluoropyridine-2-yl)methylamine in a manner similar to that in Example 5, Step 1. LC-MS (M+H) + = 236.2.

[0152] Step 2: 5-Amino-N,N-bis((3-fluoropyridin-2-yl)methyl)-6,8-dihydro-1H-furano[3,4-d]pyridine Pyrro[3,2-b]pyridine-2-carboxamide Example 7 (5 mg, 11%) was prepared from 5-amino-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and bis((3-fluoropyridin-2-yl)methyl)amine in a manner similar to that in Example 2 and Step 3. 1 H NMR (500MHz, 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.

[0153] Example 8: 5-amino-N-(2,6-difluorobenzyl)-N-(1-methoxypropyl-2-yl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Step 1: N-(2,6-difluorobenzyl)-1-methoxypropyl-2-amine The title compound (150 mg, 49%) was prepared from 2,6-difluorobenzaldehyde and 1-methoxypropyl-2-amine in a manner similar to that in Example 5, Step 1. LC-MS (M+H) + = 216.1.

[0154] Step 2: 5-Amino-N-(2,6-difluorobenzyl)-N-(1-methoxypropyl-2-yl)-6,8-dihydro-1H-furano [3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 8 (4 mg, 7%) was prepared from 5-amino-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and N-(2,6-difluorobenzyl)-1-methoxypropyl-2-amine in a manner similar to that in Example 2 and 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 = 2.7Hz, 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.

[0155] Example 9: 5-amino-N-(2,6-difluorobenzyl)-N-(1,3-dimethoxypropyl-2-yl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 9 (2 mg, 4%) was prepared in a manner similar to that in Example 2 and 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, 2H), 5.11 (s, 2H), 4.92 (d, J = 2.7 Hz, 2H), 4.80 (s, 2H), 3.64 – 3.58 (m, 2H), 3.49 – 3.44 (m, 2H), 3.15 (s, 6H). LC-MS(M+H) + = 447.1.

[0156] Example 10: (R)-5-amino-N-((3,5-difluoropyridin-4-yl)methyl)-N-(5,6,7,8-tetrahydroquinolin-8-yl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 10 (1 mg, 1%) was prepared in a manner similar to that in Example 2 and 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.

[0157] Example 11: (R)-5-amino-N-((3'-cyano-[3,4'-bipyridin]-6-yl)methyl)-N-(5,6,7,8-tetrahydroquinolin-8-yl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Step 1: 6-Formyl-[3,4'-Bipyridine]-3'-Carboxynitrile The title compound (160 mg, 26%) was prepared from 5-bromopyridinecarboxaldehyde and 4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)nicotinonitrile in a manner similar to that in Example 6, Step 1. LC-MS (M+H) + = 210.1.

[0158] Step 2: (R)-6-(((5,6,7,8-tetrahydroquinoline-8-yl)amino)methyl)-[3,4'-bipyridine]-3'-carboxynitrile The title compound (88 mg, 64%) was prepared from 6-formyl-[3,4'-bipyridine]-3'-carboxynitrile and (R)-5,6,7,8-tetrahydroquinoline-8-amine in a manner similar to that in Example 5, Step 1. LC-MS (M+H) + = 342.2.

[0159] Step 3: (R)-5-amino-N-((3'-cyano-[3,4'-bipyridin]-6-yl)methyl)-N-(5,6,7,8-tetrahydro) Quinolino-8-yl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 11 (8 mg, 14%) was prepared from 5-amino-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and (R)-6-(((5,6,7,8-tetrahydroquinolino-8-yl)amino)methyl)-[3,4'-bipyridine]-3'-carboxynitrile in a manner similar to that in Example 2 and Step 3. 1 H 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.

[0160] Example 12: 5-amino-N-(chroman-4-yl)-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Step 1: N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)chroman-4-amine The title compound (400 mg, 85%) was prepared from chroman-4-amine and 5-(2,6-difluorophenyl)pyridinecarboxaldehyde in a manner similar to that in Example 5, Step 1. LC-MS (M+H) + = 353.2.

[0161] Step 2: 5-Amino-N-(chroman-4-yl)-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-6,8-di Hydrogen-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 12 (7 mg, 8%) was prepared from 5-amino-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)som-4-amine in a manner similar to that in Example 2 and 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.

[0162] Example 13: 5-amino-N-(2,6-difluorobenzyl)-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridin-2-carboxamide Step 1: 1-(tert-butyl)-2-ethyl-5-(bis(tert-butoxycarbonyl)amino)-6,8-dihydro-1H-furano [3,4-d]pyrrolo[3,2-b]pyridine-1,2-dicarboxylate Boc₂O (5.3 g, 24.3 mmol), DMAP (99 mg, 0.81 mmol), and Et₃N (3.28 g, 16.2 mmol) were added to a solution of 5-amino-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid ethyl ester (2.0 g, 8.09 mmol) in THF (40 mL). The mixture was stirred at 45 °C for 12 h and then cooled to room temperature. The mixture was diluted with water (30 mL) and extracted with EtOAc (15 mL x 3). The combined organic layers were 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 / EtOAc = 1:0 to 3:1) to give the title compound (2.4 g, 54%). LC-MS (M+H) + = 548.4.

[0163] Step 2: 5-((tert-butoxycarbonyl)amino)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b] Pyridine-2-carboxylic acid LiOH was added to a solution of 1-(tert-butyl)2-ethyl 5-(bis(tert-butoxycarbonyl)amino)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-1,2-dicarboxylate (2.4 g, 4.38 mmol) in THF (20 mL), MeOH (4 mL), and water (4 mL). . H₂O (221 mg, 5.26 mmol). The mixture was stirred at 45 °C for 12 h. The mixture was cooled to room temperature and diluted with water (10 mL). The mixture was washed with EtOAc (15 mL x 3). Aqueous HCl (0.5 M) was carefully added to the aqueous phase until its pH reached 4–5. The solid was collected by filtration to give the title compound (0.90 g, 49%). LC-MS (M+H) + = 320.2.

[0164] Step 3: N-(2,6-difluorobenzyl)-1-(5-(2,6-difluorophenyl)pyridin-2-yl)methylamine The title compound (260 mg, 55%) was prepared from 5-(2,6-difluorophenyl)pyridinecarboxaldehyde and (2,6-difluorophenyl)methylamine in a manner similar to that in Example 5, Step 1. LC-MS (M+H) + = 347.2.

[0165] Step 4: (2-((2,6-difluorobenzyl)((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)carbamoyl)- 6,8-Dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridin-5-yl)tert-butyl carbamate At 25 °C, BOPCl (62 mg, 0.20 mmol) and DIPEA (78 mg, 0.61 mmol) were added to a solution of N-(2,6-difluorobenzyl)-1-(5-(2,6-difluorophenyl)pyridin-2-yl)methylamine (70 mg, 0.20 mmol) and 5-((tert-butoxycarbonyl)amino)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridin-2-carboxylic acid (65 mg, 0.20 mmol) in THF (3 mL). The mixture was stirred at 40 °C for 1 h. The mixture was cooled to room temperature and diluted with water (5 mL). The mixture was extracted with EtOAc (5 mL × 4). The combined organic layers were washed with brine (5 mL x 2), dried over Na2SO4, filtered, and concentrated under vacuum to give the title compound (85 mg, 66%). LC-MS (M+H) + = 648.3.

[0166] Step 5: 5-Amino-N-(2,6-difluorobenzyl)-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-6, 8-Dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide A mixture of (2-((2,6-difluorobenzyl)((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)carbamoyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridin-5-yl)carbamate (85 mg, 0.13 mmol) in methanol-HCl (3 M, 3 mL) was stirred at 25 °C for 1 h and then concentrated under reduced pressure. The residue was purified by preparative HPLC to give 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 (brs, 3H). LC-MS (M+H) + = 548.2.

[0167] 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-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Step 1: (3R,4R)-3-(((2',3,6'-trifluoro-[1,1'-biphenyl]-4-yl)methyl)amino)tetrahydro-2H- pyran-4-ol 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-carboxaldehyde in a manner similar to that in Example 4, Step 1. LC-MS (M+H) + =338.2.

[0168] Step 2: ((3R,4R)-4-hydroxytetrahydro-2H-pyran-3-yl)((2',3,6'-trifluoro-[1,1'-biphenyl]- 4-yl)methyl)tert-butyl carbamate 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 in a manner similar to that in Example 4, Step 2. LC-MS (M+H) + =438.3.

[0169] Step 3: ((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)((2',3,6'-trifluoro-[1,1'-biphenyl)) 4-yl)methyl)tert-butyl carbamate 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 ester in a manner similar to that in Example 4, Step 3. LC-MS (M+H)+ = 452.3.

[0170] Step 4: (3R,4R)-4-methoxy-N-((2',3,6'-trifluoro-[1,1'-biphenyl]-4-yl)methyl)tetrahydro- 2H-pyran-3-amine hydrochloride The title compound (510 mg, 99%) was prepared from ((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)((2',3,6'-trifluoro-[1,1'-biphenyl]-4-yl)methyl)carbamate tert-butyl ester in a manner similar to that in Example 4, Step 4. LC-MS (M+H) + =352.2.

[0171] Step 5: (2-(((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)((2',3,6'-trifluoro-[1,1'-bi)) [Phenyl]-4-yl)methyl)carbamoyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridin-5-yl) tert-butyl carbamate 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-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid in a manner similar to that in Example 13, step 4. LC-MS (M+H) + =653.4.

[0172] 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-furano[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-furano[3,4-d]pyrrolo[3,2-b]pyridin-5-yl)tert-butyl carbamate (15 mg, 0.020 mmol) in HCl (4 M, 2 mL) in dioxane was stirred at room temperature for 1 h, and then concentrated under vacuum. The residue was purified by preparative HPLC to give Example 14 (2 mg, 19%). 1 HNMR (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.

[0173] 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-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Step 1: (3R,4R)-N-((3',5'-difluoro-[3,4'-bipyridine]-6-yl)methyl)-4-methoxytetrahydro- 2H-pyran-3-amine 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-carboxaldehyde in a manner similar to that in Example 4, Step 1. LC-MS (M+H) + = 336.2.

[0174] Step 2: 5-Amino-N-((3',5'-difluoro-[3,4'-bipyridine]-6-yl)methyl)-N-((3R,4R)-4-methyl (k-2H-pyran-3-yl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 15 (1 mg, 5%) was prepared from 5-amino-6,8-dihydro-1H-furano[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 in a manner similar to that in Example 2 and 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.

[0175] Example 16: 5-amino-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-N-(1,3-dimethoxypropyl-2-yl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridin-2-carboxamide Step 1: N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-1,3-dimethoxypropyl-2-amine The title compound (0.20 g, 76%) was prepared from 1,3-dimethoxyprop-2-one and (5-(2,6-difluorophenyl)pyridin-2-yl)methylamine in a manner similar to that in Example 5, Step 1. 1 H NMR (400 MHz, DMSO- d6 ) δ 8.57 (s, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.60-7.48 (m, 2H), 7.32-7.22 (m, 2H), 3.94 (s,2H), 3.34 (d, J = 5.6 Hz, 4H), 3.24 (s, 6H), 2.89 (quin, J = 5.6 Hz, 1H). LC-MS (M+H)+ = 323.2.

[0176] Step 2: (2-(((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)(1,3-dimethoxypropyl-2-yl)amino (formyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridin-5-yl) tert-butyl carbamate The title compound (40 mg, 30%) was prepared from 5-((tert-butoxycarbonyl)amino)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-1,3-dimethoxypropyl-2-amine in a manner similar to that in Example 13, step 4. LC-MS (M+H) + = 624.3.

[0177] Step 3: 5-Amino-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-N-(1,3-dimethoxypropyl-2-yl) 6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 16 (1 mg, 5%) was prepared from tert-butyl carbamate (2-(((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)(1,3-dimethoxypropyl-2-yl)carbamoyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridin-5-yl)carbamate in a manner similar to that 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.

[0178] Examples 17 and 18: (S)-5-amino-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-N-(1-(pyrimidin-2-yl)ethyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide and (R)-5-amino-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-N-(1-(pyrimidin-2-yl)ethyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide and Step 1: N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-1-(pyrimidin-2-yl)ethyl-1-amine NaBH(OAc)3 (192 mg, 0.91 mmol) was added to a solution of (5-(2,6-difluorophenyl)pyridin-2-yl)methylamine (0.10 g, 0.45 mmol) and 1-(pyrimidin-2-yl)ethyl-1-one (55 mg, 0.45 mmol) in DCM (2.7 mL) and MeOH (0.9 mL). The mixture was stirred at 20 °C for 1 h. Saturated NaHCO3 (10 mL) was added, and the mixture was extracted with DCM (2 mL x 4). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (PE / EtOAc = 1 / 0 to 0 / 1) to give the title compound (70 mg, 47%). LC-MS (M+H) + = 327.3.

[0179] Step 2: (2-(((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)(1-(pyrimidin-2-yl)ethyl)aminomethyl Acyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridin-5-yl) tert-butyl carbamate BOPCl (82 mg, 0.32 mmol) and DIPEA (139 mg, 1.07 mmol) were added to a solution of N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-1-(pyrimidin-2-yl)ethyl-1-amine (70 mg, 0.21 mmol) and 5-((tert-butoxycarbonyl)amino)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid (72 mg, 0.23 mmol) in THF (1 mL) and DMF (0.5 mL). The mixture was stirred at 40 °C for 1 h. The mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by silica gel chromatography (PE / EtOAc = 3 / 1 to 0 / 1) to give the title compound (50 mg, 37%). LC-MS (M+H) + = 628.3.

[0180] Step 3: (S)-5-amino-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-N-(1-(pyrimidin-2-yl) (Ethyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide and (R)-5-amino-N-((5- (2,6-Difluorophenyl)pyridin-2-yl)methyl)-N-(1-(pyrimidin-2-yl)ethyl)-6,8-dihydro-1H-furano[3,4-d] Pyrrolo[3,2-b]pyridine-2-carboxamide A solution of tert-butyl (2-(((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)(1-(pyrimidin-2-yl)ethyl)carbamoyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridin-5-yl)carbamate (50 mg, 0.080 mol) in methanol-HCl (4 M, 0.50 mL) was stirred at 20 °C for 12 h and then concentrated under vacuum. The residue was purified by preparative HPLC and then by preparative SFC to give Example 17 (10 mg, 24%) and Example 18 (7 mg, 17%).

[0181] The analytical chiral SFC conditions are as follows: Column: Chiralcel OJ-3; Column size: 4.6 x 50 mm, 3 μm; Mobile phase: A: CO2, B: 14 mM NH3 in MeOH; 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℃.

[0182] Example 17: Analytical 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.

[0183] Example 18: Analytical 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.

[0184] Examples 19 and 20: (R)-5-amino-N-(3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-N-((2',3,6'-trifluoro-[1,1'-biphenyl]-4-yl)methyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide and (S)-5-amino-N-(3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-N-((2',3,6'-trifluoro-[1,1'-biphenyl]-4-yl)methyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide and Step 1: N-((2',3,6'-trifluoro-[1,1'-biphenyl]-4-yl)methyl)-3,4-dihydro-2H-pyrano[3, 2-b]pyridine-4-amine To a mixture of 3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-amine (330 mg, 2.2 mmol) and 2',3,6'-trifluoro-[1,1'-biphenyl]-4-carboxaldehyde (470 mg, 2.0 mmol) in DCM (20 mL), NaBH(OAc)3 (848 mg, 4.0 mmol) was added, and the mixture was stirred at room temperature for 2 h. The mixture was diluted with DCM (30 mL) and 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 give the title compound (620 mg, 83%). LC-MS (M+H) + = 371.4.

[0185] Step 2: (2-((3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)((2',3,6'-trifluoro-[1,1'-bi) [Phenyl]-4-yl)methyl)carbamoyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridin-5-yl) tert-butyl carbamate The title compound (140 mg, 83%) was prepared from 5-((tert-butoxycarbonyl)amino)-6,8-dihydro-1H-furano[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 in a manner similar to that in Examples 17 and 18, step 2. LC-MS (M+H) + = 672.4.

[0186] Step 3: (R)-5-amino-N-(3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-N-((2',3,6'- Trifluoro-[1,1'-biphenyl]-4-yl)methyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-methyl Amides and (S)-5-amino-N-(3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-N-((2',3,6'-trifluoro-[1, 1'-Biphenyl]-4-yl)methyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide To a solution of (2-((3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)((2',3,6'-trifluoro-[1,1'-biphenyl]-4-yl)methyl)carbamoyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridin-5-yl)carbamate (140 mg, 0.21 mmol) in DCM (3 mL), HCl (4 M, 8 mL) in dioxane 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 give Example 19 (19 mg, 16%) and Example 20 (18 mg, 15%).

[0187] The analytical chiral-HPLC conditions are as follows: Column: CHIRALPAK OD-H; Column size: 4.6 x 150 mm, 5 μm; Mobile phase: hexane: (0.1% diethylamine in EtOH) = 9:1 isocratic; Flow rate: 1.0 mL / min; Temperature: 25 °C.

[0188] Example 19: Analytical chiral-HPLC tR = 18.65 min. 1 H NMR (500 MHz, DMSO- d6 ) δ13.02-12.68 (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.

[0189] Example 20: Analytical chiral-HPLC tR = 22.16 min. 1 H NMR (500 MHz, DMSO- d6 ) δ13.02-12.68 (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.

[0190] Example 21: (R)-5-amino-N-(4-cyano-2,6-difluorobenzyl)-N-(5,6,7,8-tetrahydroquinolin-8-yl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Step 1: (R)-3,5-difluoro-4-(((5,6,7,8-tetrahydroquinoline-8-yl)amino)methyl)benzonitrile The title compound (200 mg, 56%) was prepared from (R)-5,6,7,8-tetrahydroquinoline-8-amine and 3,5-difluoro-4-carboxybenzonitrile in a manner similar to that in Example 5, Step 1. LC-MS (M+H) + = 300.1.

[0191] Step 2: (R)-(2-((4-cyano-2,6-difluorobenzyl)(5,6,7,8-tetrahydroquinoline-8-yl)carbamoyl 6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridin-5-yl) tert-butyl carbamate The title compound (30 mg, 30%) was prepared from 5-((tert-butoxycarbonyl)amino)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and (R)-3,5-difluoro-4-(((5,6,7,8-tetrahydroquinolino-8-yl)amino)methyl)benzonitrile in a manner similar to that in Step 2 of Examples 17 and 18. LC-MS (M+H) + = 601.3.

[0192] Step 3: (R)-5-amino-N-(4-cyano-2,6-difluorobenzyl)-N-(5,6,7,8-tetrahydroquinoline-8-yl)-6, 8-Dihydro-1H-furano[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-furano[3,4-d]pyrrolo[3,2-b]pyridin-5-yl)carbamate in a manner similar to that 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.

[0193] Example 22: 5-amino-N-(4-cyano-2,6-difluorobenzyl)-N-(2,6-difluorobenzyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Step 1: 4-(((2,6-difluorobenzyl)amino)methyl)-3,5-difluorobenzonitrile To a mixture of 3,5-difluoro-4-carboxybenzonitrile (350 mg, 2.09 mmol) and (2,6-difluorophenyl)methylamine (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 h. The mixture was diluted with DCM (30 mL) and 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 give the title compound (370 mg, 60%). LC-MS (M+H) + = 295.2.

[0194] Step 2: (2-((4-cyano-2,6-difluorobenzyl)(2,6-difluorobenzyl)carbamoyl)-6,8-dihydro-1H- Furano[3,4-d]pyrrolo[3,2-b]pyridin-5-yl)tert-butyl carbamate The title compound (50 mg, 93%) was prepared from 5-((tert-butoxycarbonyl)amino)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and 4-(((2,6-difluorobenzyl)amino)methyl)-3,5-difluorobenzonitrile in a manner similar to that in Step 2 of Examples 17 and 18. LC-MS (M+H)+ = 596.3.

[0195] Step 3: 5-Amino-N-(4-cyano-2,6-difluorobenzyl)-N-(2,6-difluorobenzyl)-6,8-dihydro-1H-furyl Brno[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-furano[3,4-d]pyrrolo[3,2-b]pyridin-5-yl)carbamate (50 mg, 0.084 mmol) in HCl (4 M, 2 mL) in dioxane was stirred at room temperature for 3 h. The mixture was concentrated under vacuum. The residue was purified by preparative HPLC to give 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 = 1.7Hz, 1H), 5.60 (s, 2H), 5.24 – 5.07 (m, 2H), 5.08 – 4.67 (m, 6H). LC-MS(M+H) + =496.3.

[0196] Examples 23 and 24: (R)-5-amino-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-N-((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)-6-methyl-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide and (S)-5-amino-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-N-((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)-6-methyl-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide and Step 1: 2-Methyl-4-oxotetrahydrofuran-3-carboxynitrile Methyl glycolate (20.0 g, 0.222 mol) was added to a suspension of NaH (60%, 4.44 g, 0.11 mol) in THF (150 mL) at 0 °C. The mixture was stirred at 60 °C for 30 min. Crotonium (17.8 g, 0.266 mmol) was added dropwise in THF (50 mL) at 60 °C. The mixture was stirred at 70 °C for 2 h. 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 EtOAc (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 / EtOAc = 1 / 1) to give 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).

[0197] Step 2: 4-Cyano-5-methyl-2,5-dihydrofuran-3-yltrifluoromethanesulfonate Tf₂O (13.5 g, 48 mmol) was added dropwise to a mixture of 2-methyl-4-oxotetrahydrofuran-3-carboxynitrile (5.0 g, 40 mmol) and DIPEA (6.7 g, 52 mmol) in DCM (100 mL) at -78 °C, and the mixture was stirred at -78 °C for 2 h. The mixture was diluted with DCM (100 mL), washed successively 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 / EtOAc = 3 / 1) to give the title compound (8.5 g, 83%). 1 HNMR (500 MHz, CDCl3) δ 5.13-5.06 (m, 1H), 4.94 – 4.76(m, 2H), 1.49 (d, J = 6.3 Hz, 3H).

[0198] Step 3: 4-((tert-butoxycarbonyl)amino)-5-(4-cyano-5-methyl-2,5-dihydrofuran-3-yl)-1H- Ethyl pyrrole-2-carboxylate 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 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). The mixture was stirred at 75 °C for 3 h and cooled to room temperature. The solids were filtered off and the filtrate was concentrated under vacuum. The crude product 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 h. The mixture was cooled to room temperature and diluted with EtOAc (100 mL). The mixture was washed with brine (50 mL), and the aqueous layer was back-extracted with EtOAc (50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / EtOAc = 3 / 1) to give the title compound (2.0 g, 62%). LC-MS (M+H) + =362.1.

[0199] Step 4: 5-Amino-6-methyl-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid Ethyl ester Ethyl 4-((tert-butoxycarbonyl)amino)-5-(4-cyano-5-methyl-2,5-dihydrofuran-3-yl)-1H-pyrrole-2-carboxylate (2.0 g, 5.5 mmol) in dioxane (10 mL) was added to the solution and the mixture was stirred at room temperature for 5 h. The mixture was concentrated under reduced pressure, and the crude product 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 h 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 give the title compound (1.0 g, 69%). LC-MS (M+H) + = 262.1.

[0200] Step 5: 5-Amino-6-methyl-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid At 50 °C, 1.0 g (3.8 mmol) of 5-amino-6-methyl-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid ethyl ester and LiOH were reacted. . A mixture of H₂O (0.32 g, 7.6 mmol) in MeOH (20 mL) and water (10 mL) was stirred for 3 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (500 mg, 56%). LCMS (M+H) + = 234.1.

[0201] Step 6: (R)-5-amino-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-N-((3R,4R)-4-methyl (Oxytetrahydro-2H-pyran-3-yl)-6-methyl-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-methyl Amides and (S)-5-amino-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-N-((3R,4R)-4-methoxytetrahydro- 2H-pyran-3-yl)-6-methyl-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Under nitrogen atmosphere, HATU (832 mg, 2.19 mmol) was added to a mixture of 5-amino-6-methyl-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid (170 mg, 0.73 mmol), (3R,4R)-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-4-methoxytetrahydro-2H-pyran-3-amine hydrochloride (270 mg, 0.73 mmol), and DIPEA (471 mg, 3.65 mmol) in anhydrous DMF (5 mL), and the mixture was stirred at 70 °C for 2 h. The mixture was cooled to room temperature and diluted with EtOAc (20 mL). The mixture was washed with water (20 mL) and brine (20 mL). The aqueous layer was back-extracted with EtOAc (20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude products were purified by preparative HPLC and chiral SFC to give Example 23 (47 mg, 12%) and Example 24 (45 mg, 11%).

[0202] The analytical chiral-HPLC conditions were as follows: Column: CHIRALPAK IE-3; Column size: 4.6 x 50 mm, 3 μm; Mobile phase: (0.1% diethylamine in MTBE): MeOH: DCM = 3:1:1 isocratic; Flow rate: 1.0 mL / min; Temperature: 25 °C.

[0203] Example 23: Analytical chiral-HPLC tR = 2.26 min. 1 H NMR (500 MHz, DMSO- d6) δ11.92 – 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.

[0204] Example 24: Analytical chiral-HPLC tR = 2.97 min. 1 H NMR (500 MHz, DMSO- d6 ) δ11.90 – 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.

[0205] Example 25: (R)-5-amino-N-((5-(1-methyl-1H-1,2,4-triazol-5-yl)pyridin-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinolin-8-yl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridin-2-carboxamide Step 1: 2-(1,3-dioxolane-2-yl)-5-(1-methyl-1H-1,2,4-triazol-5-yl)pyridine To a mixture of (6-(1,3-dioxolane-2-yl)pyridin-3-yl)boronic acid (2.0 g, 10.3 mmol) 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 h and 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:EtOAc = 5:1 to 0:1) to give the title compound (1.3 g, 55%). LC-MS (M+H) + =233.3.

[0206] Step 2: 5-(1-Methyl-1H-1,2,4-triazol-5-yl)pyridinecarboxaldehyde Concentrated HCl (6.5 mL) was added to a mixture of 2-(1,3-dioxolane-2-yl)-5-(1-methyl-1H-1,2,4-triazol-5-yl)pyridine (1.2 g, 5.17 mmol) in water (6 mL) and dioxane (12 mL), and the mixture was stirred at 60 °C for 3 h. The mixture was cooled to room temperature and neutralized with saturated NaHCO3 until pH reached 7–8. The mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the title compound (0.60 g, 62%). LC-MS (M+H) + = 189.3.

[0207] Step 3: (R)-N-((5-(1-methyl-1H-1,2,4-triazol-5-yl)pyridin-2-yl)methyl)-5,6,7,8-tetra- Hydroquinoline-8-amine 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-triazol-5-yl)pyridinecarboxaldehyde in a manner similar to that in Example 5, Step 1. LC-MS (M+H) + = 321.1.

[0208] Step 4: (R)-(2-(((5-(1-methyl-1H-1,2,4-triazol-5-yl)pyridin-2-yl)methyl)(5,6,7,8- Tetrahydroquinoline-8-yl)carbamoyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridin-5-yl)amino tert-butyl carbamate The title compound (30 mg, 32%) was prepared from 5-((tert-butoxycarbonyl)amino)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and (R)-N-((5-(1-methyl-1H-1,2,4-triazol-5-yl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinoline-8-amine in a manner similar to that in Step 2 of Examples 17 and 18. LC-MS (M+H) + = 622.1.

[0209] Step 5: (R)-5-amino-N-((5-(1-methyl-1H-1,2,4-triazol-5-yl)pyridin-2-yl)methyl)-N- (5,6,7,8-Tetrahydroquinolin-8-yl)-6,8-dihydro-1H-furano[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-triazol-5-yl)pyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinoline-8-yl)carbamoyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridin-5-yl)carbamate tert-butyl ester in a manner similar to that in Example 22, step 3. 1 H NMR (500MHz, 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.

[0210] Example 26: 5-amino-N-((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Step 1: (3R,4R)-4-methoxy-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)tetrahydro-2H-pyran-3- amine The title compound (50 mg, 55%) was prepared from (3R,4R)-4-methoxytetrahydro-2H-pyran-3-amine and 5-(trifluoromethyl)pyridinecarboxaldehyde in a manner similar to that in Example 4, Step 1. LC-MS (M+H) + = 291.3.

[0211] Step 2: (2-(((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)((5-(trifluoromethyl)pyridin-2-yl) (Methyl)carbamoyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridin-5-yl)tert-butylcarbamate ester The title compound (60 mg, 59%) was prepared from 5-((tert-butoxycarbonyl)amino)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and (3R,4R)-4-methoxy-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)tetrahydro-2H-pyran-3-amine in a manner similar to that in Step 2 of Examples 17 and 18. LC-MS (M+H) + = 592.4.

[0212] Step 3: 5-Amino-N-((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)-N-((5-(trifluoromethyl)pyranyl) (P-2-yl)methyl)-6,8-dihydro-1H-furano[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)pyridin-2-yl)methyl)carbamoyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridin-5-yl)carbamate tert-butyl ester. 1 H 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.

[0213] Example 27: 5-amino-N-((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)-N-((5-phenylpyridin-2-yl)methyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Step 1: (3R,4R)-4-methoxy-N-((5-phenylpyridin-2-yl)methyl)tetrahydro-2H-pyran-3-amine The title compound (0.050 g, 58%) was prepared from 5-phenylpyridinecarboxaldehyde and (3R,4R)-4-methoxytetrahydro-2H-pyran-3-amine in a manner similar to that in Example 4, Step 1. LC-MS (M+H) + = 299.1.

[0214] Step 2: (2-(((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)((5-phenylpyridin-2-yl)methyl) tert-butyl carbamate (carbamoyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridin-5-yl)carbamate The title compound (60 mg, 57%) was prepared from 5-((tert-butoxycarbonyl)amino)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and (3R,4R)-4-methoxy-N-((5-phenylpyridin-2-yl)methyl)tetrahydro-2H-pyran-3-amine in a manner similar to that in Examples 17 and 18, step 2. LC-MS (M+H) + = 600.2.

[0215] Step 3: 5-Amino-N-((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)-N-((5-phenylpyridine-2-yl) (methyl)-6,8-dihydro-1H-furano[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-phenylpyridin-2-yl)methyl)carbamoyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridin-5-yl)carbamate tert-butyl ester in a manner similar to that in Example 22, step 3. ¹H NMR (500 MHz, DMSO- d6 ) δ11.57 (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.

[0216] Example 28: N-([3,4'-bipyridine]-6-ylmethyl)-5-amino-N-((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Step 1: [3,4'-Bipyridine]-6-carboxaldehyde The title compound (1.0 g, 100%) was prepared from 5-bromopyridinecarboxaldehyde and pyridine-4-ylboronic acid in a manner similar to that in Example 6, Step 1. LC-MS (M+H) + = 185.0.

[0217] Step 2: (3R,4R)-N-([3,4'-bipyridine]-6-ylmethyl)-4-methoxytetrahydro-2H-pyran-3-amine The title compound (40 mg, 29%) was prepared from [3,4'-bipyridine]-6-carboxaldehyde and (3R,4R)-4-methoxytetrahydro-2H-pyran-3-amine in a manner similar to that in Example 4, Step 1. LC-MS (M+H) + = 300.1.

[0218] Step 3: (2-(([3,4'-bipyridine]-6-ylmethyl)((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl) tert-butyl carbamate (carbamoyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridin-5-yl)carbamate The title compound (35 mg, 29%) was prepared from 5-((tert-butoxycarbonyl)amino)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and (3R,4R)-N-([3,4'-bipyridin]-6-ylmethyl)-4-methoxytetrahydro-2H-pyran-3-amine in a manner similar to that in Step 2 of Examples 17 and 18. LC-MS (M+H) + = 601.2.

[0219] Step 4: N-([3,4'-bipyridine]-6-ylmethyl)-5-amino-N-((3R,4R)-4-methoxytetrahydro-2H-pyridine) (3-yl)-6,8-dihydro-1H-furano[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-furano[3,4-d]pyrrolo[3,2-b]pyridin-5-yl)carbamate tert-butyl ester in a manner similar to that in Example 22, step 3. 1 H NMR (500 MHz, DMSO- d6) δ11.56 (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 = 9.7Hz, 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.

[0220] Example 29: N-([3,4'-bipyridine]-6-ylmethyl)-5-amino-N-(2,6-difluorobenzyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Step 1: 1-([3,4'-bipyridine]-6-yl)-N-(2,6-difluorobenzyl)methylamine The title compound (40 mg, 23%) was prepared from [3,4'-bipyridine]-6-carboxaldehyde and (2,6-difluorophenyl)methylamine in a manner similar to that in Example 3, Step 1. LC-MS (M+H) + = 312.1.

[0221] Step 2: (2-(([3,4'-bipyridine]-6-ylmethyl)(2,6-difluorobenzyl)carbamoyl)-6,8-dihydro- 1H-furano[3,4-d]pyrrolo[3,2-b]pyridin-5-yl)tert-butyl carbamate The title compound (20 mg, 26%) was prepared from 5-((tert-butoxycarbonyl)amino)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and 1-([3,4'-bipyridin]-6-yl)-N-(2,6-difluorobenzyl)methylamine in a manner similar to that in Examples 17 and 18, step 2. LC-MS (M+H) + = 613.2.

[0222] Step 3: N-([3,4'-bipyridine]-6-ylmethyl)-5-amino-N-(2,6-difluorobenzyl)-6,8-dihydro-1H- Furano[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-furano[3,4-d]pyrrolo[3,2-b]pyridin-5-yl)carbamate in a manner similar to that 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 = 8.0Hz, 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.

[0223] Example 30: 5-amino-N-((3',5'-difluoro-[3,4'-bipyridin]-6-yl)methyl)-N-(2,6-difluorobenzyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Step 1: 1-(3',5'-difluoro-[3,4'-bipyridine]-6-yl)-N-(2,6-difluorobenzyl)methylamine The title compound (130 mg, 75%) was prepared from 3',5'-difluoro-[3,4'-bipyridine]-6-carboxaldehyde and (2,6-difluorophenyl)methylamine in a manner similar to that in Example 3, Step 1. LC-MS (M+H) + = 348.2.

[0224] Step 2: 5-Amino-N-((3',5'-difluoro-[3,4'-bipyridine]-6-yl)methyl)-N-(2,6-difluorobenzyl) 6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 30 (15 mg, 27%) was prepared from 5-amino-6,8-dihydro-1H-furano[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)methylamine in a manner similar to that in Example 2 and 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.

[0225] Example 31: 5-amino-N-(2,6-dichlorobenzyl)-N-((3',5'-difluoro-[3,4'-bipyridin]-6-yl)methyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Step 1: N-(2,6-dichlorobenzyl)-1-(3',5'-difluoro-[3,4'-bipyridine]-6-yl)methylamine The title compound (140 mg, 74%) was prepared from 3',5'-difluoro-[3,4'-bipyridine]-6-carboxaldehyde and (2,6-dichlorophenyl)methylamine in a manner similar to that in Example 5, Step 1. LC-MS (M+H) + = 380.1 Step 2: 5-Amino-N-(2,6-dichlorobenzyl)-N-((3',5'-difluoro-[3,4'-bipyridine]-6-yl)methyl 6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 31 (14 mg, 24%) was prepared from 5-amino-6,8-dihydro-1H-furano[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)methylamine in a manner similar to that in Example 2 and 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.

[0226] Example 32: 5-amino-N-((5-cyanopyridin-2-yl)methyl)-N-(2,6-difluorobenzyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Step 1: 6-(((2,6-difluorobenzyl)amino)methyl)nicotinonitrile The title compound (260 mg, 100%) was prepared from (2,6-difluorophenyl)methylamine and 6-formylnicotinonitrile in a manner similar to that in Example 3, Step 1. LC-MS (M+H) + = 260.2.

[0227] Step 2: 5-Amino-N-((5-cyanopyridin-2-yl)methyl)-N-(2,6-difluorobenzyl)-6,8-dihydro-1H- Furano[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-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid in a manner similar to that in Example 2 and Step 3. 1 HNMR (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.

[0228] Example 33: 5-amino-N-(cyclopropylmethyl)-N-(2,6-difluorobenzyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Step 1: 1-Cyclopropyl-N-(2,6-Difluorobenzyl)methylamine The title compound (80 mg, 58%) was prepared from (2,6-difluorophenyl)methylamine and cyclopropaneformaldehyde in a manner similar to that in Example 3, Step 1. LC-MS (M+H) + = 198.3.

[0229] Step 2: 5-Amino-N-(cyclopropylmethyl)-N-(2,6-difluorobenzyl)-6,8-dihydro-1H-furano[3,4- d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 33 (9 mg, 16%) was prepared from 5-amino-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and 1-cyclopropyl-N-(2,6-difluorobenzyl)methylamine in a manner similar to that in Example 2 and 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.

[0230] Example 34: 5-amino-N-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)methyl)-N-((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridin-2-carboxamide Step 1: (3R,4R)-N-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)methyl)-4-methoxytetrahydro-2H-pyridine 3-amino nan- Triethylamine (575 mg, 5.7 mmol) was added to a mixture of 3-fluoro-5-(trifluoromethyl)pyridinecarboxaldehyde (1.0 g, 5.18 mmol) and (3R,4R)-4-methoxytetrahydro-2H-pyran-3-amine (747 mg, 5.7 mmol) in DCM (50 mL), and the mixture was stirred at room temperature for 10 min. NaBH(OAc)3 (2.2 g, 10.36 mmol) was added, and the mixture was stirred again at room temperature for 2 h. The mixture was quenched with saturated NaHCO3, diluted with DCM (40 mL), washed successively 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 give the title compound (1.3 g, 82%). LC-MS (M+H) + =309.2.

[0231] Step 2: (2-(((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)methyl)((3R,4R)-4-methoxytetrahydro-2H- Pyran-3-yl)carbamoyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridin-5-yl)carbamoyl tert-butyl ester The title compound (1.5 g, 58%) was prepared from 5-((tert-butoxycarbonyl)amino)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and (3R,4R)-N-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)methyl)-4-methoxytetrahydro-2H-pyran-3-amine in a manner similar to that in Example 13, step 4. LC-MS (M+H) + =610.3.

[0232] Step 3: 5-Amino-N-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)methyl)-N-((3R,4R)-4-methoxy Tetrahydro-2H-pyran-3-yl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 34 (970 mg, 77%) was prepared from (2-(((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)methyl)((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)carbamoyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridin-5-yl)carbamate tert-butyl ester in a manner similar to that 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.

[0233] Example 35: (R)-5-amino-N-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)methyl)-N-(1-(pyrimidin-2-yl)ethyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Step 1: (R)-N-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)methyl)-1-(pyrimidin-2-yl)ethyl-1-amine NaBH(OAc)3 (220 mg, 1.04 mmol) was added to a mixture of 3-fluoro-5-(trifluoromethyl)pyridinecarboxaldehyde (100 mg, 0.52 mmol) and (R)-1-(pyrimidin-2-yl)ethyl-1-amine dihydrochloride (122 mg, 0.62 mmol) in DCM (2 mL) and MeOH (0.2 mL). The mixture was stirred at 25 °C for 1 h and then quenched with a mixture of saturated NaHCO3 (5 mL) and water (5 mL). The mixture was extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (100 mg, 64%). LC-MS (M+H) + =301.1.

[0234] Step 2: (R)-(2-(((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)methyl)(1-(pyrimidin-2-yl)ethyl)amino 6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridin-5-yl) tert-butyl carbamate BOPCl (170 mg, 0.67 mmol) and DIPEA (129 mg, 1.0 mmol) were added to a mixture of (R)-N-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)methyl)-1-(pyrimidin-2-yl)ethyl-1-amine (100 mg, 0.33 mmol) and 5-((tert-butoxycarbonyl)amino)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid (106 mg, 0.33 mmol) in THF (5 mL). The mixture was stirred at 40 °C for 1 h and cooled to room temperature. The mixture was diluted with water (15 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (100 mg, 50%). LC-MS (M+H-Boc) + =502.3.

[0235] Step 3: (R)-5-amino-N-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)methyl)-N-(1-(pyrimidin-2-yl) (Hydroxy)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide HCl (4 M in MeOH, 1 mL, 4.0 mmol) was added to a solution of (R)-(2-(((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)methyl)(1-(pyrimidin-2-yl)ethyl)carbamoyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridin-5-yl)carbamate (100 mg, 0.167 mmol) in MeOH (1 mL). The mixture was stirred at 40 °C for 1 h and cooled to room temperature. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to give 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.

[0236] Example 36: 5-amino-N-((5-cyclopropylpyridin-2-yl)methyl)-N-((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Step 1: 5-Cyclopropylpyridine carboxaldehyde Cyclopropylboronic acid (550 mg, 6.46 mmol) was added to a mixture of 5-bromopyridinecarboxaldehyde (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). The mixture was stirred at 100 °C under nitrogen for 3 h, then cooled to room temperature. The mixture was diluted with EtOAc (100 mL), washed successively 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 give the title compound (450 mg, 57%). LC-MS (M+H) + =148.2.

[0237] Step 2: (3R,4R)-N-((5-cyclopropylpyridin-2-yl)methyl)-4-methoxytetrahydro-2H-pyran-3-amine The title compound (280 mg, 87%) was prepared from 5-cyclopropylpyridinecarboxaldehyde and (3R,4R)-4-methoxytetrahydro-2H-pyran-3-amine in a manner similar to that in Example 34, Step 1. LC-MS (M+H) + =263.3.

[0238] Step 3: (2-(((5-cyclopropylpyridin-2-yl)methyl)((3R,4R)-4-methoxytetrahydro-2H-pyran-3- (carbamoyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridin-5-yl)carbamate tert-butyl ester The title compound (90 mg, 42%) was prepared from 5-((tert-butoxycarbonyl)amino)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and (3R,4R)-N-((5-cyclopropylpyridin-2-yl)methyl)-4-methoxytetrahydro-2H-pyran-3-amine in a manner similar to that in Example 13, step 4. LC-MS (M+H) + =564.4.

[0239] Step 4: 5-Amino-N-((5-cyclopropylpyridin-2-yl)methyl)-N-((3R,4R)-4-methoxytetrahydro-2H- pyran-3-yl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 36 (43 mg, 58%) was prepared from (2-(((5-cyclopropylpyridin-2-yl)methyl)((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)carbamoyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridin-5-yl)carbamate tert-butyl ester in a manner similar to that in Example 14, step 6. 1 H NMR (400 MHz, DMSO-d6 ) δ11.51 (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.

[0240] Example 37: 5-amino-N-(2,6-difluorobenzyl)-N-((6-(trifluoromethyl)pyridazin-3-yl)methyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Step 1: 6-(trifluoromethyl)pyridazine-3-carboxaldehyde DIBAL-H (5.57 mL, 8.36 mmol) was added to a solution of 6-(trifluoromethyl)pyridazine-3-carboxyethyl ester (920 mg, 4.18 mmol) in DCM (10 mL) at -78 °C under nitrogen atmosphere. The mixture was stirred at -78 °C for 3 h. The mixture was poured into a saturated NH4Cl solution (100 mL) and extracted with DCM (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (350 mg, 48%). LC-MS (M+H) + =177.1.

[0241] Step 2: N-(2,6-difluorobenzyl)-1-(6-(trifluoromethyl)pyridazin-3-yl)methylamine The title compound (38 mg, 35%) was prepared from 6-(trifluoromethyl)pyridazine-3-carboxaldehyde and (2,6-difluorophenyl)methylamine in a manner similar to that in Example 5, Step 1. LC-MS (M+H) + = 304.3.

[0242] Step 3: 5-Amino-N-(2,6-difluorobenzyl)-N-((6-(trifluoromethyl)pyridazine-3-yl)methyl)-6,8-di Hydrogen-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 37 (18 mg, 28%) was prepared from 5-amino-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and N-(2,6-difluorobenzyl)-1-(6-(trifluoromethyl)pyridazin-3-yl)methylamine in a manner similar to that in Example 2 and 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.

[0243] Example 38: (R)-5-amino-N-((3-fluoropyridin-2-yl)methyl)-6-methyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Step 1: (S)-5-amino-6-methyl-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2- Ethyl formate and (R)-5-amino-6-methyl-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid Ethyl ester and A solution of HCl in dioxane (100 mL, 4 M) was added to a solution of 4-((tert-butoxycarbonyl)amino)-5-(4-cyano-5-methyl-2,5-dihydrofuran-3-yl)-1H-pyrrole-2-carboxylic acid ethyl ester (20 g, 55 mmol) in dioxane (100 mL), and the mixture was stirred at room temperature for 5 h. The mixture was concentrated under reduced pressure. The crude product 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 h, 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 give a racemic mixture (5.0 g). The materials were separated by SFC to give (S)-5-amino-6-methyl-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid ethyl ester (2.25 g, 16%) and (R)-5-amino-6-methyl-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid ethyl ester (2.34 g, 16%).

[0244] The analytical chiral SFC conditions are as follows: Column: CHIRALPAK IC-3; Column size: 3.0 x 100 mm, 3 μm; Mobile phase: 10 μM NH3 in methanol: CO2, 1:9 to 1:1 over 2 min, 1:1 for 1 min; Flow rate: 2.0 mL / min; Temperature: 35 °C; Back pressure: 1500 psi.

[0245] (S)-5-amino-6-methyl-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid ethyl ester: analytical SFC tR = 2.01 min. LC-MS (M+H) + = 262.1.

[0246] (R)-5-amino-6-methyl-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid ethyl ester: analytical SFC tR = 2.36 min. LC-MS (M+H) + = 262.1.

[0247] Step 2: (R)-5-amino-6-methyl-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2- Formic acid At 50 °C, (R)-5-amino-6-methyl-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid ethyl ester (1.5 g, 5.7 mmol) and LiOH were reacted. . A mixture of H₂O (0.32 g, 7.6 mmol) in MeOH (20 mL) and water (10 mL) was stirred for 3 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (1.2 g, 90%). LC-MS (M+H) + = 234.1.

[0248] Step 3: 1-(3-Fluoropyridin-2-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)methylamine The title compound (100 mg, 60%) was prepared from 5-(trifluoromethyl)pyridinecarboxaldehyde and (3-fluoropyridin-2-yl)methylamine in a manner similar to that in Example 5, Step 1. LC-MS (M+H) + = 286.2.

[0249] Step 4: (R)-5-amino-N-((3-fluoropyridin-2-yl)methyl)-6-methyl-N-((5-(trifluoromethyl)pyridin- 2-yl)methyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 38 (18 mg, 43%) was prepared from 1-(3-fluoropyridin-2-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)methylamine and (R)-5-amino-6-methyl-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid in a manner similar to that in Example 2 and 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.

[0250] Examples 39 and 40: (R)-5-amino-N-methyl-N-(7-(trifluoromethyl)isochroman-4-yl)-6,8-dihydro-1H-furano[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-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide and Step 1: 2-((allyloxy)methyl)-1-bromo-4-(trifluoromethyl)benzene At 0 °C, over a 1-hour period, NaH (60%, 941 mg, 23.5 mmol) was added to a solution of (2-bromo-5-(trifluoromethyl)phenyl)methanol (5.0 g, 19.6 mmol) in THF (100 mL). Allyl bromide (3.08 g, 25.5 mmol) was added dropwise at 0 °C. The mixture was stirred at room temperature for 11 h. The mixture was diluted with water (100 mL). The mixture was extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / EtOAc = 1 / 0 to 10 / 1) to give the title compound (8.0 g, 69%). 1 H 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).

[0251] Step 2: 4-Methylene-7-(trifluoromethyl)isocyanate 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 and purged three times with nitrogen, and the mixture was stirred at 90 °C for 12 h. The mixture was cooled to room temperature and diluted with water (100 mL). The mixture was extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / EtOAc = 1 / 0 to 5 / 1) to give 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).

[0252] Step 3: 7-(trifluoromethyl)isochroman-4-one Potassium osmium (VI) dihydrate (843 mg, 2.29 mmol), 2,6-dimethylpyridine (4.90 g, 45.8 mmol), and sodium periodate (19.6 g, 91.5 mmol) were added to a solution of 4-methylene-7-(trifluoromethyl)isocyanate (4.9 g, 22.9 mmol) in dioxane (100 mL) and water (20 mL). The mixture was stirred at 25 °C for 2 h. The mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / EtOAc = 1 / 0 to 5 / 1) to give 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).

[0253] Step 4: 7-(trifluoromethyl)isochroman-4-one oxime Hydroxylamine hydrochloride (804 mg, 11.6 mmol) and pyridine (5.4 mL) were added to a solution of 7-(trifluoromethyl)isocyano-4-one (500 mg, 2.32 mmol) in MeOH (10 mL). The mixture was stirred at 65 °C for 1 h and then cooled to room temperature. The mixture was concentrated under reduced pressure and diluted with water (10 mL). Aqueous HCl (1 M) was added until pH reached 5. The mixture was extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / EtOAc = 1 / 0 to 3 / 1) to give the title compound (500 mg, 94%). 1 H 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).

[0254] Step 5: 7-(trifluoromethyl)isochroman-4-amine Under nitrogen atmosphere, Raney nickel (371 mg) was added to a solution of 7-(trifluoromethyl)isocyanate-4-one oxime (500 mg, 2.16 mmol) in MeOH (10 mL). The suspension was degassed and purged three times with hydrogen. The mixture was stirred at 40 °C under hydrogen (30 psi) for 1 h, then cooled to room temperature. The solid was filtered off and the filtrate was concentrated under reduced pressure to give the title compound (400 mg, 85%). LCMS (M+H) + = 218.1.

[0255] Step 6: (7-(trifluoromethyl)isocyanate-4-yl)tert-butyl carbamate Boc₂O (352 mg, 1.61 mmol) and DIPEA (417 mg, 3.22 mmol) were added to a solution of 7-(trifluoromethyl)isocyano-4-amine (350 mg, 1.61 mmol) in THF (4 mL). The mixture was stirred at room temperature for 1 h and then diluted with water (10 mL). The mixture was extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / EtOAc = 1 / 0 to 10 / 1) to give the title compound (400 mg, 78%). LCMS (M+H-tBu) + = 262.0.

[0256] Step 7: (7-(trifluoromethyl)isocyano-4-yl)tert-butylmethyl carbamate At 0 °C, a solution of (7-(trifluoromethyl)isocyano-4-yl)carbamate tert-butyl ester (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). The resulting mixture was stirred at 0 °C for 10 min, and MeI (172 mg, 1.21 mmol) was added dropwise. The mixture was heated to room temperature and stirred for 12 h. The mixture was diluted with water (30 mL) and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / EtOAc = 1 / 0 to 10 / 1) to give the title compound (300 mg, 82%). LCMS (M+H-tBu) + = 276.2.

[0257] Step 8: N-Methyl-7-(trifluoromethyl)isocyanate-4-amine hydrochloride HCl (4 M in MeOH, 3 mL) was added to a solution of (300 mg, 0.91 mmol) tert-butylmethyl 7-(7-(trifluoromethyl)isocyano-4-yl)carbamate in MeOH (3 mL). The mixture was stirred at room temperature for 12 h. The mixture was concentrated under reduced pressure to give the title compound (200 mg, 82%). LC-MS (M+H) + = 232.2.

[0258] Step 9: (2-(methyl(7-(trifluoromethyl)isocyano-4-yl)carbamoyl)-6,8-dihydro-1H-furano [3,4-d]pyrrolo[3,2-b]pyridin-5-yl)tert-butyl carbamate DIPEA (559 mg, 4.33 mmol) and BOPCl (440 mg, 1.73 mmol) were added to a solution of N-methyl-7-(trifluoromethyl)isocyano-4-amine hydrochloride (200 mg, 0.75 mmol) and 5-((tert-butoxycarbonyl)amino)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid (276 mg, 0.87 mmol) in THF (5 mL). The mixture was stirred at room temperature for 1 h and then diluted with water (5 mL). The mixture was extracted with EtOAc (5.0 mL x 3). The combined organic layers were washed with brine (5.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (300 mg, 75%). LC-MS (M+H) + = 533.1.

[0259] Step 10: (R)-5-amino-N-methyl-N-(7-(trifluoromethyl)isochroman-4-yl)-6,8-dihydro-1H-furan [3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide and (S)-5-amino-N-methyl-N-(7-(trifluoromethyl)isocyanate- 4-yl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide HCl (4 M in MeOH, 4 mL) was added to a solution of tert-butyl carbamate (300 mg, 0.56 mmol) in MeOH (4 mL). The mixture was stirred at 25 °C for 1 h and concentrated under reduced pressure. The residue was purified by preparative HPLC and further separated by SFC to give Example 39 (21 mg, 9%) and Example 40 (20 mg, 8%).

[0260] The analytical chiral SFC conditions are as follows: Column: CHIRALPAK AD-3; Column size: 4.6 x 50 mm, 3 μm; Mobile phase: 14 mM NH3 in methanol: CO2 1: 1 isocratic; Flow rate: 4.0 mL / min; Temperature: 35 °C; Back pressure: 1800 psi.

[0261] Example 39: Analytical 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.

[0262] Example 40: Analytical SFC tR = 2.14 min. 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.

[0263] Example 41: (R)-5-amino-N-((5-bromo-3-fluoropyridin-2-yl)methyl)-N-(1-(pyrimidin-2-yl)ethyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Step 1: (R)-N-((5-bromo-3-fluoropyridin-2-yl)methyl)-1-(pyrimidin-2-yl)ethyl-1-amine The title compound (90 mg, 59%) was prepared from 5-bromo-3-fluoropyridinecarboxaldehyde and (R)-1-(pyrimidin-2-yl)ethyl-1-amine dihydrochloride in a manner similar to that in Example 35, Step 1. LC-MS (M+H) + =311.1.

[0264] Step 2: (R)-(2-(((5-bromo-3-fluoropyridin-2-yl)methyl)(1-(pyrimidin-2-yl)ethyl)carbamoyl 6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridin-5-yl) tert-butyl carbamate The title compound (90 mg, 57%) was prepared from 5-((tert-butoxycarbonyl)amino)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and (R)-N-((5-bromo-3-fluoropyridin-2-yl)methyl)-1-(pyrimidin-2-yl)ethyl-1-amine in a manner similar to that in Example 35, step 2. LC-MS (M+H) + =612.2.

[0265] Step 3: (R)-5-amino-N-((5-bromo-3-fluoropyridin-2-yl)methyl)-N-(1-(pyrimidin-2-yl)ethyl)- 6,8-Dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 41 (30 mg, 40%) was prepared from (R)-(2-(((5-bromo-3-fluoropyridin-2-yl)methyl)(1-(pyrimidin-2-yl)ethyl)carbamoyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridin-5-yl)carbamate in a manner similar to that 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.

[0266] Example 42: 5-amino-N-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)methyl)-N-(pyrimidin-2-ylmethyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridin-2-carboxamide Step 1: 1-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-N-(pyrimidin-2-ylmethyl)methylamine The title compound (45 mg, 17%) was prepared from pyrimidin-2-ylmethylamine and 3-fluoro-5-(trifluoromethyl)pyridinecarboxaldehyde in a manner similar to that in Example 3, Step 1. LC-MS (M+H) += 287.0.

[0267] Step 2: (2-(((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)methyl)(pyrimidin-2-ylmethyl)carbamoyl 6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridin-5-yl) tert-butyl carbamate The title compound (60 mg, 58%) was prepared from 5-((tert-butoxycarbonyl)amino)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and 1-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-N-(pyrimidin-2-ylmethyl)methylamine in a manner similar to that in Examples 17 and 18, step 2. LC-MS (M+H) + = 588.1.

[0268] Step 3: 5-Amino-N-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)methyl)-N-(pyrimidin-2-ylmethyl)- 6,8-Dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 42 (30 mg, 35%) was prepared from (2-(((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)methyl)(pyrimidin-2-ylmethyl)carbamoyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridin-5-yl)carbamate tert-butyl ester in a manner similar to that in Example 22, step 3. 1 H 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.

[0269] Example 43: 5-amino-N-(4-cyano-2,6-difluorobenzyl)-N-((3-fluoropyridin-2-yl)methyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Step 1: 3,5-Difluoro-4-((((3-fluoropyridin-2-yl)methyl)amino)methyl)benzonitrile The title compound (70 mg, 25%) was prepared from (3-fluoropyridin-2-yl)methylamine hydrochloride and 3,5-difluoro-4-carboxybenzonitrile in a manner similar to that in Example 3, Step 1. LC-MS (M+H) + = 278.2.

[0270] Step 2: (2-((4-cyano-2,6-difluorobenzyl)((3-fluoropyridin-2-yl)methyl)carbamoyl)-6,8- Dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridin-5-yl)tert-butyl carbamate The title compound (35 mg, 24%) was prepared from 5-((tert-butoxycarbonyl)amino)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and 3,5-difluoro-4-((((3-fluoropyridin-2-yl)methyl)amino)methyl)benzonitrile in a manner similar to that in Examples 17 and 18, step 2. LC-MS (M+H) + = 579.3.

[0271] Step 3: 5-Amino-N-(4-cyano-2,6-difluorobenzyl)-N-((3-fluoropyridin-2-yl)methyl)-6,8-di Hydrogen-1H-furano[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-fluoropyridin-2-yl)methyl)carbamoyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridin-5-yl)carbamate tert-butyl ester in a manner similar to that 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.

[0272] Example 44: (R)-5-amino-N-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)methyl)-N-(1-methoxypropyl-2-yl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridin-2-carboxamide Step 1: 5-Bromo-4-((tert-butoxycarbonyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl ethyl 1H-pyrrole-2-carboxylic acid ester K₂CO₃ (332 g, 2.40 mol) and SEMCl (400 g, 2.40 mol) were added to a solution of ethyl 5-bromo-4-((tert-butoxycarbonyl)amino)-1H-pyrrole-2-carboxylate (320 g, 960 mmol) in DMF (4000 mL). The mixture was stirred at 45 °C for 12 h 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 EtOAc (800 mL x 3). The combined organic layers were washed with brine (500 mL x 2), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE:EtOAc = 1:0 to 5:1) to give the title compound (310 g, 70%). LC-MS (M+Na) + = 485.2.

[0273] Step 2: 4-((tert-butoxycarbonyl)amino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxane- 2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carboxylic acid ethyl ester 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-dioxane (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 at 80 °C under nitrogen for 12 h. The mixture was cooled to room temperature, and the solids were filtered off. The filtrate was concentrated under reduced pressure to give the title compound (300 g, crude). The material was used directly in step 3 of Example 44. LC-MS (M+Na) + = 533.3.

[0274] Step 3: 5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-furano[3, [4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid ethyl ester Add K₂CO₃ (244 g, 1.76 mol) and Pd(dppf)Cl₂ to a solution of 4-((tert-butoxycarbonyl)amino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carboxylic acid ethyl ester (300 g crude) and 4-cyano-2,5-dihydrofuran-3-yltrifluoromethanesulfonate (214 g, 881 mmol) in dioxane (3900 mL) and water (780 mL). . CH2Cl2 (24.0 g, 29.4 mmol). The mixture was stirred at 80 °C under nitrogen for 12 h. 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 EtOAc (500 mL x 3). The combined organic layers were washed with brine (500 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE:EtOAc = 1:0 to 0:1) to give the title compound (100 g, 44% after 2 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.

[0275] Step 4: 5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-furano[3, [4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid LiOH was added to a solution of 65 g, 172 mmol of 5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid ethyl ester in MeOH (150 mL), THF (450 mL), and water (150 mL). .H2O (14.5 g, 344 mmol). The mixture was stirred at 45 °C for 12 h. 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). Aqueous HCl (1 M) was added to the aqueous phase until its pH reached 2–3. The solid was collected by filtration and then milled with MTBE (500 mL) for 1 h. The solid was collected by filtration and dried under vacuum to give the title compound (49.4 g, 82%). 1 H 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); (-COO H (Not obvious). LC-MS (M+H) + = 350.2.

[0276] Step 5: (R)-N-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)methyl)-1-methoxypropyl-2-amine To a solution of (R)-1-methoxypropyl-2-amine (691 mg, 7.7 mmol) in DCM (30 mL), 3-fluoro-5-(trifluoromethyl)pyridinecarboxaldehyde (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 h. The mixture was carefully added to an aqueous layer 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 give the title compound (1.9 g, 91%). LC-MS (M+H) + =267.3.

[0277] Step 6: (R)-5-amino-N-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)methyl)-N-(1-methoxypropyl- 2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2- b] Pyridine-2-carboxamide Add 5-amino-1-((2-(trimethylsilyl)pyridin-2-yl)methyl)-1-methoxypropyl-2-amine (1.75 g, 6.6 mmol) to a solution of (R)-N-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)methyl)-1-methoxypropyl-2-amine (1.75 g, 6.6 mmol) in THF (30 mL) to a solution of (R)-N-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)methyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridin-2-carboxylic acid (2.3 g, 6.6 mmol), BOPCl (2.5 g, 9.9 mmol), and DIPEA (2.54 g, 19.7 mmol). Stir the mixture at 60 °C for 16 h and then cool to room temperature. Pour the mixture into water (100 mL) and extract with EtOAc (100 mL x 2). Wash the combined organic layers with brine (100 mL), dry to Na₂SO₄, filter, and concentrate under reduced pressure. The residue was purified by silica gel chromatography (DCM:MeOH = 20:1) to give the title compound (3.0 g, 76%). LC-MS (M+H) + =598.1.

[0278] Step 7: (R)-5-amino-N-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)methyl)-N-(1-methoxypropyl- 2-yl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide TFA (15 mL) was added to a solution of (R)-5-amino-N-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)methyl)-N-(1-methoxypropyl-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide (3.0 g, 5.0 mmol) in DCM (15 mL). The mixture was stirred at room temperature for 3 h and then concentrated under reduced pressure. MeOH (30 mL) and ammonia (28%, 3 mL) (in water) were added, and the mixture was stirred at room temperature for 3 h. The mixture was poured into water (100 mL) and extracted with EtOAc (100 x 2 mL). The combined organic layers were 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 give 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.

[0279] Example 45: (R)-5-amino-N-((5-bromopyridin-2-yl)methyl)-N-(1-methoxypropyl-2-yl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Step 1: (R)-N-((5-bromopyridin-2-yl)methyl)-1-methoxypropyl-2-amine The title compound (130 mg, 94%) was prepared from (R)-1-methoxypropyl-2-amine and 5-bromopyridinecarboxaldehyde in a manner similar to that in Example 44, step 5. LC-MS (M+H) + = 259.1.

[0280] Step 2: (R)-(2-(((5-bromopyridin-2-yl)methyl)(1-methoxypropyl-2-yl)carbamoyl)-6,8- Dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridin-5-yl)tert-butyl carbamate The title compound (174 mg, 73%) was prepared from 5-((tert-butoxycarbonyl)amino)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and (R)-N-((5-bromopyridin-2-yl)methyl)-1-methoxypropyl-2-amine in a manner similar to that in Examples 17 and 18, step 2. LC-MS (M+H) + = 560.2.

[0281] Step 3: (R)-5-amino-N-((5-bromopyridin-2-yl)methyl)-N-(1-methoxypropyl-2-yl)-6,8-di Hydrogen-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 45 (27 mg, 17%) was prepared from (R)-(2-(((5-bromopyridin-2-yl)methyl)(1-methoxypropyl-2-yl)carbamoyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridin-5-yl)carbamate in a manner similar to that 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, 2H), 5.12 (s, 2H), 4.91 (s, 3H), 4.68 (s, 2H), 3.48 (brs, 1H), 3.34- 3.39 (m, 1H), 3.13 (s, 3H), 1.18 (d, J = 6.2 Hz, 3H). LC-MS (M+H) + = 460.1.

[0282] Example 46: (R)-5-amino-N-(4-cyano-2,6-difluorobenzyl)-N-(1-methoxypropyl-2-yl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Step 1: (R)-3,5-difluoro-4-(((1-methoxypropyl-2-yl)amino)methyl)benzonitrile The title compound (140 mg, 97%) was prepared from (R)-1-methoxypropyl-2-amine and 3,5-difluoro-4-carboxybenzonitrile in a manner similar to that in Example 44, step 5. LC-MS (M+H) + = 241.2.

[0283] Step 2: (R)-(2-((4-cyano-2,6-difluorobenzyl)(1-methoxypropyl-2-yl)carbamoyl)-6,8- Dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridin-5-yl)tert-butyl carbamate The title compound (33 mg, 15%) was prepared from 5-((tert-butoxycarbonyl)amino)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and (R)-3,5-difluoro-4-(((1-methoxypropyl-2-yl)amino)methyl)benzonitrile in a manner similar to that in Examples 17 and 18, step 2. LC-MS (M+H) + = 542.2.

[0284] Step 3: (R)-5-amino-N-(4-cyano-2,6-difluorobenzyl)-N-(1-methoxypropyl-2-yl)-6,8-di Hydrogen-1H-furano[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-methoxypropyl-2-yl)carbamoyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridin-5-yl)carbamate in a manner similar to that 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.

[0285] Example 47: 5-amino-N-((3-fluoropyridin-2-yl)methyl)-N-(2,4,6-trifluorobenzyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Step 1: 1-(3-Fluoropyridin-2-yl)-N-(2,4,6-trifluorobenzyl)methylamine The title compound (180 mg, 67%) was prepared from 2,4,6-trifluorobenzaldehyde and (3-fluoropyridin-2-yl)methylamine in a manner similar to that in Example 3, Step 1. LC-MS (M+H) + = 271.1.

[0286] Step 2: (2-(((3-fluoropyridin-2-yl)methyl)(2,4,6-trifluorobenzyl)carbamoyl)-6,8-dihydro- 1H-furano[3,4-d]pyrrolo[3,2-b]pyridin-5-yl)tert-butyl carbamate The title compound (60 mg, 42%) was prepared from 5-((tert-butoxycarbonyl)amino)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and 1-(3-fluoropyridin-2-yl)-N-(2,4,6-trifluorobenzyl)methylamine in a manner similar to that in Examples 17 and 18, step 2. LC-MS (M+H) + = 572.3.

[0287] Step 3: 5-Amino-N-((3-fluoropyridin-2-yl)methyl)-N-(2,4,6-trifluorobenzyl)-6,8-dihydro-1H- Furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 47 (26 mg, 50%) was prepared from (2-(((3-fluoropyridin-2-yl)methyl)(2,4,6-trifluorobenzyl)carbamoyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridin-5-yl)carbamate in a manner similar to that 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 =8.7 Hz, 2H), 6.46 (s, 1H), 5.53 (s, 2H), 5.09 (s, 2H), 4.99 (s, 2H), 4.88 (s, 4H). LC-MS(M+H) + = 472.2.

[0288] Example 48: (R)-5-amino-N-((5-cyclopropylpyridin-2-yl)methyl)-N-(1-(pyrimidin-2-yl)ethyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Step 1: (R)-N-((5-cyclopropylpyridin-2-yl)methyl)-1-(pyrimidin-2-yl)ethyl-1-amine The title compound (60 mg, 35%) was prepared from 5-cyclopropylpyridinecarboxaldehyde and (R)-1-(pyrimidin-2-yl)ethyl-1-amine dihydrochloride in a manner similar to that in Example 3, Step 1. LC-MS (M+H) + = 255.3.

[0289] Step 2: (R)-(2-(((5-cyclopropylpyridin-2-yl)methyl)(1-(pyrimidin-2-yl)ethyl)carbamoyl 6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridin-5-yl) tert-butyl carbamate The title compound (60 mg, 45%) was prepared from 5-((tert-butoxycarbonyl)amino)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and (R)-N-((5-cyclopropylpyridin-2-yl)methyl)-1-(pyrimidin-2-yl)ethyl-1-amine in a manner similar to that in Example 13, step 4. LC-MS (M+H)+ = 556.4.

[0290] Step 3: (R)-5-amino-N-((5-cyclopropylpyridin-2-yl)methyl)-N-(1-(pyrimidin-2-yl)ethyl)-6, 8-Dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 48 (20 mg, 40%) was prepared from (R)-(2-(((5-cyclopropylpyridin-2-yl)methyl)(1-(pyrimidin-2-yl)ethyl)carbamoyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridin-5-yl)carbamate in a manner similar to that in Example 14, step 6. 1 H 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.

[0291] Example 49: (R)-5-amino-N-((5-bromo-3-fluoropyridin-2-yl)methyl)-N-(1-methoxypropyl-2-yl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Step 1: (R)-N-((5-bromo-3-fluoropyridin-2-yl)methyl)-1-methoxypropyl-2-amine The title compound (231 mg, 57%) was prepared from (R)-1-methoxypropyl-2-amine and 5-bromo-3-fluoropyridinecarboxaldehyde in a manner similar to that in Example 44, step 5. LC-MS (M+H) + = 277.1.

[0292] Step 2: (R)-5-amino-N-((5-bromo-3-fluoropyridin-2-yl)methyl)-N-(1-methoxypropyl-2-yl)-1- ((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine- 2-Formamide The title compound (234 mg, 43%) was prepared from 5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and (R)-N-((5-bromo-3-fluoropyridin-2-yl)methyl)-1-methoxypropyl-2-amine in a manner similar to that in Example 44, step 6. LC-MS (M+H) + = 608.1.

[0293] Step 3: (R)-5-amino-N-((5-bromo-3-fluoropyridin-2-yl)methyl)-N-(1-methoxypropyl-2-yl)-6, 8-Dihydro-1H-furano[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-fluoropyridin-2-yl)methyl)-N-(1-methoxypropyl-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide in a manner similar to that 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, 2H), 5.00 - 4.39 (m, 5H), 3.56 (dd, J = 7.8, 9.7 Hz, 1H), 3.39 (dd, J = 5.2, 10.2 Hz, 1H), 3.17 (s, 3H), 1.23 (d, J = 7.6 Hz, 3H). LC-MS (M+H) + = 478.2.

[0294] Example 50: (R)-5-amino-N-((5-bromopyridin-2-yl)methyl)-N-((3-fluoropyridin-2-yl)methyl)-6-methyl-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Step 1: 1-(5-bromopyridin-2-yl)-N-((3-fluoropyridin-2-yl)methyl)methylamine The title compound (100 mg, 65%) was prepared from 5-bromopyridinecarboxaldehyde and (3-fluoropyridine-2-yl)methylamine in a manner similar to that in Example 5, Step 1. LC-MS (M+H) + = 296.2.

[0295] Step 2: (R)-5-amino-N-((5-bromopyridin-2-yl)methyl)-N-((3-fluoropyridin-2-yl)methyl)-6-methyl 6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 50 (52 mg, 60%) was prepared from 1-(5-bromopyridin-2-yl)-N-((3-fluoropyridin-2-yl)methyl)methylamine and (R)-5-amino-6-methyl-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid in a manner similar to that in Example 2 and 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.

[0296] Example 51: (R)-5-amino-N-((5-iodopyridin-2-yl)methyl)-N-(1-(pyrimidin-2-yl)ethyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Step 1: 5-Iodopyridine carboxaldehyde The title compound (136 mg, 77%) was prepared from methyl 5-iodopyridinecarboxylate in a manner similar to that in Example 37, Step 1. LC-MS (M+H) + = 233.9.

[0297] Step 2: (R)-N-((5-iodopyridin-2-yl)methyl)-1-(pyrimidin-2-yl)ethyl-1-amine The title compound (84 mg, 67%) was prepared from 5-iodopyridinecarboxaldehyde and (R)-1-(pyrimidin-2-yl)ethyl-1-amine dihydrochloride in a manner similar to that in Example 34, Step 1. LC-MS (M+H) + = 341.3.

[0298] Step 3: (R)-5-amino-N-((5-iodopyridin-2-yl)methyl)-N-(1-(pyrimidin-2-yl)ethyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-methyl amide The title compound (80 mg, 48%) was prepared from 5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and (R)-N-((5-iodopyridin-2-yl)methyl)-1-(pyrimidin-2-yl)ethyl-1-amine in a manner similar to that in Example 44, Step 6. + = 672.3.

[0299] Step 4: (R)-5-amino-N-((5-iodopyridin-2-yl)methyl)-N-(1-(pyrimidin-2-yl)ethyl)-6,8-di Hydrogen-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 51 (20 mg, 31%) was prepared from (R)-5-amino-N-((5-iodopyridin-2-yl)methyl)-N-(1-(pyrimidin-2-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide in a manner similar to that 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.

[0300] Example 52: (R)-5-amino-N-((5-cyclopropyl-3-fluoropyridin-2-yl)methyl)-N-(1-(pyrimidin-2-yl)ethyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Step 1: (R)-N-((5-cyclopropyl-3-fluoropyridin-2-yl)methyl)-1-(pyrimidin-2-yl)ethyl-1-amine To a solution of 5-cyclopropyl-3-fluoropyridinecarboxaldehyde (84 mg, 0.51 mmol) in DCM (3 mL), (R)-1-(pyrimidin-2-yl)ethyl-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 h. 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 give the title compound (61 mg, 44%). LC-MS (M+H) + =273.4.

[0301] Step 2: (R)-5-amino-N-((5-cyclopropyl-3-fluoropyridin-2-yl)methyl)-N-(1-(pyrimidin-2-yl)ethyl 6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 52 (27 mg, 25%) was prepared from 5-amino-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and (R)-N-((5-cyclopropyl-3-fluoropyridin-2-yl)methyl)-1-(pyrimidin-2-yl)ethyl-1-amine in a manner similar to that in Example 2 and 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.

[0302] Example 53: (R)-5-amino-N-((5-cyclopropylpyrazin-2-yl)methyl)-N-(1-methoxypropyl-2-yl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Step 1: 5-Cyclopropylpyrazine-2-formaldehyde The title compound (0.60 g, 29%) was prepared from 5-chloropyrazine-2-carboxaldehyde and cyclopropylboronic acid in a manner similar to that in Example 36, Step 1. LC-MS (M+H) + =149.1.

[0303] Step 2: (R)-N-((5-cyclopropylpyrazin-2-yl)methyl)-1-methoxypropyl-2-amine The title compound (190 mg, 85%) was prepared from (R)-1-methoxypropyl-2-amine and 5-cyclopropylpyrazine-2-carboxaldehyde in a manner similar to that in Example 44, step 5. LC-MS (M+H) + =222.2.

[0304] Step 3: (R)-5-amino-N-((5-cyclopropylpyrazin-2-yl)methyl)-N-(1-methoxypropyl-2-yl)-1- ((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine- 2-Formamide The title compound (234 mg, 43%) was prepared from 5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and (R)-N-((5-cyclopropylpyrazin-2-yl)methyl)-1-methoxypropyl-2-amine in a manner similar to that in Example 44, Step 6. + =553.4.

[0305] Step 4: (R)-5-amino-N-((5-cyclopropylpyrazin-2-yl)methyl)-N-(1-methoxypropyl-2-yl)-6,8- Dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 53 (25 mg, 30%) was prepared from (R)-5-amino-N-((5-cyclopropylpyrazin-2-yl)methyl)-N-(1-methoxypropyl-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide in a manner similar to that in Example 44, step 7. 1 H 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.

[0306] Examples 54 and 55: (S)-5-amino-N-ethyl-N-(7-(trifluoromethyl)isocyano-4-yl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide and (R)-5-amino-N-ethyl-N-(7-(trifluoromethyl)isocyano-4-yl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide and Step 1: (7-(trifluoromethyl)isocyanate-4-yl)tert-butylethyl carbamate The title compound (0.50 g, 92%) was prepared from (7-(trifluoromethyl)isocyano-4-yl)carbamate tert-butyl ester and EtI in a manner similar to that in Examples 39 and 40, step 7. LCMS (M+H-tBu) + = 290.1.

[0307] Step 2: N-Ethyl-7-(trifluoromethyl)isocyanate-4-amine hydrochloride The title compound (0.20 g, 62%) was prepared from tert-butylethyl (7-(trifluoromethyl)isocyano-4-yl)carbamate in a manner similar to that in step 8 of Examples 39 and 40. LC-MS (M+H) + = 246.1.

[0308] Step 3: (2-(ethyl(7-(trifluoromethyl)isocyano-4-yl)carbamoyl)-6,8-dihydro-1H-furano [3,4-d]pyrrolo[3,2-b]pyridin-5-yl)tert-butyl carbamate The title compound (0.40 g, 90%) was prepared from 5-((tert-butoxycarbonyl)amino)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and N-ethyl-7-(trifluoromethyl)isocyano-4-amine hydrochloride in a manner similar to that in Examples 39 and 40, step 9. LC-MS (M+H) + = 547.2.

[0309] Step 4: (S)-5-amino-N-ethyl-N-(7-(trifluoromethyl)isocyano-4-yl)-6,8-dihydro-1H-furan [3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide and (R)-5-amino-N-ethyl-N-(7-(trifluoromethyl)isocyanate- 4-yl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide In a manner similar to that in Examples 39 and 40, step 10, tert-butyl carbamate and N-Ethyl-7-(trifluoromethyl)isocyano-4-amine hydrochloride Preparations were made in Example 54 (22 mg, 14%) and Example 55 (23 mg, 14%).

[0310] The analytical chiral SFC conditions are as follows: Column: CHIRALPAK AD-3; Column size: 4.6 x 50 mm, 3 μm; Mobile phase: (ethanol containing 0.2% 7 M methanol NH3): CO2, 1:19 for 0.2 min, 1:19 to 1:1 within 1.0 min, 1:1 for 1 min, 1:1 to 1:19 within 0.4 min; Flow rate: 3.4 mL / min; Temperature: 35 °C; Back pressure: 1800 psi.

[0311] Example 54: Analytical 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.

[0312] Example 55: Analytical SFC tR = 2.14 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.

[0313] Example 56: (R)-5-amino-N-((5-cyclopropyl-3-fluoropyridin-2-yl)methyl)-N-(1-methoxypropyl-2-yl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Step 1: (R)-N-((5-cyclopropyl-3-fluoropyridin-2-yl)methyl)-1-methoxypropyl-2-amine The title compound (110 mg, 51%) was prepared from (R)-1-methoxypropyl-2-amine and 5-cyclopropyl-3-fluoropyridinecarboxaldehyde in a manner similar to that in Example 44, step 5. LC-MS (M+H) + = 239.1.

[0314] Step 2: (R)-(2-(((5-cyclopropyl-3-fluoropyridin-2-yl)methyl)(1-methoxypropyl-2-yl)carbamoyl 6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridin-5-yl) tert-butyl carbamate The title compound (100 mg, 40%) was prepared from 5-((tert-butoxycarbonyl)amino)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and (R)-N-((5-cyclopropyl-3-fluoropyridin-2-yl)methyl)-1-methoxypropyl-2-amine in a manner similar to that in Example 13, step 4. LC-MS (M+H) + = 540.1.

[0315] Step 3: (R)-5-amino-N-((5-cyclopropyl-3-fluoropyridin-2-yl)methyl)-N-(1-methoxypropyl-2-yl) 6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Example 56 (30 mg, 37%) was prepared from (R)-(2-(((5-cyclopropyl-3-fluoropyridin-2-yl)methyl)(1-methoxypropyl-2-yl)carbamoyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridin-5-yl)carbamate in a manner similar to that 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.

[0316] Examples 57, 58, 59, and 60: 5-amino-N-methyl-N-((1R,4R)-1-methyl-7-(trifluoromethyl)isochroman-4-yl)-6,8-dihydro-1H-furano[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-furano[3,4-d]pyrrolo[3,2- [b]Pyridine-2-carboxamide and 5-amino-N-methyl-N-((1S,4S)-1-methyl-7-(trifluoromethyl)isochroman-4-yl)-6,8-dihydro-1H-furano[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-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide and and and Step 1: 1-(2-bromo-5-(trifluoromethyl)phenyl)ethyl-1-ol MeMgBr (3 M in Et2O, 19.8 mL, 59.3 mmol) was added to a solution of 2-bromo-5-(trifluoromethyl)benzaldehyde (15.0 g, 59.3 mmol) in THF (150 mL) at 0 °C, and the mixture was stirred at 0 °C for 1 h. The mixture was quenched with saturated NH4Cl (100 mL) and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / EtOAc = 1 / 0 to 5 / 1) to give the title compound (12.0 g, 75% yield). 1 H 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).

[0317] Step 2: 2-(1-(allyloxy)ethyl)-1-bromo-4-(trifluoromethyl)benzene The title compound (9.7 g, 70%) was prepared from 1-(2-bromo-5-(trifluoromethyl)phenyl)ethyl-1-ol and allyl bromide in a manner similar to that 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).

[0318] Step 3: 1-Methyl-4-methylene-7-(trifluoromethyl)isocyanate The title compound (4.6 g, 64%) was prepared from 2-(1-(allyloxy)ethyl)-1-bromo-4-(trifluoromethyl)benzene in a manner similar to that in Step 2 of Example 40. LC-MS (M+H) + = 229.1.

[0319] Step 4: 1-Methyl-7-(trifluoromethyl)isochroman-4-one The title compound (3.3 g, 71%) was prepared from 1-methyl-4-methylene-7-(trifluoromethyl)isocyanate in a manner similar to that 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 = 17.2Hz, 2H), 1.71 (d, J = 6.8 Hz, 3H). LC-MS (M+H) + = 231.2.

[0320] Step 5: 1-Methyl-7-(trifluoromethyl)isochroman-4-one oxime The title compound (0.75 g, 70%) was prepared from 1-methyl-7-(trifluoromethyl)isochroman-4-one in a manner similar to that 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 = 6.5Hz, 1H), 1.65 (d, J = 6.4 Hz, 3H). LC-MS (M+H) + = 246.2.

[0321] Step 6: 1-Methyl-7-(trifluoromethyl)isocyanate-4-amine The title compound (0.26 g, 79%) was prepared from 1-methyl-7-(trifluoromethyl)isochroman-4-one oxime in a manner similar to that in Example 40, step 5. LC-MS (M+H) + = 232.1.

[0322] Step 7: (1-Methyl-7-(trifluoromethyl)isocyanate-4-yl)tert-butyl carbamate The title compound (0.30 g, 87%) was prepared from 1-methyl-7-(trifluoromethyl)isochroman-4-amine in a manner similar to that in Example 40, step 6. LCMS (M+H-tBu) + = 276.2.

[0323] Step 8: (1-Methyl-7-(trifluoromethyl)isocyanate-4-yl)tert-butylmethyl carbamate The title compound (0.30 g, 87%) was prepared from tert-butyl (1-methyl-7-(trifluoromethyl)isocyano-4-yl)carbamate in a manner similar to that in Example 40, step 7. LCMS (M+H-tBu) + = 290.2.

[0324] Step 9: N,1-Dimethyl-7-(trifluoromethyl)isocyanate-4-amine hydrochloride The title compound (0.20 g, 94%) was prepared from tert-butylmethyl (1-methyl-7-(trifluoromethyl)isocyano-4-yl)carbamate in a manner similar to that in Example 40, step 8. LC-MS (M+H) + = 246.1.

[0325] Step 10: (2-(methyl(1-methyl-7-(trifluoromethyl)isocyano-4-yl)carbamoyl)-6,8-dihydro- 1H-furano[3,4-d]pyrrolo[3,2-b]pyridin-5-yl)tert-butyl carbamate The title compound (0.15 g, 51%) was prepared from 5-((tert-butoxycarbonyl)amino)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and N,1-dimethyl-7-(trifluoromethyl)isocyano-4-amine hydrochloride in a manner similar to that in Example 40, step 9. LC-MS (M+H) + = 547.4.

[0326] Step 11: 5-Amino-N-methyl-N-((1R,4R)-1-methyl-7-(trifluoromethyl)isochroman-4-yl)-6,8- Dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide and 5-amino-N-methyl-N-((1S,4R)-1- Methyl-7-(trifluoromethyl)isocyano-4-yl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-methyl Amides and 5-amino-N-methyl-N-((1S,4S)-1-methyl-7-(trifluoromethyl)isochroman-4-yl)-6,8-dihydro-1H-furan Brønno[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide and 5-amino-N-methyl-N-((1R,4S)-1-methyl-7-(tri-) Fluoromethyl)isochromo-4-yl)-6,8-dihydro-1H-furano[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 (2-(methyl(1-methyl-7-(trifluoromethyl)isochroman-4-yl)carbamoyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridin-5-yl)carbamate in a manner similar to that in Example 40 and Step 10, and isomers were separated by chiral SFC.

[0327] Analytical chiral SFC conditions 1: Column: CHIRALPAK AD-3; Column size: 4.6 x 50 mm, 3 μm; Mobile phase: (ethanol containing 0.2% 7 M methanol NH3): CO2 1: 1 isocratic; Flow rate: 4 mL / min; Temperature: 35 °C; Back pressure: 1800 psi.

[0328] Analytical chiral SFC conditions 2: Column: CHIRALPAK OJ-3; Column size: 4.6 x 50 mm, 3 μm; Mobile phase: Ethanol (containing 0.2% 7 M methanol NH3): CO2, 1:19 for 0.2 min, 1:19 to 1:1 within 1.0 min, 1:1 for 1 min, 1:1 to 1:19 within 0.4 min; Flow rate: 3.4 mL / min; Temperature: 35 °C; Back pressure: 1800 psi.

[0329] Example 57: Analytical SFC (Condition 1) tR = 0.64 min. 1 H NMR (400 MHz, DMSO- d6 ) δ11.68 (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 = 6.0Hz, 3H). LC-MS (M+H) + = 447.2.

[0330] Example 58: Analytical SFC (Condition 2) tR = 1.18 min. 1H NMR (400 MHz, DMSO- d6 ) δ11.93 (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.

[0331] Example 59: Analytical SFC (Condition 2) tR = 1.38 min. 1 H NMR (400 MHz, DMSO- d6 ) δ12.50 (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.

[0332] Example 60: Analytical SFC (Condition 1) tR = 1.32 min. 1 H NMR (400 MHz, DMSO- d6) δ11.69 (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.

[0333] Examples 61 and 62: (S)-5-amino-N-((5-bromo-3-fluoropyridin-2-yl)methyl)-N-(1-(pyrazin-2-yl)ethyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide and (R)-5-amino-N-((5-bromo-3-fluoropyridin-2-yl)methyl)-N-(1-(pyrazin-2-yl)ethyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide and Step 1: N-((5-bromo-3-fluoropyridin-2-yl)methyl)-1-(pyrazin-2-yl)ethyl-1-amine The title compound (90 mg, 40%) was prepared from (5-bromo-3-fluoropyridin-2-yl)methylamine and 1-(pyrazin-2-yl)ethyl-1-one in a manner similar to that in Step 1 of Examples 17 and 18. LC-MS (M+H) + = 311.0.

[0334] Step 2: (2-(((5-bromo-3-fluoropyridin-2-yl)methyl)(1-(pyrazin-2-yl)ethyl)carbamoyl)-6, 8-Dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridin-5-yl)tert-butyl carbamate The title compound (120 mg, 76%) was prepared from 5-((tert-butoxycarbonyl)amino)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and N-((5-bromo-3-fluoropyridin-2-yl)methyl)-1-(pyrazin-2-yl)ethyl-1-amine in a manner similar to that in Examples 17 and 18, step 2. LC-MS (M+H) + = 612.2.

[0335] Step 3: (S)-5-amino-N-((5-bromo-3-fluoropyridin-2-yl)methyl)-N-(1-(pyrazin-2-yl)ethyl)- 6,8-Dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide and (R)-5-amino-N-((5-bromo-3-fluoro) pyridin-2-yl)methyl)-N-(1-(pyrazin-2-yl)ethyl)-6,8-dihydro-1H-furano[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-fluoropyridin-2-yl)methyl)(1-(pyrazin-2-yl)ethyl)carbamoyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridin-5-yl)carbamate tert-butyl ester, and the enantiomers were separated by chiral SFC.

[0336] The analytical chiral SFC conditions are as follows: Column: CHIRALPAK IG-3; Column size: 4.6 x 50 mm, 3 μm; Mobile phase: 14 mM NH3 in isopropanol: CO23 : 2 isocratic; Flow rate: 4 mL / min; Temperature: 35 °C; Back pressure: 1800 psi.

[0337] Example 61: Analytical SFC tR = 1.28 min. 1 H NMR (400 MHz, DMSO- d6 ) δ 11.55 (brs, 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.

[0338] Example 62: Analytical SFC tR = 2.17 min. 1 H NMR (400 MHz, DMSO- d6 ) δ 11.55 (brs, 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.

[0339] Examples 63 and 64: (S)-5-amino-N-(7-bromoisocyanate-4-yl)-N-methyl-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide and (R)-5-amino-N-(7-bromoisocyanate-4-yl)-N-methyl-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide and Step 1: 7-Bromoisocyanate-4-ol At 0 °C, NaBH4 (91 mg, 2.4 mmol) was added to a mixture of 7-bromoisocyanate-4-one (500 mg, 2.2 mmol) in MeOH (20 mL), and the mixture was stirred at room temperature for 30 min. The mixture was diluted with water (10 mL), and the MeOH was evaporated under reduced pressure. The mixture was extracted with EtOAc (20 mL). The organic layer was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated to give the title compound (500 mg, 99%). LC-MS (M+H) + = 229.1.

[0340] Step 2: 7-Bromo-4-chloroisochromic A mixture of 7-bromoisocyanate-4-ol (500 mg, 2.2 mmol) and SOCl2 (524 mg, 4.4 mmol) in THF (15 mL) was stirred for 2 h at 60 °C. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / EtOAc = 20 / 1) to give the title compound (300 mg, 55%). LC-MS (M+H) + = 247.1.

[0341] Step 3: 7-Bromo-N-methylisochroman-4-amine A mixture of 7-bromo-4-chloroisocyanuric acid (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 for 15 hr at 100 °C and then cooled to room temperature. The mixture was diluted with EtOAc (20 mL), washed successively 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 give the title compound (80 mg, 55%). LC-MS (M+H) + = 242.1.

[0342] Step 4: 5-Amino-N-(7-bromoisocyanate-4-yl)-N-methyl-1-((2-(trimethylsilyl)ethoxy) methyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide The title compound (110 mg, 58%) was prepared from 5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and 7-bromo-N-methylisochroman-4-amine in a manner similar to that in Example 44, step 6. LC-MS (M+H) + = 573.2.

[0343] Step 5: (S)-5-amino-N-(7-bromoisocyanate-4-yl)-N-methyl-6,8-dihydro-1H-furano[3,4-d] Pyrrolo[3,2-b]pyridine-2-carboxamide and (R)-5-amino-N-(7-bromoisocyano-4-yl)-N-methyl-6,8-dihydro- 1H-furano[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-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide in a manner similar to that in Example 44 and Step 7, and the enantiomers were separated by chiral SFC.

[0344] The analytical chiral SFC conditions are as follows: Column: CHIRALPAK AS-H; Column size: 20 x 250 mm, 5 μm; Mobile phase: (0.1% Et2NH in MeOH): CO2 1: 2 isocratic; Flow rate: 40 mL / min; Temperature: 35 °C; Back pressure: 1450 psi.

[0345] Example 63: Analytical 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.

[0346] Example 64: Analytical SFC tR = 8.07 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.

[0347] Example 65: 5-amino-N-cyclopentyl-N-((5-cyclopropyl-3-fluoropyridin-2-yl)methyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Step 1: N-((5-cyclopropyl-3-fluoropyridin-2-yl)methyl)cyclopentanamine The title compound (60 mg, 85%) was prepared from 5-cyclopropyl-3-fluoropyridinecarboxaldehyde and cyclopentylamine in a manner similar to that in Example 5, Step 1. LC-MS (M+H) + = 235.2.

[0348] Step 2: 5-Amino-N-cyclopentyl-N-((5-cyclopropyl-3-fluoropyridin-2-yl)methyl)-1-((2-(trimethyl) Silyl)ethoxy)methyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide The title compound (120 mg, 83%) was prepared from 5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and N-((5-cyclopropyl-3-fluoropyridin-2-yl)methyl)cyclopentanamine in a manner similar to that in Example 44, step 6. LC-MS (M+H) + = 566.4.

[0349] Step 3: 5-Amino-N-cyclopentyl-N-((5-cyclopropyl-3-fluoropyridin-2-yl)methyl)-6,8-dihydro-1H-furyl Brno[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-fluoropyridin-2-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide in a manner similar to that 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 (m, 5H), 2.05 - 1.77 (m, 3H), 1.73 - 1.42 (m, 6H), 1.56 (d, J=55.7, 6H), 1.07 - 0.95 (m, 2H), 0.84 - 0.73 (m, 2H). LC-MS(M+H) + =436.4.

[0350] Example 66: 5-amino-N-((5-cyclopropyl-3-fluoropyridin-2-yl)methyl)-N-isopropyl-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Step 1: N-((5-cyclopropyl-3-fluoropyridin-2-yl)methyl)propyl-2-amine NaBH(OAc)3 (154 mg, 0.73 mmol) was added to a solution of 5-cyclopropyl-3-fluoropyridinecarboxaldehyde (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 h, and then slowly added to saturated NaHCO3 (10 mL). The mixture was extracted with EtOAc (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 give the title compound (57 mg, 75%). 1 H NMR (400 MHz, DMSO- d6 ) δ8.32 – 8.15 (m, 1H), 7.28 (dd, J = 11.3, 1.6 Hz, 1H), 3.77 (d, J = 1.8 Hz, 2H), 2.69 (hept, 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.

[0351] Step 2: 5-amino-N-((5-cyclopropyl-3-fluoropyridin-2-yl)methyl)-N-isopropyl-1-((2-(trimethyl) Silyl)ethoxy)methyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Add 5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)propyl-2-amine (57 mg, 0.27 mmol) to a solution of N-((5-cyclopropyl-3-fluoropyridin-2-yl)methyl)prop-2-amine (57 mg, 0.27 mmol) in THF (5 mL) with 80 mg, 0.23 mmol, BOPCl (88 mg, 0.35 mmol), and DIPEA (148 mg, 1.15 mmol). Stir the mixture at 70 °C for 2 h and then cool to room temperature. Pour the mixture into water (20 mL) and extract with EtOAc (10 x 2 mL). Wash the combined organic layers with brine (10 mL), dry to Na₂SO₄, filter, and concentrate under reduced pressure. The residue was purified by silica gel chromatography (DCM:MeOH = 20:1) to give the title compound (60 mg, 41%). LC-MS (M+H)+ =540.3.

[0352] Step 3: 5-Amino-N-((5-cyclopropyl-3-fluoropyridin-2-yl)methyl)-N-isopropyl-6,8-dihydro-1H-furyl Brno[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide TFA (1 mL) was added to a solution of 5-amino-N-((5-cyclopropyl-3-fluoropyridin-2-yl)methyl)-N-isopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide (60 mg, 0.11 mmol) in DCM (1 mL). The mixture was stirred at room temperature for 3 h 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 h and then cooled to room temperature. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to give Example 66 (28 mg, 61%). 1 H 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.

[0353] Example 67: (R)-5-amino-N-(sec-butyl)-N-((5-cyclopropyl-3-fluoropyridin-2-yl)methyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Step 1: (R)-N-((5-cyclopropyl-3-fluoropyridin-2-yl)methyl)but-2-amine The title compound (118 mg, 73%) was prepared from 5-cyclopropyl-3-fluoropyridinecarboxaldehyde and (R)-but-2-amine hydrochloride in a manner similar to that in Example 66, Step 1. LC-MS (M+H) + = 223.2.

[0354] Step 2: (R)-5-amino-N-(sec-butyl)-N-((5-cyclopropyl-3-fluoropyridin-2-yl)methyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-methyl amide The title compound (145 mg, 61%) was prepared from 5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and (R)-N-((5-cyclopropyl-3-fluoropyridin-2-yl)methyl)but-2-amine in a manner similar to that in Example 66, step 2. + = 554.3.

[0355] Step 3: (R)-5-amino-N-(sec-butyl)-N-((5-cyclopropyl-3-fluoropyridin-2-yl)methyl)-6,8-di Hydrogen-1H-furano[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-fluoropyridin-2-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide in a manner similar to that 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.

[0356] Example 68: (R)-5-amino-N,6-dimethyl-N-((S)-7-(trifluoromethyl)isocyano-4-yl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Step 1: (S)-(7-(trifluoromethyl)isocyanate-4-yl)tert-butyl carbamate The racemic product of (7-(trifluoromethyl)isocyano-4-yl)carbamate tert-butyl ester (13.0 g, 41.0 mmol) was isolated by SFC to give the title compound (5.0 g, 38%).

[0357] The analytical chiral SFC conditions are as follows: Column: CHIRALPAK IC-3; Column size: 4.6 x 100 mm, 3 μm; Mobile phase: 14 mM NH3 in methanol: CO2, 1:9 for 0.2 min, then 1:9 to 1:1 over 2.2 min, 1:1 for 1 min; Flow rate: 3.4 mL / min; Temperature: 35 °C; Back pressure: 2000 psi.

[0358] (S)-(7-(trifluoromethyl)isocyano-4-yl)tert-butyl carbamate: analytical 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.

[0359] (R)-(7-(trifluoromethyl)isocyano-4-yl)tert-butyl carbamate: analytical SFC tR = 0.66 min.

[0360] Step 2: (S)-Methyl(7-(trifluoromethyl)isocyanate-4-yl)tert-butyl carbamate The title compound (1.5 g, 72%) was prepared from (S)-(7-(trifluoromethyl)isocyano-4-yl)carbamate in a manner similar to that in step 7 of Examples 39 and 40. LCMS (M+H-tBu) + = 276.1.

[0361] Step 3: (S)-N-methyl-7-(trifluoromethyl)isocyanate-4-amine hydrochloride The title compound (1.4 g, 100%) was prepared from (S)-methyl (7-(trifluoromethyl)isocyano-4-yl)carbamate tert-butyl ester in a manner similar to that in Step 8 of Examples 39 and 40. LC-MS (M+H) + = 232.0.

[0362] Step 4: (R)-5-amino-N,6-dimethyl-N-((S)-7-(trifluoromethyl)isocyanate-4-yl)-6,8-dihydro- 1H-furano[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-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid in a manner similar to that in Example 2 and Step 3. 1 H 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.

[0363] Example 69: 5-amino-N-cyclobutyl-N-((5-cyclopropyl-3-fluoropyridin-2-yl)methyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Step 1: N-((5-cyclopropyl-3-fluoropyridin-2-yl)methyl)cyclobutylamine The title compound (20 mg, 15%) was prepared from 5-cyclopropyl-3-fluoropyridinecarboxaldehyde and cyclobutylamine in a manner similar to that in Example 66, Step 1. LC-MS (M+H) + = 221.2.

[0364] Step 2: 5-Amino-N-cyclobutyl-N-((5-cyclopropyl-3-fluoropyridin-2-yl)methyl)-1-((2-(trimethyl) Silyl)ethoxy)methyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide The title compound (20 mg, 40%) was prepared from N-((5-cyclopropyl-3-fluoropyridin-2-yl)methyl)cyclobutamine and 5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid in a manner similar to that in Example 66, step 2. LC-MS (M+H) + = 552.3.

[0365] Step 3: 5-Amino-N-cyclobutyl-N-((5-cyclopropyl-3-fluoropyridin-2-yl)methyl)-6,8-dihydro-1H-furyl Brno[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-fluoropyridin-2-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide in a manner similar to that 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.

[0366] Example 70: (R)-5-amino-N-((5-cyclopropyl-3-fluoropyridin-2-yl)methyl)-N-(3-methylbut-2-yl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Step 1: (R)-N-((5-cyclopropyl-3-fluoropyridin-2-yl)methyl)-3-methylbut-2-amine The title compound (110 mg, 77%) was prepared from 5-cyclopropyl-3-fluoropyridinecarboxaldehyde and (R)-3-methylbut-2-amine in a manner similar to that in Example 66, step 1. LC-MS (M+H) + = 237.0.

[0367] Step 2: (R)-5-amino-N-((5-cyclopropyl-3-fluoropyridin-2-yl)methyl)-N-(3-methylbut-2-yl)- 1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyrrolo Pyridine-2-carboxamide The title compound (40 mg, 33%) was prepared from (R)-N-((5-cyclopropyl-3-fluoropyridin-2-yl)methyl)-3-methylbut-2-amine and 5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid in a manner similar to that in Example 66, step 2. LC-MS (M+H) + = 568.3.

[0368] Step 3: (R)-5-amino-N-((5-cyclopropyl-3-fluoropyridin-2-yl)methyl)-N-(3-methylbut-2-yl)- 6,8-Dihydro-1H-furano[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-fluoropyridin-2-yl)methyl)-N-(3-methylbut-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide in a manner similar to that 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.

[0369] Examples 71 and 72: (R)-5-amino-N-((R)-7-bromoisocyanate-4-yl)-N,6-dimethyl-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide and (R)-5-amino-N-((S)-7-bromoisocyanate-4-yl)-N,6-dimethyl-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide and Examples 71 (47 mg, 35%) and 72 (43 mg, 32%) were prepared from (R)-5-amino-6-methyl-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and 7-bromo-N-methylisochroman-4-amine in a manner similar to that in Example 124 and Example 125, and the diastereomers were separated by chiral-HPLC.

[0370] The analytical chiral-HPLC conditions are as follows: Column: YMC Cellulose-C; Column size: 4.6 x 250 mm, 5 μm; Mobile phase: (0.1% 2.0 M methanol NH3 in EtOH): hexane, 1:1 isocratic; Flow rate: 1.0 mL / min; Temperature: 25 °C.

[0371] Example 71: Analytical chiral-HPLC tR = 7.07 min. 1 H NMR (400 MHz, DMSO- d6 ) δ11.59 (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 = 6.1Hz, 3H). LCMS (M+H) + = 457.2.

[0372] Example 72: Analytical chiral-HPLC tR = 8.84 min. 1 H NMR (400 MHz, DMSO- d6) δ11.59 (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 = 6.1Hz, 3H). LCMS (M+H) + = 457.2.

[0373] Examples 73 and 74: (S)-5-amino-N-(7-chloroisocyano-4-yl)-N-ethyl-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide and (R)-5-amino-N-(7-chloroisocyano-4-yl)-N-ethyl-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide and Step 1: 2-(bromomethyl)-4-chlorobenzoic acid methyl ester NBS (5.3 g, 29.7 mmol) and AIBN (2.2 g, 13.5 mmol) were added to a solution of methyl 4-chloro-2-methylbenzoate (5.0 g, 27.1 mmol) in CCl4 (100 mL). 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:EtOAc = 50:1) to give the title compound (6.3 g, 88%). LC-MS (M+H) + =263.1.

[0374] Step 2: 4-Chloro-2-((2-methoxy-2-oxoethoxy)methyl)benzoate methyl ester At 0 °C, NaH (60%, 1.92 g, 47.9 mmol) was added to a mixture of methyl 2-hydroxyacetate (4.3 g, 47.9 mmol) in DMF (100 mL). The mixture was stirred at room temperature for 30 min 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 min. Saturated NH4Cl (40 mL) was added dropwise, and the mixture was then partitioned between water (100 mL) and EtOAc (150 mL). The organic layer was washed with brine (2 x 60 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (PE:EtOAc = 4:1) to give the title compound (3.8 g, 58%). LC-MS (M+Na) + =295.1.

[0375] Step 3: 2-((carboxymethoxy)methyl)-4-chlorobenzoic acid A solution of NaOH (2.5 g, 62.5 mmol) in water (14 mL) was added to a solution of methyl 4-chloro-2-((2-methoxy-2-oxoethoxy)methyl)benzoate (3.8 g, 13.97 mmol) in EtOH (20 mL). The mixture was stirred at room temperature for 1 h. 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 give the title compound (3.3 g, 97%). LC-MS (M+H) + = 245.1.

[0376] Step 4: Acetic acid 7-chloro-4-oxoisochromic 3-carboxylic anhydride 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 h. The mixture was cooled to room temperature and partitioned between ice water (100 mL) and EtOAc (120 mL). The aqueous phase was extracted with EtOAc (50 mL). The combined organic layers were washed with brine (60 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum to give the title compound (2.2 g, 61%).

[0377] Step 5: 7-Chloroisocyano-4-one A solution of NaOH (1.64 g, 41.0 mmol) in water (20 mL) was added to a solution of acetic acid 7-chloro-4-oxoisocyanate-3-carboxylic anhydride (2.2 g, 8.21 mmol) in EtOH (60 mL). The mixture was stirred at room temperature for 15 min and then partitioned between EtOAc (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:EtOAc = 10:1) to give the title compound (1.3 g, 87%). LC-MS (M+H) + =183.1.

[0378] Step 6: 7-Chloroisocyano-4-ol To a solution of 7-chloroisocyanuric-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 h. Saturated NH4Cl (30 mL) was added with stirring, and the mixture was extracted sequentially with EA (80 + 50 mL). The combined organic layers were washed with brine (60 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give the title compound (950 mg, 94%). LC-MS (M+H) + =185.1.

[0379] Step 7: 4,7-Dichloroisochromic SOCl2 (1.96 g, 16.5 mmol) was added dropwise to a mixture of 7-chloroisocyanuric-4-ol (950 mg, 5.16 mmol) in THF (15 mL), and the mixture was stirred at 80 °C for 30 min. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was redissolved in EtOAc (50 mL) and washed successively with saturated NaHCO3 (30 mL) and brine (20 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum to give the title compound (810 mg, 78%). LC-MS (M+H) + =203.1.

[0380] Step 8: 7-Chloro-N-ethylisocyano-4-amine Ethylamine hydrochloride (492 mg, 6.0 mmol), K₂CO₃ (1.1 g, 7.97 mmol), and KI (400 mg, 2.41 mmol) were added to a mixture of 4,7-dichloroisocyanuric acid (404 mg, 2.0 mmol) in DMA (10 mL). The mixture was stirred overnight at 100 °C. The mixture was cooled to room temperature, diluted with EtOAc (50 mL), and washed successively 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:EtOAc = 1:1) to give the title compound (100 mg, 24%). LC-MS (M+H) + =212.3.

[0381] Step 9: 5-Amino-N-(7-chloroisocyanuran-4-yl)-N-ethyl-1-((2-(trimethylsilyl)ethoxy) methyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide DIPEA (303 mg, 3.0 mmol) and BOPCl (203 mg, 0.80 mmol) were added to a mixture of 5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid (166 mg, 0.47 mmol) and 7-chloro-N-ethylisocyano-4-amine (100 mg, 0.47 mmol) in THF (10 mL). The mixture was stirred at 60 °C for 2 h. The mixture was diluted with EtOAc (50 mL) and washed successively 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 give the title compound (160 mg, 62%). LC-MS (M+H) + =543.3.

[0382] Step 10: (S)-5-amino-N-(7-chloroisocyanuran-4-yl)-N-ethyl-6,8-dihydro-1H-furano[3,4- d]pyrrolo[3,2-b]pyridine-2-carboxamide and (R)-5-amino-N-(7-chloroisocyanuran-4-yl)-N-ethyl-6,8-dihydro- 1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide At room temperature, a mixture of 5-amino-N-(7-chloroisocyanuran-4-yl)-N-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide (160 mg, 0.29 mmol) in TFA (5 mL) was stirred for 30 min. 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 min. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC and further purified by SFC to give Example 73 (27 mg, 22%) and Example 74 (28 mg, 23%).

[0383] The analytical chiral SFC conditions are as follows: Column: CHIRALPAK IH; Column size: 4.6 x 100 mm, 5 μm; Mobile phase: 0.2% diethylamine in MeOH: CO2, 1:9 to 4:6 within 3 min, 4:6 for 2 min, 4:6 to 1:9 within 0.1 min, 1:9 for 1.9 min; Flow rate: 2.0 mL / min; Temperature: 35 °C; Back pressure: 1500 psi.

[0384] Example 73: Analytical SFC tR = 3.82 min. 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.

[0385] Example 74: Analytical SFC tR = 4.09 min. 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.

[0386] Examples 75 and 76: (S)-5-amino-N-(5,7-difluoroisocyano-4-yl)-N-ethyl-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide and (R)-5-amino-N-(5,7-difluoroisocyano-4-yl)-N-ethyl-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide and Step 1: (2-Bromo-3,5-Difluorophenyl)methanol NaBH4 (942 mg, 24.9 mmol) was added to a solution of 2-bromo-3,5-difluorobenzaldehyde (5.0 g, 22.6 mmol) in MeOH (50 mL) at 0 °C under nitrogen atmosphere. The mixture was stirred at 25 °C for 0.5 h. Saturated NH4Cl (10 mL) was added to the reaction mixture at 0 °C, and the mixture was stirred at 25 °C for 1 h. The mixture was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / EtOAc = 1 / 0 to 5 / 1) to give the title compound (4.8 g, 95%). LCMS (M+Na) + =246.0.

[0387] Step 2: 1-((allyloxy)methyl)-2-bromo-3,5-difluorobenzene Under nitrogen atmosphere at 0 °C, allyl bromide (2.82 g, 23.3 mmol) and NaH (60%, 861 mg, 21.5 mmol) were added to a solution of (2-bromo-3,5-difluoro-phenyl)methanol (4.0 g, 17.9 mmol) in THF (40 mL). The mixture was stirred at 25 °C for 2 h. The mixture was poured into ice water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / EtOAc = 1 / 0 to 5 / 1) to give the title compound (4.3 g, 91%). 1 H NMR (400 MHz, CD3OD) δ7.20-7.12 (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).

[0388] Step 3: 5,7-Difluoro-4-methylene isochromium 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 to a solution of 1-(allyloxymethyl)-2-bromo-3,5-difluorobenzene (4.5 g, 17.1 mmol) in DMF (90 mL), and the container was degassed and purged three times with N₂. The mixture was stirred at 90 °C under nitrogen for 16 h. The mixture was cooled to room temperature and diluted with water (100 mL). The mixture was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / EtOAc = 1 / 0 to 5 / 1) to give the title compound (1.5 g, 48%). 1 H NMR (400 MHz, CD3OD) δ6.92-6.82 (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).

[0389] Step 4: 5,7-Difluoroisochroman-4-one At 25 °C under nitrogen, potassium (VI) osmium tetroxide dihydrate (303 mg, 823 μmol), 2,6-dimethylpyridine (1.76 g, 16.47 mmol), and sodium periodate (7.04 g, 32.9 mmol) were added to a mixture of 5,7-difluoro-4-methylene-isochloromethane (1.5 g, 8.23 ​​mmol) in dioxane (20 mL) and water (4 mL). The mixture was stirred at 25 °C for 2 h. The mixture was quenched with saturated Na₂S₂O₃ (5 mL), diluted with water (100 mL), and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / EtOAc = 1 / 0 to 5 / 1) to give 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).

[0390] Step 5: 5,7-Difluoroisochroman-4-ketooxime The title compound (0.92 g, 85%) was prepared from 5,7-difluoroisochroman-4-one in a manner similar to that in Step 4 of Examples 39 and 40. LC-MS (M+H) + = 200.2.

[0391] Step 6: 5,7-Difluoroisocyano-4-amine The title compound (822 mg, 96%) was prepared from 5,7-difluoroisochroman-4-one oxime in a manner similar to that in Examples 39 and 40, step 5. LC-MS (M+H) + = 186.1.

[0392] Step 7: (5,7-Difluoroisocyanate-4-yl)tert-butyl carbamate The title compound (820 mg, 65%) was prepared from 5,7-difluoroisochroman-4-amine in a manner similar to that in Step 6 of Examples 39 and 40. LCMS (M+H-tBu) + = 230.1.

[0393] Step 8: (5,7-Difluoroisocyanate-4-yl)(ethyl)carbamate tert-butyl ester The title compound (100 mg, 91%) was prepared from (5,7-difluoroisocyano-4-yl)carbamate tert-butyl ester and EtI in a manner similar to that in Example 39 and Example 40, step 7. LCMS (M+H-tBu) + = 258.1.

[0394] Step 9: N-Ethyl-5,7-difluoroisocyanate-4-amine hydrochloride The title compound (125 mg, 100%) was prepared from (5,7-difluoroisocyano-4-yl)(ethyl)carbamate in a manner similar to that in step 8 of Examples 39 and 40. LC-MS (M+H) + = 214.1.

[0395] Step 10: 5-Amino-N-(5,7-difluoroisocyano-4-yl)-N-ethyl-1-((2-(trimethylsilyl)ethyl) (Oxy)methyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide The title compound (260 mg, 100%) was prepared from N-ethyl-5,7-difluoroisocyano-4-amine hydrochloride and 5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid in a manner similar to that in Examples 73 and 74, step 9. LC-MS (M+H) + = 545.3.

[0396] Step 11: (R)-5-amino-N-(5,7-difluoroisocyano-4-yl)-N-ethyl-6,8-dihydro-1H-furano [3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide and (S)-5-amino-N-(5,7-difluoroisocyano-4-yl)-N-ethyl- 6,8-Dihydro-1H-furano[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-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide in a manner similar to that in Examples 73 and 74, step 10, and the enantiomers were separated by chiral SFC.

[0397] The analytical chiral SFC conditions are as follows: Column: ChiralPak IH; Column size: 4.6 x 100 mm, 3 μm; Mobile phase: (isopropanol containing 0.2% 7 M methanol NH3): CO2; 1:9 for 0.2 min, 1:9 to 1:1 within 2.4 min, 1:1 for 1 min, 1:1 to 1:9 within 0.6 min; Flow rate: 3.4 mL / min; Temperature: 35 °C; Back pressure: 2000 psi.

[0398] Example 75: Analytical SFC tR = 2.10 min. 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.

[0399] Example 76: Analytical SFC tR = 2.54 min. 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.

[0400] Example 77: (S)-5-amino-N-ethyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Step 1: (S)-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)tert-butyl carbamate The title compound (300 mg, 99%) was prepared from (S)-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine hydrochloride in a manner similar to that in Step 6 of Examples 39 and 40. LC-MS (M+Na) + = 326.1.

[0401] Step 2: (S)-Ethyl(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)carbamate tert-butyl ester The title compound (240 mg, 73%) was prepared from (S)-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)carbamate tert-butyl ester and EtI in a manner similar to that in step 7 of Examples 39 and 40. LC-MS (M+H-tBu) + =276.1.

[0402] Step 3: (S)-N-ethyl-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine HCl (4.0 M in dioxane, 5 mL) was added to (S)-ethyl(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)carbamate (240 mg, 0.72 mmol), and the mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure. The residue was partitioned between saturated NaHCO3 (50 mL) and EtOAc (40 mL). The aqueous layer was extracted sequentially with EtOAc (2 x 40 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (120 mg, 79%). LC-MS (M+H) + = 232.1.

[0403] Step 4: (S)-5-amino-N-ethyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-methyl amide 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-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid in a manner similar to that in Examples 73 and 74, step 9. LC-MS (M+H) + =563.4.

[0404] Step 5: (S)-5-amino-N-ethyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)-6,8-di Hydrogen-1H-furano[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-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide in a manner similar to that 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, 2H), 5.12 (s, 2H), 4.98 - 4.78 (m, 3H), 4.72 -4.61 (m, 1H), 3.65 - 3.35 (m, 2H), 1.05 (t, J = 6.0 Hz, 3H). LC-MS (M+H) + =433.3.

[0405] Examples 78, 79, 80, and 81: 5-amino-N-((1S,4R)-7-bromo-1-methylisochroman-4-yl)-N-methyl-6,8-dihydro-1H-furano[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-furano[3,4-d]pyrrolo[3,2- [b]Pyridine-2-carboxamide and 5-amino-N-((1S,4S)-7-bromo-1-methylisochroman-4-yl)-N-methyl-6,8-dihydro-1H-furano[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-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide and and and Step 1: 1-(5-bromo-2-iodophenyl)ethyl-1-ol The title compound (22 g, 84%) was prepared from 5-bromo-2-iodobenzaldehyde and MeMgBr in a manner similar to that in Step 1 of Examples 57, 58, 59 and 60. 1 H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 1.6Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.11 (dd, J = 8.4, 2.4 Hz, 1H), 5.01 (q, J = 6.4Hz, 1H), 1.99 (br s, 1H), 1.46 (d, J = 6.4 Hz, 3H).

[0406] Step 2: 2-(1-(allyloxy)ethyl)-4-bromo-1-iodobenzene The title compound (19 g, 77%) was prepared from 1-(5-bromo-2-iodophenyl)ethyl-1-ol and allyl bromide in a manner similar to that in Step 1 of Examples 39 and 40. 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).

[0407] Step 3: 7-Bromo-1-methyl-4-methylene isochromium The title compound (2.6 g, 21%) was prepared from 2-(1-(allyloxy)ethyl)-4-bromo-1-iodobenzene in a manner similar to that in step 2 of Examples 39 and 40. 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 = 6.8Hz, 3H).

[0408] Step 4: 7-Bromo-1-methylisochroman-4-one The title compound (2.2 g, 83%) was prepared from 7-bromo-1-methyl-4-methylene isochorium in a manner similar to that 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.

[0409] Step 5: 7-Bromo-1-methylisochroman-4-ol At 0 °C, NaBH4 (449 mg, 11.9 mmol) was added to a solution of 7-bromo-1-methylisochroman-4-one (2.2 g, 9.13 mmol) in MeOH (30 mL). The mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched with saturated NH4Cl (10 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / EtOAc = 100 / 1 to 5 / 1) to give the title compound (1.9 g, 86%). LC-MS (M+H-H2O) + = 225.0.

[0410] Step 6: 4-Azide-7-bromo-1-methylisochroman At 0 °C, DPPA (2.31 g, 8.39 mmol) was added to a solution of 7-bromo-1-methylisocyanuric-4-ol (1.7 g, 6.99 mmol) in toluene (17 mL). A solution of DBU (1.60 g, 10.5 mmol) in toluene (4 mL) was added dropwise. The mixture was stirred at 25 °C for 12 h. The mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (40 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by silica gel chromatography (PE / EtOAc = 1 / 0 to 10 / 1) to give the title compound (1.4 g, 75%). LC-MS (M+H-N₂) + = 240.0.

[0411] Step 7: 7-Bromo-1-methylisochroman-4-amine A solution of PPh3 (2.74 g, 10.44 mmol) and KOH (732 mg, 13.0 mmol) in water (3 mL) was added to a solution of 4-azido-7-bromo-1-methylisochloromethane (1.4 g, 5.22 mmol) in THF (15 mL). The mixture was stirred at 50 °C for 1 h and then at 25 °C for 12 h. The pH of the mixture was adjusted to approximately 2 with hydrochloric acid (2 M), and the mixture was washed with EtOAc (3 x 10 mL). The pH of the aqueous layer was adjusted to approximately 11 with saturated KOH solution, and the mixture was then extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude title compound (0.9 g, 71%). LC-MS (M+H) + = 242.0.

[0412] Step 8: (7-Bromo-1-methylisocyano-4-yl)tert-butyl carbamate The title compound (1.2 g, 94%) was prepared from 7-bromo-1-methylisochroman-4-amine in a manner similar to that in Examples 39 and 40, step 6. LCMS (M+H-tBu) + = 286.1.

[0413] Step 9: (7-Bromo-1-methylisochroman-4-yl)(methyl)carbamate tert-butyl ester The title compound (900 mg, 72%) was prepared from (7-bromo-1-methylisocyano-4-yl)carbamate tert-butyl ester and MeI in a manner similar to that in Example 39 and Example 40, step 7. LCMS (M+H-tBu) + = 300.0.

[0414] Step 10: 7-Bromo-N,1-Dimethylisocyano-4-amine hydrochloride The title compound (650 mg, 88%) was prepared from (7-bromo-1-methylisochroman-4-yl)(methyl)carbamate in a manner similar to that in step 8 of Examples 39 and 40. LC-MS (M+H) + = 256.1.

[0415] Step 11: 5-Amino-N-(7-bromo-1-methylisochroman-4-yl)-N-methyl-1-((2-(trimethylsilane) (Hydrogenyl)ethoxy)methyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide The title compound (0.6 g, 40%) was prepared from 5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid and 7-bromo-N,1-dimethylisocyano-4-amine hydrochloride in a manner similar to that in Examples 73 and 74, step 9. LC-MS (M+H) + = 587.3.

[0416] Step 12: 5-Amino-N-((1S,4R)-7-bromo-1-methylisochroman-4-yl)-N-methyl-6,8-dihydro-1H- Furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide and 5-amino-N-((1R,4R)-7-bromo-1-methylisocyanate- 4-yl)-N-methyl-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide and 5-amino-N- ((1S,4S)-7-bromo-1-methylisochroman-4-yl)-N-methyl-6,8-dihydro-1H-furano[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-furano[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-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide in a manner similar to that in Examples 73 and 74, step 10, and isomers were separated by chiral SFC.

[0417] The analytical chiral SFC conditions are as follows: Column: CHIRALPAK OJ-3; Column size: 4.6 x 50 mm, 3 μm; Mobile phase: (ethanol containing 0.2% 7 M methanol NH3): CO2, 1:19 for 0.2 min, 1:19 to 1:1 within 1.0 min, 1:1 for 1 min, 1:1 to 1:19 within 0.4 min; 1:19 for 0.4 min; Flow rate: 3.4 mL / min; Temperature: 35 °C; Back pressure: 1800 psi.

[0418] Example 78: Analytical SFC tR = 1.45 min. 1 H NMR (400 MHz, DMSO- d6 ) δ 11.57 (brs, 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.

[0419] Example 79: Analytical SFC tR = 1.52 min. 1 H NMR (400 MHz, DMSO- d6 ) δ 11.60 (brs, 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.

[0420] Example 80: Analytical SFC tR = 1.87 min. 1 H NMR (400 MHz, DMSO- d6 ) δ 11.60 (brs, 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.

[0421] Example 81: Analytical SFC tR = 2.23 min. 1H NMR (400 MHz, DMSO- d6 ) δ 11.57 (brs, 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.

[0422] Example 82: (S)-5-amino-N-(5-fluoro-7-(trifluoromethyl)isochroman-4-yl)-N-methyl-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Step 1: 2-Bromo-6-fluoro-4-(trifluoromethyl)aniline NBS (26.1 g, 146.6 mmol) was added to a solution of 2-fluoro-4-(trifluoromethyl)aniline (25 g, 140 mmol) in DMF (200 mL) at 0 °C. The mixture was stirred at 25 °C for 12 h. The mixture was diluted with water (500 mL) and then extracted with ethyl acetate (3 x 150 mL). The combined organic layers were washed with brine (3 x 150 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / EtOAc = 1 / 0 to 10 / 1) to give 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.

[0423] Step 2: Methyl 2-amino-3-fluoro-5-(trifluoromethyl)benzoate 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 at 80 °C under CO for 24 h. The solid was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / EtOAc = 1 / 0 to 10 / 1) to give 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.

[0424] Step 3: 2-Bromo-3-fluoro-5-(trifluoromethyl)benzoate methyl ester CuBr2 (18.4 g, 82.2 mmol) was added to a solution of methyl 2-amino-3-fluoro-5-(trifluoromethyl)benzoate (15 g, 63.3 mmol) in MeCN (100 mL), and the mixture was stirred at 25 °C for 1 h. Tert-butyl nitrite (7.83 g, 75.9 mmol) was added, and the mixture was stirred at 25 °C for 4 h. The mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / EtOAc = 1 / 0 to 100 / 1) to give 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).

[0425] Step 4: (2-bromo-3-fluoro-5-(trifluoromethyl)phenyl)methanol At 0 °C, methyl 2-bromo-3-fluoro-5-(trifluoromethyl)benzoate (12.5 g, 41.5 mmol) in THF (120 mL) was added to a solution of methyl 2-bromo-3-fluoro-5-(trifluoromethyl)benzoate in THF (2.0 M, 83.0 mL, 166 mmol). The mixture was stirred at 20 °C under nitrogen for 3 h. The mixture was quenched with saturated NH4Cl (150 mL) and then extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / EtOAc = 1 / 0 to 10 / 1) to give 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).

[0426] Step 5: 1-((allyloxy)methyl)-2-bromo-3-fluoro-5-(trifluoromethyl)benzene At 0 °C, allyl bromide (9.31 g, 76.9 mmol) and NaH (60%, 3.08 g, 76.9 mmol) were added to a solution of (2-bromo-3-fluoro-5-(trifluoromethyl)phenyl)methanol (10.5 g, 38.5 mmol) in DMF (100 mL). The mixture was stirred at 25 °C under nitrogen for 12 h. The mixture was poured into ice water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / EtOAc = 1 / 0 to 10 / 1) to give 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).

[0427] Step 6: 5-Fluoro-4-methylene-7-(trifluoromethyl)isochromic PPh3 (377 mg, 1.44 mmol), Pd(OAc)2 (143 mg, 639 μmol), and Cs2CO3 (1.25 g, 3.83 mmol) were added to a solution of 1-((allyloxy)methyl)-2-bromo-3-fluoro-5-(trifluoromethyl)benzene (1.0 g, 3.19 mmol) in DMF (100 mL). The mixture was stirred at 90 °C under nitrogen for 12 h. The mixture was cooled to room temperature and diluted with water (100 mL). The mixture was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / EtOAc = 1 / 0 to 10 / 1) to give 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).

[0428] Step 7: 5-Fluoro-7-(trifluoromethyl)isochroman-4-one Potassium osmium (VI) dihydrate (905 mg, 2.46 mmol), sodium periodate (21.0 g, 98.2 mmol), and 2,6-dimethylpyridine (5.26 g, 49.1 mmol) were added to a solution of 5-fluoro-4-methylene-7-(trifluoromethyl)isocyanate (5.7 g, 24.6 mmol) in dioxane (150 mL) and water (30 mL). The mixture was stirred at 25 °C under nitrogen for 2 h. The mixture was quenched with saturated Na₂S₂O₃ (20 mL), diluted with water (50 mL), and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / EtOAc = 1 / 0 to 5 / 1) to give the title compound (4.4 g, 77%). 1 H NMR (DMSO- d6 , 400MHz) δ 7.77 (d,J = 10.9 Hz, 1H), 7.72 (s, 1H), 4.97 (s, 2H), 4.37 (s, 2H).

[0429] Step 8: (R)-5-fluoro-7-(trifluoromethyl)isochroman-4-ol Under hydrogen atmosphere, [(S,S)-N-(2-amino-1,2-diphenylethyl)-p-toluenesulfonamide]chloro(p-cymene)ruthenium(II) (599 mg, 940 μmol) was added to a mixture of 5-fluoro-7-(trifluoromethyl)isocyanam-4-one (4.4 g, 18.8 mmol) in a formic acid-Et3N complex (5:2, 20 mL). The mixture was stirred at 0 °C for 2 h, then slowly heated to 25 °C and stirred for 12 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / EtOAc = 30 / 1 to 4 / 1) to give 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 = 15.6Hz, 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).

[0430] Step 9: (S)-N-(5-fluoro-7-(trifluoromethyl)isochroman-4-yl)-N-methyl-2-nitrobenzenesulfonamide At 0 °C, PPh3 (1.22 g, 4.66 mmol) and DIAD (941.85 mg, 4.66 mmol) were added to a solution of (R)-5-fluoro-7-(trifluoromethyl)isocyanuric-4-ol (1.0 g, 4.23 mmol) and N-methyl-2-nitrobenzenesulfonamide (1.01 g, 4.66 mmol) in THF (16 mL). The mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / EtOAc = 5 / 1 to 1 / 1) to give the title compound (1.8 g, 98%). LC-MS (M+Na) + = 457.1.

[0431] Step 10: (S)-5-fluoro-N-methyl-7-(trifluoromethyl)isochroman-4-amine At 0 °C, lithium hydroxide monohydrate (3.0 g, 72.5 mmol) and dodecane-1-thiol (14.7 g, 72.5 mmol) were added to a solution of (S)-N-(5-fluoro-7-(trifluoromethyl)isocyanuric-4-yl)-N-methyl-2-nitrobenzenesulfonamide (6.3 g, 14.5 mmol) in THF (63 mL) and DMF (6.3 mL). The mixture was stirred at 25 °C for 12 h. The pH of the mixture was adjusted to approximately 2 with hydrochloric acid (2 M), and the mixture was washed with EtOAc (3 x 50 mL). The pH of the aqueous layer was adjusted to approximately 13 with aqueous NaOH (2 M), and the mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (70 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (1.1 g, 30%). LC-MS (M+H) + = 250.2.

[0432] Step 11: (S)-5-amino-N-(5-fluoro-7-(trifluoromethyl)isocyanate-4-yl)-N-methyl-1-((2-(trimethyl) (methylsilyl)ethoxy)methyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide BOPCl (398 mg, 1.56 mmol) and DIPEA (467 mg, 3.61 mmol) were added to a solution of (S)-5-fluoro-N-methyl-7-(trifluoromethyl)isocyano-4-amine (0.30 g, 1.20 mmol) and 5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid (463 mg, 1.32 mmol) in THF (10 mL). The mixture was stirred at 40 °C for 2 h and cooled to room temperature. The mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (0.55 g, 79%). LC-MS (M+H) + = 581.3.

[0433] Step 12: (S)-5-amino-N-(5-fluoro-7-(trifluoromethyl)isocyanate-4-yl)-N-methyl-6,8-dihydro- 1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide A solution of (S)-5-amino-N-(5-fluoro-7-(trifluoromethyl)isocyano-4-yl)-N-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide (0.55 g, 0.95 mmol) in TFA (4 mL) was stirred for 0.5 h at 40 °C. The mixture was cooled to room temperature and concentrated under reduced pressure. Methanol-ammonia (7.0 M, 4 mL) was added to the residue, and the mixture was stirred at 25 °C for 0.5 h. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to give 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.

[0434] Example 83: (R)-5-amino-N,6-dimethyl-N-((1R,4S)-1-methyl-7-(trifluoromethyl)isocyano-4-yl)-6,8-dihydro-1H-furano[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxamide Step 1: (R)-1-(2-bromo-5-(trifluoromethyl)phenyl)ethane-1-ol [(R,R)-N-(2-amino-1,2-diphenylethyl)-p-toluenesulfonamide]chloro(p-cymene)ruthenium(II) (1.33 g, 2.1 mmol) was added to a mixture of 1-(2-bromo-5-(trifluoromethyl)phenyl)ethyl-1-one (11.2 g, 41.9 mmol) in a formic acid-Et3N complex (5:2, 11 mL) at -18 °C under hydrogen atmosphere. The mixture was stirred at 0 °C for 2 h and then at room temperature for 12 h. The mixture was partitioned between saturated NaHCO3 (150 mL) and EtOAc (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:EtOAc = 20:1) to give the title compound (10.5 g, 93%). LC-MS (M+H) + = 269.1.

[0435] Step 2: (R)-2-(1-(allyloxy)ethyl)-1-bromo-4-(trifluoromethyl)benzene NaH (60%, 1.78 g, 44.6 mmol) was added to a solution of (R)-1-(2-bromo-5-(trifluoromethyl)phenyl)ethyl-1-ol (10.0 g, 37.2 mmol) in DMF (100 mL) at 0 °C under nitrogen atmosphere. After 30 min, allyl bromide (5.85 g, 48.3 mol) was added, and the mixture was stirred at 25 °C for 3 h. The reaction mixture was poured into water (150 mL) and extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (PE:EtOAc = 20:1) to give the title compound (10.4 g, 90%). 1 H 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.

[0436] Step 3: (R)-1-Methyl-4-methylene-7-(trifluoromethyl)isocyanate 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 to a solution of (R)-2-(1-(allyloxy)ethyl)-1-bromo-4-(trifluoromethyl)benzene (10.4 g, 33.7 mmol) in DMF (250 mL). The mixture was stirred at 100 °C under nitrogen for 16 h and cooled to room temperature. The mixture was poured into water (300 mL) and extracted with EtOAc (2 x 400 mL). The combined organic layers were washed with brine (3 x 300 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The crude product was purified by silica gel chromatography (PE: EtOAc = 30: 1) to give the title compound (5.7 g, 74%). 1 H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 8.2Hz, 1H), 7.48 (d, J = 7.9 Hz, 1H), 7.37 (s, 1H), 5.69 (s, 1H), 5.13 (s, 1H), 4.89 (q, J = 6.4 Hz, 1H), 4.57, 4.37 (ABq, J = 13.4 Hz, 2H), 1.60 (d, J = 6.5 Hz, 3H).

[0437] Step 4: (R)-1-Methyl-7-(trifluoromethyl)isocyanate-4-one Add potassium (VI) osmium tetroxide dihydrate (920 mg, 2.5 mmol), sodium periodate (21.4 g, 100 mmol), and 2,6-dimethylpyridine (5.4 g, 50 mmol) to a solution of (R)-1-methyl-4-methylene-7-(trifluoromethyl)isocyanate (5.7 g, 25 mmol) in dioxane (150 mL) and water (30 mL). Stir the mixture at 25 °C for 2 h. Filter the solid, dilute the filtrate with water (250 mL), and extract with EtOAc (2 x 350 mL). Wash the combined organic layers sequentially with saturated Na₂S₂O₃ (350 mL), hydrochloric acid (1 M, 300 mL), and brine (200 mL). Dry the organic layers with Na₂SO₄, filter, and concentrate under vacuum. The residue was purified by silica gel chromatography (PE:EtOAc = 20:1) to give the title compound (5.6 g, 97%). 1 H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 8.1 Hz, 1H), 7.68 (d, J =8.0 Hz, 1H), 7.51 (s, 1H), 4.96 (q, J = 6.4 Hz, 1H), 4.56, 4.33 (ABq, J = 17.1Hz, 2H), 1.70 (d, J = 6.6 Hz, 3H). LC-MS (M+H) + =231.3.

[0438] Step 5: (1R,4R)-1-methyl-7-(trifluoromethyl)isochroman-4-ol At –18 °C, BH3 (1.0 M, 25.6 mmol, 25.6 mL) in THF was added to a solution of (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxoniborone (674 mg, 2.43 mmol) in THF (10 mL). The mixture was stirred for 10 min, and a solution of (R)-1-methyl-7-(trifluoromethyl)isocyanam-4-one (5.6 g, 24.3 mmol) in THF (70 mL) was added dropwise. The mixture was stirred at –10 °C under nitrogen for 1 h. MeOH (10 mL) was added dropwise, and the mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE:EtOAc = 4:1) to give the title compou...

Claims

1. A compound having formula (I): (I) Or its N-oxide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analogue, wherein: L is a single bond or -C(R) 8 R 9 )-; R 1 and R 2 Each is independently selected from hydrogen and -C 1-8 Alkyl, -C3-C8 cycloalkyl, -C3-C 12 Cycloalkenyl, 3- to 12-membered heterocyclic groups, -C6-C 12 aryl and 5- to 12-membered heteroaryl, wherein the -C 1-8 Alkyl, -C3-C8 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 Each of the aryl and 5- to 12-membered heteroaryl groups is optionally substituent R. 1a Replace; or R 1 and R 2 Together with the nitrogen atoms to which they are attached, they form 3- to 8-membered unsaturated or saturated rings, the rings containing 0-3 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the rings are optionally substituents R. 1a replace; R 1a Independently, it is hydrogen, halogen, deuterium, -C 1-8 Alkyl, -C3-C8 cycloalkyl, -C3-C 12 Cycloalkenyl, 3- to 12-membered heterocyclic groups, -C6-C 12 Aryl, 5- to 12-membered 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, wherein the -C 1-8 Alkyl, -C3-C8 cycloalkyl, -C3-C 12 Cycloalkenyl, 3- to 12-membered heterocyclic groups, -C6-C 12 Each of the aryl and 5- to 12-membered heteroaryl groups is optionally substituent R. 1d Replace; or Two Rs 1a Together with one or more atoms to which they are attached, they form 3- to 8-membered unsaturated or saturated rings, the rings comprising 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the rings optionally being substituents R. 1d replace; R 1b and R 1c Each is independently selected from hydrogen and -C 1-8 Alkyl, -C3-C8 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 aryl and 5- to 12-membered heteroaryl, wherein the -C 1-8 Alkyl, -C3-C8 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 Each of the aryl and 5- to 12-membered heteroaryl groups is optionally substituent R. 1e replace; R 1d and R 1e Each is independently hydrogen, halogen, -C 1-8 Alkyl, -C3-C8 cycloalkyl, -C3-C 12 Cycloalkenyl, 3- to 12-membered heterocyclic groups, -C6-C 12 Aryl, 5- to 12-membered 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, wherein the -C 1-8 Alkyl, -C3-C8 cycloalkyl, -C3-C 12 Cycloalkenyl, 3- to 12-membered heterocyclic groups, -C6-C 12 Each of the aryl and 5- to 12-membered heteroaryl groups is optionally substituent R. 1h replace; R 1f and R 1g Each is independently selected from hydrogen and -C 1-8 Alkyl, -C3-C8 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 aryl and 5- to 12-membered heteroaryl, wherein the -C 1-8 Alkyl, -C3-C8 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 Each of the aryl and 5- to 12-membered heteroaryl groups is optionally substituent R. 1i replace; R 1h and R 1i Each is independently hydrogen, halogen, -C 1-8 Alkyl, -C3-C8 cycloalkyl, -C3-C 12 Cycloalkenyl, 3- to 12-membered heterocyclic groups, -C6-C 12 Aryl, 5- to 12-membered 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, wherein the -C 1-8 Alkyl, -C3-C8 cycloalkyl, -C3-C 12 Cycloalkenyl, 3- to 12-membered heterocyclic groups, -C6-C 12 Each of the aryl and 5- to 12-membered heteroaryl groups is optionally substituted with at least one substituent selected from the group consisting of: halogen, -C 1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 alkenyl, -C 2-8 Alkyne group, -C3-C8 cycloalkyl group, 3- to 8-membered heterocyclic group, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, -CN, -OH, -NH2 or oxo; R 1j and R 1k Each is independently selected from hydrogen and -C 1-8 Alkyl, -C3-C8 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 aryl and 5- to 12-membered heteroaryl, wherein the -C 1-8 Alkyl, -C3-C8 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 Each of the aryl and 5- to 12-membered heteroaryl groups is optionally substituted with at least one substituent selected from the group consisting of: halogen, -C 1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 alkenyl, -C 2-8 Alkyne group, -C3-C8 cycloalkyl group, 3- to 8-membered heterocyclic group, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, -CN, -OH, -NH2 or oxo; R 3 Selected from hydrogen, halogens, -C 1-8 Alkyl, -C3-C8 cycloalkyl, -CN, -OH, or -NH2, wherein the -C 1-8 Each of the alkyl and -C3-C8 cycloalkyl groups is optionally substituted with at least one substituent selected from the group consisting of: halogen, -C 1-8 Alkoxy, -C 1-8 Alkyl groups, -C3-C8 cycloalkyl groups, and 3- to 8-membered heterocyclic groups; R 4 R 5 R 6 R 7 R 8 and R 9 Each is independently selected from hydrogen, halogen, -C 1-8 Alkyl or -C3-C8 cycloalkyl, wherein the -C 1-8 Each of the alkyl and -C3-C8 cycloalkyl groups is optionally substituted with at least one substituent selected from the group consisting of: halogen, -C 1-8 Alkoxy, -C 1-8 Alkyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic groups, C6-C 12 Aryl, 5- to 12-membered 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 ; R 4a and R 4b Each is independently hydrogen, -C 1-8 Alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic groups, -C6-C 12 aryl, or 5- to 12-membered heteroaryl; the -C 1-8 Alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic groups, -C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted by at least one of the following substituents: halogen, -OH, -C. 1-8 Alkyl, -C 1-8 Alkoxy, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 alkenyl, -C 2-8 Alkyne group, -C3-C8 cycloalkyl group, 3- to 8-membered heterocyclic group, -C6-C 12 Aryl, or 5 to 12-membered heteroaryl.

2. The compound of claim 1, wherein the compound has formula (IIa) or (IIb): Or its N-oxide, or its pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analogue.

3. The compound of claim 2, wherein the compound has formula (IIc) or (IId): Or its N-oxide, or its pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analogue.

4. The compound of claim 3, wherein the compound has the formula (IIe), (IIIf), (IIg), or (IIh): Or its N-oxide, or its pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analogue.

5. The compound of claim 1, wherein the compound has formula (IIIa): (IIIa), Or its N-oxide, or its pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analogue, wherein n1 is 0, 1, 2, or 3.

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

7. The compound of claim 6, wherein n1 is 1.

8. The compound according to any one of claims 5-7, wherein the compound has formula (IIIb): (IIIb), Or its N-oxide, or its pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analogue.

9. The compound according to any one of claims 5-8, wherein the compound has formula (IIIc): (IIIc), Or its N-oxide, or its pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analogue.

10. The compound according to any one of claims 5-9, wherein the compound has the formula (IIId), (IIIe), (IIIf), or (IIIg): Or its N-oxide, or its pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analogue.

11. The compound according to any one of claims 5-10, wherein the compound has the formula (IIIh), (IIIi), (IIIj), or (IIIk): Or its N-oxide, or its pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analogue.

12. The compound of claim 1, wherein the compound has the formula (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (IVg), or (IVh): (IVa); (IVb); (IVc); (IVd); (IVe); (IVf); (IVh); Or its N-oxide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analogue thereof, wherein n2 is 0, 1, 2, or 3.

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

14. The compound of claim 12 or 13, wherein the compound has the formula (IV1), (IV2), (IV3), (IV4), (IV5), (IV6), (IV7), (IV8), (IV9), (IV1), (IV2), (IV1), (IV2), (IV3), (IV4), (IV5), (IV6), (IV7), or (IV8): Or its N-oxide, or its pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analogue.

15. The compound of claim 1, wherein the compound has the formula (Va): (And), Or its N-oxide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analogue, wherein: n3 is 0, 1, 2, 3, or 4; and Each occurrence of X is independently either N or CH.

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

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

18. The compound of claim 16, wherein the compound has the formula (Vb), (Vc), (Vd), (Ve), or (Vf): Or its N-oxide, or its pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analogue.

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

20. The compound of claim 19, wherein n3 is 1.

21. The compound according to any one of claims 15-20, wherein the compound has the formula (Vg), (Vh), (Vi), (Vj), (Vk), (Vl), (Vm), (Vn), or (Vo): Or its N-oxide, or its pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analogue.

22. The compound of claim 21, wherein the compound has the formula (Vp), (Vq), (Vr), (Vs), (Vt), (Vu), (Vv), (Vw), (Vx), (Vy), or (Vz): Or its N-oxide, or its pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analogue.

23. A compound having formula (VI), (WE) Or its N-oxide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analogue, wherein: R 1 and R 2 Each is independently selected from hydrogen and -C 1-8 Alkyl, -C3-C8 cycloalkyl, -C3-C 12 Cycloalkenyl, 3- to 12-membered heterocyclic groups, -C6-C 12 aryl and 5- to 12-membered heteroaryl, wherein the -C 1-8 Alkyl, -C3-C8 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 Each of the aryl and 5- to 12-membered heteroaryl groups is optionally substituent R. 1a Replace; or R 1 and R 2 Together with the nitrogen atoms to which they are attached, they form 3- to 8-membered unsaturated or saturated rings, the rings containing 0-3 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the rings are optionally substituents R. 1a replace; R 1a Independently, it is hydrogen, halogen, deuterium, -C 1-8 Alkyl, -C3-C8 cycloalkyl, -C3-C 12 Cycloalkenyl, 3- to 12-membered heterocyclic groups, -C6-C 12 Aryl, 5- to 12-membered 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, wherein the -C 1-8 Alkyl, -C3-C8 cycloalkyl, -C3-C 12 Cycloalkenyl, 3- to 12-membered heterocyclic groups, -C6-C 12 Each of the aryl and 5- to 12-membered heteroaryl groups is optionally substituent R. 1d Replace; or Two Rs 1a Together with one or more atoms to which they are attached, they form 3- to 8-membered unsaturated or saturated rings, the rings comprising 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the rings optionally being substituents R. 1d replace; R 1b and R 1c Each is independently selected from hydrogen and -C 1-8 Alkyl, -C3-C8 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 aryl and 5- to 12-membered heteroaryl, wherein the -C 1-8 Alkyl, -C3-C8 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 Each of the aryl and 5- to 12-membered heteroaryl groups is optionally substituent R. 1e replace; R 1d and R 1e Each is independently hydrogen, halogen, -C 1-8 Alkyl, -C3-C8 cycloalkyl, -C3-C 12 Cycloalkenyl, 3- to 12-membered heterocyclic groups, -C6-C 12 Aryl, 5- to 12-membered 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, wherein the -C 1-8 Alkyl, -C3-C8 cycloalkyl, -C3-C 12 Cycloalkenyl, 3- to 12-membered heterocyclic groups, -C6-C 12 Each of the aryl and 5- to 12-membered heteroaryl groups is optionally substituent R. 1h replace; R 1f and R 1g Each is independently selected from hydrogen and -C 1-8 Alkyl, -C3-C8 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 aryl and 5- to 12-membered heteroaryl, wherein the -C 1-8 Alkyl, -C3-C8 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 Each of the aryl and 5- to 12-membered heteroaryl groups is optionally substituent R. 1i replace; R 1h and R 1i Each is independently hydrogen, halogen, -C 1-8 Alkyl, -C3-C8 cycloalkyl, -C3-C 12 Cycloalkenyl, 3- to 12-membered heterocyclic groups, -C6-C 12 Aryl, 5- to 12-membered 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, wherein the -C 1-8 Alkyl, -C3-C8 cycloalkyl, -C3-C 12 Cycloalkenyl, 3- to 12-membered heterocyclic groups, -C6-C 12 Each of the aryl and 5- to 12-membered heteroaryl groups is optionally substituted with at least one substituent selected from the group consisting of: halogen, -C 1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 alkenyl, -C 2-8 Alkyne group, -C3-C8 cycloalkyl group, 3- to 8-membered heterocyclic group, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, -CN, -OH, -NH2 or oxo; R 1j and R 1k Each is independently selected from hydrogen and -C 1-8 Alkyl, -C3-C8 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 aryl and 5- to 12-membered heteroaryl, wherein the -C 1-8 Alkyl, -C3-C8 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 Each of the aryl and 5- to 12-membered heteroaryl groups is optionally substituted with at least one substituent selected from the group consisting of: halogen, -C 1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 alkenyl, -C 2-8 Alkyne group, -C3-C8 cycloalkyl group, 3- to 8-membered heterocyclic group, -C6-C 12 aryl, 5- to 12-membered heteroaryl, -CN, -OH, -NH2, or oxo; and R 6 and R 7 Each is independently selected from hydrogen or methyl.

24. The compound of claim 23, wherein the compound has formula (VIIa): (VIIa), Or its N-oxide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analogue, wherein: n4 is 0, 1, 2, 3, or 4; and Each occurrence of Y is independently either N or CH.

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

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

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

28. The compound according to any one of claims 25-27, wherein the compound has the formula (VIIb), (VIIc), (VIId), (VIIe), or (VIIf): Or its N-oxide, or its pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analogue.

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

30. The compound of claim 29, wherein n4 is 1.

31. The compound according to any one of claims 23-30, wherein the compound has the formula (VIIg), (VIIh), (VIIi), (VIIj), (VIIk), (VIIl), (VIIm), (VIIn), (VIIo), (VIIp), or (VIIq): Or its N-oxide, or its pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analogue.

32. The compound of claim 23, wherein the compound has formula (VIIIa): (VIIIa) Or its N-oxide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analogue, wherein: n5 is 0, 1, 2, 3 or 4; Z 1 and Z 2 Each is independently selected from O or CH2; and Z 3 and Z 4 Each is independently selected from N or CH.

33. The compound of claim 32, wherein the compound has the formula (VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIg), (VIIIh), (VIIIi), (VIIIj), (VIIIk), (VIIIl), (VIIIm), (VIIIn), or (VIIIo): Or its N-oxide, or its pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analogue.

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

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

36. The compound according to any one of claims 1-35, wherein R 1 and R 2 Each is independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C3-C 12 Cycloalkenyl, 3- to 12-membered heterocyclic, phenyl, and 5- to 12-membered heteroaryl, wherein each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 12-membered heterocyclic, phenyl, and 5- to 12-membered heteroaryl groups is optionally substituent R. 1a Replace; or R 1 and R 2 Together with the nitrogen atoms to which they are attached, they form 3-, 4-, 5-, 6-, 7-, or 8-membered unsaturated or saturated rings, said rings containing 0, 1, 2, or 3 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur, and said rings are optionally substituents R. 1a replace; R 1a Independently, it is hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C3-C 12 Cycloalkenyl, 3- to 12-membered heterocyclic, phenyl, 5- to 12-membered 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 Oxylated or -CN, wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C3-C 12 Each of the cycloalkenyl, 3- to 12-membered heterocyclic, phenyl, or 5- to 12-membered heteroaryl groups is optionally substituent R. 1d Replace; or Two Rs 1a Together with one or more atoms to which they are attached, they form 3-, 4-, 5-, 6-, 7-, or 8-membered unsaturated or saturated rings, said rings comprising 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and said rings optionally being substituents R. 1d replace; R 1b and R 1c Each of the following groups is independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 12-membered heterocyclic groups, phenyl, or 5- to 12-membered heteroaryl groups, wherein each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 12-membered heterocyclic groups, phenyl, or 5- to 12-membered heteroaryl groups is optionally substituent R. 1e replace; R 1d and R 1e Each of the following is independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C3-C 12 Cycloalkenyl, 3- to 12-membered heterocyclic, phenyl, 5- to 12-membered 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 Oxylated or -CN, wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C3-C 12 Each of the cycloalkenyl, 3- to 12-membered heterocyclic, phenyl, and 5- to 12-membered heteroaryl groups is optionally substituent R. 1h replace; R 1f and R 1g Each of the following groups is independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 12-membered heterocyclic groups, phenyl, or 5- to 12-membered heteroaryl groups, wherein each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 12-membered heterocyclic groups, phenyl, or 5- to 12-membered heteroaryl groups is optionally substituent R. 1i replace; R 1h and R 1i Each of the following is independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C3-C 12 Cycloalkenyl, 3- to 12-membered heterocyclic, phenyl, 5- to 12-membered 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 Oxylated or -CN, wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C3-C 12 Each of the cycloalkenyl, 3- to 12-membered heterocyclic, phenyl, and 5- to 12-membered heteroaryl groups is optionally substituted by at least one of the following substituents: -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, -C 2-8 alkenyl, -C 2-8 Alkyne, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic groups, phenyl, 5- to 12-membered heteroaryl, -CN, -OH, -NH2 or oxo; R 1j and R 1k Each is independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 12-membered heterocyclic groups, phenyl, and 5- to 12-membered heteroaryl groups. Each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 12-membered heterocyclic groups, phenyl, and 5- to 12-membered heteroaryl groups is optionally substituted by at least one of the following substituents: -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, -C 2-8 alkenyl, -C 2-8 Alkyne, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic groups, phenyl, 5- to 12-membered heteroaryl, -CN, -OH, -NH2 or oxo.

37. The compound according to any one of claims 1-36, wherein R 1 and R 2 Each of the following is independently selected from hydrogen, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, chromanyl, isochoryl, dihydropyranopyridyl, pyrimidinyl, tetrahydro-2H-pyranyl, pyrazinyl, pyrazinyl, dihydrofuranopyridyl, tetrahydronaphthalenyl, benzo[d]thiazolyl, triazolyl, pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl, or tetrahydrofuranopyridyl, wherein the methyl Each of the following groups is optionally substituent R: ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, chromanyl, isochoryl, dihydropyranopyridyl, pyrimidinyl, tetrahydro-2H-pyranyl, pyrazinyl, pyrazinyl, dihydrofuranopyridyl, tetrahydronaphthalenyl, benzo[d]thiazolyl, triazolyl, pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl, or tetrahydrofuranopyridyl. 1a Replace; or R 1 and R 2 Together with the nitrogen atoms to which they are attached, they form 3-, 4-, 5-, 6-, 7-, or 8-membered unsaturated or saturated rings, said rings containing 0, 1, 2, or 3 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur; said rings are optionally substituents R. 1a replace; R 1a Independently, it is hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, chromanyl, isochoryl, dihydropyranopyridyl, pyrimidinyl, tetrahydro-2H-pyranyl, pyrazinyl, pyrazinyl, dihydrofuranopyridyl, tetrahydronaphthalenyl, benzo[d]thiazolyl, triazolyl, pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, tetrahydrofuranopyridyl-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 Oxylated or -CN, wherein each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, chromanyl, isochoryl, dihydropyranopyridyl, pyrimidinyl, tetrahydro-2H-pyranyl, pyrazinyl, pyrazinyl, dihydrofuranopyridyl, tetrahydronaphthalenyl, benzo[d]thiazolyl, triazolyl, pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl, or tetrahydrofuranopyridyl is optionally substituent R. 1d Replace; or Two Rs 1a Together with one or more atoms to which they are attached, they form ternary, quaternary, quinary, or hexaternary unsaturated or saturated rings, said rings containing 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said rings are optionally substituents R. 1d replace; R 1b and R 1c Each of the following is independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, chromanyl, isochoryl, dihydropyranopyridyl, pyrimidinyl, tetrahydro-2H-pyranyl, pyrazinyl, pyrazinyl, dihydrofuranopyridyl, tetrahydronaphthalenyl, benzo[d]thiazolyl, triazolyl, pyridyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl, or tetrahydrofuranopyridyl, wherein the methyl Each of the following groups is optionally substituent R: ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, chromanyl, isochoryl, dihydropyranopyridyl, pyrimidinyl, tetrahydro-2H-pyranyl, pyrazinyl, pyrazinyl, dihydrofuranopyridyl, tetrahydronaphthalenyl, benzo[d]thiazolyl, triazolyl, pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl, or tetrahydrofuranopyridyl. 1e replace; R 1d and R 1e Each of the following is independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, chromanyl, isochoryl, dihydropyranopyridyl, pyrimidinyl, tetrahydro-2H-pyranyl, pyrazinyl, pyrazinyl, dihydrofuranopyridyl, tetrahydronaphthalenyl, benzo[d]thiazolyl, triazolyl, pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl, tetrahydrofuranopyridyl, -OR 1f -SO2R 1f -COR 1f -CO2R 1f -CONR 1f R 1g -NR 1f R 1g -NR 1f COR 1g -NR 1f CO2R 1g Oxylated or -CN, wherein each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, chromanyl, isochoryl, dihydropyranopyridyl, pyrimidinyl, tetrahydro-2H-pyranyl, pyrazinyl, pyrazinyl, dihydrofuranopyridyl, tetrahydronaphthalenyl, benzo[d]thiazolyl, triazolyl, pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl, or tetrahydrofuranopyridyl is optionally substituent R. 1h replace; R 1f and R 1g Each of the following is independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, chromanyl, isochoryl, dihydropyranopyridyl, pyrimidinyl, tetrahydro-2H-pyranyl, pyrazinyl, pyrazinyl, dihydrofuranopyridyl, tetrahydronaphthalenyl, benzo[d]thiazolyl, triazolyl, pyridyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl, or tetrahydrofuranopyridyl, wherein the methyl Each of the following groups is optionally substituent R: ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, chromanyl, isochoryl, dihydropyranopyridyl, pyrimidinyl, tetrahydro-2H-pyranyl, pyrazinyl, pyrazinyl, dihydrofuranopyridyl, tetrahydronaphthalenyl, benzo[d]thiazolyl, triazolyl, pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl, or tetrahydrofuranopyridyl. 1i replace; R 1h and R 1i Each of the following is independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, chromanyl, isochoryl, dihydropyranopyridyl, pyrimidinyl, tetrahydro-2H-pyranyl, pyrazinyl, pyrazinyl, dihydrofuranopyridyl, tetrahydronaphthalenyl, benzo[d]thiazolyl, triazolyl, pyridyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl, tetrahydrofuranopyridyl, -OR 1j -COR 1j -CO2R 1j -CONR 1j R 1k -NR 1j R 1k -NR 1j COR 1k -NR 1j CO2R 1k Oxylated or -CN, wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, chromanyl, isochoryl, dihydropyranopyridyl, pyrimidinyl, tetrahydro-2H-pyranyl, pyrazinyl, pyrazinyl, dihydrofuranopyridyl, tetrahydronaphthalenyl, benzo[d]thiazolyl, triazolyl, pyridyl, quinolinyl, iso Each of quinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl, or tetrahydrofuranopyridyl is optionally substituted with at least one of the following substituents: -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, -C 2-8 alkenyl, -C 2-8 Alkyne, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, pyridyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl, tetrahydrofuranopyridyl, -CN, -OH, -NH2 or oxo; and R 1j and R 1k Each of the following is independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, chromanyl, isochoryl, dihydropyranopyridyl, pyrimidinyl, tetrahydro-2H-pyranyl, pyrazinyl, pyrazinyl, dihydrofuranopyridyl, tetrahydronaphthalenyl, benzo[d]thiazolyl, triazolyl, pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl, or tetrahydrofuranopyridyl, wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ... Each of the following groups is optionally substituted by at least one of the following substituents: cycloheptyl, cyclooctyl, phenyl, chromanyl, isochoryl, dihydropyranopyridyl, pyrimidinyl, tetrahydro-2H-pyranyl, pyrazinyl, pyrazinyl, dihydrofuranopyridyl, tetrahydronaphthalenyl, benzo[d]thiazolyl, triazolyl, pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl, or tetrahydrofuranopyridyl, and is optionally substituted by at least one of the following substituents: -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, -C 2-8 alkenyl, -C 2-8 Alkyne, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, pyridyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl, tetrahydrofuranopyridyl, -CN, -OH, -NH2 or oxo.

38. The compound of claim 37, wherein R 1 and R 2 Each of the following is independently selected from hydrogen, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, chromanyl, isochoryl, dihydropyranopyridyl, pyrimidinyl, tetrahydro-2H-pyranyl, pyrazinyl, pyrazinyl, dihydrofuranopyridyl, tetrahydronaphthalenyl, benzo[d]thiazolyl, triazolyl, pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl, or tetrahydrofuranopyridyl, wherein the methyl Each of the following groups is optionally substituent R: ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, chromanyl, isochoryl, dihydropyranopyridyl, pyrimidinyl, tetrahydro-2H-pyranyl, pyrazinyl, pyrazinyl, dihydrofuranopyridyl, tetrahydronaphthalenyl, benzo[d]thiazolyl, triazolyl, pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl, or tetrahydrofuranopyridyl. 1a Replace; or R 1 and R 2 Together with the nitrogen atoms to which they are attached, they form 3-, 4-, 5-, 6-, 7-, or 8-membered unsaturated or saturated rings, said rings containing 0, 1, 2, or 3 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur; said rings are optionally substituents R. 1a replace; R 1a Independently, it is hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, chromanyl, isochoryl, dihydropyranopyridyl, pyrimidinyl, tetrahydro-2H-pyranyl, pyrazinyl, pyrazinyl, dihydrofuranopyridyl, tetrahydronaphthalenyl, benzo[d]thiazolyl, triazolyl, pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl, tetrahydrofuranopyridyl, -OR 1b or -CN, wherein each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, chromanyl, isochoryl, dihydropyranopyridyl, pyrimidinyl, tetrahydro-2H-pyranyl, pyrazinyl, pyrazinyl, dihydrofuranopyridyl, tetrahydronaphthalenyl, benzo[d]thiazolyl, triazolyl, pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl, or tetrahydrofuranopyridyl is optionally substituent R. 1d Replace; or Two Rs 1a Together with one or more atoms to which they are attached, they form ternary, quaternary, quinary, or hexaternary unsaturated or saturated rings, said rings containing 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said rings are optionally substituents R. 1d replace; R 1b Each can be independently hydrogen, methyl, ethyl, propyl, cyclopropyl, or cyclobutyl; R 1d Each of the following is independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, chromanyl, isochoryl, dihydropyranopyridyl, pyrimidinyl, tetrahydro-2H-pyranyl, pyrazinyl, pyrazinyl, dihydrofuranopyridyl, tetrahydronaphthalenyl, benzo[d]thiazolyl, triazolyl, pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl, tetrahydrofuranopyridyl, -OR 1f -NR 1f R 1g -NR 1f COR 1g , oxo, -SO2R 1f or -CN, wherein each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, chromanyl, isochoryl, dihydropyranopyridyl, pyrimidinyl, tetrahydro-2H-pyranyl, pyrazinyl, pyrazinyl, dihydrofuranopyridyl, tetrahydronaphthalenyl, benzo[d]thiazolyl, triazolyl, pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl, or tetrahydrofuranopyridyl is optionally substituent R. 1h replace; R 1f and R 1g Each of the following is independently selected from hydrogen, methyl, ethyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, chromanyl, isochoryl, dihydropyranopyridyl, pyrimidinyl, tetrahydro-2H-pyranyl, pyrazinyl, pyrazinyl, dihydrofuranopyridyl, tetrahydronaphthalenyl, benzo[d]thiazolyl, triazolyl, pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl, or tetrahydrofuranopyridyl, wherein the methyl, Ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, chromanyl, isochoryl, dihydropyranopyridyl, pyrimidinyl, tetrahydro-2H-pyranyl, pyrazinyl, pyrazinyl, dihydrofuranopyridyl, tetrahydronaphthalenyl, benzo[d]thiazolyl, triazolyl, pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl, or tetrahydrofuranopyridyl are optionally substituents R. 1i Replace; and R 1h and R 1i Each of these can be independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, chromanyl, isochoryl, dihydropyranopyridyl, pyrimidinyl, tetrahydro-2H-pyranyl, pyrazinyl, pyrazinyl, dihydrofuranopyridyl, tetrahydronaphthalenyl, benzo[d]thiazolyl, triazolyl, pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl, tetrahydrofuranopyridyl, -OH, or -CN.

39. The compound of claim 38, wherein R 1 and R 2 Each of the following groups is independently selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, chromanyl, isochoryl, dihydropyranopyridyl, pyrimidinyl, tetrahydro-2H-pyranyl, pyrazinyl, pyrazinyl, dihydrofuranopyridyl, tetrahydronaphthalenyl, benzo[d]thiazolyl, pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl, or tetrahydrofuranopyridyl pyridyl, wherein each of the methyl, ethyl, propyl, phenyl, chromanyl, isochoryl, dihydropyranopyridyl, pyrimidinyl, tetrahydro-2H-pyranyl, pyrazinyl, pyrazinyl, dihydrofuranopyridyl, tetrahydronaphthalenyl, benzo[d]thiazolyl, pyridyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl, or tetrahydrofuranopyridyl is optionally substituent R. 1a Replace; or R 1 and R 2 Together with the nitrogen atoms to which they are attached, they form a 6-membered unsaturated or saturated ring, which is optionally substituent R. 1a replace; R 1a Independently, it is hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrimidinyl, pyridazinyl, pyrazinyl, dihydrofuranopyridinyl, benzo[d]thiazolyl, pyridinyl, quinolinyl, isoquinolinyl, thiazolyl, -OR 1b or -CN, wherein each of the methyl, ethyl, propyl, phenyl, pyrimidinyl, pyridazinyl, pyrazinyl, dihydrofuranopyridinyl, benzo[d]thiazolyl, pyridinyl, quinolinyl, isoquinolinyl, or thiazolyl groups is optionally substituent R. 1d replace; R 1b Each can be independently hydrogen, methyl, ethyl, propyl, cyclopropyl, or cyclobutyl; R 1d Each of the following is independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, phenyl, pyrimidinyl, tetrahydro-2H-pyranyl, pyridazinyl, triazolyl, pyridinyl, pyrazolyl, imidazoleyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl, tetrahydrofuranopyridyl, -OR 1f -SO2R 1f or -CN, wherein each of the methyl, ethyl, propyl, butyl, phenyl, pyrimidinyl, tetrahydro-2H-pyranyl, pyridazinyl, pyrazinyl, triazolyl, pyridinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl, or tetrahydrofuranopyridyl is optionally substituent R. 1h replace; R 1f Each is independently selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or phenyl, wherein each of the methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or phenyl groups is optionally substituented by at least one substituent R. 1i replace; R 1h and R 1i Each can be independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -OH, or -CN.

40. The compound according to any one of claims 1-35, wherein R 1 and R 2 Each is independently selected from -C 1-8 Alkyl, -C3-C8 cycloalkyl, -C3-C 12 Cycloalkenyl and 3- to 12-membered heterocyclic groups, wherein the -C 1-8 Alkyl, -C3-C8 cycloalkyl, -C3-C 12 Each of the cycloalkenyl and 3- to 12-membered heterocyclic groups is optionally substituent R. 1a Replace; or R 1 and R 2 Together with the nitrogen atoms to which they are attached, they form 3- to 8-membered unsaturated or saturated rings, the rings containing 0-3 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the rings are optionally substituents R. 1a replace; R 1a Independently, it is hydrogen, halogen, deuterium, -C 1-8 Alkyl, -C3-C8 cycloalkyl, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, -OR 1b Or -CN, where -C 1-8 Alkyl, -C3-C8 cycloalkyl, -C6-C 12 Each of the aryl and 5- to 12-membered heteroaryl groups is optionally substituent R. 1d Replace; or Two Rs 1a Together with one or more atoms to which they are attached, they form 3- to 8-membered unsaturated or saturated rings, the rings comprising 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the rings optionally being substituents R. 1d replace; R 1b Each is independently selected from hydrogen and -C 1-8 Alkyl, wherein the -C 1-8 The alkyl group is optionally substituent for at least one R group. 1e replace; R 1d and R 1e Each is independently hydrogen, halogen, -C 1-8 Alkyl, -C3-C8 cycloalkyl, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, -OR 1f -SO2R 1f Or -CN, where -C 1-8 Alkyl, -C6-C 12 Each of the aryl and 5- to 12-membered heteroaryl groups is optionally substituent R. 1h replace; R 1f Each is independently selected from hydrogen and -C 1-8 Alkyl and -C3-C8 cycloalkyl, wherein the -C 1-8 Each of the alkyl and -C3-C8 cycloalkyl groups is optionally substituent R. 1i Replace; and R 1h and R 1i Each is independently hydrogen, halogen, -C 1-8 Alkyl or -CN.

41. The compound of claim 40, wherein R 1 and R 2 Each of the following groups is independently selected from methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, chromium, isochromium, pyridyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl, or tetrahydrofuranopyridyl, wherein each of the following groups is optionally substituent R: methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, chromium, isochromium, pyridyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl, or tetrahydrofuranopyridyl. 1a Replace; or R 1 and R 2 Together with the nitrogen atoms to which they are attached, they form 3-, 4-, 5-, 6-, 7-, or 8-membered unsaturated or saturated rings, said rings containing 0, 1, 2, or 3 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur; said rings are optionally substituents R. 1a replace; R 1a Independently, it is 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, dihydrofuranopyridyl, tetrahydrofuranopyridyl-OR 1b or -CN, wherein each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl, pyrimidinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl, or tetrahydrofuranopyridyl is optionally substituent R. 1d Replace; or Two Rs 1a Together with one or more atoms to which they are attached, they form ternary, quaternary, quinary, or hexaternary unsaturated or saturated rings, said rings containing 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said rings are optionally substituents R. 1d replace; R 1b Each of the following is independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl, wherein each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl groups is optionally substituent R. 1e replace; R 1d and R 1e Each of the following is independently 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, dihydrofuranopyridyl, tetrahydrofuranopyridyl, -OR 1f -SO2R 1f or -CN, wherein each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, phenyl, pyridyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl, or tetrahydrofuranopyridyl is optionally substituent R. 1h replace; R 1f Each of the following groups is independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, wherein each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl groups is optionally substituent R. 1i replace; R 1h and R 1i Each can be independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, or -CN.

42. The compound according to any one of claims 1-41, wherein R 1 and R 2 Each is independently selected from -Me, -Et, -Pr, -Bu, pentyl, -CF3, -CH2CF3, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ;or R 1 and R 2 Together with the nitrogen atoms to which they are attached, they form , , or .

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

44. The compound according to any one of claims 1-41 and 43, wherein R 1a Independently selected from hydrogen, methyl, ethyl, propyl, halogenated, methyl groups substituted with one or more halogens, C 3-5 cycloalkyl or -CN, or two R 1a Attached to the same atom to form C 3-5 Cycloalkyl.

45. The compound of claim 44, wherein R 1a Independently selected from hydrogen, methyl, ethyl, -F, -Cl, -Br, -I, -CF3, cyclopropyl, or -CN, or two Rs. 1a It attaches to the same atom to form a cyclopropyl group.

46. ​​The compound according to any one of claims 1-41 and 43-45, wherein R 1d Independently selected from hydrogen, halogenated, C 1-4 Alkyl groups, C substituted with one or more halogens 1-4 Alkyl groups, C groups substituted with -OH 1-4 Alkyl, -OC 1-4 Alkyl groups, -OC groups substituted with one or more halogens 1-4 Alkyl groups, C groups optionally substituted with fluorine 3-5 cycloalkyl, -SO2-C 1-4 Alkyl or -CN.

47. The compound of claim 46, wherein R 1d It is independently selected from hydrogen, -F, -Br, -Cl, -I, methyl, ethyl, propyl, butyl, -CF3, hydroxypropyl, methoxy, trifluoromethoxy, cyclopropyl, fluorocyclopropyl, cyclobutyl, -SO2CH3, or -CN.

48. The compound according to any one of claims 1-47, wherein R 2 It is C 1-8 alkyl.

49. The compound of claim 48, wherein R 2 It is methyl, ethyl, propyl, or butyl.

50. The compound according to any one of claims 1, 2, 5-22 and 36-49, wherein R 3 Selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -CN, -OH or -NH2.

51. The compound of claim 50, wherein R 3 Selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -CN, or -OH.

52. The compound of claim 51, wherein R 3 Selected from hydrogen, -F, -Cl, methyl, ethyl, propyl, and butyl.

53. The compound of claim 52, wherein R 3 It is hydrogen.

54. The compound according to any one of claims 1-3 and 5-53, wherein R 4 R 5 R 6 R 7 R 8 and R 9 Each of the following groups is independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, wherein each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl groups is optionally substituted by at least one of the following substituents: -F, -Cl, -Br, -I, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic group, phenyl, 5- to 12-membered heteroaryl group, 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 ;and R 4a and R 4b Each of the following is independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic group, phenyl, or 5- to 12-membered heteroaryl group; each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic group, phenyl, or 5- to 12-membered heteroaryl group is optionally substituted by at least one of the following substituents: -F, -Cl, -Br, -I, -OH, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 alkenyl, -C 2-8 Alkyne, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic groups, phenyl or 5- to 12-membered heteroaryl groups.

55. The compound of claim 54, wherein R 4 R 5 R 6 R 7 R 8 and R 9 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. The compound of claim 55, wherein R 4 R 5 R 6 R 7 R 8 and R 9 Each is independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, cyclopropyl, or cyclobutyl.

57. The compound of claim 56, wherein R 4 R 5 R 6 R 7 R 8 and R 9 Each is independently selected from hydrogen, -F, -Cl, -Br, -I, or methyl.

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

59. The compound according to any one of claims 1, 32, and 36-58, wherein the compound has the formula (VIIIp): Or its N-oxide, or its pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analogue, or its N-oxide, or its pharmaceutically acceptable salt, or its stereoisomer, or its tautomer, or its deuterated analogue, wherein: R 1a 'Independently selected from hydrogen, methyl, or ethyl; R 1a '' is hydrogen; or R 1a 'and R 1a Together with the atoms to which they are attached, they form C 3-5 cycloalkyl; and n5' is 0, 1, or 2.

60. The compound of claim 59, wherein: R 1a Independently selected from halogenated, methyl groups substituted by one or more halogenations, C 3-5 cycloalkyl or -CN; R 2 It is C 1-8 alkyl; R 6 It is hydrogen or methyl; and R 7 It is hydrogen.

61. The compound of claim 59 or 60, wherein R 1a It is independently selected from -F, -Cl, -Br, -I, -CF3, cyclopropyl or -CN.

62. The compound according to any one of claims 59-63, wherein (i) R 1a 'Is methyl; or (iii) R 1a 'and R 1a Together with the atoms to which they are attached, they form cyclopropyl groups.

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

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

65. The compound according to any one of claims 1, 24, and 36-58, wherein the compound has the formula (VIIr): (VIIr), Or its N-oxide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analogue thereof, wherein Y' is N or C(R) 1d ).

66. The compound of claim 65, wherein: R 1a It is hydrogen or methyl; R 1d Independently selected from hydrogen, halogenated, methyl groups substituted with one or more halogenated groups, and C groups optionally substituted with fluorine. 3-5 cycloalkyl, or -CN; R 2 It is C 1-8 alkyl; R 6 It is hydrogen or methyl; and R 7 It is hydrogen.

67. The compound of claim 65 or 66, wherein R 1d It is independently selected from hydrogen, -F, -Br, -I, -CF3, cyclopropyl, fluorocyclopropyl, cyclobutyl or -CN.

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

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

70. A compound, or its N-oxide, or its pharmaceutically acceptable salt, or its stereoisomer, or its tautomer, or its deuterated analogue, selected from:

71. A pharmaceutical composition comprising the compound of any one of claims 1-70, its N-oxide, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its deuterated analogue, and a pharmaceutically acceptable excipient.

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

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

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

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

76. The method of claim 74 or 75, wherein the cancer comprises methionine phosphorylase (MTAP)-empty solid tumor.

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

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