1-(1-oxo-1,2-dihydrophthalazine-6-yl)cycloalkyl-1-carboxamide derivatives as MTA synergistic PRMT5 inhibitors

Abstract

The present disclosure provides compounds containing 1-(1-oxo-1,2-dihydrophthalazine-6-yl)cycloalkyl-1-carboxamide derivatives of Formula (I), their use for treating a subject having a cancer that harbors a deficiency in MTA DEL mutant tumors, the use of the compounds to selectively inhibit PRMT5 activity in conjunction with MTA, and pharmaceutical compositions comprising the compounds as treatments for a variety of diseases, including cancer.

Description

Cross-references to related applications

[0001] This application claims priority to International Application No. PCT / CN2023 / 122617, filed on September 28, 2023, the disclosure of which is hereby incorporated by reference in its entirety. Technical Field

[0002] This disclosure provides compounds containing a 1-(1-oxo-1,2-dihydrophthalazin-6-yl)cycloalkyl-1-carboxamide derivative, which are used in carrying MTAP DEL Use in synergistic selective inhibition of PRMT5 activity with MTA in mutated tumors, and pharmaceutical compositions comprising the compound as treatments for a variety of diseases, including cancer. Background Technology

[0003] Epigenetic modification is a process that alters genetic output, thereby changing the original DNA sequence. Epigenetic modification plays a crucial role in many aspects, including gene expression and regulation, protein production, and cell differentiation. Typically, this process is reversible and selective in its effects on DNA, its regulatory proteins such as histones, and other proteins such as transcription factors. Bradbury, E. M., BioEssays, 1992, 14 (1): pp. 9-16 PMTs (protein methyltransferases) are major participants in epigenetic modification and consist of two subfamilies: PKMTs (protein lysine methyltransferases) and PRMTs (protein arginine methyltransferases). Copel and RA et al. Oncogene, 2012. 32 (8): pp. 939-46 PMT is associated with a variety of human diseases and is considered a potential therapeutic target. Copel and RA et al. Oncogene, 2012, 32 (8): Pages 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 sDMA (symmetric dimethyl arginine); and Type III (PRMT7) catalyzes the formation of MMA (monomethyl arginine). Yang, Y. et al. Nature Reviews Cancer 2012, 13 (1): Pages 37-50In addition, type I / II PRMTs can also catalyze the formation of MMA 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, namely the SAM pocket and the substrate pocket. The methylation process involves the transfer of an activated methyl group from the cofactor SAM to a guanidinium group on the arginine residue, similar to the SAM group. N The mechanism of 2. Bedford, MT et al. Molecular Cell, 2005, 18 (3): pp. 263-72 The byproduct of this process is SAH (S-adenosine-L-homocysteine).

[0005] For Arg:aDMA:MMA:sDMA, the total arginine level in cells is approximately 1500:3:2:1, and PRMT5 accounts for the vast majority of sDMA formation. Dhar, S. et al. , Scientific Reports,2013, 3: 1311 In contrast to PRMT1 (the major type I PRMT that functions on its own within the cell), PRMT5 binds to MEP50 (methyltransferase complex protein 50) to form a heterozygous complex, which is frequently elevated in cancer cells and is associated with poor 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, 2011, 36 (12): 633-41 In addition to its epigenetic role, PRMT5 may also regulate RNA-binding proteins, such as splicing factors. For example, reproducible events have been observed in PRMT5 knockout mice in which exon 6 of MDM4 (mouse two-microsome 4) skips and releases p53, upregulating the p53 pathway. Gerhart, SV et al. , Scientific Reports,2018, 8: 9711 Additionally, PRMT5 can be accessed via p53 []. Jansson, M. et al. , Nature Cell Biology, 2008, 10 (12): pp. 1431-9 Page ]、EGFR [ Hsu, J.-M. et al. Nature Cell Biology, 2011, 13(2): 174-81 ]、PI3K[ Wei, T.-YW, et al. Cellular Signaling, 2014, 26 (12): 2940-50 PRMT5 directly affects key proliferation pathways through direct methylation of substances such as PRMT5. Therefore, PRMT5 is likely to become a clinically relevant target.

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

[0007] Homozygous deletion of the tumor suppressor CDKN2A (cyclin-dependent kinase inhibitor 2A) occurs in approximately 15% of all tumor types. Interestingly, this mutation frequently involves co-deletion of neighboring genes present in 9p21, including the gene encoding MTAP (methionine phosphorylase). Firestone, RS et al. Journal of American Chemical Society, 2017, 139 (39): pp. 13754-60 Due to MTAP deficiency, the substrate MTA (methionine) accumulates. MTA is structurally associated with SAM and is a weak ligand / inhibitor of PRMT5, which occupies 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 ineffectiveness and PRMT5 dependence can be established through MTA concentration levels to provide precise tumor therapy.

[0008] Currently, most clinically-developed PRMT5 inhibitors, based on SAM / MTA competition mechanisms (JNJ64619178, PF06939999, PRT543, and PRT811) or non-MTA synergistic mechanisms (GSK3326595), cannot distinguish between normal and cancer cells. Therefore, there remains an unmet and ongoing medical need for potent and selective MTA-synergistic PRMT5 inhibitors. Summary of the Invention

[0009] One object of the present invention is to provide compounds and derivatives that act as PRMT5 inhibitors, as well as their preparation methods and uses.

[0010] Aspect 1. A compound of formula (I): Or its N-oxide, or its pharmaceutically acceptable salt, or its stereoisomer, or its tautomer, or its deuterated analogue, wherein: n is 1, 2, 3 or 4; m can be 1, 2, 3, or 4; R 1 and R 2 Each is independently selected from hydrogen, halogen, -C 1-8 Alkyl, -C3-C8 cycloalkyl, -CN, -OR 1a -NR 1a R 1b -COR 1a-CO2R 1a -CONR 1a R 1b or -NR 1a COR 1b , where -C 1-8 Each of the alkyl group and the -C3-C8 cycloalkyl group is optionally substituted by at least one substituent selected from the following: halogen, -C 1-8 Alkoxy, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, C6-C 12 aryl, 5- to 12-membered heteroaryl, oxoyl, -CN, -OR 1c -SO2R 1c -SO2NR 1c R 1d -COR 1c -CO2R 1c -CONR 1c R 1d -NR 1c R 1d -NR 1c COR 1d -NR 1c CO2R 1d Or –NR 1c SO2R 1d ; R 1a and R 1b Each is independently hydrogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, -C6-C 12 aryl or 5 to 12-membered heteroaryl; the -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, -C6-C 12 Each of the aryl group or the 5- to 12-membered heteroaryl group is optionally bonded by at least one halogen, -OH, or -C. 1-8 Alkyl, -C 1-8 Alkoxy, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 alkenyl, -C 2-8 Alkyne, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, -C6-C 12 Aryl or 5 to 12 heteroaryl substitutions; R 1cand R 1d Each is independently hydrogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, -C6-C 12 aryl or 5 to 12-membered heteroaryl; the -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, -C6-C 12 Each of the aryl group or the 5- to 12-membered heteroaryl group is optionally bonded by at least one halogen, -OH, or -C. 1-8 Alkyl, -C 1-8 Alkoxy, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 alkenyl, -C 2-8 Alkyne, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, -C6-C 12 Aryl or 5 to 12 heteroaryl substitutions; R 3 R 4 R 5 and R 6 Each is independently selected from hydrogen, halogen, -C 1-8 Alkyl, -C3-C8 cycloalkyl, -CN, -OR 3a -NR 3a R 3b -COR 3a -CO2R 3a -CONR 3a R 3b or -NR 3a COR 3b , where -C 1-8 Each of the alkyl group and the -C3-C8 cycloalkyl group is optionally substituted by at least one substituent selected from the following: 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, oxoyl, -CN, -OR 3c -SO2R 3c -SO2NR 3c R 3d -COR 3c -CO2R 3c -CONR 3c R 3d -NR 3c R 3d -NR3c COR 3d -NR 3c CO2R 3d Or –NR 3c SO2R 3d ; R 3a R 3b R 3c and R 3d Each is independently hydrogen, -C 1-8 Alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, -C6-C 12 aryl or 5 to 12-membered heteroaryl; the -C 1-8 Alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, -C6-C 12 Each of the aryl group or the 5- to 12-membered heteroaryl group is optionally bonded by at least one halogen, -OH, or -C. 1-8 Alkyl, -C 1-8 Alkoxy, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 alkenyl, -C 2-8 Alkyne, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, -C6-C 12 Aryl or 5 to 12 heteroaryl substitutions; R 7 and R 8 Each is independently selected from hydrogen and -C 1-8 Alkyl, -C3-C8 cycloalkyl or -C6-C 12 Aryl, where -C 1-8 Alkyl, -C3-C8 cycloalkyl and -C6-C 12 Each of the aryl groups may optionally be substituted by at least one substituent selected from the following: hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -NR 7a R 7b -OR 7a , oxoyl group, -C3-C8 cycloalkyl group, 3 to 8 membered heterocyclic group, -C6-C 12 aryl, 5 to 12-membered heteroaryl or -CN; R 7a and R 7b Each is independently selected from hydrogen and -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkyne, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, -C6-C 12 aryl or 5 to 12-membered heteroaryl, wherein the -C 1-8 Alkyl, -C2-8 alkenyl, -C 2-8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, C6-C 12 Each of the aryl or 5 to 12 heteroaryl groups is optionally substituent R. 7c replace; R 7c Independently halogen, hydroxyl, -C 1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 alkenyl, -C 2-8 Alkyne, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, -C6-C 12 aryl, 5 to 12-membered heteroaryl, or -CN, wherein the -C 1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 alkenyl, -C 2-8 Alkyne, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, -C6-C 12 Each of the aryl group and the 5- to 12-membered heteroaryl group is optionally bound by at least one hydrogen, halogen, hydroxyl group, or -C group. 1-8 Alkyl, -C 1-8 Alkoxy, -CN, -NH2, or oxo groups are substituted; R 9 and R 10 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 group and the 5 to 12 heteroaryl groups is optionally substituent R. 9a Replace; or R 9 and R 10 Together with the nitrogen atom to which it is attached, it forms a 3- to 8-membered unsaturated or saturated ring, the ring containing 0-3 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the ring is optionally substituented by at least one R. 9a replace; R 9a Independently 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 9b -SO2R 9b-SO2NR 9b R 9c -COR 9b -CO2R 9b -CONR 9b R 9c -NR 9b R 9c -NR 9b COR 9c -NR 9b CO2R 9c –NR 9b SO2R 9c , oxo group 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 group and the 5 to 12 heteroaryl groups is optionally substituent R. 9d Replace; or Two Rs 9a Together with the atoms to which it is attached, it forms a 3- to 8-membered unsaturated or saturated ring, the ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the ring optionally being substituented by at least one R. 9d replace; R 9b and R 9c 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 group and the 5 to 12 heteroaryl groups is optionally substituent R. 9e replace; R 9d and R 9e 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 9f -SO2R 9f -SO2NR 9f R 9g -COR 9f -CO2R 9f -CONR 9f R 9g -NR 9f R9g -NR 9f COR 9g -NR 9f CO2R 9g –NR 9f SO2R 9g , oxo group, -SF5 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 group and the 5 to 12 heteroaryl groups is optionally substituent R. 9h replace; R 9f and R 9g 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 group and the 5 to 12 heteroaryl groups is optionally substituent R. 9i replace; R 9h and R 9i 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 9j -SO2R 9j -SO2NR 9j R 9k -COR 9j -CO2R 9j -CONR 9j R 9k -NR 9j R 9k -NR 9j COR 9k -NR 9j CO2R 9k –NR 9j SO2R 9k , oxo group or -CN, wherein the -C 1-8 Alkyl, -C3-C8 cycloalkyl, -C3-C 12 Cycloalkenyl, 3 to 12-membered heterocyclic groups, -C6-C 12Each of the aryl and 5 to 12 heteroaryl groups may optionally be substituted by 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, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, -C6-C 12 Aryl, 5 to 12-membered heteroaryl, -CN, -OH, -NH2 or oxo group; R 9j and R 9k 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 heteroaryl groups may optionally be substituted by 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, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, -C6-C 12 Aryl, 5 to 12 heteroaryl, -CN, -OH, -NH2 or oxo group.

[0011] Aspect 2. The compound as described in aspect 1, wherein the compound is of formula (IIa) or (IIb): (IIa); (IIb); Preferably, the compound is selected from formula (IIc) or (IId): (IIc); (IId).

[0012] Aspect 3. The compound as described in aspect 1, wherein the compound is of formula (IIIa): (IIIa); Preferably, the compound is selected from formula (IIIb): (IIIb); More preferably, the compound is selected from formula (IIIc): (IIIc); More preferably, the compound is selected from formula (IIId): (IIId).

[0013] Aspect 4. The compound as described in aspect 1, wherein the compound is of formula (IVa) or (IVb): (IVa), (IVb); Preferably, the compound is selected from formula (IVc) or (IVd): (IVc); (IVd); More preferably, the compound is selected from formula (IVe) or (IVf): (IVe); (IVf); Even more preferably, the compound is selected from formula (IVg) or (IVh): (IVd); (IVh); Even more preferably, the compound is selected from formula (IVi) or (IVj): (IVi); (IVj).

[0014] Aspect 5. The compound as described in aspect 1, wherein the compound is of formula (Va): (Va) Preferably, the compound is selected from formula (Vb) or (Vc): (Vb); (Vc); More preferably, the compound is selected from formula (Vd) or (Ve): (Vd); (Ve); Even more preferably, the compound is selected from formula (Vf) or (Vg): (Vf); (Vg); Even more preferably, the compound is selected from formula (Vh) or (Vi): (Vh); (Vi); Among them, R 9a As defined in aspect 1.

[0015] Aspect 6. The compound as described in any of the foregoing aspects, wherein R 1 and R 2 Each is independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -CN, -OR 1a -NR 1a R 1b -COR 1a -CO2R 1a -CONR 1a R 1b or -NR 1a COR 1b Each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, 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, heptoxy, octyloxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -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 groups, oxoyl groups, -CN, -OR 1c -SO2R 1c -SO2NR 1c R 1d -COR 1c -CO2R 1c -CONR 1c R 1d -NR 1c R 1d -NR 1c COR 1d -NR 1c CO2R 1d Or –NR 1c SO2R 1d ; R 1a and R 1b Each of the following is independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 Alkyne, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclic, phenyl, or 5 to 12-membered heteroaryl; wherein methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8Each of the following groups is optionally surrounded by at least one of the following: alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclic, phenyl, or 5 to 12-membered heteroaryl, and is further distinguished by at least one of the following: -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, phenyl or 5 to 12-membered heteroaryl substitution; R 1c and R 1d Each of the following is independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 Alkyne, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclic, phenyl, or 5 to 12-membered heteroaryl; wherein methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 Each of the following groups is optionally surrounded by at least one of the following: alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclic, phenyl, or 5 to 12-membered heteroaryl, and is further distinguished by at least one of the following: -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, phenyl or 5 to 12-membered heteroaryl substitution.

[0016] Aspect 7. The compound as described in any of the foregoing aspects, wherein R 1 and R 2 Each is independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -CN, -OR 1a -NR 1a R 1b -COR 1a -CO2R 1a -CONR 1a R 1b or -NR 1aCOR 1b ; R 1a and R 1b Each of the following is independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 Alkyne, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclic, phenyl, or 5 to 12-membered heteroaryl; wherein methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 Each of the following groups is optionally surrounded by at least one of the following: alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclic, phenyl, or 5 to 12-membered heteroaryl, and is further distinguished by at least one of the following: -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, phenyl or 5 to 12-membered heteroaryl substitution; Preferably, R 1 and R 2 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, cyclooctyl, -CN; More preferably, R 1 and R 2 Each is independently selected from hydrogen, -F, -Cl, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), cyclopropyl, and cyclobutyl.

[0017] Even more preferably, R 1 and R 2 Each is independently selected from hydrogen or methyl.

[0018] Aspect 8. The compound as described in any of the foregoing aspects, wherein R 3 R 4 R 5 and R 6Each 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, cyclooctyl, -CN, -OR 3a -NR 3a R 3b -COR 3a -CO2R 3a -CONR 3a R 3b or -NR 3a COR 3b Each of the following groups is optionally substituted by at least one substituent selected from: -F, -Cl, -Br, -I, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexyloxy, heptoxy, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl: -F, -Cl, -Br, -I, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, 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 group, oxo group, -CN, -OR 3c -SO2R 3c -SO2NR 3c R 3d -COR 3c -CO2R 3c -CONR 3c R 3d -NR 3c R 3d -NR 3c COR 3d -NR 3c CO2R 3d Or –NR 3c SO2R 3d ; R 3a R 3b R 3c and R 3dEach 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, cyclo Each of propyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclic, phenyl, or 5 to 12-membered heteroaryl is optionally bounded by at least one of -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 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 alkenyl, -C 2-8 Alkyne, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclic, phenyl or 5 to 12-membered heteroaryl substitution; Preferably, R 3 R 4 R 5 and R 6 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, cyclooctyl, -CN, -OR 3a -NR 3a R 3b -COR 3a -CO2R 3a -CONR 3a R 3b or -NR 3a COR 3b ; R 3a and R 3bEach 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, cyclo Each of propyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclic, phenyl, or 5 to 12-membered heteroaryl is optionally bounded by at least one of -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 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 alkenyl, -C 2-8 Alkyne, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclic, phenyl or 5 to 12-membered heteroaryl substitution; More preferably, R 3 R 4 R 5 and R 6 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, cyclooctyl, -CN, -OH, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy; Even more preferably, R 3 R 4 R 5 and R 6 Each is independently 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 R 4 R 5 and R 6 Each is independently selected from hydrogen.

[0019] Aspect 9. The compound as described in any of the foregoing aspects, wherein R 7 and R 8Each 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, or phenyl, wherein each of the following groups is optionally substituted by at least one substituent 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, or phenyl, and is optionally substituted by at least one substituent 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, -C 2-8 alkenyl, -C 2-8 alkynyl, -NR 7a R 7b -OR 7a Oxyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl (3 to 8 membered heterocyclic groups), phenyl, (5 to 12 membered heteroaryl groups) or -CN; R 7a and R 7b 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, -C 2-8 alkenyl, -C 2-8 Alkyne, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclic, 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, -C 2-8 alkenyl, -C 2-8 Each of the following groups is optionally substituent R: alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclic, phenyl, or 5 to 12-membered heteroaryl. 7c replace; R 7c Independently, -F, -Cl, -Br, -I, hydroxyl, 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 2-8Alkyne, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclic, phenyl, 5 to 12-membered heteroaryl, or -CN, wherein the hydroxyl, 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 Each of the following groups is optionally separated by at least one hydrogen, halogen, hydroxyl, -C: alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclic group, phenyl, or 5 to 12-membered heteroaryl. 1-8 Alkyl, -C 1-8 Alkoxy, -CN, -NH2, or oxo groups are substituted; Preferably, R 7 and R 8 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, or phenyl, wherein each of the following groups is optionally substituted by at least one substituent 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, or phenyl, and is optionally substituted by at least one substituent 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, -C 2-8 alkenyl, -C 2-8 alkynyl, -NR 7a R 7b -OR 7a Oxyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl (3 to 8 membered heterocyclic groups), phenyl, (5 to 12 membered heteroaryl groups) or -CN; R 7a and R 7b 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, -C 2-8 alkenyl, -C 2-8 Alkyne, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclic, phenyl or 5 to 12-membered heteroaryl; More preferably, R 7 and R 8Each is independently selected from hydrogen, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), cyclopropyl, cyclobutyl, and cyclopentyl; Even more preferably, R 7 and R 8 Each is independently selected from hydrogen.

[0020] Aspect 10. The compound as described in any of the foregoing aspects, wherein R 9 and R 10 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 12 Cycloalkenyl, 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. 9a Replace; or R 9 and R 10 Together with the nitrogen atom to which it is attached, it forms a 3, 4, 5, 6, 7, or 8-membered unsaturated or saturated ring, the ring containing 0, 1, 2, or 3 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the ring is optionally substituented by at least one R. 9a replace; R 9a Independently, it can be hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl, or tert-butyl), pentyl, naphthyl, 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 9b -SO2R 9b -SO2NR 9b R 9c -COR 9b -CO2R 9b -CONR 9b R 9c -NR 9b R 9c -NR 9b COR 9c -NR 9b CO2R 9c –NR9b SO2R 9c , oxo group 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 following groups is optionally substituent R: cycloalkenyl, 3- to 12-membered heterocyclic, phenyl, or 5- to 12-membered heteroaryl. 9d Replace; or Two Rs 9a Together with the atoms to which it is attached, it forms a 3, 4, 5, 6, 7, or 8-membered unsaturated or saturated ring, the ring containing 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the ring is optionally substituented by at least one R. 9d replace; R 9b and R 9c 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, phenyl, or 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, or 5 to 12-membered heteroaryl is optionally substituent R. 9e replace; R 9d and R 9e Each of the following can be independently represented as 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 9f -SO2R 9f -SO2NR 9f R 9g -COR 9f -CO2R 9f -CONR 9f R 9g -NR 9f R 9g -NR 9f COR 9g -NR 9f CO2R9g –NR 9f SO2R 9g Oxoyl group, -SF5 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. 9h replace; R 9f and R 9g 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, phenyl, naphthyl, or 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, naphthyl, or 5 to 12-membered heteroaryl is optionally substituent R. 9i replace; R 9h and R 9i Each of the following can be independently represented as 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 9j -SO2R 9j -SO2NR 9j R 9k -COR 9j -CO2R 9j -CONR 9j R 9k -NR 9j R 9k -NR 9j COR 9k -NR 9j CO2R 9k –NR 9j SO2R 9k, oxo group 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 following groups is optionally substituents: cycloalkenyl, 3- to 12-membered heterocyclic, phenyl, and 5- to 12-membered heteroaryl: -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, 3 to 8-membered heterocyclic group, phenyl, 5 to 12-membered heteroaryl, -CN, -OH, -NH2 or oxo-substituted; R 9j and R 9k 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. 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 are optionally substituents of at least one of the following: -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 group, phenyl, 5 to 12-membered heteroaryl, -CN, -OH, -NH2 or oxo-substituted.

[0021] Aspect 11. The compound as described in any of the preceding aspects, wherein R 9 and R 10Each 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, chromoalkyl, isochromoalkyl, 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), 6,7-dihydro-5H-cyclopento[b]pyridyl, pyrimidinyl Tetrahydro-2H-pyranyl, pyridazinyl, pyrazinyl, dihydrofuranopyridyl (preferably 2,3-dihydrofurano[2,3-b]pyridyl), tetrahydronaphthyl (preferably 1,2,3,4-tetrahydronaphthyl), 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, chromoalkyl, isochromoalkyl, 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), 6,7-dihydro-5H-cyclopentano[b]pyridyl, pyrimidinyl, tetrahydro-2H-pyranyl Each of the following groups is optionally substituent R: pyrazinyl, pyrazinyl, dihydrofuranopyridyl (preferably 2,3-dihydrofurano[2,3-b]pyridyl), tetrahydronaphthyl (preferably 1,2,3,4-tetrahydronaphthyl), 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. 9a Replace; or R 9 and R 10 Together with the nitrogen atom to which it is attached, it forms a 3, 4, 5, 6, 7, or 8-membered unsaturated or saturated ring, the ring containing 0, 1, 2, or 3 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur; the ring is optionally substituented by at least one R. 9a replace; R 9aIndependently, 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, naphthyl, chromoalkyl, isochromoalkyl, 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]pyridine). ), pyrimidinyl, tetrahydro-2H-pyranyl, pyridazinyl, pyrazinyl, dihydrofuranopyridyl (preferably, 2,3-dihydrofurano[2,3-b]pyridyl), tetrahydronaphthyl (preferably, 1,2,3,4-tetrahydronaphthyl), 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 9b -SO2R 9b -SO2NR 9b R 9c -COR 9b -CO2R 9b -CONR 9b R 9c -NR 9b R 9c -NR 9b COR 9c -NR 9b CO2R 9c –NR 9b SO2R 9c , oxo 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, naphthyl, chromoalkyl, isochromoalkyl, 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-pyran The following groups are optionally substituents: pyrazinyl, pyrazinyl, dihydrofuranopyridyl (preferably 2,3-dihydrofurano[2,3-b]pyridyl), tetrahydronaphthyl (preferably 1,2,3,4-tetrahydronaphthyl), 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 of which is optionally substituented by at least one R.9d Replace; or Two Rs 9a Together with the atoms to which it is attached, it forms a 3, 4, 5, or 6-membered unsaturated or saturated ring, the ring containing 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the ring is optionally substituented by at least one R. 9d replace; R 9b and R 9c 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, phenyl, chromoalkyl, isochromoalkyl, 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, pyrazinyl, dihydrofuranopyridyl (preferably 2,3-dihydrofurano[2,3-b]pyridyl), tetrahydronaphthyl (preferably 1,2,3,4-tetrahydronaphthyl), 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, chromoalkyl, isochromoalkyl, 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 Each of the following groups is optionally substituent R: pyrazinyl, pyrazinyl, dihydrofuranopyridyl (preferably 2,3-dihydrofurano[2,3-b]pyridyl), tetrahydronaphthyl (preferably 1,2,3,4-tetrahydronaphthyl), 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. 9e replace; R 9d and R 9eEach 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, chromoalkyl, isochromoalkyl, 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), pyrimidine Tetrahydro-2H-pyranyl, pyridazinyl, pyrazinyl, dihydrofuranopyridyl (preferably 2,3-dihydrofurano[2,3-b]pyridyl), tetrahydronaphthyl (preferably 1,2,3,4-tetrahydronaphthyl), 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 9f -SO2R 9f -COR 9f -CO2R 9f -CONR 9f R 9g -NR 9f R 9g -NR 9f COR 9g -NR 9f CO2R 9g , oxo, -SF5 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, chromoalkyl, isochromoalkyl, 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-pyridyl The following groups are optionally substituents: uranyl, pyrazinyl, dihydrofuranopyridyl (preferably 2,3-dihydrofurano[2,3-b]pyridyl), tetrahydronaphthyl (preferably 1,2,3,4-tetrahydronaphthyl), 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 of which is optionally substituented by at least one substituent R. 9h replace; R 9f and R 9gEach 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, chromoalkyl, isochromoalkyl, 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, pyrazinyl, dihydrofuranopyridyl (preferably 2,3-dihydrofurano[2,3-b]pyridyl), tetrahydronaphthyl (preferably 1,2,3,4-tetrahydronaphthyl), 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, chromoalkyl, isochromoalkyl, 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 Each of the following groups is optionally substituent R: pyrazinyl, pyrazinyl, dihydrofuranopyridyl (preferably 2,3-dihydrofurano[2,3-b]pyridyl), tetrahydronaphthyl (preferably 1,2,3,4-tetrahydronaphthyl), 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. 9i replace; R 9h and R 9iEach 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, phenyl, chromogenic alkyl, isochromogenic alkyl, 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, pyrazinyl, pyrazinyl, dihydrofuranopyridyl (preferably 2,3-dihydrofurano[2,3-b]pyridyl), tetrahydronaphthyl (preferably 1,2,3,4-tetrahydronaphthyl), 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 9j -COR 9j -CO2R 9j -CONR 9j R 9k -NR 9j R 9k -NR 9j COR 9k -NR 9j CO2R 9kOxoyl 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, chromoalkyl, isochromoalkyl, 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 substituented by at least one of the following groups: tetrahydronaphthyl (preferably 1,2,3,4-tetrahydronaphthyl), 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: -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-substituted groups; R 9j and R 9kEach is independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, chromoalkyl, isochromoalkyl, 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, pyrazinyl, dihydrofuranopyridyl (preferably) , 2,3-dihydrofurano[2,3-b]pyridyl), tetrahydronaphthyl (preferably, 1,2,3,4-tetrahydronaphthyl), 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, cyclo Hexyl, cycloheptyl, cyclooctyl, phenyl, chromoalkyl, isochromoalkyl, 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 (preferably 1,2,3,4-tetrahydronaphthyl), benzene Each of the following groups is optionally substituents: 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 substituented by at least one of the following: -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-substituted groups; Preferably, R 9 and R 10Each 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, chromoalkyl, isochromoalkyl, 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), 6,7-dihydro-5H-cyclopento[b]pyridyl, pyrimidinyl Tetrahydro-2H-pyranyl, pyridazinyl, pyrazinyl, dihydrofuranopyridyl (preferably 2,3-dihydrofurano[2,3-b]pyridyl), tetrahydronaphthyl (preferably 1,2,3,4-tetrahydronaphthyl), 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, chromoalkyl, isochromoalkyl, 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), 6,7-dihydro-5H-cyclopentano[b]pyridyl, pyrimidinyl, tetrahydro-2H-pyranyl Each of the following groups is optionally substituent R: pyrazinyl, pyrazinyl, dihydrofuranopyridyl (preferably 2,3-dihydrofurano[2,3-b]pyridyl), tetrahydronaphthyl (preferably 1,2,3,4-tetrahydronaphthyl), 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. 9a Replace; or R 9 and R 10 Together with the nitrogen atom to which it is attached, it forms a 3, 4, 5, 6, 7, or 8-membered unsaturated or saturated ring, the ring containing 0, 1, 2, or 3 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur; the ring is optionally substituented by at least one R. 9a replace; R 9aIndependently, it 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, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, chromoalkyl, isochromoalkyl, 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 (preferably 1,2,3,4-tetrahydronaphthyl), 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 9b 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, naphthyl, chromoalkyl, isochromoalkyl, 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 (preferably 1,2,3,4-tetrahydronaphthyl), 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 are optionally substituents R. 9d Replace; or Two Rs 9a Together with the atoms to which it is attached, it forms a 3, 4, 5, or 6-membered unsaturated or saturated ring, the ring containing 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the ring is optionally substituented by at least one R. 9d replace; R 9b Each can be independently hydrogen, methyl, ethyl, propyl (isopropyl or n-propyl), cyclopropyl or cyclobutyl; R 9dEach 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, chromoalkyl, isochromoalkyl, 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), pyrimidine Tetrahydro-2H-pyranyl, pyridazinyl, pyrazinyl, dihydrofuranopyridyl (preferably 2,3-dihydrofurano[2,3-b]pyridyl), tetrahydronaphthyl (preferably 1,2,3,4-tetrahydronaphthyl), 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 9f -NR 9f R 9g -NR 9f COR 9g , Oxide group, -SO2R 9f -SF5 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, chromoalkyl, isochromoalkyl, 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 Each of the following groups is optionally substituent R: pyrazinyl, pyrazinyl, dihydrofuranopyridyl (preferably 2,3-dihydrofurano[2,3-b]pyridyl), tetrahydronaphthyl (preferably 1,2,3,4-tetrahydronaphthyl), 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. 9h replace; R 9f and R 9gEach 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, chromoalkyl, isochromoalkyl, 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, pyrazinyl, dihydrofuranopyridyl (preferably, 2,3-dihydrofurano[2,3-b]pyridyl), tetrahydronaphthyl (preferably, 1,2,3,4-tetrahydronaphthyl), 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, chromoalkyl, isochromoalkyl, 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, pyrazine The group consisting of pyridyl, dihydrofuranopyridyl (preferably 2,3-dihydrofurano[2,3-b]pyridyl), tetrahydronaphthyl (preferably 1,2,3,4-tetrahydronaphthyl), 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 substituented by at least one substituent R. 9i replace; R 9h and R 9iEach 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, chromogenic alkyl, isochromogenic alkyl, 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, tetra Hydrogen-2H-pyranyl, pyridazinyl, pyrazinyl, dihydrofuranopyridyl (preferably, 2,3-dihydrofurano[2,3-b]pyridyl), tetrahydronaphthyl (preferably, 1,2,3,4-tetrahydronaphthyl), 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 9 and R 10Each is independently selected from hydrogen, methyl, ethyl, propyl (isopropyl or n-propyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, chromoalkyl, isochromoalkyl, 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), 6,7-dihydro-5H-cyclo Pento[b]pyridyl, pyrimidinyl, tetrahydro-2H-pyranyl, pyrazinyl, pyrazinyl, dihydrofuranopyridyl (preferably 2,3-dihydrofurano[2,3-b]pyridyl), tetrahydronaphthyl (preferably 1,2,3,4-tetrahydronaphthyl), benzo[d]thiazolyl, pyridyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl or tetrahydrofuranopyridyl pyridyl, wherein the methyl, ethyl, propyl (isopropyl or n-propyl), phenyl, chromoalkyl, isochromoalkyl, 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), 6,7-dihydro-5H-cyclopentano[b]pyridyl, pyrimidinyl, tetrahydro-2H- Pyranyl, pyridazinyl, pyrazinyl, dihydrofuranopyridyl (preferably 2,3-dihydrofurano[2,3-b]pyridyl), tetrahydronaphthyl (preferably 1,2,3,4-tetrahydronaphthyl), benzo[d]thiazolyl, pyridyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl, or tetrahydrofuranopyridyl are optionally substituents R. 9a Replace; or R 9 and R 10 Together with the nitrogen atom to which it is attached, it forms a 6-membered unsaturated or saturated ring, which is optionally substituent R. 9a replace; R 9a Independently, it can be hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (isopropyl or n-propyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyrimidinyl, pyridazinyl, pyrazinyl, dihydrofuranopyridyl (preferably 2,3-dihydrofurano[2,3-b]pyridyl), benzo[d]thiazolyl, pyridyl, quinolinyl, isoquinolinyl, thiazolyl, -OR 9bor -CN, wherein each of the following groups—methyl, ethyl, propyl (isopropyl or n-propyl), phenyl, naphthyl, pyrimidinyl, pyridazinyl, pyrazinyl, dihydrofuranopyridinyl (preferably 2,3-dihydrofurano[2,3-b]pyridinyl), benzo[d]thiazolyl, pyridinyl, quinolinyl, isoquinolinyl, or thiazolyl—is optionally substituent R. 9d replace; R 9b Each can be independently hydrogen, methyl, ethyl, propyl (isopropyl or n-propyl), cyclopropyl or cyclobutyl; R 9d Each of the following groups 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 9f -SO2R 9f -SF5 or -CN, wherein each of the following groups—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 substituented by at least one substituent R. 9h replace; R 9f 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. 9i replace; R 9h and R 9i 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] Aspect 12. The compound as described in any of the preceding aspects, wherein R 9 and R 10 Each is independently selected from -C1-8 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. 9a Replace; or R 9 and R 10 Together with the nitrogen atom to which it is attached, it forms a 3- to 8-membered unsaturated or saturated ring, the ring containing 0-3 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the ring is optionally substituented by at least one R. 9a replace; R 9a Independently hydrogen, halogen, deuterium, -C 1-8 Alkyl, -C3-C8 cycloalkyl, -C6-C 12 aryl, 5- to 12-membered heteroaryl, -OR 9b Or -CN, where -C 1-8 Alkyl, -C3-C8 cycloalkyl, -C6-C 12 Each of the aryl group and the 5 to 12 heteroaryl groups is optionally substituent R. 9d Replace; or Two Rs 9a Together with the atoms to which it is attached, it forms a 3- to 8-membered unsaturated or saturated ring, the ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the ring optionally being substituented by at least one R. 9d replace; R 9b 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. 9e replace; R 9d and R 9e Each is independently hydrogen, halogen, -C 1-8 Alkyl, -C3-C8 cycloalkyl, -C6-C 12 aryl, 5- to 12-membered heteroaryl, -OR 9f -SO2R 9f -SF5 or -CN, wherein -C 1-8 Alkyl, -C6-C 12 Each of the aryl group and the 5 to 12 heteroaryl groups is optionally substituent R. 9h replace; R 9f Each is independently selected from hydrogen and -C 1-8Alkyl and -C3-C8 cycloalkyl, -C6-C 12 Aryl, wherein the -C 1-8 Alkyl, -C6-C 12 Each of the aryl and -C3-C8 cycloalkyl groups is optionally substituent R. 9i replace; R 9h and R 9i Each is independently hydrogen, halogen, -C 1-8 Alkyl or -CN; Preferably, R 9 and R 10 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, chromoalkyl, isochromoalkyl, 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, chromoalkyl, isochromoalkyl, pyridyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl, or tetrahydrofuranopyridyl. 9a Replace; or R 9 and R 10 Together with the nitrogen atom to which it is attached, it forms a 3, 4, 5, 6, 7, or 8-membered unsaturated or saturated ring, the ring containing 0, 1, 2, or 3 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur; the ring is optionally substituented by at least one R. 9a replace; R 9a 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 9bor -CN, wherein each of the following groups—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. 9d Replace; or Two Rs 9a Together with the atoms to which it is attached, it forms a 3, 4, 5, or 6-membered unsaturated or saturated ring, the ring containing 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the ring is optionally substituented by at least one R. 9d replace; R 9b 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. 9e replace; R 9d and R 9e Each of the following can be independently represented as 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 9f -SO2R 9f -SF5 or -CN, wherein each of the following groups—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. 9h replace; R 9fEach 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, phenyl, or naphthyl, 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, phenyl, or naphthyl groups is optionally substituent R. 9i replace; R 9h and R 9i 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, heptyl, octyl or -CN.

[0023] Aspect 13. The compound as described in any of the foregoing aspects, wherein R 9 and R 10 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 R 9 and R 10 Together with the nitrogen atom it is attached to, it forms ( , , or ), ( , , or ), ( , , or ), ( , , or ).

[0024] Aspect 14. The compound as described in any of the preceding aspects, wherein the compound is selected from... Aspect 15. A pharmaceutical composition comprising any one of the compounds described in aspects 1-14 or a pharmaceutically acceptable salt, stereoisomer, tautomer or prodrug thereof, and a pharmaceutically acceptable excipient.

[0025] Aspect 16. A method for reducing PRMT5 activity by inhibition, the method comprising administering to an individual a compound of any one of Aspects 1-14 or a pharmaceutically acceptable salt thereof, including a compound of formula (I) or a specific compound illustrated herein.

[0026] Aspect 17. The method as described in aspect 16, wherein the disease is selected from cancer.

[0027] Aspect 18. Use of any of the compounds described in Aspects 1-14, or pharmaceutically acceptable salts, stereoisomers, tautomers, or prodrugs thereof, in the preparation of medicaments for treating diseases regulated by PRMT5.

[0028] Aspect 19. Use as described in aspect 18, wherein the disease is cancer.

[0029] Aspect 20. Use as described in aspect 18, wherein the disease is an MTAP-deficient solid tumor, including but not limited to lung cancer, bladder cancer, melanoma, pancreatic cancer, esophageal cancer, gastric adenocarcinoma, breast cancer, or glioblastoma. Detailed Implementation

[0030] The following terms have the meanings indicated throughout this specification: Unless otherwise expressly defined elsewhere in this document, all other technical and scientific terms used herein shall have the meanings commonly understood by one of ordinary skill in the art to which this invention pertains.

[0031] The following terms have the meanings indicated throughout this specification: As used herein (including the appended claims), unless the context clearly specifies otherwise, the singular forms of words such as “a / an” and “the” include their corresponding plural referents.

[0032] Unless the context clearly specifies otherwise, the term “or” is used to mean “and / or” and is used interchangeably with the term “and / or”.

[0033] The term "alkyl" includes alkyl groups selected from straight-chain and branched saturated hydrocarbon groups containing 1 to 18 carbon atoms (such as 1 to 12, further such as 1 to 10, even further such as 1 to 8, or 1 to 6, or 1 to 4). Alkyl groups containing 1 to 6 carbon atoms (i.e., C16, C26, C36, C46, ​​C56, C6 ... 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.

[0034] The term "propyl" includes 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr").

[0035] 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”).

[0036] 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.

[0037] 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.

[0038] The term "alkylene" refers to a divalent alkyl group produced by removing two hydrogen atoms from an alkane. Alkylenes include, but are not limited to, methylene, ethylene, and propylene.

[0039] The term "halogen" includes fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0040] The term "alkenyl" includes hydrocarbon groups selected from straight-chain and branched hydrocarbon groups comprising at least one C=C double bond and 2 to 18 (such as 2 to 8, further such as 2 to 6) carbon atoms. Alkenyl (e.g., C...) 2-6Examples of alkenyl groups include, but are not limited to, ethenyl (or vinyl), propenyl, propenyl-2-alkenyl, 2-methylpropenyl, butenyl, butenyl-2-alkenyl, butenyl-3-alkenyl, butenyl-1,3-dienyl, 2-methylbutenyl-1,3-dienyl, hexenyl-1-alkenyl, hexenyl-2-alkenyl, hexenyl-3-alkenyl, hexenyl-4-alkenyl, and hexenyl-1,3-dienyl.

[0041] The term "alkenyl" refers to a divalent alkenyl group produced by removing two hydrogens from an olefin. Alkenyl groups include, but are not limited to, vinylene and butene.

[0042] The term "alkynyl" includes hydrocarbon groups selected from straight-chain and branched hydrocarbon groups comprising at least one C≡C triple bond and 2 to 18 (such as 2 to 8, further such as 2 to 6) carbon atoms. Alynyl (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.

[0043] The term "ynynyl" refers to a divalent ynyl group produced by removing two hydrogens from an alkyne. Iynyl groups include, but are not limited to, ethynylene.

[0044] The term "cycloalkyl" includes hydrocarbon groups selected from saturated cyclic hydrocarbon groups, including monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups, including fused, bridged, or screwed cycloalkyl groups.

[0045] For example, a cycloalkyl group can contain 3 to 12 carbon atoms (such as 3 to 10, further such as 3 to 8, further such as 3 to 6, 3 to 5, or 3 to 4). Even further, the cycloalkyl group can be selected from monocyclic groups containing 3 to 12 carbon atoms (such as 3 to 10, further such as 3 to 8, 3 to 6). Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. 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. In a preferred embodiment, the cycloalkyl group is a monocyclic ring (abbreviated as C16) containing 3 to 6 carbon atoms. 3-6Cycloalkyl groups, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of bicyclic cycloalkyl groups include those having 7 to 12 ring atoms arranged in a fused bicyclic arrangement selected from the [4,4], [4,5], [5,5], [5,6], and [6,6] ring systems, or arranged in a bridged bicyclic arrangement selected from bicyclic [2.2.1]heptane, bicyclic [2.2.2]octane, and bicyclic [3.2.2]nonane. Other examples of bicyclic cycloalkyl groups include those bicyclic arrangements selected from the [5,6] and [6,6] ring systems.

[0046] The term "spirocycloalkyl" includes cyclic structures containing carbon atoms and formed by at least two rings sharing an atom.

[0047] 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.

[0048] 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.

[0049] 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. A preferred embodiment is an 8- to 9-membered fused ring; in the above examples, this refers to a cyclic structure containing 8 to 9 ring atoms.

[0050] The term "aryl" used alone or in combination with other terms includes groups selected from: 5- and 6-membered carbocyclic aromatic rings, for example, phenyl; Bicyclic systems, such as 7- to 12-membered bicyclic systems, wherein at least one ring is a carbocyclic and aromatic, such as naphthyl and indanyl; 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 fluorene.

[0051] The terms "aromatic ring" and "aryl" are used interchangeably throughout this disclosure. In some embodiments, the monocyclic or bicyclic aromatic ring has 5 to 10 cyclic carbon atoms (i.e., C64, C16, C2 ... 5-10Aryl). 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 benzene ring. In some embodiments, the aromatic hydrocarbon ring is a phenyl ring.

[0052] Specifically, the term "bicyclic fused aryl" includes bicyclic aryl rings as defined herein. A typical bicyclic fused aryl is naphthalene.

[0053] 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), for example, 1 to 4 (or in some embodiments, 1 to 3, in some embodiments, 1 to 2) heteroatoms, with the remaining ring atoms being carbon. A 7- to 12-membered bicyclic ring comprising at least one heteroatom selected from N, O, and S, for example, 1 to 4, or in some embodiments 1 to 3, or in other embodiments 1 or 2 heteroatoms, the remaining ring atoms being 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 ring contains at least one heteroatom selected from N, O, and S, for example, 1 to 4, or 1 to 3 in some embodiments, or 1 or 2 heteroatoms in other embodiments, the remaining ring atoms being carbon, and at least one ring being aromatic and at least one heteroatom being present in the aromatic ring.

[0054] 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 is no greater than 2. In some embodiments, the total number of S and O atoms in an aromatic heterocycle is no greater than 1. When a heteroaryl group contains more than one heteroatom ring member, the heteroatoms can be the same or different. The nitrogen atom in one or more rings of a heteroaryl group can be oxidized to form an N-oxide.

[0055] Specifically, the term "bicyclic fused heteroaryl" includes 7- to 12-membered, preferably 7- to 10-membered, 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. The groups can be attached to the remainder of the molecule via either ring.

[0056] "Heterocyclic group", "heterocyclic" or "heterocyclic" are interchangeable and include non-aromatic heterocyclic groups containing one or more heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring members, with the remaining ring members being carbon, including monocyclic, fused, bridging and spirocyclic groups, i.e. containing monocyclic heterocyclic groups, bridging heterocyclic groups, spirocyclic groups and fused heterocyclic groups.

[0057] 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 they conform to the theory of valence. 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.

[0058] The term "divalent" refers to a linking group capable of forming covalent bonds with two other moieties. For example, "divalent cycloalkyl" refers to a cycloalkyl group obtained by removing two hydrogens from the corresponding cycloalkane to form a linking group. The terms "divalent aryl," "divalent heterocyclic," or "divalent heteroaryl" should be understood in a similar manner.

[0059] 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. Where the compounds disclosed herein have two or more asymmetric centers, they may also exist as diastereomers. Enantiomers and diastereomers belong to a broader class of stereoisomers. It is intended to include all such possible stereoisomers in the form of substantially pure, separated enantiomers, racemic mixtures thereof, and mixtures of diastereomers. It is intended to include all stereoisomers of the compounds disclosed herein and / or their pharmaceutically acceptable salts. Unless otherwise specifically indicated, reference to one isomer applies to any possible isomer. All possible isomers are included unless the isomer composition is specified.

[0060] Unless otherwise stated, when the compounds disclosed herein contain alkene double bonds, such double bonds are intended to include both E and Z geometric isomers.

[0061] When the compounds disclosed herein contain a disubstituted ring system, the substituents found on such a ring system can be in cis or trans configurations. The cis configuration means that both substituents are located above the two substituent positions on the carbon atom, while the trans configuration means that they are located on opposite sides. For example, a disubstituted ring system can be a cyclohexyl ring or a cyclobutyl ring.

[0062] It may be advantageous to separate the reaction products from each other and / or from the starting materials. The desired products of each step or series of steps are separated and / or purified (hereinafter, separated) to the desired degree of homogeneity using techniques commonly used in the art. Typically, such separations involve 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 chromatography; size exclusion chromatography; ion exchange chromatography; high-pressure, medium-pressure, and low-pressure liquid chromatography methods and apparatus; small-scale analytical chromatography; simulated moving bed (“SMB”) chromatography and preparative thin-layer or thick-layer chromatography, as well as small-scale thin-layer and rapid chromatography techniques. Those skilled in the art can select and apply the technique most likely to achieve the desired separation.

[0063] "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 well 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 agent, such as a chiral alcohol or Mosher's acid chloride) to convert the enantiomer mixture into a diastereomer mixture, separating the diastereomers, and converting (e.g., hydrolyzing) the individual diastereomers into their respective pure enantiomers. Enantiomers can also be separated using a chiral HPLC column.

[0064] A single stereoisomer (e.g., a substantially pure enantiomer) can be obtained by resolving a racemic mixture using a method such as forming diastereomers using an optically active resolving agent. Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. New York: John Wiley & Sons, Inc., 1994; Lochmuller, CH et al. "Chromatographic resolution of enantiomers: Selective “Review.” J. Chromatogr., 113(3) (1975): pp. 283-302 The racemic mixtures of the chiral compounds of the present invention can be separated and isolated by any suitable method, the method comprising: (1) forming ionic diastereomeric salts with the chiral compounds and separating them by stepwise crystallization or other methods; (2) forming diastereomeric compounds with chiral derivatizing agents, separating the diastereomeric compounds and converting them into pure stereoisomers; and (3) directly separating substantially pure or enriched stereoisomers under chiral conditions. See also: Wainer, Irving W. (Editor of Drug) Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker, Inc., 1993 .

[0065] Some of the compounds disclosed herein may have different hydrogen bonding sites, referred to as tautomers. For example, compounds including a carbonyl -CH2C(O)- group (keto form) can undergo tautomerism to form a hydroxyl -CH=C(OH)- group (enol form). Where applicable, both single keto and enol forms, as well as mixtures thereof, are also intended to be included.

[0066] In some implementation schemes, the structure " "Can be transformed into a structure" ".

[0067] A "prodrug" is an active agent derivative that needs to be converted in vivo to release the active agent. In some implementations, this conversion is enzymatic. Prodrugs are typically (but not necessarily) pharmacologically inactive before being converted into the active agent.

[0068] "Pharmaceutically acceptable salts" refer to those salts that, within reasonable medical judgment, are suitable for contact with tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., and in proportion to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compounds disclosed herein, or individually by reacting a free base functional group with a suitable organic acid or by reacting an acidic group with a suitable base. The term also includes salts of stereoisomers (such as enantiomers and / or diastereomers), tautomers, and prodrugs of the compounds of the present invention.

[0069] Furthermore, if the compounds disclosed herein are obtained as acid addition salts, the free base can be obtained by alkalizing a 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 dissolving the free base in a suitable organic solvent and treating the solution with acid, according to conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize that various synthetic methods are available for preparing non-toxic, pharmaceutically acceptable addition salts without excessive experimentation.

[0070] When applied to animals, humans, experimental subjects, cells, tissues, organs, or biological fluids, the terms “administration,” “administering,” “treating,” and “treatment” herein mean contact between an exogenous drug, therapeutic agent, 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 “treatment” also mean, for example, in vitro and ex vivo treatment of cells by means of a reagent, diagnostic agent, conjugated compound, or by means of another cell. The term “subject” herein includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, and rabbit), and most preferably a human.

[0071] The term "effective amount" or "therapeutic effective amount" refers to the amount of an active ingredient (such as a compound) that, when administered to a subject to treat a disease, or at least one clinical symptom of a disease or condition, is sufficient to affect treatment for said disease, condition, or symptom. The term "therapeutic effective amount" can vary depending on the compound, the disease, condition, and / or the symptoms of the disease or condition, the severity of the disease, condition, and / or the age and / or weight of the subject being treated. In any given case, an appropriate amount may be obvious to those skilled in the art or may 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 stereoisomer, tautomer, or prodrug and / or at least one pharmaceutically acceptable salt thereof that effectively "treats" a subject's disease or condition as defined herein. 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, condition, or ailment.

[0072] The term “disease” means any illness, discomfort, pain, symptom or indication, and is interchangeable with the terms “symptom” or “illness”.

[0073] Throughout this specification and the appended claims, unless the context otherwise requires, the term "comprise" and its variations (such as "comprises / 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."

[0074] Throughout this specification and the appended claims, the term "C" is used. n-mThe indicator includes a range of endpoints, where n and m are integers and indicate the number of carbons. Examples include C. 1-8 C 1-6 wait.

[0075] Unless otherwise expressly defined elsewhere in this document, all other technical and scientific terms used herein shall have the meanings commonly understood by one of ordinary skill in the art to which this invention pertains.

[0076] Example General Synthesis The compounds disclosed herein (including their salts) can be prepared using known organic synthetic techniques and can be synthesized according to any of the many possible synthetic routes.

[0077] The reactions used to prepare 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 during which the reaction takes place (e.g., temperatures within the boiling point range of the solvent). A given reaction can be carried out in a single solvent or a mixture of solvents.

[0078] 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 may be introduced before, after, or between any steps. Depending on the reaction conditions, the protecting groups shown in the synthetic scheme may or may not be used. The order of the reactions may vary and provide similar results.

[0079] The reaction can be monitored using any suitable method known in the art, such as 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.

[0080] abbreviation Example 1: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-(5,6,7,8-tetrahydroquinoline-8-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)cyclopropane-1-carboxamide Step 1: 5-Bromo-3-((dimethylamino)methylene)isobenzofuran-1(3H)-one 1-tert-butoxy-N,N,N',N'-tetramethyl-methanediamine (98.1 g, 563 mmol) was added to a solution of 5-bromo-3H-isobenzofuran-1-one (100 g, 469 mmol) in toluene (600 mL). The mixture was stirred at 90 °C for 12 h. The mixture was cooled to room temperature, and the solid was collected by filtration. The solid was washed with EtOAc (100 mL) and dried under vacuum to give the title compound (80.0 g, 64%). 1 H NMR (400 MHz, DMSO- d6 ) δ 7.97 (d, J = 0.8Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.29 (dd, J = 1.4, 8.4 Hz, 1H), 7.00 (s, 1H), 3.10 (s, 6H).

[0081] Step 2: 6-Bromo-4-((dimethylamino)methyl)phthalazine-1(2H)-one Hydrazine monohydrate (29.0 g, 579 mmol) was added to a solution of 5-bromo-3-((dimethylamino)methylene)isobenzofuran-1(3H)-one (80.0 g, 298 mmol) in EtOH (480 mL). The mixture was stirred at 80 °C for 12 h. The mixture was cooled to room temperature, and the solid was collected by filtration. The solid was dried under vacuum to give the title compound (70.0 g, 83%). LC-MS (M+H) + =282.0.

[0082] Step 3: 6-Bromo-4-(chloromethyl)phthalazine-1(2H)-one Under nitrogen atmosphere and at 0–5 °C, isobutyl chloroformate (116 g, 850 mmol) was added dropwise to a solution of 6-bromo-4-((dimethylamino)methyl)phthalazin-1(2H)-one (60.0 g, 212 mmol) in anhydrous THF (360 mL). The solid was collected by filtration and dried under vacuum to give the title compound (36.0 g, 62%).

[0083] Step 4: 2-((7-bromo-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)isoindoline-1,3-dione Potassium phthalate (31.4 g, 154 mmol) was added to a solution of 6-bromo-4-(chloromethyl)phthalazine-1(2H)-one (31.0 g, 113 mmol) in DMF (180 mL). The mixture was stirred at 25 °C for 12 hours. The solid was collected by filtration and dried under vacuum to give the title compound (40.0 g, 92%).

[0084] Step 5: 4-(aminomethyl)-6-bromophthalazine-1(2H)-one Hydrazine monohydrate (53.1 g, 1.04 mol) was added to a solution of 2-((7-bromo-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)isoindoline-1,3-dione (40.0 g, 104 mmol) in EtOH (210 mL). The mixture was stirred at 80 °C for 12 h. The mixture was cooled to room temperature, and the solid was collected by filtration. The solid was dried under vacuum to give the title compound (20.0 g, 76%). 1 H NMR (400 MHz, DMSO- d6 ) δ 8.37 (d, J = 1.6 Hz, 1H), 8.18 (d, J =8.4 Hz, 1H), 8.12 - 8.06 (m, 2H), 8.03 (dd, J = 1.8, 8.6 Hz, 1H), 7.88 - 7.81(m, 2H), 4.00 (s, 2H).

[0085] Step 6: ((7-bromo-4-oxo-3,4-dihydrophthalazine-1-yl)methyl)tert-butyl carbamate Boc₂O (34.3 g, 157 mmol) and triethylamine (23.9 g, 236 mmol) were added to a solution of 4-(aminomethyl)-6-bromophthalazine-1(2H)-one (20.0 g, 78.7 mmol) in DCM (144 mL). The mixture was stirred at 20 °C for 12 h. The solid was collected by filtration and dried under vacuum to give the title compound (20.0 g, 72%). 1 H NMR (400MHz, DMSO- d6 ) δ 12.7 (br s, 1H), 8.28 (s, 1H), 8.18 (d, J = 8.2 Hz, 1H), 8.04 (d, J= 8.2 Hz, 1H), 7.48 (br s, 1H), 5.78 (s, 1H), 4.53 - 4.31 (m, 2H), 1.42 (s, 10H).

[0086] Step 7: 1-(4-(((tert-butoxycarbonyl)amino)methyl)-1-oxo-1,2-dihydrophthalazine-6-yl)cyclopropyl Ethyl alkyl-1-carboxylate Under nitrogen atmosphere and at room temperature, 1,2-dibromoethane (1.94 g, 10.3 mmol) was added to a suspension of zinc powder (9.9 g, 154.6 mmol) in anhydrous THF (70 mL). The reaction mixture was stirred at 65 °C for 5 min and then cooled to room temperature. This activation process was repeated three times. Trimethylchlorosilane (0.559 g, 5.18 mmol) was added, and the resulting suspension was stirred at room temperature for 15 min. The mixture was warmed to 65 °C, and a solution of 1-bromocyclopropane-1-carboxylic acid ethyl ester (10.0 g, 51.8 mmol) in anhydrous THF (30 mL) was added at a rate maintained under reflux. The reaction mixture was refluxed again for 5 h and then cooled to room temperature. Stirring was stopped to allow the solids to settle. The supernatant was injected into a solution of ((7-bromo-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)tert-butyl carbamate (10.0 g, 28.3 mmol) in THF (100 mL), followed by the addition of Pd2(dba)3 (1.29 g, 1.41 mmol) and Qphos (2.0 g, 2.83 mmol). The mixture was stirred at 40 °C for 16 hours under nitrogen. The mixture was cooled to room temperature and filtered. The filtrate was concentrated under vacuum, and the filter cake was washed with EtOAc (200 mL). The combined filtrates were concentrated under vacuum. The residue was purified by silica gel chromatography (PE:EtOAc = 1:1) to give the title compound (8.0 g, 73%). LC-MS (M+H) + =388.3.

[0087] Step 8: 1-(4-(((tert-butoxycarbonyl)amino)methyl)-1-oxo-1,2-dihydrophthalazine-6-yl)cyclopropyl Alkyl-1-carboxylic acid LiOH (2.6 g, 62 mol) was added to a solution of ethyl 1-(4-(((tert-butoxycarbonyl)amino)methyl)-1-oxo-1,2-dihydrophthalazin-6-yl)cyclopropane-1-carboxylate (8.0 g, 20.6 mmol) in THF (60 mL), water (20 mL), and MeOH (20 mL). The mixture was stirred at 60 °C for 16 h and cooled to room temperature. The reaction mixture was cooled to room temperature, concentrated under vacuum, diluted to water (150 mL), and extracted with EtOAc (150 mL x 2). The organic layer was discarded, and the aqueous layer was acidified with citric acid. The mixture was extracted with EtOAc (150 mL x 2). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give the title compound (4.0 g, 54%). 1 H NMR (500 MHz, DMSO- d6 ) δ 12.53 (s, 2H), 8.23-8.14 (m, 1H), 7.99-7.76 (m, 2H), 7.46-7.34 (m,1H), 4.55-4.34 (m, 2H), 1.61-1.46 (m, 2H), 1.47-1.31 (m, 9H), 1.32-1.23 (m, 2H). LC-MS(M+H) + =360.1.

[0088] Step 9: N-((5-(trifluoromethyl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinoline-8-amine At 15 °C, with stirring, 5-(trifluoromethyl)pyridinecarboxaldehyde (354 mg, 2.02 mmol) and AcOH (12 mg, 0.202 mmol) were added to a solution of 5,6,7,8-tetrahydroquinoline-8-amine (0.30 g, 2.02 mmol) in MeOH (5 mL). After 1 hour, NaBH3CN (153 mg, 2.43 mmol) was added and the mixture was stirred at 15 °C for 12 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (PE / EtOAc = 1 / 0 to 0 / 1) to give the title compound (98 mg, 16%). 1 H NMR (400 MHz, CDCl3) δ 8.84 (s, 1H), 8.43 (d, J =4.0 Hz, 1H), 7.89 (dd, J =8.4, 2.2 Hz, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.40 (d, J =8.0 Hz, 1H), 7.10 (dd, J =8.4, 4.8 Hz, 1H), 4.19 (s, 2H), 3.93-3.85 (m, 1H), 2.90-2.73 (m,2H), 2.21-2.14 (m, 1H), 2.07-1.98 (m, 2H), 1.84-1.68 (m, 3H). LC-MS(M+H) + =308.1.

[0089] Step 10: ((4-oxo-7-(1-((5,6,7,8-tetrahydroquinoline-8-yl)((5-(trifluoromethyl)pyridin-2-yl)) methyl)carbamoyl)cyclopropyl)-3,4-dihydrophthalazine-1-yl)methyl)tert-butyl carbamate To a solution of 1-(4-(((tert-butoxycarbonyl)amino)methyl)-1-oxo-1,2-dihydrophthalazin-6-yl)cyclopropane-1-carboxylic acid (55 mg, 0.15 mmol) in DMF (2.5 mL), HATU (64 mg, 0.17 mmol), N-((5-(trifluoromethyl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinoline-8-amine (51.7 mg, 0.17 mmol) and DIPEA (39.5 mg, 0.31 mmol) were added. The solution was stirred at 50 °C for 3 hours. The mixture was cooled to room temperature, diluted with water (100 mL), and then extracted with EtOAc (100 mL). 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 (DCM:MeOH = 20:1) to give the title compound (43 mg, 44%). LC-MS (M+H) + =649.2.

[0090] Step 11: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazine-6-yl)-N-(5,6,7,8-tetrahydroquinoline- 8-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)cyclopropane-1-carboxamide TFA (1 mL) was added to a solution of ((4-oxo-7-(1-((5,6,7,8-tetrahydroquinoline-8-yl)((5-(trifluoromethyl)pyridin-2-yl)methyl)carbamoyl)cyclopropyl)-3,4-dihydrophthalazin-1-yl)methyl)carbamate (4 mL). The mixture was stirred at room temperature for 1 hour, and then concentrated under vacuum. The residue was purified by preparative HPLC to give Example 1 (20 mg, 55%). 1 H NMR (500 MHz, DMSO- d6) δ12.55-12.33 (m, 1H), 8.96-8.57 (m, 1H), 8.50-7.40 (m, 7H), 7.29-7.12 (m, 1H), 5.60-5.46 (m, 1H), 5.01-3.58 (m, 4H), 2.84-2.53 (m, 2H), 2.25-1.29 (m, 8H), 1.13-0.88 (m, 2H). LC-MS(M+H) + = 549.3.

[0091] Examples 2A and 2B: (R)-1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-(5,6,7,8-tetrahydroquinoline-8-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)cyclopropane-1-carboxamide and (S)-1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-(5,6,7,8-tetrahydroquinoline-8-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)cyclopropane-1-carboxamide and Example 1 (20 mg) was separated by chiral preparative HPLC to obtain Example 2A (7 mg, 35%) and Example 2B (5 mg, 25%). The analytical chiral HPLC conditions were as follows: Column: CHIRALPAK IC-3; Column size: 4.6 x 50 mm, 3 μm; Mobile phase: (hexane:DCM = 3:1, containing 0.1% diethylamine):EtOH = 70:30; Flow rate: 1 mL / min; Temperature: 25 °C.

[0092] Example 2A: Chiral HPLC t R =3.29 min. 1 H NMR (500 MHz, DMSO) δ 12.79-12.42 (m,1H), 8.96-8.56 (m, 1H), 8.50-7.40 (m, 7H), 7.26-7.16 (m, 1H), 5.65-5.28 (m,1H), 5.03-3.62 (m, 4H), 2.80-2.59 (m, 2H), 2.22-1.36 (m, 8H), 1.00-0.79 (m, 2H). LC-MS(M+H) + = 549.3 Example 2B: Chiral HPLC t R=4.05 min. 1H NMR (500 MHz, DMSO) δ 12.55-12.33(m, 1H), 8.96-8.57 (m, 1H), 8.50-7.40 (m, 7H), 7.25-7.15 (m, 1H), 5.62-5.29(m, 1H), 5.04-3.56 (m, 4H), 2.82-2.62 (m, 2H), 2.25-1.29 (m, 8H), 1.13-0.80 (m, 2H). LC-MS(M+H) + = 549.3.

[0093] Example 3: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-((5-(2,6-dichlorophenyl)pyridin-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinoline-8-yl)cyclopropane-1-carboxamide Step 1: ((5-(2,6-dichlorophenyl)pyridin-2-yl)methyl)tert-butyl carbamate Under nitrogen atmosphere, K3PO4 (33.3 g, 157 mmol) and Pd(dppf)Cl2 (4.59 g, 6.27 mmol) were added to a solution of ((5-bromopyridin-2-yl)methyl)carbamate (18.0 g, 62.7 mmol) and (2,6-dichlorophenyl)boronic acid (23.9 g, 125 mmol) in dioxane (80 mL), toluene (40 mL), and water (40 mL). The mixture was stirred at 85 °C for 12 hours and cooled to room temperature. The mixture was diluted with water (150 mL) and extracted with EtOAc (80 mL × 3). The combined organic layers were washed with brine (50 mL × 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 (9.0 g, 41%). LC-MS (M+H) + =353.1.

[0094] Step 2: (5-(2,6-dichlorophenyl)pyridin-2-yl)methylamine A mixture of ((5-(2,6-dichlorophenyl)pyridin-2-yl)methyl)carbamate tert-butyl ester (9.0 g, 25.5 mmol) in methanol-HCl (4 M, 90 mL) was stirred at 25 °C for 1 hour, and then the mixture was neutralized to pH 7 with methanol-NaOH (1 M). The mixture was concentrated to dryness under reduced pressure, and the residue was ground with DCM / MeOH (10 / 1, 10 mL). The filtrate was collected by filtration and concentrated under vacuum to give the title compound (6.0 g, 93%). 1 H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 7.66-7.58 (m, 1H), 7.54 (d, J =8.0 Hz, 1H), 7.38 (d, J =8.0 Hz, 2H), 7.30-7.24 (m, 1H), 4.58 (s, 2H).

[0095] Step 3: N-((5-(2,6-dichlorophenyl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinoline-8-amine NaBH(OAc)3 (18.1 g, 85.6 mmol) was added to a solution of (5-(2,6-dichlorophenyl)pyridin-2-yl)methylamine (10.8 g, 42.8 mmol) and 6,7-dihydroquinoline-8(5H)-one (7.0 g, 47.6 mmol) in DCM (140 mL) and MeOH (1.4 mL). The mixture was stirred at 25 °C for 2 hours. The mixture was poured into saturated NaHCO3 (100 mL). The mixture was extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (30 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 (5.5 g, 30%). 1 H NMR (400 MHz, CD3OD) δ 8.43-8.35 (m, 2H), 7.78-7.70 (m, 1H), 7.66(d, J =8.0 Hz, 1H), 7.58-7.50 (m, 3H), 7.44-7.36 (m, 1H), 7.25-7.17 (m, 1H), 4.73-4.56 (m, 2H), 3.90 (dd, J=7.6, 6.4 Hz, 1H), 2.95-2.76 (m, 2H), 2.33-2.23(m, 1H), 2.12-2.03 (m, 2H), 1.93-1.72 (m, 2H). LC-MS(M+H) + =384.0.

[0096] Step 4: ((7-(1-(((5-(2,6-dichlorophenyl)pyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinoline-8- 4-O-3,4-Dihydrophthalazine-1-yl)methyl)tert-butyl carbamate To a solution of 1-(4-(((tert-butoxycarbonyl)amino)methyl)-1-oxo-1,2-dihydrophthalazin-6-yl)cyclopropane-1-carboxylic acid (55 mg, 0.15 mmol) in DMF (2.5 mL), HATU (64 mg, 0.17 mmol), N-((5-(2,6-dichlorophenyl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinoline-8-amine (64.3 mg, 0.17 mmol) and DIPEA (39.5 mg, 0.31 mmol) were added. The mixture was stirred at 50 °C for 3 hours. The reaction mixture was cooled to room temperature, diluted with water (100 mL), and extracted with EtOAc (100 mL). 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 (DCM:MeOH = 20:1) to give the title compound (30 mg, 27%). LC-MS (M+H) + =725.3.

[0097] Step 5: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazine-6-yl)-N-((5-(2,6-dichlorophenyl) Pyridin-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinoline-8-yl)cyclopropane-1-carboxamide TFA (1 mL) was added to a solution of ((7-(1-(((5-(2,6-dichlorophenyl)pyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinoline-8-yl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate (30 mg, 0.04 mmol) in DCM (4 mL). The mixture was stirred at room temperature for 1 hour, and then concentrated under vacuum. The residue was purified by preparative HPLC to give Example 3. 1 H NMR (500 MHz, DMSO- d6) δ 12.55-12.33 (m, 1H), 8.57-8.00 (m, 4H), 7.93-7.82 (m, 1H), 7.81-7.69 (m, 1H), 7.67-7.55 (m, 2H), 7.55-7.41 (m, 2H), 7.39-7.30 (m, 1H), 7.27-7.13 (m, 1H), 5.68-4.00 (m, 4H), 3.70-3.55 (m, 1H), 2.87-2.60 (m, 2H), 2.10-1.38 (m, 8H), 1.12-0.68 (m, 2H). LC-MS(M+H) + = 625.3.

[0098] Examples 4A and 4B: (R)-1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-((5-(2,6-dichlorophenyl)pyridin-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinoline-8-yl)cyclopropane-1-carboxamide and (S)-1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-((5-(2,6-dichlorophenyl)pyridin-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinoline-8-yl)cyclopropane-1-carboxamide and Example 3 (21 mg) was separated by chiral preparative HPLC to obtain Example 4A (7 mg, 33%) and Example 4B (7 mg, 33%). The analytical chiral HPLC conditions were as follows: Column: CHIRALPAK IC-3; Column size: 4.6 x 50 mm, 3 μm; Mobile phase: (hexane:DCM = 3:1, containing 0.1% diethylamine):EtOH = 50:50; Flow rate: 1 mL / min; Temperature: 25 °C.

[0099] Example 4A: Chiral HPLC t R =3.32 min. 1 H NMR (500 MHz, DMSO- d6) δ 12.54-12.30(m, 1H), 8.56-8.00 (m, 4H), 7.93-7.82 (m, 1H), 7.80-7.70 (m, 1H), 7.67-7.55(m, 2H), 7.53-7.42 (m, 2H), 7.40-7.29 (m, 1H), 7.28-7.15 (m, 1H), 5.67-3.88(m, 4H), 3.66-3.48 (m, 1H), 2.86-2.59 (m, 2H), 2.12-1.31 (m, 8H), 1.14-0.73(m, 2H). LC-MS(M+H) + = 625.3.

[0100] Example 4B: Chiral HPLC t R =5.38 min. 1 H NMR (500 MHz, DMSO- d6 ) δ 12.55-12.34(m, 1H), 8.57-7.99 (m, 4H), 7.93-7.82 (m, 1H), 7.81-7.69 (m, 1H), 7.67-7.55(m, 2H), 7.55-7.41 (m, 2H), 7.39-7.30 (m, 1H), 7.27-7.15 (m, 1H), 5.68-4.00(m, 4H), 3.71-3.54 (m, 1H), 2.87-2.62 (m, 2H), 2.10-1.38 (m, 8H), 1.12-0.65(m, 2H). LC-MS(M+H) + = 625.3.

[0101] Example 5: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-((3,3-dimethyl-2,3-dihydrofurano[2,3-b]pyridin-6-yl)methyl)-N-(5,6,7,8-tetrahydroquinoline-8-yl)cyclopropane-1-carboxamide Step 1: 3-Iodo-2-((2-methylallyl)oxy)pyridine Under nitrogen atmosphere and at 25 °C, 2-methylprop-2-en-1-ol (4.5 g, 62.41 mmol) was added dropwise to a mixture of NaH (60%, 4.99 g, 125 mmol) and THF (450 mL). The mixture was stirred at 25 °C for 10 min, followed by the addition of 2-fluoro-3-iodopyridine (13.9 g, 62.4 mmol). After 30 min, the mixture was diluted with ice water (400 mL). The mixture was extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (PE / EtOAc = 1 / 0 to 10 / 1) to give the title compound (10.3 g, 60%). 1 H NMR (400 MHz, CDCl3) δ 8.10 (dd, J = 4.8, 1.6 Hz, 1H), 8.04 (dd, J = 7.6, 1.6 Hz, 1H), 6.66 (dd, J = 7.6, 4.8 Hz, 1H), 5.19-5.15 (m, 1H), 5.00-4.96 (m,1H), 4.79 (s, 2H), 1.88 (s, 3H).

[0102] Step 2: 3,3-Dimethyl-2,3-dihydrofurano[2,3-b]pyridine Under nitrogen atmosphere, HCOONa (2.30 g, 33.8 mmol), TBAC (9.40 g, 33.8 mmol), K₂CO₃ (14.0 g, 101 mmol), and Pd(OAc)₂ (759 mg, 3.38 mmol) were added to a solution of 3-iodo-2-((2-methylallyl)oxy)pyridine (9.3 g, 33.8 mmol) in DMF (90 mL). The mixture was heated to 100 °C and stirred for 16 hours. The mixture was cooled to room temperature and diluted with water (200 mL). The mixture was extracted with EtOAc (100 mL x 3). The combined organic layers were washed with water (50 mL x 2) and concentrated under vacuum. The residue was purified by silica gel chromatography (PE / EtOAc = 1 / 0 to 10 / 1) to give the title compound (2.5 g, 50%). 1 H NMR (400 MHz, CDCl3) δ 8.01 (dd, J = 5.2, 2.0 Hz, 1H), 7.39 (dd, J= 7.0, 5.8 Hz, 1H), 6.81 (dd, J = 7.2, 5.2 Hz, 1H), 4.27 (s, 2H), 1.37 (s, 6H).

[0103] Step 3: 3,3-Dimethyl-2,3-dihydrofurano[2,3-b]pyridine 7-oxide At 0 °C, mCPBA (85%, 5.10 g, 25.1 mmol) was added to a solution of 3,3-dimethyl-2,3-dihydrofurano[2,3-b]pyridine (2.5 g, 16.76 mmol) in DCM (50 mL). The mixture was stirred at 25 °C for 12 h and then quenched with 10% Na2S2O3 (20 mL). The mixture was extracted with DCM (15 mL x 12). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / EtOAc = 1 / 1 to 0 / 1) to give the title compound (2.5 g, 91%). 1 H NMR (400 MHz, CDCl3) δ 7.95 (dd, J = 6.6, 5.0 Hz, 1H), 7.39-7.25 (m, 1H), 6.97-6.91 (m, 1H), 4.47 (s, 2H), 1.34 (s, 6H).

[0104] Step 4: 3,3-Dimethyl-2,3-dihydrofurano[2,3-b]pyridine-6-carboxynitrile TMSCN (5.28 g, 53.3 mmol) and triethylamine (1.96 g, 19.4 mmol) were added to a solution of 3,3-dimethyl-2,3-dihydrofurano[2,3-b]pyridine 7-oxide (1.0 g, 6.05 mmol) in acetonitrile (10 mL). The mixture was stirred at 100 °C for 1 hour. The mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by silica gel chromatography (PE / EtOAc = 1 / 0 to 1 / 1) to give the title compound (0.80 g, 76%). 1 H NMR (400 MHz, DMSO- d6 ) δ7.88 (d, J = 7.2 Hz, 1H), 4.36 (s, 2H), 1.34 (s, 6H).

[0105] Step 5: (3,3-Dimethyl-2,3-dihydrofurano[2,3-b]pyridin-6-yl)methylamine At 0 °C, NaBH4 (347 mg, 9.18 mmol) was added in portions to a mixture of 3,3-dimethyl-2,3-dihydrofurano[2,3-b]pyridin-6-carboxynitrile (0.40 g, 2.30 mmol), (Boc)2O (1.0 g, 4.59 mmol), and NiCl2 (89 mg, 0.69 mmol) in MeOH (6 mL). The mixture was heated to 25 °C and stirred for 2 hours. Saturated NH4Cl (1 mL) was added dropwise to the reaction mixture. After the gas escaping stopped, the mixture was concentrated under reduced pressure. The residue was ground in EtOAc and filtered. The filtrate was concentrated under reduced pressure to give crude ((3,3-dimethyl-2,3-dihydrofurano[2,3-b]pyridin-6-yl)methyl)tert-butyl carbamate (0.70 g). Methanol (HCl, 4 M, 1 mL) was added to the crude product, and the mixture was stirred at 25 °C for 0.5 h. The mixture was concentrated under vacuum, and the residue was redissolved in MeOH (1 mL). The mixture was neutralized to pH 7 with methanol (NaOH, 1 M). The mixture was milled in DCM (10 mL). The filtrate was collected by filtration and concentrated under vacuum to give the title compound (160 mg, 39%). LC-MS (M+H) + =179.3.

[0106] Step 6: N-((3,3-dimethyl-2,3-dihydrofurano[2,3-b]pyridin-6-yl)methyl)-5,6,7,8-tetramethyl Hydroquinoline-8-amine trifluoroacetate At 25 °C, NaBH(OAc)3 (238 mg, 1.12 mmol) was added to a solution of (3,3-dimethyl-2,3-dihydrofurano[2,3-b]pyridin-6-yl)methylamine (0.15 g, 0.84 mmol) and 6,7-dihydroquinoline-8(5H)-one (83 mg, 0.56 mmol) in DCM (2 mL) and MeOH (0.2 mL). After 30 min, saturated NaHCO3 (5 mL) was added, and the mixture was extracted with DCM (3 mL × 5). The combined organic layers were washed with brine (3 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC to give the title compound (105 mg, 60%). LC-MS (M+H) + =310.0.

[0107] Step 7: ((7-(1-(((3,3-dimethyl-2,3-dihydrofurano[2,3-b]pyridin-6-yl)methyl)(5,6, 7,8-Tetrahydroquinoline-8-yl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazine-1-yl)methyl)tert-carbamate Butyl acetate To a solution of 1-(4-(((tert-butoxycarbonyl)amino)methyl)-1-oxo-1,2-dihydrophthalazin-6-yl)cyclopropane-1-carboxylic acid (30 mg, 0.08 mmol) in DMF (2.5 mL), HATU (35 mg, 0.09 mmol), N-((3,3-dimethyl-2,3-dihydrofurano[2,3-b]pyridin-6-yl)methyl)-5,6,7,8-tetrahydroquinoline-8-amine trifluoroacetate (28 mg, 0.065 mmol) and DIPEA (21 mg, 0.17 mmol) were added. The mixture was stirred at 40 °C for 3 hours. The reaction mixture was cooled to room temperature and diluted with water (100 mL). The mixture was extracted with EtOAc (100 mL). 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 (DCM:MeOH = 20:1) to give the title compound (20 mg, 47%). LC-MS (M+H) + =651.2.

[0108] Step 8: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazine-6-yl)-N-((3,3-dimethyl-2,3-di) Hydrofurano[2,3-b]pyridin-6-yl)methyl)-N-(5,6,7,8-tetrahydroquinolin-8-yl)cyclopropane-1-carboxamide TFA (1 mL) was added to a solution of ((7-(1-(((3,3-dimethyl-2,3-dihydrofurano[2,3-b]pyridin-6-yl)methyl)(5,6,7,8-tetrahydroquinoline-8-yl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazine-1-yl)methyl)tert-butyl carbamate (20 mg, 0.03 mmol) in DCM (4 mL). The mixture was stirred at room temperature for 1 hour and then concentrated under vacuum. The residue was purified by preparative HPLC to give Example 5 (10 mg, 60%). 1 H NMR (500 MHz, DMSO-) d6 ) δ 12.65-12.20 (m, 1H), 8.49-8.36 (m, 1H), 8.32-7.63 (m,3H), 7.60-7.09 (m, 3H), 6.76-6.61 (m, 1H), 5.62-3.88 (m, 6H), 3.30-3.20 (m,1H), 2.83-2.57 (m, 2H), 2.31-1.79 (m, 3H), 1.78-1.34 (m, 5H), 1.35-1.05 (m,7H), 0.93-0.75 (m, 1H). LC-MS(M+H) + = 551.4.

[0109] Example 6: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-((5-(2-hydroxypropyl-2-yl)pyridin-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinoline-8-yl)cyclopropane-1-carboxamide Step 1: 6-(((tert-butoxycarbonyl)amino)methyl)nicotinic acid methyl ester Under nitrogen atmosphere and at 25 °C, Boc₂O (13.5 g, 61.7 mmol) and Pd / C (10%, 0.50 g) were added to a solution of methyl 6-cyanonicotinate (5.0 g, 30.8 mmol) in MeOH (100 mL). The mixture was purged three times with hydrogen and stirred at 25 °C for 12 hours at 15 psi. The mixture was filtered, and the residue was washed with EtOAc (30 mL). Water (30 mL) was added to the filtrate, and the mixture was extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (10 mL × 3), dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (PE / EtOAc = 3 / 1) to give the title compound (7.0 g, 85%). LC-MS (M+H) + = 267.1.

[0110] Step 2: ((5-(2-hydroxypropyl-2-yl)pyridin-2-yl)methyl)tert-butyl carbamate Under nitrogen atmosphere and at 0 °C, a solution of methyl 6-(((tert-butoxycarbonyl)amino)methyl)nicotinate (0.50 g, 1.88 mmol) in THF (4 mL) was slowly added to a solution of MeMgBr in THF (3.0 M, 1.88 mL, 5.6 mmol) in THF (6 mL). The mixture was stirred at 25 °C for 12 h, and an aqueous solution of HCl (0.5 M, 10 mL) was carefully added. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (PE / EtOAc = 1 / 0 to 1 / 1) to give the title compound (0.30 g, 60%). 1 H NMR (400 MHz, DMSO- d6 ) δ 8.58-8.55 (m,1H), 7.79 (dd, J = 8.0, 2.4 Hz, 1H), 7.17 (d,J = 8.0 Hz 1H), 5.16 (s, 1H), 4.19(d, J = 6.0 Hz 1H), 1.43 (s, 6H), 1.40 (s, 9H).

[0111] Step 3: 2-(6-(((5,6,7,8-tetrahydroquinoline-8-yl)amino)methyl)pyridin-3-yl)prop-2-ol A solution of tert-butyl ((5-(2-hydroxypropyl-2-yl)pyridin-2-yl)methyl)carbamate (0.30 g, 1.13 mmol) in methanol-HCl (4 M, 0.5 mL) was stirred at 25 °C for 0.5 h, and the mixture was concentrated under reduced pressure. The residue was redissolved in DCM (2 mL) and MeOH (0.2 mL), followed by the addition of 6,7-dihydroquinoline-8(5H)-one (89 mg, 0.60 mmol) and NaBH(OAc)3 (255 mg, 1.20 mmol) at 25 °C. After 0.5 h, the mixture was carefully quenched with saturated NaHCO3 (5 mL) and extracted with DCM (3 mL × 5). The combined organic layers were washed with brine (3 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC to give the title compound (72 mg, 40%). LC-MS (M+H) + = 298.2.

[0112] Step 4: ((7-(1-(((5-(2-hydroxypropyl-2-yl)pyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinoline-8- 4-O-3,4-Dihydrophthalazine-1-yl)methyl)tert-butyl carbamate To a solution of 1-(4-(((tert-butoxycarbonyl)amino)methyl)-1-oxo-1,2-dihydrophthalazin-6-yl)cyclopropane-1-carboxylic acid (30 mg, 0.08 mmol) in DMF (2.5 mL), HATU (35 mg, 0.09 mmol), 2-(6-(((5,6,7,8-tetrahydroquinoline-8-yl)amino)methyl)pyridin-3-yl)prop-2-ol (27.3 mg, 0.09 mmol), and DIPEA (21.5 mg, 0.17 mmol) were added. The mixture was stirred at 40 °C for 3 hours. The mixture was cooled to room temperature, diluted with water (100 mL), and then extracted with EtOAc (100 mL). The organic layer was separated, washed with brine (100 mL x 2), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (DCM:MeOH = 20:1) to give the title compound (20 mg, 56%). LC-MS (M+H) +=639.2.

[0113] Step 5: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-((5-(2-hydroxypropyl-2-yl) Pyridin-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinoline-8-yl)cyclopropane-1-carboxamide TFA (1 mL) was added to a solution of ((7-(1-(((5-(2-hydroxypropyl-2-yl)pyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinoline-8-yl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazine-1-yl)methyl)carbamate (20 mg, 0.03 mmol) in DCM (3 mL). The mixture was stirred at room temperature for 1 hour, and then concentrated under vacuum. The residue was purified by preparative HPLC to give Example 6 (9 mg, 53%). 1 H NMR (500 MHz, DMSO- d6 ) δ 12.77-12.16 (m, 1H), 8.65-8.19 (m, 3H), 8.14-7.35 (m, 4H), 7.27-7.01(m, 2H), 5.64-4.32 (m, 3H), 4.06-3.79 (m, 2H), 3.59-3.37 (m, 1H), 2.85-2.56 (m, 2H), 2.29-1.01 (m, 15H), 0.99-0.79 (m, 1H). LC-MS(M+H) + = 539.5.

[0114] Example 7: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-((4-methyl-5-(trifluoromethyl)pyridin-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinoline-8-yl)cyclopropane-1-carboxamide Step 1: 4-Methyl-5-(trifluoromethyl)pyridinecarboxynitrile Zn(CN)₂ (1.20 g, 10.23 mmol) and Pd(PPh₃)₄ (295 mg, 0.26 mmol) were added to a solution of 2-chloro-4-methyl-5-(trifluoromethyl)pyridine (500 mg, 2.56 mmol) in DMF (5 mL). The mixture was degassed and purged three times with nitrogen, then heated to 80 °C. After 3 hours, the mixture was cooled to room temperature, diluted with water (20 mL), and extracted with EtOAc (10 mL x 3). 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 = 1:0 to 1:1) to give the title compound (200 mg, 42%) by LC-MS (M+H). + = 187.2.

[0115] Step 2: ((4-methyl-5-(trifluoromethyl)pyridin-2-yl)methyl)tert-butyl carbamate At 0 °C, NaBH4 (122 mg, 3.22 mmol) was added to a mixture of 4-methyl-5-(trifluoromethyl)pyridinium (300 mg, 1.61 mmol), NiCl2 (62 mg, 0.48 mmol), and Boc2O (704 mg, 3.22 mmol) in MeOH (4.5 mL). The mixture was heated to 25 °C and stirred for 2 hours. Water (10 mL) was added, and the mixture was extracted with EtOAc (5 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 = 10:1 to 1:1) to give the title compound (300 mg, 1.03 mmol, 64% yield). 1 H NMR (400 MHz, CDCl3) δ 8.71 (s, 1H), 7.22 (s, 1H), 5.53 (br s,1H), 4.46 (d, J = 5.6 Hz, 2H), 2.50 (s, 3H), 1.47 (s, 9H).

[0116] Step 3: N-((4-methyl-5-(trifluoromethyl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinoline-8-amine The title compound (130 mg, 37%) was prepared from ((4-methyl-5-(trifluoromethyl)pyridin-2-yl)methyl)carbamate and 6,7-dihydroquinoline-8(5H)-one in a manner similar to step 3 of Example 6. LCMS (M+H)+ =322.1.

[0117] Step 4: ((7-(1-(((4-methyl-5-(trifluoromethyl)pyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinoline- 8-yl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazine-1-yl)methyl)tert-butyl carbamate The title compound (30 mg, 41%) was prepared from 1-(4-(((tert-butoxycarbonyl)amino)methyl)-1-oxo-1,2-dihydrophthalazin-6-yl)cyclopropane-1-carboxylic acid and N-((4-methyl-5-(trifluoromethyl)pyridin-2-yl)-methyl)-5,6,7,8-tetrahydroquinoline-8-amine, similar to step 4 of Example 6. LCMS (M+H) + = 663.4.

[0118] Step 5: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazine-6-yl)-N-((4-methyl-5-(trifluoromethyl) (5,6,7,8-tetrahydroquinoline-8-yl)cyclopropane-1-carboxamide Example 7 (10 mg, 39%) was prepared from ((7-(1-(((4-methyl-5-(trifluoromethyl)pyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinoline-8-yl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazine-1-yl)methyl)tert-butyl carbamate in a manner similar to step 5 of Example 6. 1 H NMR (500 MHz, DMSO- d6 ) δ 12.54-12.34 (m, 1H), 8.78 – 8.44 (m, 1H), 8.43-8.39 (m, 1H), 8.31-8.27 (m, 1H), 8.08 – 7.96 (m, 1H), 7.94 – 7.64 (m, 1H), 7.61 – 7.20 (m, 2H), 7.20 – 7.12(m, 1H), 5.61 – 4.97 (m, 1H), 4.70-4.61 (m, 1H), 4.09 – 3.85 (m, 2H), 3.63-3.54 (m 1H), 2.71 – 2.58 (m, 2H), 2.42 – 2.01 (m, 3H), 1.94 – 1.84 (m, 1H), 1.72 – 1.23 (m, 6H), 1.00 – 0.83 (m, 1H). LCMS (M+H) + = 563.4.

[0119] Example 8: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-((6-methyl-5-phenylpyridin-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinoline-8-yl)cyclopropane-1-carboxamide Step 1: ((6-methyl-5-phenylpyridin-2-yl)methyl)tert-butyl carbamate The title compound (0.60 g, 49%) was prepared from 6-methyl-5-phenylpyridinecarboxynitrile in a manner similar to step 2 of Example 7. LCMS (M+H) + = 299.2.

[0120] Step 2: N-((6-methyl-5-phenylpyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinoline-8-amine The title compound (65 mg, 39%) was prepared from ((6-methyl-5-phenylpyridin-2-yl)methyl)carbamate tert-butyl ester and 6,7-dihydroquinoline-8(5H)-one in a manner similar to step 3 of Example 6. LCMS (M+H) + = 330.2.

[0121] Step 3: ((7-(1-(((6-methyl-5-phenylpyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinoline-8-yl)amino) (Cyclopropyl)-4-oxo-3,4-dihydrophthalazine-1-yl)methyl)tert-butyl carbamate The title compound (20 mg, 35%) was prepared from 1-(4-(((tert-butoxycarbonyl)amino)methyl)-1-oxo-1,2-dihydrophthalazin-6-yl)cyclopropane-1-carboxylic acid and N-((6-methyl-5-phenylpyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinoline-8-amine, similar to step 4 of Example 6. LC-MS (M+H) + =671.4.

[0122] Step 4: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazine-6-yl)-N-((6-methyl-5-phenylpyridine) (Pyridine-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinolin-8-yl)cyclopropane-1-carboxamide Example 8 (8 mg, 47%) was prepared from ((7-(1-(((6-methyl-5-phenylpyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinoline-8-yl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazine-1-yl)methyl)carbamate tert-butyl ester in a manner similar to step 5 of Example 6. 1 H NMR (400 MHz, DMSO- d6) δ 12.6-12.2 (s,1H), 8.48-8.41(m, 1H), 8.29-8.25(m, 2H), 8.10-8.06(m, 1H), 7.89-7.68(m, 1H),7.56-7.38(m, 6H), 7.23-7.06(m, 3H), 5.56-5.61(m,1H), 4.86-4.70 (m, 1H), 4.18-4.10(m, 2H), 3.52-3.48 (m, 2H), 2.78-2.56 (m, 2H), 2.4-2.37(m, 3H), 2.23-2.13(m, 1H), 2.02-1.88(m, 1H), 1.72-1.27(m, 6H), 0.94-0.85(m, 1H). LC-MS(M+H) + =571.4.

[0123] Example 9: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-(2-chloro-6-fluorobenzyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)cyclopropane-1-carboxamide Step 1: N-(2-chloro-6-fluorobenzyl)-1-(5-(trifluoromethyl)pyridin-2-yl)methylamine The title compound (90 mg, 43%) was prepared from (5-(trifluoromethyl)pyridin-2-yl)methylamine and 2-chloro-6-fluorobenzaldehyde in a manner similar to step 3 of Example 3. LC-MS (M+H) + =319.1.

[0124] Step 2: ((7-(1-((2-chloro-6-fluorobenzyl)((5-(trifluoromethyl)pyridin-2-yl)methyl)carbamoyl) Cyclopropyl-4-oxo-3,4-dihydrophthalazine-1-yl)methyl)tert-butyl carbamate The title compound (15 mg, 23%) was prepared from 1-(4-(((tert-butoxycarbonyl)amino)methyl)-1-oxo-1,2-dihydrophthalazin-6-yl)cyclopropane-1-carboxylic acid and N-(2-chloro-6-fluorobenzyl)-1-(5-(trifluoromethyl)pyridin-2-yl)methylamine, similar to step 4 of Example 6. LC-MS (M+H) + =660.4.

[0125] Step 3: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-(2-chloro-6-fluorobenzyl)-N- ((5-(trifluoromethyl)pyridin-2-yl)methyl)cyclopropane-1-carboxamide Example 9 (6 mg, 47%) was prepared from ((7-(1-((2-chloro-6-fluorobenzyl)((5-(trifluoromethyl)pyridin-2-yl)methyl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazine-1-yl)methyl)carbamoyl tert-butyl carbamate in a manner similar to step 5 of Example 6. 1 H NMR (400 MHz, DMSO- d6 ) δ 12.41 (s, 1H), 8.74 (s,1H), 8.25 – 7.01 (m, 8H), 4.84 – 4.57 (m, 4H), 4.03 – 3.90 (m, 2H), 1.66 –1.24 (m, 4H). LC-MS(M+H) + =560.3.

[0126] Example 10: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-((5-phenylpyridin-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinoline-8-yl)cyclopropane-1-carboxamide Step 1: ((5-Phenyridin-2-yl)methyl)tert-butyl carbamate The title compound (170 mg, 86%) was prepared from tert-butyl ((5-bromopyridin-2-yl)methyl)carbamate and phenylboronic acid in a manner similar to step 1 of Example 3. LC-MS (M+H) + =285.1.

[0127] Step 2: N-((5-phenylpyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinoline-8-amine The title compound (188 mg, 78%) was prepared from ((5-phenylpyridin-2-yl)methyl)carbamate tert-butyl ester and 6,7-dihydroquinoline-8(5H)-one in a manner similar to step 3 of Example 6. LCMS (M+H) + = 316.2.

[0128] Step 3: ((4-oxo-7-(1-(((5-phenylpyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinoline-8-yl)amino) 3,4-Dihydrophthalazine-1-yl)methyl)tert-butyl carbamate The title compound (30 mg, 46%) was prepared from N-((5-phenylpyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinoline-8-amine and 1-(4-(((tert-butoxycarbonyl)amino)methyl)-1-oxo-1,2-dihydrophthalazine-6-yl)cyclopropane-1-carboxylic acid, similar to step 4 of Example 6. LC-MS (M+H)+ = 657.5.

[0129] Step 4: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-((5-phenylpyridin-2-yl) methyl)-N-(5,6,7,8-tetrahydroquinolin-8-yl)cyclopropane-1-carboxamide Example 10 (15 mg, 59%) was prepared from ((4-oxo-7-(1-(((5-phenylpyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinoline-8-yl)carbamoyl)cyclopropyl)-3,4-dihydrophthalazine-1-yl)methyl)aminomethyl tert-butyl ester in a manner similar to step 5 of Example 6. 1 H NMR (400 MHz, DMSO- d6 ) δ 12.55-12.32 (m, 1H), 8.81 – 8.59 (m, 1H), 8.47 – 8.41 (m, 1H), 8.35 – 7.36 (m, 11H), 7.24 – 7.17(m, 1H), 5.58 – 4.74 (m, 2H), 4.09 – 3.99 (m, 2H), 3.55 – 3.52 (m, 1H), 2.75- 2.58 (m, 2H), 2.32 – 0.88 (m, 10H). LC-MS(M+H) + =557.4.

[0130] Examples 11A and 11B: (R)-1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-((5-phenylpyridin-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinoline-8-yl)cyclopropane-1-carboxamide and (S)-1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-((5-phenylpyridin-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinoline-8-yl)cyclopropane-1-carboxamide and Example 10 (38 mg) was separated by chiral preparative HPLC to obtain Example 11A (7 mg, 18%) and Example 11B (9 mg, 24%). The analytical chiral HPLC conditions were as follows: Column: CHIRALPAK IC-3; Column size: 4.6 x 50 mm, 3 μm; Mobile phase: (hexane:DCM = 1:1, containing 0.1% diethylamine):EtOH = 50:50; Flow rate: 1 mL / min; Temperature: 25 °C.

[0131] Example 11A: Chiral HPLC t R =2.71 min. 1 H NMR (400 MHz, DMSO- d6 ) δ 12.55-12.30(s, 1H), 8.83 – 8.55 (m, 1H), 8.47 – 8.41 (m, 1H), 8.35 – 7.36 (m, 11H), 7.24– 7.17 (m, 1H), 5.58 – 4.74 (m, 2H), 4.09 – 3.99 (m, 2H), 3.55 – 3.52 (m,1H), 2.75 – 2.58 (m, 2H), 2.32 – 0.88 (m, 10H). LC-MS(M+H) + =557.4.

[0132] Example 11B: Chiral HPLC t R =5.90 min. 1 H NMR (400 MHz, DMSO- d6 ) δ 12.55-12.30(s, 1H), 8.83 – 8.55 (m, 1H), 8.47 – 8.41 (m, 1H), 8.35 – 7.36 (m, 11H), 7.24– 7.17 (m, 1H), 5.58 – 4.74 (m, 2H), 4.09 – 3.99 (m, 2H), 3.55 – 3.52 (m,1H), 2.75 – 2.58 (m, 2H), 2.32 – 0.88 (m, 10H). LC-MS(M+H) + =557.4.

[0133] Example 12: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-((5-iodo-4-methylthiazo-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinoline-8-yl)cyclopropane-1-carboxamide Step 1: 2-(1,3-dioxolane-2-yl)-4-methylthiazole Ethylene glycol (1.46 g, 23.6 mmol) and TsOH monohydrate (449 mg, 2.36 mmol) were added to a solution of 4-methylthiazol-2-carboxaldehyde (1.0 g, 7.86 mmol) in toluene (10 mL), and the mixture was stirred at 110 °C for 12 h. The mixture was cooled to room temperature 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, 74%). 1 H NMR (400 MHz, CDCl3) δ 6.92 (s, 1H), 6.12 (s, 1H), 4.20-4.03 (m, 4H), 2.47 (s, 3H).

[0134] Step 2: 2-(1,3-dioxolane-2-yl)-5-iodo-4-methylthiazole At -78 °C, n-BuLi (2.5 M, 2.34 mL, 4.58 mmol) was added dropwise to a solution of 2-(1,3-dioxolane-2-yl)-4-methylthiazole (1.0 g, 5.84 mmol) in anhydrous THF (30 mL), followed by the addition of I2 (1.48 g, 5.84 mmol). The mixture was stirred at -78 °C for 2 h, then quenched with saturated NH4Cl (30 mL), warmed to room temperature, and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (10 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 (1.0 g, 58%). 1 H NMR (400 MHz, CDCl3) δ 6.09 (s, 1H), 4.15-4.05 (m, 4H), 2.47 (s, 3H).

[0135] Step 3: 5-Iodo-4-methylthiazole-2-carboxaldehyde Concentrated HCl (4.2 mL) was added to a solution of 2-(1,3-dioxolane-2-yl)-5-iodo-4-methylthiazole (1.0 g, 3.37 mmol) in acetone (10 mL) and water (4 mL), and the mixture was stirred at 60 °C for 3 h. The mixture was cooled to room temperature and neutralized with saturated NaHCO3 solution until the pH reached 7. The mixture was extracted with DCM (5 mL x 5). The combined organic layers were washed with brine (10 mL) and concentrated under vacuum. The residue was purified by silica gel chromatography (PE / EtOAc = 1 / 0 to 10 / 1) to give the title compound (0.50 g, 59%). 1 H NMR (400 MHz, CDCl3) δ 9.85 (s,1H), 2.58 (s, 3H).

[0136] Step 4: N-((5-iodo-4-methylthiazolyl-2-yl)methyl)-5,6,7,8-tetrahydroquinoline-8-amine At 25 °C, NaBH(OAc)3 (286 mg, 1.35 mmol) was added to a solution of 5,6,7,8-tetrahydroquinoline-8-amine (150 mg, 1.01 mmol) and 5-iodo-4-methylthiazol-2-carboxaldehyde (171 mg, 0.67 mmol) in DCM (2 mL) and MeOH (0.2 mL). The mixture was stirred at 25 °C for 0.5 h, then extracted with an aqueous solution of NaHCO3 (5 mL). The mixture was extracted with DCM (3 mL × 5). The combined organic layers were washed with brine (3 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC to give the title compound (31 mg, 12%). LC-MS (M+H) + = 386.0.

[0137] Step 5: ((7-(1-(((5-iodo-4-methylthiazolyl-2-yl)methyl)(5,6,7,8-tetrahydroquinoline-8-yl)amino) (formyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazine-1-yl)methyl)tert-butyl carbamate The title compound (30 mg, 51%) was prepared from 1-(4-(((tert-butoxycarbonyl)amino)methyl)-1-oxo-1,2-dihydrophthalazin-6-yl)cyclopropane-1-carboxylic acid and N-((5-iodo-4-methylthiazo-2-yl)methyl)-5,6,7,8-tetrahydroquinoline-8-amine, similar to step 4 of Example 6. LC-MS (M+H) + = 727.1.

[0138] Step 6: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazine-6-yl)-N-((5-iodo-4-methylthiazole- 2-yl)methyl)-N-(5,6,7,8-tetrahydroquinoline-8-yl)cyclopropane-1-carboxamide Example 12 (8 mg, 32%) was prepared from ((7-(1-(((5-iodo-4-methylthiazolyl-2-yl)methyl)(5,6,7,8-tetrahydroquinoline-8-yl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazine-1-yl)methyl)tert-butyl carbamate in a manner similar to step 5 of Example 6. 1 H NMR (500 MHz, DMSO- d6 ) δ 12.60 (s, 1H),8.35 (d, J = 4.4 Hz, 1H), 8.21 (q, J = 5.8 Hz, 2H), 7.89 – 7.82 (m, 2H), 7.51(d, J = 7.5 Hz, 1H), 7.21 (dd, J = 7.6, 4.7 Hz, 1H), 5.51-5.48 (m, 1H), 4.74-4.71 (m, 1H), 4.17 – 4.01 (m, 2H), 3.72-3.69 (m, 1H), 2.72-2.60 (m, 2H), 2.28(s, 3H), 1.92 – 1.83 (m, 1H), 1.74 – 1.54 (m, 4H), 1.50 – 1.34 (m, 2H), 1.10 (t, J = 7.1 Hz, 1H), 0.97-0.94 (m, 1H). LC-MS(M+H) + = 627.1.

[0139] Example 13: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-((5-(2-chloro-6-cyanophenyl)pyridin-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinoline-8-yl)cyclopropane-1-carboxamide Step 1: ((5-(2-chloro-6-cyanophenyl)pyridin-2-yl)methyl)tert-butyl carbamate Under nitrogen atmosphere, tert-butyl ((5-bromopyridin-2-yl)methyl)carbamate (1.0 g, 3.48 mmol) was mixed with BPD (884 mg, 3.48 mmol), KOAc (854 mg, 8.71 mmol), and Pd(dppf)Cl2 (255 mg, 0.35 mmol) in a solution of dioxane (10 mL). The mixture was stirred at 85 °C for 16 hours, cooled to room temperature, and filtered. The filtrate was concentrated to give crude product (2.0 g). One-quarter of the crude product (0.50 g), 3-chloro-2-iodobenzyl nitrile (418 mg, 1.59 mmol) was dissolved in dioxane (2.5 mL), toluene (1.3 mL), and water (1.3 mL), followed by the addition of Pd(dppf)Cl2 (145 mg, 0.20 mmol) and K3PO4 (1.05 g, 4.96 mmol). The mixture was stirred at 85°C for 3 hours under nitrogen. The mixture was cooled to room temperature, diluted with water (10 mL), and extracted with EtOAc (8.0 mL x 2). The combined organic layers were washed with brine (5.0 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 (240 mg, 80%). LC-MS (M+H) + = 344.1.

[0140] Step 2: 3-Chloro-2-(6-(((5,6,7,8-tetrahydroquinoline-8-yl)amino)methyl)pyridin-3-yl)benzylnitrile The title compound (90 mg, 53%) was prepared from ((5-(2-chloro-6-cyanophenyl)pyridin-2-yl)methyl)carbamate tert-butyl ester and 6,7-dihydroquinoline-8(5H)-one in a manner similar to step 3 of Example 6. LC-MS (M+H) + =375.1.

[0141] Step 3: ((7-(1-(((5-(2-chloro-6-cyanophenyl)pyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinoline- 8-yl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazine-1-yl)methyl)tert-butyl carbamate The title compound (30 mg, 83%) was prepared from 1-(4-(((tert-butoxycarbonyl)amino)methyl)-1-oxo-1,2-dihydrophthalazin-6-yl)cyclopropane-1-carboxylic acid and 3-chloro-2-(6-(((5,6,7,8-tetrahydroquinoline-8-yl)amino)methyl)pyridin-3-yl)benzyl nitrile in a manner similar to step 4 of Example 6. LC-MS (M+H) + = 716.2.

[0142] Step 4: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-((5-(2-chloro-6-cyanobenzene) (5,6,7,8-tetrahydroquinoline-8-yl)cyclopropane-1-carboxamide Example 13 (8 mg, 32%) was prepared from ((7-(1-(((5-(2-chloro-6-cyanophenyl)pyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinoline-8-yl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazine-1-yl)methyl)tert-butyl carbamate in a manner similar to step 5 of Example 6. 1 H NMR (500 MHz, DMSO- d6 ) δ 12.64 (s,1H), 8.59 (d, J = 1.6 Hz, 1H), 8.43 (d, J = 4.2 Hz, 1H), 8.28-8.22 (m, 1H),8.03 – 7.87 (m, 5H), 7.70 – 7.61 (m, 1H), 7.50 (t, J = 8.4 Hz, 1H), 7.39 (d,J = 8.1 Hz, 1H), 7.24-7.19 (m, 1H), 5.56 (dd, J = 10.7, 6.0 Hz, 1H), 4.79-4.75 (m, 1H), 4.27-4.21 (m, 2H), 3.66-3.62 (m, 1H), 2.75-2.59 (m, 2H), 1.91(d, J = 4.8 Hz, 1H), 1.78 – 1.57 (m, 4H), 1.43-1.41 (m, 1H), 1.26 (s, 1H), 0.93 (s, 1H). LC-MS(M+H) + = 616.2.

[0143] Example 14: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-((5-(tert-butyl)pyridin-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinoline-8-yl)cyclopropane-1-carboxamide Step 1: 5-(tert-butyl)-N-methoxy-N-methylpyridine amide A mixture of 5-tert-butylpyridin-2-carboxylic acid (130 mg, 0.73 mmol), N,O-dimethylhydroxylamine hydrochloride (92 mg, 0.94 mmol), HATU (303 mg, 0.80 mmol), and DIPEA (281 mg, 2.18 mmol) in DMF (3 mL) was stirred at 25 °C for 12 hours under nitrogen. The mixture was diluted with water (10 mL) and extracted with EtOAc (5 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 1:1) to give the title compound (140 mg, 87%). LC-MS (M+H) + = 223.2.

[0144] Step 2: 5-(tert-butyl)pyridine carbaldehyde At -78 °C, DIBAL-H (1.0 M, 0.45 mL, 0.45 mmol) was added to a solution of 5-(tert-butyl)-N-methoxy-N-methylpyridineamide (100 mg, 0.45 mmol) in anhydrous THF (2 mL). The mixture was stirred at -78 °C for 2 h, then quenched with saturated Rochelle salt (5 mL), heated to 20 °C, and stirred for 1 h. The mixture was extracted with EtOAc (5 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 5:1) to give the title compound (50 mg, 68%). 1 H NMR (400 MHz, CDCl3) δ 10.08 (s, 1H), 8.84 (d, J = 2.0 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.87 (dd, J = 8.0, 2.0 Hz, 1H), 1.41 (s, 9H).

[0145] Step 3: N-((5-(tert-butyl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinoline-8-amine The title compound (84 mg, 71%) was prepared from 5,6,7,8-tetrahydroquinoline-8-amine and 5-(tert-butyl)pyridinecarboxaldehyde in a manner similar to step 4 of Example 12. LC-MS (M+H) + = 296.3.

[0146] Step 4: ((7-(1-(((5-(tert-butyl)pyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinoline-8-yl)amino) (formyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazine-1-yl)methyl)tert-butyl carbamate The title compound (50 mg, 47%) was prepared from 1-(4-(((tert-butoxycarbonyl)amino)methyl)-1-oxo-1,2-dihydrophthalazin-6-yl)cyclopropane-1-carboxylic acid and N-((5-(tert-butyl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinoline-8-amine) in a manner similar to step 4 of Example 6. LC-MS (M+H) + = 637.2.

[0147] Step 5: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-((5-(tert-butyl)pyridine-2- (5,6,7,8-tetrahydroquinoline-8-yl)cyclopropane-1-carboxamide Example 14 (36 mg, 85%) was prepared from ((7-(1-(((5-(tert-butyl)pyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinoline-8-yl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazine-1-yl)methyl)carbamate tert-butyl)carbamate in a manner similar to step 5 of Example 6. 1 H NMR (500 MHz, DMSO- d6 ) δ 12.95-12.84 (m,1H), 8.58 – 8.32 (m, 5H), 8.09-8.04 (m, 1H), 7.87 – 7.76 (m, 1H), 7.51 (d, J= 8.9 Hz, 1H), 7.27 – 7.13 (m, 1H), 5.56-4.40 (m, 4H), 3.55-3.52 (m, 2H), 2.85-2.57 (m, 2H), 2.20 (s, 1H), 2.04 – 1.42 (m, 5H), 1.32 (s, 4H), 1.18 (s, 4H), 0.99-0.95 (m, 1H). LC-MS(M+H) + = 537.2.

[0148] Example 15: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-((4-bromoisoquinoline-1-yl)methyl)-N-(5,6,7,8-tetrahydroquinoline-8-yl)cyclopropane-1-carboxamide Step 1: 4-Bromoisoquinoline 2-oxide At 0 °C, mCPBA (80%, 1.35 g, 6.25 mmol) was added to a solution of 4-bromoisoquinoline (1.0 g, 4.81 mmol) in DCM (10 mL). The mixture was heated to 25 °C and stirred for 1 hour. The mixture was quenched by slow addition of 10% Na₂S₂O₃ aqueous solution (10 mL). The mixture was extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (EtOAc:MeOH = 1:0 to 10:1) to give the title compound (900 mg, 84%). LC-MS (M+H) + = 224.0.

[0149] Step 2: 4-Bromoisoquinoline-1-formonitrile DBU (1.37 g, 9.00 mmol) was added to a solution of 4-bromoisoquinoline 2-oxide (900 mg, 4.02 mmol) and TMSCN (438 mg, 4.42 mmol) in THF (27 mL). The mixture was stirred at 70 °C for 0.5 h, cooled to room temperature, 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 (800 mg, 85%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 8.86 (s, 1H), 8.38 (d, J =8.4 Hz, 1H), 8.29 (d, J = 8.4 Hz, 1H), 7.97 (t, J = 8.4 Hz, 1H), 7.89 (t, J = 8.4Hz, 1H).

[0150] Step 3: (4-bromoisoquinoline-1-yl)methylamine Under Ar atmosphere, romaine Ni (4 mg, 0.05 mmol) was added to a reaction flask, followed by AcOH (3 mL). A solution of 4-bromoisoquinoline-1-carboxynitrile (100 mg, 0.43 mmol) in AcOH (2 mL) was added. The suspension was degassed under vacuum and purged three times with hydrogen. The mixture was stirred at 25 °C for 4 hours under hydrogen (50 psi). The solid was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (30 mg, 29%). LC-MS (M+H) + = 237.1.

[0151] Step 4: N-((4-bromoisoquinoline-1-yl)methyl)-5,6,7,8-tetrahydroquinoline-8-amine The title compound (107 mg, 41%) was prepared from (4-bromoisoquinoline-1-yl)methylamine and 6,7-dihydroquinoline-8(5H)-one in a manner similar to step 3 of Example 3. LC-MS (M+H) + = 367.9.

[0152] Step 5: ((7-(1-(((4-bromoisoquinoline-1-yl)methyl)(5,6,7,8-tetrahydroquinoline-8-yl)carbamoyl) 1-(cyclopropyl)-4-oxo-3,4-dihydrophthalazine-1-yl)methyl)tert-butyl carbamate The title compound (20 mg, 33%) was prepared from 1-(4-(((tert-butoxycarbonyl)amino)methyl)-1-oxo-1,2-dihydrophthalazin-6-yl)cyclopropane-1-carboxylic acid and N-((4-bromoisoquinoline-1-yl)methyl)-5,6,7,8-tetrahydroquinoline-8-amine, similar to step 4 of Example 6. LC-MS (M+H)+ = 709.4.

[0153] Step 6: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-((4-bromoisoquinoline-1-yl) methyl)-N-(5,6,7,8-tetrahydroquinolin-8-yl)cyclopropane-1-carboxamide Example 15 (5 mg, 29%) was prepared from tert-butyl ((7-(1-(((4-bromoisoquinoline-1-yl)methyl)(5,6,7,8-tetrahydroquinoline-8-yl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazine-1-yl)methyl) in a manner similar to step 5 of Example 6. 1 H NMR (400 MHz, DMSO- d6) δ 12.5 (s, 1H), 8.83 (s, 1H),8.44-8.35 (m, 2H), 8.19-8.13 (m, 2H), 7.97-7.56 (m, 4H), 7.49-7.12 (m, 2H),5.49-5.26 (m, 2H), 4.11-4.07 (m, 3H), 2.68-2.53 (m, 3H), 2.04-1.24 (m, 8H), 0.94-0.85 (m, 1H). LC-MS(M+H) + =609.3.

[0154] Example 16: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-((5-(1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinoline-8-yl)cyclopropane-1-carboxamide Step 1: ((5-(1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)methyl)tert-butyl carbamate The title compound (150 mg, 36%) was prepared from ((5-bromopyridin-2-yl)methyl)carbamate tert-butyl and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)-1H-pyrazole in a manner similar to step 1 of Example 3. LC-MS (M+H) + =289.3.

[0155] Step 2: N-((5-(1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinoline-8- amine The title compound (104 mg, 44%) was prepared from ((5-(1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)methyl)carbamate tert-butyl ester and 6,7-dihydroquinoline-8(5H)-one, similar to step 3 of Example 6. LC-MS (M+H) + =320.2.

[0156] Step 3: ((7-(1-(((5-(1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinone) (Lin-8-yl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazine-1-yl)methyl)tert-butyl carbamate The title compound (30 mg, 65%) was prepared from 1-(4-(((tert-butoxycarbonyl)amino)methyl)-1-oxo-1,2-dihydrophthalazin-6-yl)cyclopropane-1-carboxylic acid and N-((5-(1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinoline-8-amine) in a manner similar to step 4 of Example 6. LC-MS (M+H) + = 661.3.

[0157] Step 4: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazine-6-yl)-N-((5-(1-methyl-1H-pyridine) (5-(5,6,7,8-tetrahydroquinoline-8-yl)cyclopropane-1-carboxamide) Example 16 (8 mg, 17%) was prepared from ((7-(1-(((5-(1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinoline-8-yl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazine-1-yl)methyl)tert-butyl carbamate in a manner similar to step 5 of Example 6. 1 H NMR (500 MHz, DMSO- d6 ) δ 12.72(s, 1H), 8.68 (d, J = 1.9 Hz, 1H), 8.43 (d, J = 3.0 Hz, 1H), 8.33-8.25 (m, 2H), 8.00 – 7.89 (m, 3H), 7.58 – 7.41 (m, 3H), 7.38 – 7.16 (m, 2H), 6.53 (d, J = 1.9Hz, 1H), 5.56-5.53 (m, 1H), 4.75- 4.72 (m, 1H), 4.32-4.24 (m, 2H), 3.89 (s,3H), 3.72 (s, 1H), 3.60-3.58 (m, 1H), 2.72 – 2.66 (m, 2H), 2.54 (s, 2H),1.93-1.89 (m, 1H), 1.78 – 1.66 (m, 2H), 1.59-1.55 (m, 2H), 1.44-1.41 (m, 1H),1.26 (s, 1H), 0.97 – 0.89 (m, 1H). LC-MS(M+H) + = 561.3.

[0158] Example 17: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-(4-methoxy-5,6,7,8-tetrahydroquinoline-8-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)cyclopropane-1-carboxamide Step 1: 4-Methoxy-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinoline-8-amine The title compound (60 mg, 29%) was prepared from (5-(trifluoromethyl)pyridin-2-yl)methylamine and 4-methoxy-6,7-dihydroquinoline-8(5H)-one in a manner similar to step 3 of Example 3. LC-MS (M+H) + = 338.1.

[0159] Step 2: ((7-(1-((4-methoxy-5,6,7,8-tetrahydroquinoline-8-yl)((5-(trifluoromethyl)pyridine-2-) 4-O-3,4-Dihydrophthalazine-1-yl)methyl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazine-1-yl)methyl)tert-butyl carbamate The title compound (30 mg, 71%) was prepared from 1-(4-(((tert-butoxycarbonyl)amino)methyl)-1-oxo-1,2-dihydrophthalazin-6-yl)cyclopropane-1-carboxylic acid and 4-methoxy-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinoline-8-amine, similar to step 4 of Example 6. LC-MS (M+H) + = 679.3.

[0160] Step 3: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazine-6-yl)-N-(4-methoxy-5,6,7,8-) Tetrahydroquinoline-8-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)cyclopropane-1-carboxamide Example 17 (13 mg, 51%) was prepared from ((7-(1-((4-methoxy-5,6,7,8-tetrahydroquinoline-8-yl)((5-(trifluoromethyl)pyridin-2-yl)methyl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazine-1-yl)methyl)carbamate tert-butyl)carbamate in a manner similar to step 5 of Example 6. 1 H NMR (500 MHz, DMSO- d6) δ 12.98– 12.58 (m, 1H), 8.42 – 8.29 (m, 2H), 8.26 – 7.94 (m, 3H), 7.84 – 7.12 (m,3H), 6.95 – 6.85 (m, 1H), 5.55 – 5.28 (m, 1H), 4.93 – 4.61 (m, 1H), 4.47 –4.20 (m, 2H), 3.90 – 3.78 (m, 3H), 3.62 – 3.49 (m, 2H), 2.68 – 2.54 (m, 3H), 2.43 – 1.87 (m, 3H), 1.75 – 0.80 (m, 9H).

[0161] Example 18: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinoline-8-yl)cyclopropane-1-carboxamide Step 1: ((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)tert-butyl carbamate BPD (5.31 g, 20.9 mmol), Pd(dppf)Cl2 (1.27 g, 1.74 mmol), and KOAc (4.27 g, 43.5 mmol) were added to a solution of ((5-bromopyridin-2-yl)methyl)carbamate (5.0 g, 17.4 mmol) in dioxane (50 mL). The mixture was stirred at 85 °C for 12 hours. The mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The crude material was redissolved in dioxane (25 mL), toluene (12 mL), and water (12 mL), followed by the addition of 1,3-difluoro-2-iodobenzene (4.28 g, 17.8 mmol), K3PO4 (6.32 g, 29.8 mmol), and Pd(dppf)Cl2 (871 mg, 1.19 mmol). The mixture was stirred at 85 °C for 3 hours. The mixture was cooled to room temperature, diluted with water (30 mL), and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (10 mL × 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 (3.0 g, 54%). 1 H NMR (400 MHz, CDCl3) δ 8.64 (s, 1H), 7.78 (d,J = 8.4 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.36-7.28 (m, 1H), 7.06-6.96 (m, 1H), 5.62 (br s, 1H), 4.50(d, J = 5.6 Hz, 2H), 7.47 (s, 9H). LC-MS(M+H) + =321.1.

[0162] Step 2: (5-(2,6-difluorophenyl)pyridin-2-yl)methylamine A mixture of ((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)carbamate tert-butyl ester (3.0 g, 9.37 mmol) in HCl methanol solution (4 M, 50 mL) was stirred for 2 hours at 25 °C, and then the mixture was neutralized to pH 7 with NaOH methanol solution (1 M). The mixture was concentrated to dryness under reduced pressure, and the residue was wet-milled with DCM / MeOH (10 / 1, 10 mL). The filtrate was collected by filtration and concentrated under vacuum to give the title compound (1.5 g, 73%). 1 H NMR (400 MHz, CD3OD) δ 8.72 (s, 1H), 7.97 (d, J = 6.0 Hz, 1H), 7.60 (d, J = 6.0 Hz, 1H), 7.54-7.45 (m, 1H), 7.20-7.10 (m, 1H), 4.37 (s, 2H). LC-MS(M+H) + =221.1.

[0163] Step 3: N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinoline-8-amine To a solution of 6,7-dihydroquinoline-8(5H)-one (0.25 g, 1.70 mmol) and (5-(2,6-difluorophenyl)pyridin-2-yl)methylamine (449 mg, 2.04 mmol) in DCM (4 mL) and MeOH (0.4 mL), NaBH(OAc)3 (720 mg, 3.40 mmol) was added. The mixture was stirred at 25 °C for 2 hours, then slowly poured into saturated NaHCO3 (4.0 mL). The mixture was extracted with DCM (3.0 mL x 2). The combined organic layers were washed with brine (3.0 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC to give the title compound (176 mg, 30%). LC-MS (M+H) + =352.1.

[0164] Step 4: ((7-(1-(((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinoline-8- 4-O-3,4-Dihydrophthalazine-1-yl)methyl)tert-butyl carbamate To a solution of 1-(4-(((tert-butoxycarbonyl)amino)methyl)-1-oxo-1,2-dihydrophthalazin-6-yl)cyclopropane-1-carboxylic acid (155 mg, 0.43 mmol) in DMF (2.5 mL), HATU (180 mg, 0.47 mmol), N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinoline-8-amine (166 mg, 0.47 mmol) and DIPEA (111 mg, 0.86 mmol) were added. The solution was stirred at 50 °C for 6 hours. The mixture was cooled to room temperature, poured into water (100 mL), and extracted with EtOAc (100 mL). 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 (DCM:MeOH = 20:1) to give the title compound (200 mg, 67%). LC-MS (M+H) + =693.4.

[0165] Step 5: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazine-6-yl)-N-((5-(2,6-difluorophenyl) Pyridin-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinoline-8-yl)cyclopropane-1-carboxamide TFA (1 mL) was added to a solution of ((7-(1-(((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinoline-8-yl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate (200 mg, 0.29 mmol) in DCM (4 mL). The mixture was stirred at room temperature for 1 hour, and then concentrated under vacuum. The residue was purified by preparative HPLC to give Example 18 (149 mg, 87%). 1 H NMR (500 MHz, DMSO- d6 ) δ 13.05 – 12.73 (m, 1H), 8.64 – 8.31 (m, 5H), 8.20 – 8.04 (m, 1H), 7.93 –7.47 (m, 4H), 7.35 – 7.18 (m, 3H), 5.73 – 5.35 (m, 1H), 5.02 – 4.29 (m,3H), 3.71 – 3.59 (m, 1H), 2.88 –2.56 (m, 3H), 2.24 – 0.94 (m, 8H).

[0166] Examples 19A and 19B: (R)-1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinoline-8-yl)cyclopropane-1-carboxamide and (S)-1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinoline-8-yl)cyclopropane-1-carboxamide and Example 18 (146 mg) was separated by chiral preparative HPLC to obtain Example 19A (53 mg, 36%) and Example 19B (48 mg, 33%). The analytical chiral HPLC conditions were as follows: Column: CHIRALPAK IC-3; Column size: 4.6 x 50 mm, 3 μm; Mobile phase: (hexane:DCM = 1:1, containing 0.1% diethylamine):EtOH = 75:25; Flow rate: 1 mL / min; Temperature: 25 °C.

[0167] Example 19A: Chiral HPLC t R =2.97 min. 1 H NMR (500 MHz, DMSO-d6 ) δ 12.83-12.42(m, 1H), 8.71-8.40 (m, 2H), 8.34-7.69 (m, 4H), 7.62-7.44 (m, 2H), 7.39-7.13(m, 4H), 5.72-5.26 (m, 1H), 5.17-4.39 (m, 2H), 4.30-4.13 (m, 2H), 3.73-3.54(m, 1H), 2.87-2.59 (m, 2H), 2.21-0.88 (m, 8H). LC-MS(M+H) + =593.4; Example 19B: Chiral HPLC t R =4.13 min. 1 H NMR (500 MHz, DMSO- d6 ) δ 12.83-12.42(m, 1H), 8.71-8.40 (m, 2H), 8.34-7.69 (m, 4H), 7.62-7.44 (m, 2H), 7.39-7.13(m, 4H), 5.72-5.26 (m, 1H), 5.17-4.39 (m, 2H), 4.30-4.13 (m, 2H), 3.73-3.54(m, 1H), 2.87-2.59 (m, 2H), 2.21-0.88 (m, 8H). LC-MS(M+H) + = 593.4.

[0168] Example 20: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-((5-phenoxypyridin-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinoline-8-yl)cyclopropane-1-carboxamide Step 1: 5-Phenoxypyridine carboxaldehyde Phenol (181 mg, 1.92 mmol) and K₂CO₃ (663 mg, 4.80 mmol) were added to a solution of 5-fluoropyridinecarboxaldehyde (0.20 g, 1.60 mmol) in DMF (2 mL) at room temperature. The mixture was heated to 110 °C and stirred for 1 hour. The mixture was cooled to room temperature and partitioned between EtOAc (80 mL) and water (40 mL). The organic phase was separated, dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (PE:EtOAc = 1:0 to 1:1) to give the title compound (0.27 g, 85%). LC-MS (M+H) + = 200.2.

[0169] Step 2: N-((5-phenoxypyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinoline-8-amine The title compound (316 mg, 70%) was prepared from 5,6,7,8-tetrahydroquinoline-8-amine and 5-phenoxypyridinecarboxaldehyde in a manner similar to step 4 of Example 12. LC-MS (M+H) + = 332.2.

[0170] Step 3: ((4-oxo-7-(1-(((5-phenoxypyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinoline-8-yl)) (carbamoyl)cyclopropyl)-3,4-dihydrophthalazine-1-yl)methyl)tert-butyl carbamate The title compound (10 mg, 24%) was prepared from 1-(4-(((tert-butoxycarbonyl)amino)methyl)-1-oxo-1,2-dihydrophthalazin-6-yl)cyclopropane-1-carboxylic acid and N-((5-phenoxypyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinoline-8-amine, similar to step 4 of Example 6. LC-MS (M+H) + = 673.4.

[0171] Step 4: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazine-6-yl)-N-((5-phenoxypyridine-2-yl) (5,6,7,8-tetrahydroquinoline-8-yl)cyclopropane-1-carboxamide Example 20 (2 mg, 23%) was prepared from ((4-oxo-7-(1-(((5-phenoxypyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinoline-8-yl)carbamoyl)cyclopropyl)-3,4-dihydrophthalazine-1-yl)methyl)tert-butyl carbamate in a manner similar to step 4 of Example 6. 1 H NMR (500 MHz, DMSO- d6) δ 12.60 – 12.37 (m,1H), 8.49 – 8.36 (m, 1H), 8.31 – 8.05 (m, 2H), 8.00 – 7.68 (m, 2H), 7.54 –7.30 (m, 4H), 7.29 – 7.13 (m, 3H), 7.09 – 6.82 (m, 2H), 5.60 – 5.26 (m, 1H), 4.89 – 4.66 (m, 1H), 4.10 – 3.92 (m, 2H), 3.55 – 3.37 (m, 1H), 2.81 – 2.57(m, 2H), 2.03 – 0.81 (m, 10H). LC-MS (M+H) + = 573.4.

[0172] Example 21: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-N-(8-fluoro-1,2,3,4-tetrahydronaphthyl-1-yl)cyclopropane-1-carboxamide Step 1: N-((5-bromopyridin-2-yl)methyl)-8-fluoro-1,2,3,4-tetrahydronaphthyl-1-amine Ti(OEt)4 (695 mg, 3.05 mmol) was added to a solution of 8-fluoro-3,4-dihydronaphthyl-1(2H)-one (100 mg, 0.61 mmol) and (5-bromopyridin-2-yl)methylamine (125 mg, 0.67 mmol) in dioxane (3 mL). The mixture was heated to 60 °C and stirred for 2 hours. The mixture was cooled to room temperature and NaBH(OAc)3 (258 mg, 1.22 mmol) was added. After 2 hours, the mixture was diluted with water (3 mL) and extracted with EtOAc (2 mL x 3). The combined organic layers were washed with brine (2 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 (50 mg, 24%). LC-MS (M+H) + = 335.1.

[0173] Step 2: N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-8-fluoro-1,2,3,4-tetrahydronaphthyl-1-amine The title compound (26 mg, 47%) was prepared from N-((5-bromopyridin-2-yl)methyl)-8-fluoro-1,2,3,4-tetrahydronaphth-1-amine and (2,6-difluorophenyl)boronic acid, similar to step 1 of Example 3. LC-MS (M+H) + = 369.1.

[0174] Step 3: ((7-(1-(((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)(8-fluoro-1,2,3,4-tetrahydronaphthalene-) 1-yl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazine-1-yl)methyl)tert-butyl carbamate The title compound (7 mg, 18%) was prepared from 1-(4-(((tert-butoxycarbonyl)amino)methyl)-1-oxo-1,2-dihydrophthalazin-6-yl)cyclopropane-1-carboxylic acid and N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-8-fluoro-1,2,3,4-tetrahydronaphthyl-1-amine) in a manner similar to step 4 of Example 6. LC-MS (M+H) + = 710.4.

[0175] Step 4: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazine-6-yl)-N-((5-(2,6-difluorophenyl) Pyridin-2-yl)methyl)-N-(8-fluoro-1,2,3,4-tetrahydronaphth-1-yl)cyclopropane-1-carboxamide Example 21 (1 mg, 17%) was prepared from ((7-(1-(((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)(8-fluoro-1,2,3,4-tetrahydronaphthyl-1-yl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)tert-butyl carbamate in a manner similar to step 4 of Example 6. 1 H NMR (500 MHz, DMSO- d6 ) δ 12.77– 12.30 (m, 1H), 8.59 – 8.41 (m, 1H), 8.36 – 8.11 (m, 1H), 8.10 – 7.47 (m,4H), 7.34 – 7.10 (m, 4H), 7.04 – 6.81 (m, 2H), 5.79 – 5.37 (m, 1H), 4.66 –4.49 (m, 1H), 4.15 – 3.98 (m, 2H), 3.89 – 3.74 (m, 1H), 2.67 – 2.54 (m, 2H), 2.11 – 0.72 (m, 10H). LC-MS(M+H) + = 610.4.

[0176] Example 22: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-(4-bromo-2-fluorobenzyl)-N-(5,6,7,8-tetrahydroquinoline-8-yl)cyclopropane-1-carboxamide Step 1: N-(4-bromo-2-fluorobenzyl)-5,6,7,8-tetrahydroquinoline-8-amine The title compound (74 mg, 33%) was prepared from 5,6,7,8-tetrahydroquinoline-8-amine and 4-bromo-2-fluorobenzaldehyde in a manner similar to step 4 of Example 12. LC-MS (M+H) + = 335.0.

[0177] Step 2: ((7-(1-((4-bromo-2-fluorobenzyl)(5,6,7,8-tetrahydroquinoline-8-yl)carbamoyl)cyclopropane 4-oxo-3,4-dihydrophthalazine-1-yl)methyl)tert-butyl carbamate The title compound (30 mg, 44%) was prepared from 1-(4-(((tert-butoxycarbonyl)amino)methyl)-1-oxo-1,2-dihydrophthalazin-6-yl)cyclopropane-1-carboxylic acid and N-(4-bromo-2-fluorobenzyl)-5,6,7,8-tetrahydroquinoline-8-amine, similar to step 4 of Example 6. LC-MS (M+H) + =676.4.

[0178] Step 3: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-(4-bromo-2-fluorobenzyl)-N- (5,6,7,8-Tetrahydroquinolin-8-yl)cyclopropane-1-carboxamide Example 22 (8 mg, 31%) was prepared from ((7-(1-((4-bromo-2-fluorobenzyl)(5,6,7,8-tetrahydroquinoline-8-yl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazine-1-yl)methyl)tert-butyl carbamate in a manner similar to step 4 of Example 6. 1 H NMR (400 MHz, DMSO- d6 ) δ 12.45 (s, 1H), 8.48 – 8.04 (m, 2H), 7.97 – 7.69 (m, 2H), 7.51 – 6.96 (m, 5H), 5.60 – 4.53 (m, 2H), 4.08– 4.00 (m, 2H), 3.42 – 3.39 (m, 1H), 2.73 – 2.57 (m, 2H), 1.92 – 0.85 (m, 8H). LC-MS(M+H) + =576.4.

[0179] Example 23: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-((5-(3,5-dimethyl-1H-pyrazol-4-yl)pyridin-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinoline-8-yl)cyclopropane-1-carboxamide Step 1: N-((5-bromopyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinoline-8-amine The title compound (3.0 g, 50%) was prepared from 6,7-dihydroquinoline-8(5H)-one and (5-bromopyridin-2-yl)methylamine in a manner similar to step 3 of Example 18. LC-MS (M+H) + =318.1.

[0180] Step 2: N-((5-(3,5-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl) methyl)-5,6,7,8-tetrahydroquinoline-8-amine The title compound (104 mg, 26%) was prepared from N-((5-bromopyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinoline-8-amine and 3,5-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1H-pyrazole, similar to step 1 of Example 3. LC-MS (M+H) + =418.2.

[0181] Step 3: ((7-(1-(((5-(3,5-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyridine) (Pyridine-2-yl)methyl)(5,6,7,8-tetrahydroquinoline-8-yl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazine-1- tert-butyl carbamate The title compound (30 mg, 48%) was prepared from 1-(4-(((tert-butoxycarbonyl)amino)methyl)-1-oxo-1,2-dihydrophthalazin-6-yl)cyclopropane-1-carboxylic acid and N-((5-(3,5-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinoline-8-amine) in a manner similar to step 4 of Example 6. LC-MS (M+H) + =759.1.

[0182] Step 4: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazine-6-yl)-N-((5-(3,5-dimethyl-1H-) (pyrazol-4-yl)pyridin-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinoline-8-yl)cyclopropane-1-carboxamide Example 23 (16 mg, 70%) was prepared from ((7-(1-(((5-(3,5-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinoline-8-yl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazine-1-yl)methyl)tert-butyl carbamate, in a manner similar to step 4 of Example 6. 1 H NMR (500 MHz, DMSO-) d6 ) δ 12.58-12.26 (m, 2H), 8.57-8.37 (m, 2H), 8.34-8.00 (m,2H), 7.99-7.62 (m, 2H), 7.55-7.46 (m, 1H), 7.34-7.14 (m, 2H), 5.64-4.57 (m,2H), 4.16-3.93 (m, 2H), 3.64-3.48 (m, 1H), 2.86-2.60 (m, 2H), 2.34-1.97 (m,8H), 1.99-1.31 (m, 7H), 0.98-0.84 (m, 1H). LC-MS(M+H) + = 575.4.

[0183] Example 24: (±)-4-(aminomethyl)-6-(1-((2S,6S)-2-methyl-6-(5-(trifluoromethyl)pyridin-2-yl)piperidin-1-carbonyl)cyclopropyl)phthalazine-1(2H)-one Step 1: tert-butyl 2-methyl-6-(5-(trifluoromethyl)pyridin-2-yl)piperidine-1-carboxylate Four identical reactions were set up in parallel as described below. A mixture of 2-chloro-5-(trifluoromethyl)pyridine (75 mg, 0.41 mmol), 1-(tert-butoxycarbonyl)-6-methylpiperidin-2-carboxylic acid (100 mg, 0.41 mmol), nickel(II) ethylene glycol dimethyl ether complex (9 mg, 0.041 mmol), Cs₂CO₃ (335 mg, 1.0 mmol), dtbbpy (17 mg, 0.062 mmol), and bis[2-(2,4-difluorophenyl)-5-methylpyridine-N,C₂O]-4,40-di-tert-butyl-2,20-bipyridine iridium hexafluorophosphate (III) (4.2 mg, 0.004 mmol) in DMF (2 mL) was degassed and purged three times with nitrogen. The mixture was then stirred for 12 hours under blue LED (34 W, 455 nm) irradiation.

[0184] The mixtures from all four apparatuses were combined, diluted with water (15 mL), and extracted with EtOAc (10 mL x 3). 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 = 1:0 to 10:1) to give the title compound (75 mg, 13%). LC-MS (M+H) + = 345.3.

[0185] Step 2: (±)-2-((2S,6S)-6-methylpiperidin-2-yl)-5-(trifluoromethyl)pyridine A solution of tert-butyl 2-methyl-6-(5-(trifluoromethyl)pyridin-2-yl)piperidin-1-carboxylate (100 mg, 0.29 mmol) in methanol-HCl (4 M, 1 mL) was stirred at 25 °C for 0.5 h. The mixture was concentrated under vacuum, and the residue was purified by preparative HPLC to give the title compound (12 mg, 17%). LC-MS (M+H) + = 245.1.

[0186] Step 3: (±)-((7-(1-((2S,6S)-2-methyl-6-(5-(trifluoromethyl)pyridin-2-yl)piperidine-1-carbonyl) 1-(cyclopropyl)-4-oxo-3,4-dihydrophthalazine-1-yl)methyl)tert-butyl carbamate The title compound (4 mg, 14%) was prepared from 1-(4-(((tert-butoxycarbonyl)amino)methyl)-1-oxo-1,2-dihydrophthalazin-6-yl)cyclopropane-1-carboxylic acid and (±)-2-((2S,6S)-6-methylpiperidin-2-yl)-5-(trifluoromethyl)pyridine in a manner similar to step 4 of Example 6. LC-MS (M+H) + = 586.2.

[0187] Step 4: (±)-4-(aminomethyl)-6-(1-((2S,6S)-2-methyl-6-(5-(trifluoromethyl)pyridine-2- (I)piperidine-1-carbonyl)cyclopropyl)phthalazine-1(2H)-one Example 24 (0.7 mg, 21%) was prepared from (±)-((7-(1-((2S,6S)-2-methyl-6-(5-(trifluoromethyl)pyridin-2-yl)piperidin-1-carbonyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate tert-butyl ester in a manner similar to step 4 of Example 6. 1 H NMR (500 MHz, DMSO- d6) δ 12.75 – 12.33 (m,1H), 9.09 – 8.69 (m, 1H), 8.28 – 8.11 (m, 2H), 7.93 – 7.61 (m, 2H), 7.56 –7.25 (m, 1H), 6.06 – 5.38 (m, 1H), 4.53 – 4.36 (m, 1H), 4.19 – 4.05 (m, 2H), 2.82 – 2.69 (m, 1H), 2.11 – 1.25 (m, 10H), 0.36 – 0.17 (m, 2H). LC-MS(M+H) + =486.4.

[0188] Example 25: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-cyclobutyl-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)cyclopropane-1-carboxamide Step 1: 5-(2,6-difluorophenyl)pyridinecarboxaldehyde Pd(dppf)Cl2 (3.14 g, 4.29 mmol) and K3PO4 (18.2 g, 85.8 mmol) were added to a mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)pyridinecarboxaldehyde (20.0 g, 85.8 mmol) and 1,3-difluoro-2-iodobenzene (20.6 g, 85.8 mmol) in dioxane (100 mL), toluene (50 mL), and water (50 mL). The mixture was stirred at 85 °C for 16 hours. The mixture was cooled to room temperature and poured into water (100 mL). The organic layers were separated, and the aqueous phase was extracted with EtOAc (80 mL x 2). The combined organic phases were washed with brine (50 mL), dried over anhydrous 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 (2.6 g, 14%). LC-MS (M+H) + = 220.2.

[0189] Step 2: N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)cyclobutylamine The title compound (47 mg, 19%) was prepared from 5-(2,6-difluorophenyl)pyridinecarboxaldehyde and cyclobutylamine in a manner similar to step 4 of Example 12. LC-MS (M+H) + = 275.1.

[0190] Step 3: ((7-(1-(cyclobutyl((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)carbamoyl)cyclopropyl) 4-oxo-3,4-dihydrophthalazine-1-yl)methyl)tert-butyl carbamate The title compound (15 mg, 14%) was prepared from 1-(4-(((tert-butoxycarbonyl)amino)methyl)-1-oxo-1,2-dihydrophthalazin-6-yl)cyclopropane-1-carboxylic acid and N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)cyclobutylamine in a manner similar to step 4 of Example 6. LC-MS (M+H) + = 615.3.

[0191] Step 4: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazine-6-yl)-N-cyclobutyl-N-((5-(2,6-) (difluorophenyl)pyridin-2-yl)methyl)cyclopropane-1-carboxamide Example 25 (7 mg, 56%) was prepared from ((7-(1-(cyclobutyl((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazine-1-yl)methyl)carbamate tert-butyl ester, similar to step 4 of Example 6. ¹H NMR (500 MHz, DMSO-) d6 ) δ 12.57 (s, 1H), 8.80 – 8.40 (m, 1H), 8.35 – 7.65 (m, 4H), 7.63 – 7.02 (m, 4H), 4.88 – 4.61 (m, 3H), 4.29– 3.98 (m, 2H), 2.05 – 1.95 (m, 2H), 1.69 – 1.10 (m, 10H). LC-MS(M+H) + =516.4.

[0192] Example 26: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-((5-(2-chloro-6-fluorophenyl)pyridin-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinoline-8-yl)cyclopropane-1-carboxamide Step 1: ((5-(2-chloro-6-fluorophenyl)pyridin-2-yl)methyl)tert-butyl carbamate The title compound (180 mg, 69%) was prepared from ((5-bromopyridin-2-yl)methyl)carbamate tert-butyl ester and 1-chloro-3-fluoro-2-iodobenzene, similar to step 1 of Example 18. LC-MS (M+H) + = 337.2.

[0193] Step 2: N-((5-(2-chloro-6-fluorophenyl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinoline-8-amine The title compound (60 mg, 29%) was prepared from ((5-(2-chloro-6-fluorophenyl)pyridin-2-yl)methyl)carbamate tert-butyl ester and 6,7-dihydroquinoline-8(5H)-one in a manner similar to step 3 of Example 6. LC-MS (M+H) + =368.1.

[0194] Step 3: ((7-(1-(((5-(2-chloro-6-fluorophenyl)pyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinoline-8- 4-O-3,4-Dihydrophthalazine-1-yl)methyl)tert-butyl carbamate The title compound (30 mg, 38%) was prepared from 1-(4-(((tert-butoxycarbonyl)amino)methyl)-1-oxo-1,2-dihydrophthalazin-6-yl)cyclopropane-1-carboxylic acid and N-((5-(2-chloro-6-fluorophenyl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinoline-8-amine) in a manner similar to step 4 of Example 6. LC-MS (M+H) + = 709.4.

[0195] Step 4: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-((5-(2-chloro-6-fluorophenyl)) Pyridin-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinoline-8-yl)cyclopropane-1-carboxamide Example 26 (14 mg, 55%) was prepared from ((7-(1-(((5-(2-chloro-6-fluorophenyl)pyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinoline-8-yl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazine-1-yl)methyl)tert-butyl carbamate in a manner similar to step 5 of Example 6. 1 H NMR (400 MHz, DMSO- d6 ) δ 12.53-12.33 (m, 1H), 8.53 – 8.45 (m, 1H), 8.44-8.32 (m, 1H), 8.30 – 8.08 (m, 1H), 8.05-8.00 (m, 1H), 7.91 – 7.74 (m, 2H), 7.56 – 7.30 (m, 5H), 7.25-7.15 (m,1H), 5.60-5.52 (m, 1H), 4.91-4.69 (m, 1H), 4.12 – 3.92 (m, 2H), 3.64-3.56 (m,1H), 2.80-2.57 (m, 2H), 1.91-1.82 (m, 1H), 1.78 – 1.14 (m, 6H), 1.00 – 0.83 (m, 1H). LC-MS(M+H) + = 609.4.

[0196] Example 27: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-((5-bromoquinoline-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinoline-8-yl)cyclopropane-1-carboxamide Step 1: ((5-bromoquinoline-2-yl)methyl)tert-butyl carbamate The title compound (222 mg, 26%) was prepared from 5-bromoquinoline-2-carboxynitrile in a manner similar to step 2 of Example 7. LC-MS (M+H) + = 337.2.

[0197] Step 2: N-((5-bromoquinoline-2-yl)methyl)-5,6,7,8-tetrahydroquinoline-8-amine The title compound (50 mg, 16%) was prepared from ((5-bromoquinoline-2-yl)methyl)carbamate tert-butyl ester and 6,7-dihydroquinoline-8(5H)-one in a manner similar to step 3 of Example 6. LC-MS (M+H) + = 368.1.

[0198] Step 3: ((7-(1-(((5-bromoquinoline-2-yl)methyl)(5,6,7,8-tetrahydroquinoline-8-yl)carbamoyl) Cyclopropyl-4-oxo-3,4-dihydrophthalazine-1-yl)methyl)tert-butyl carbamate The title compound (30 mg, 51%) was prepared from 1-(4-(((tert-butoxycarbonyl)amino)methyl)-1-oxo-1,2-dihydrophthalazin-6-yl)cyclopropane-1-carboxylic acid and N-((5-bromoquinoline-2-yl)methyl)-5,6,7,8-tetrahydroquinoline-8-amine, similar to step 4 of Example 6. LC-MS (M+H) + = 709.3.

[0199] Step 4: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazine-6-yl)-N-((5-bromoquinoline-2-yl)methyl (5,6,7,8-tetrahydroquinoline-8-yl)cyclopropane-1-carboxamide Example 27 (7 mg, 27%) was prepared from ((7-(1-(((5-bromoquinoline-2-yl)methyl)(5,6,7,8-tetrahydroquinoline-8-yl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazine-1-yl)methyl)tert-butyl carbamate in a manner similar to step 5 of Example 6. 1 H NMR (500 MHz, DMSO- d6) δ 12.55-12.2 (m, 1H), 8.50-8.40 (m, 1H), 8.36-8.30 (m, 1H), 8.18-8.13 (m, 1H), 8.05-7.87 (m, 3H), 7.84 –7.66 (m, 1H), 7.64 – 7.45 (m, 2H), 7.28 – 7.14 (m, 1H), 5.65-5.56 (m, 1H), 4.95-4.88 (m, 1H), 4.08 – 3.83 (m, 2H), 3.82-3.72 (m, 1H), 2.75-2.60 (m, 2H),1.97 – 1.83 (m, 1H), 1.76-1.20 (m, 6H), 1.01-0.92 (m, 1H). LC-MS(M+H) + =609.3.

[0200] Example 28: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-((5-(2-cyano-6-fluorophenyl)pyridin-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinoline-8-yl)cyclopropane-1-carboxamide Step 1: ((5-(2-cyano-6-fluorophenyl)pyridin-2-yl)methyl)tert-butyl carbamate The title compound (308 mg, 77%) was prepared from ((5-bromopyridin-2-yl)methyl)carbamate tert-butyl ester and 3-fluoro-2-iodobenzyl nitrile in a manner similar to step 1 of Example 18. 1 H NMR (400 MHz, DMSO- d6 ) δ 8.65 (s, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.89 (d, J = 6.8 Hz, 1H), 7.82-7.73 (m, 1H), 7.73-7.66 (m, 1H), 7.56-7.50 (m, 1H), 7.44(d, J = 8.0 Hz, 1H), 4.36-4.28 (m, 2H), 4.50 (d, J = 5.6 Hz, 2H), 1.40 (s, 9H).

[0201] Step 2: 3-Fluoro-2-(6-(((5,6,7,8-tetrahydroquinoline-8-yl)amino)methyl)pyridin-3-yl)benzylnitrile The title compound (162 mg, 34%) was prepared from ((5-(2-cyano-6-fluorophenyl)pyridin-2-yl)methyl)carbamate tert-butyl ester and 6,7-dihydroquinoline-8(5H)-one, similar to step 3 of Example 6. LC-MS (M+H) + =359.1.

[0202] Step 3: ((7-(1-(((5-(2-cyano-6-fluorophenyl)pyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinoline- 8-yl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazine-1-yl)methyl)tert-butyl carbamate The title compound (30 mg, 38%) was prepared from 1-(4-(((tert-butoxycarbonyl)amino)methyl)-1-oxo-1,2-dihydrophthalazin-6-yl)cyclopropane-1-carboxylic acid and 3-fluoro-2-(6-(((5,6,7,8-tetrahydroquinoline-8-yl)amino)methyl)pyridin-3-yl)benzyl nitrile in a manner similar to step 4 of Example 6. LC-MS (M+H) + = 700.4.

[0203] Step 4: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazine-6-yl)-N-((5-(2-cyano-6-fluorobenzene) (5,6,7,8-tetrahydroquinoline-8-yl)cyclopropane-1-carboxamide Example 28 (7 mg, 28%) was prepared from ((7-(1-(((5-(2-cyano-6-fluorophenyl)pyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinoline-8-yl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazine-1-yl)methyl)tert-butyl carbamate and TFA in a manner similar to step 5 of Example 6. 1 H NMR (500 MHz, DMSO- d6) δ12.56-12.40 (m, 1H), 8.70-8.54 (m, 1H), 8.50-8.40 (m, 1H), 8.30-8.12 (m, 1H),8.04 – 7.92 (m, 2H), 7.92-7.83 (m, 2H), 7.81-7.75 (m, 1H), 7.73-7.66 (m, 1H), 7.56-7.46 (m, 1H), 7.39 (d, J = 8.2 Hz, 1H), 7.26 – 7.16 (m, 1H), 5.62-5.52(m, 1H), 4.88 – 4.66 (m, 1H), 4.18 – 3.96 (m, 2H), 3.68-3.60 (m, 1H), 2.78 –2.58 (m, 2H), 1.90-1.83 (m, 1H), 1.76 – 1.54 (m, 4H), 1.51-1.37 (m, 1H),1.34-1.23 (m, 1H), 0.95-0.88 (m, 1H). LC-MS(M+H) + = 600.4.

[0204] Example 29: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-(1-(pyrimidin-2-yl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)cyclopropane-1-carboxamide Step 1: 1-(pyrimidin-2-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)ethyl-1-amine The title compound (5.0 g, 31%) was prepared from (5-(trifluoromethyl)pyridin-2-yl)methylamine and 1-(pyrimidin-2-yl)ethyl-1-one in a manner similar to step 3 of Example 3. LC-MS (M+H) + = 283.1.

[0205] Step 2: ((4-oxo-7-(1-((1-(pyrimidin-2-yl)ethyl)((5-(trifluoromethyl)pyridin-2-yl)methyl) (carbamoyl)cyclopropyl)-3,4-dihydrophthalazine-1-yl)methyl)tert-butyl carbamate The title compound (110 mg, 32%) was prepared from 1-(4-(((tert-butoxycarbonyl)amino)methyl)-1-oxo-1,2-dihydrophthalazin-6-yl)cyclopropane-1-carboxylic acid and 1-(pyrimidin-2-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)ethyl-1-amine, similar to step 4 of Example 6. LC-MS (M+Na) + = 646.2.

[0206] Step 3: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-(1-(pyrimidin-2-yl)ethyl) 5-(trifluoromethyl)pyridin-2-yl)methyl)cyclopropane-1-carboxamide Example 29 (31 mg, 37%) was prepared from ((4-oxo-7-(1-((1-(pyrimidin-2-yl)ethyl)((5-(trifluoromethyl)pyridin-2-yl)methyl)carbamoyl)cyclopropyl)-3,4-dihydrophthalazine-1-yl)methyl)carbamate tert-butyl ester in a manner similar to step 4 of Example 6. 1 H NMR (400 MHz, DMSO- d6 ) δ 12.89-12.76 (m,1H), 8.93-8.81 (m, 1H), 8.75-8.58 (m, 3H), 8.29-8.19 (m, 1H), 8.05 – 7.91 (m,1H), 7.81-7.21 (m, 3H), 5.75-5.16 (m, 1H), 5.12-4.88 (m, 1H), 4.87-4.26 (m, 3H), 1.70-1.12 (m, 7H). LC-MS(M+H) + = 524.2.

[0207] Example 30: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-N-(1,3-dimethoxypropyl-2-yl)cyclopropane-1-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 step 3 of Example 3. 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.

[0208] Step 2: ((7-(1-(((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)(1,3-dimethoxypropyl-2-yl) (carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazine-1-yl)methyl)tert-butyl carbamate The title compound (40 mg, 15%) was prepared from 1-(4-(((tert-butoxycarbonyl)amino)methyl)-1-oxo-1,2-dihydrophthalazin-6-yl)cyclopropane-1-carboxylic acid and N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-1,3-dimethoxypropyl-2-amine, similar to step 4 of Example 6. LC-MS (M+H) + = 664.3.

[0209] Step 3: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazine-6-yl)-N-((5-(2,6-difluorophenyl) pyridin-2-yl)methyl)-N-(1,3-dimethoxypropyl-2-yl)cyclopropane-1-carboxamide Example 30 (7 mg, 21%) was prepared from ((7-(1-(((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)(1,3-dimethoxypropyl-2-yl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazine-1-yl)methyl)carbamate tert-butyl)carbamate in a manner similar to step 5 of Example 6. 1 H NMR (400 MHz, CD3OD) δ 8.70-8.40 (m,1H), 8.38-8.22 (m, 1H), 7.92-7.86 (m, 2H), 7.76-7.42 (m, 3H), 7.20-7.05 (m,2H), 4.80-4.33 (m, 3H), 4.20-4.08 (m, 2H), 3.81-3.52(m, 1H), 3.30-3.18 (m,3H), 2.97 (s, 6H), 1.73-1.67 (m, 2H), 1.51-1.39 (m, 2H). LC-MS(M+H) + = 564.2.

[0210] Example 31: (R)-1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazine-6-yl)-N-(4-(pentafluoro-λ) 6 (-thioalkyl)benzyl)-N-(5,6,7,8-tetrahydroquinolin-8-yl)cyclopropane-1-carboxamide Step 1: (R)-N-(4-(pentafluoro-λ) 6 (-Thioalkyl)benzyl)-5,6,7,8-Tetrahydroquinoline-8-amine In a manner similar to step 4 of Example 12, 4-(pentafluoro-λ) 6 The title compound (0.20 g, 55%) was prepared by using (R)-5,6,7,8-tetrahydroquinoline-8-amine (-thioalkyl)benzaldehyde and (R)-5,6,7,8-tetrahydroquinoline-8-amine.1 H NMR (400 MHz, DMSO- d6 ) δ 8.36(d, J = 4.4 Hz, 1H), 7.84 (d, J = 8.8 Hz, 2H), 7.62 (d, J = 8.8 Hz, 2H), 7.50 (d, J =7.6 Hz, 1H), 7.18 (dd, J = 7.6, 4.4 Hz, 1H), 4.00-3.88 (m, 2H), 3.72-3.63 (m,1H), 3.13-2.98 (m, 1H), 2.82-2.68 (m, 2H), 1.72-1.60 (m, 2H). LCMS (M+H) + =365.1.

[0211] Step 2: (R)-((4-oxo-7-(1-((4-(pentafluorine-λ) 6 (-thioalkyl)benzyl)(5,6,7,8-tetrahydroquinoline-8- 3,4-Dihydrophthalazine-1-yl)methyl)tert-butyl carbamate Similar to step 4 of Example 6, 1-(4-(((tert-butoxycarbonyl)amino)methyl)-1-oxo-1,2-dihydrophthalazine-6-yl)cyclopropane-1-carboxylic acid and (R)-N-(4-(pentafluoro-λ) 6 The title compound (0.20 g, 57%) was prepared by (-thioalkyl)benzyl)-5,6,7,8-tetrahydroquinoline-8-amine. LCMS (M+H) + = 706.2.

[0212] Step 3: (R)-1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazine-6-yl)-N-(4-(pentafluoro-λ) 6 -sulfur (alkyl)benzyl)-N-(5,6,7,8-tetrahydroquinoline-8-yl)cyclopropane-1-carboxamide In a manner similar to step 5 of Example 6, (R)-((4-oxo-7-(1-((4-(pentafluorine-λ) 6 Example 31 (57 mg, 34%) was prepared by tert-butyl carbamate (-thioalkyl)benzyl)(5,6,7,8-tetrahydroquinoline-8-yl)carbamoyl)cyclopropyl)-3,4-dihydrophthalazine-1-yl)methyl)carbamate. 1H NMR (400 MHz, CD3OD) δ 8.47-8.18 (m, 2H),7.96-7.66 (m, 3H), 7.51-7.12 (m, 4H), 5.81-4.73 (m, 2H), 4.20-3.63 (m, 3H),2.96-2.68 (m, 2H), 2.24-1.95 (m, 1H), 1.86-1.09 (m, 7H). LC-MS(M+H) + = 606.1.

[0213] Example 32: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-(4-cyclopropyl-5,6,7,8-tetrahydroquinoline-8-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)cyclopropane-1-carboxamide Step 1: 4-Methoxy-5,6,7,8-Tetrahydroquinoline Under nitrogen atmosphere, 4-methoxyquinoline (20 g, 126 mmol) was added to a solution of PtO2 (3.71 g, 16.3 mmol) in TFA (200 mL). The suspension was degassed and purged three times with hydrogen. The mixture was stirred at 50 °C under hydrogen (50 psi) for 3 hours. The filtrate was collected by filtration, concentrated to approximately 50 mL, and diluted with water (100 mL). The pH of the mixture was adjusted to 9 with an aqueous solution of NaOH (1 M). The mixture was extracted with DCM (50 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (20 g, 98%). 1 H NMR (400 MHz, CD3OD) δ 8.40 (d, J = 6.4 Hz, 1H), 7.30 (d, J = 6.4 Hz, 1H), 4.11 (s,3H), 2.96 (t, J = 6.2 Hz, 2H), 2.71 (t, J = 6.2 Hz, 2H), 1.96-1.83 (m, 4H). LCMS(M+H) + = 164.2.

[0214] Step 2: 4-Bromo-5,6,7,8-Tetrahydroquinoline At 0 °C, POBr3 (89.6 g, 312 mmol) was added to a solution of 4-methoxy-5,6,7,8-tetrahydroquinoline (17 g, 104 mmol) in DMF (170 mL). The mixture was heated to 100 °C and stirred for 12 hours. The reaction mixture was cooled to 0 °C and slowly added to ice water (300 mL). The mixture was extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (50 mL × 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 (15 g). LCMS (M+H) + = 212.1.

[0215] Step 3: 4-Bromo-5,6,7,8-Tetrahydroquinoline 1-oxide To a solution of 4-bromo-5,6,7,8-tetrahydroquinoline (15 g, 70.7 mmol) in DCM (195 mL), mCPBA (80%, 30.5 g, 141 mmol) was added. The mixture was stirred at 42 °C for 2 hours, then cooled to room temperature. The mixture was washed with water (100 mL), and the aqueous phase was extracted with DCM (50 mL × 3). The combined organic layers were washed with brine (50 mL × 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 (14 g, 87%). LCMS (M+H) + = 228.2.

[0216] Step 4: 4-Bromo-5,6,7,8-Tetrahydroquinoline-8-ylacetate A mixture of 4-bromo-5,6,7,8-tetrahydroquinoline 1-oxide (14 g, 61.4 mmol) in Ac₂O (70 mL) was stirred at 55 °C for 2 hours and then cooled to room temperature. The filtrate was collected by filtration and concentrated under reduced pressure to give the title compound (14 g, 84%). LCMS (M+H) + = 270.1.

[0217] Step 5: 4-Bromo-5,6,7,8-Tetrahydroquinoline-8-ol Four identical reactions were performed in parallel as described below. K₂CO₃ (5.8 g, 42.2 mmol) was added to a solution of 4-bromo-5,6,7,8-tetrahydroquinoline-8-yl acetic acid (3.0 g, 11.1 mmol) in MeOH (15 mL). The mixture was stirred at 25 °C for 2 hours.

[0218] The four batches of reaction mixtures were combined. The filtrate was collected by filtration 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 (5.2 g, 51%). LCMS (M+H) + = 228.2.

[0219] Step 6: 4-Bromo-6,7-dihydroquinoline-8(5H)-one DMP (16.7 g, 39.5 mmol) was added to a solution of 4-bromo-5,6,7,8-tetrahydroquinoline-8-ol (5.0 g, 21.9 mmol) in DCM (260 mL). The mixture was stirred at 25 °C for 8 hours. The mixture was filtered, and 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 (4.0 g, 81%). LCMS (M+H) + = 226.1.

[0220] Step 7: 4-Cyclopropyl-6,7-Dihydroquinoline-8(5H)-one SPhos (145 mg, 0.35 mmol), Pd(OAc)₂ (99 mg, 0.44 mmol), and K₃PO₄ (2.35 g, 11.1 mmol) were added to a solution of 4-bromo-6,7-dihydroquinoline-8(5H)-one (1.0 g, 4.42 mmol) and cyclopropylboronic acid (950 mg, 11.1 mmol) in water (1 mL) and toluene (9 mL). The mixture was stirred at 90 °C for 12 h and cooled to room temperature. The mixture was diluted with water (10 mL) and extracted with EtOAc (15 mL × 3). The combined organic layers were washed with brine (15 mL × 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 (0.20 g, 24%). LCMS (M+H) + = 188.3.

[0221] Step 8: 4-Cyclopropyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinoline-8-amine The title compound (0.20 g, 54%) was prepared from 4-cyclopropyl-6,7-dihydroquinoline-8(5H)-one and (5-(trifluoromethyl)pyridin-2-yl)methylamine in a manner similar to step 3 of Example 3. LCMS (M+H) + = 348.2.

[0222] Step 9: ((7-(1-((4-cyclopropyl-5,6,7,8-tetrahydroquinoline-8-yl)((5-(trifluoromethyl)pyridine-2- 4-O-3,4-Dihydrophthalazine-1-yl)methyl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazine-1-yl)methyl)tert-butyl carbamate The title compound (0.11 g, 50%) was prepared from 1-(4-(((tert-butoxycarbonyl)amino)methyl)-1-oxo-1,2-dihydrophthalazin-6-yl)cyclopropane-1-carboxylic acid and 4-cyclopropyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinoline-8-amine, similar to step 4 of Example 6. LCMS (M+H) + = 689.3.

[0223] Step 10: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazine-6-yl)-N-(4-cyclopropyl-5,6,7,8-) Tetrahydroquinoline-8-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)cyclopropane-1-carboxamide Example 32 (57 mg, 34%) was prepared from ((7-(1-((4-cyclopropyl-5,6,7,8-tetrahydroquinoline-8-yl)((5-(trifluoromethyl)pyridin-2-yl)methyl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazine-1-yl)methyl)carbamate tert-butyl)carbamate in a manner similar to step 5 of Example 6. 1 H NMR (400 MHz, DMSO- d6 ) δ12.62-12.37 (m, 1H), 8.95-8.56 (m, 1H), 8.38-8.22 (m, 2H), 8.20-7.77 (m, 3H), 7.76-7.37 (m, 1H), 6.83-6.77 (m, 1H), 5.60-5.50 (m, 1H), 4.96-4.65 (m, 1H),4.09-3.90 (m, 2H), 3.66-3.55 (m, 2H), 2.88-2.78 (m, 1H), 2.68-2.57 (m, 1H),1.92-1.78 (m, 2H), 1.78-1.18 (m, 6H), 1.05-0.86 (m, 3H), 0.81-0.71 (m, 1H), 0.67-0.54 (m, 1H). LC-MS(M+H) + = 589.3.

[0224] Example 33: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-N-(6,7-dihydro-5H-cyclopentadieno[b]pyridin-7-yl)cyclopropane-1-carboxamide Step 1: N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-6,7-dihydro-5H-cyclopentadien[b]pyridine 7-Pyridine To a solution of 5-(2,6-difluorophenyl)pyridinecarboxaldehyde (80 mg, 0.36 mmol) in DCM (10 mL), 6,7-dihydro-5H-cyclopentadieno[b]pyridine-7-amine (49 mg, 0.36 mmol) and NaBH(OAc)3 (155 mg, 0.73 mmol) were added. The solution was stirred at room temperature for 16 hours, poured into saturated NaHCO3 (50 mL), and extracted with EtOAc (50 mL). 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 (DCM:MeOH = 10:1) to give the title compound (31 mg, 26%). LC-MS (M+H) + =338.3.

[0225] Step 2: ((7-(1-(((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)(6,7-dihydro-5H-cyclopentadiene) [b]pyridin-7-yl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)tert-butyl carbamate ester The title compound (20 mg, 36%) was prepared from 1-(4-(((tert-butoxycarbonyl)amino)methyl)-1-oxo-1,2-dihydrophthalazin-6-yl)cyclopropane-1-carboxylic acid and N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-6,7-dihydro-5H-cyclopentadien[b]pyridine-7-amine, similar to step 4 of Example 6. LC-MS (M+H)+ = 679.1.

[0226] Step 3: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazine-6-yl)-N-((5-(2,6-difluorophenyl) Pyridin-2-yl)methyl)-N-(6,7-dihydro-5H-cyclopentadien[b]pyridin-7-yl)cyclopropane-1-carboxamide Example 33 (10 mg, 59%) was prepared from ((7-(1-(((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)(6,7-dihydro-5H-cyclopentadieno[b]pyridin-7-yl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)tert-butyl carbamate in a manner similar to step 5 of Example 6. 1 H NMR (500 MHz, DMSO-d6 ) δ 12.68-12.28 (m, 1H), 8.68-8.34 (m, 2H), 8.27-8.08 (m, 1H), 8.05-7.92(m, 1H), 7.92-7.47 (m, 4H), 7.47-7.14 (m, 4H), 6.02-5.73 (m, 1H), 4.84-4.65(m, 1H), 4.33-4.09 (m, 2H), 3.92-3.78 (m, 1H), 2.95-2.57 (m, 2H), 2.30-1.50(m, 5H), 1.31-1.14 (m, 1H). LC-MS(M+H) + = 579.4.

[0227] Example 34: (R)-1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-((5-(2,6-difluorophenoxy)pyridin-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinoline-8-yl)cyclopropane-1-carboxamide Step 1: 5-(2,6-difluorophenoxy)pyridinecarboxaldehyde The title compound (0.60 g, 64%) was prepared from 5-fluoropyridinecarboxaldehyde and 2,6-difluorophenol in a manner similar to step 1 of Example 20. LCMS (M+H) + = 236.2.

[0228] Step 2: (R)-N-((5-(2,6-difluorophenoxy)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinoline-8-amine The title compound (0.13 g, 42%) was prepared from (R)-5,6,7,8-tetrahydroquinoline-8-amine and 5-(2,6-difluorophenoxy)pyridinecarboxaldehyde in a manner similar to step 4 of Example 12. LCMS (M+H) + = 368.2.

[0229] Step 3: (R)-((7-(1-(((5-(2,6-difluorophenoxy)pyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinone) (Lin-8-yl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazine-1-yl)methyl)tert-butyl carbamate The title compound (0.10 g, 74%) was prepared from 1-(4-(((tert-butoxycarbonyl)amino)methyl)-1-oxo-1,2-dihydrophthalazin-6-yl)cyclopropane-1-carboxylic acid and (R)-N-((5-(2,6-difluorophenoxy)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinoline-8-amine, similar to step 4 of Example 6. LCMS (M+H) + = 709.4.

[0230] Step 4: (R)-1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazine-6-yl)-N-((5-(2,6-difluorobenzene) (Oxy)pyridin-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinoline-8-yl)cyclopropane-1-carboxamide Example 34 (25 mg, 29%) was prepared from (R)-((7-(1-(((5-(2,6-difluorophenoxy)pyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinoline-8-yl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazine-1-yl)methyl)carbamate tert-butyl)carbamate in a manner similar to step 4 of Example 6. 1 H NMR (400 MHz, DMSO- d6 ) δ12.60-12.38 (m, 1H), 8.46-8.39 (m, 1H), 8.30-8.10 (m, 2H), 7.97-7.71 (m, 2H), 7.53-7.04 (m, 7H), 5.55-5.45 (m, 1H), 4.72-4.62 (m, 1H), 4.96-4.65 (m, 1H),4.50-3.94 (m, 2H), 3.53-3.43 (m, 1H), 2.67-2.56 (m, 2H), 1.90-1.30 (m, 6H),1.23-1.08 (m, 1H), 0.96-0.82 (m, 1H). LC-MS (M+H) + = 609.2.

[0231] Example 35: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-(5,6,7,8-tetrahydroquinoline-8-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)cyclobutane-1-carboxamide Step 1: 5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)isobenzofuran-1(3H)-one 5-bromoisobenzofuran-1(3H)-one (8.52 g, 40 mmol), BPD (13.2 g, 52.0 mmol), and Pd(dppf)Cl2 were added. .A mixture of CH₂Cl₂ (1.64 g, 2.0 mmol) and AcOK (11.8 g, 120 mmol) in dioxane (160 mL) was heated to 100 °C and stirred overnight under nitrogen. The mixture was cooled to room temperature, and the solid was filtered off and washed with DCM (400 mL). The filtrate was concentrated, and the residue was purified by silica gel chromatography (PE / EtOAc = 15 / 1) to give the title compound (8.63 g, 83%). LC-MS (M+H) + =261.2.

[0232] Step 2: 2-(1-oxo-1,3-dihydroisobenzofuran-5-yl)tert-butyl acetate A mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)isobenzofuran-1(3H)-one (8.37 g, 32.2 mmol), [Pd(allyl)Cl]2 (590 mg, 1.61 mmol), XPhos (3.06 g, 6.44 mmol), and K2CO3 (11.1 g, 80.5 mmol) in dioxane (80 mL) and water (8 mL) was stirred at 90 °C for 4 hours. The mixture was cooled to room temperature and diluted with water (100 mL), and extracted with EtOAc (100 mL x 3). The combined organic layers were concentrated, and the residue was purified by silica gel chromatography (PE / EtOAc = 10 / 1) to give the title compound (4.5 g, 56%). LCMS (M+H) + = 249.2.

[0233] Step 3: 1-(1-oxo-1,3-dihydroisobenzofuran-5-yl)cyclobutane-1-carboxylic acid tert-butyl ester Cs₂CO₃ (10 g, 30.8 mmol) was added to a solution of tert-butyl 2-(1-oxo-1,3-dihydroisobenzofuran-5-yl)acetate (3.05 g, 12.3 mmol) in DMF (60 mL), and the mixture was stirred at 0 °C under nitrogen for 0.5 h. A solution of 1,3-dibromopropane (2.73 g, 13.5 mmol) in DMF (10 mL) was added dropwise, and the mixture was warmed to room temperature and stirred overnight. Saturated NH₄Cl (200 mL) was added, and the mixture was extracted with EtOAc (80 mL x 3). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / EtOAc = 10 / 1) to give the title compound (1.6 g, 45%). LCMS (M+H) += 289.2.

[0234] Step 4: 1-(3-((dimethylamino)methylene)-1-oxo-1,3-dihydroisobenzofuran-5-yl)cyclobutane tert-butyl alkyl-1-carboxylate A mixture of tert-butyl 1-(1-oxo-1,3-dihydroisobenzofuran-5-yl)cyclobutane-1-carboxylate (1.4 g, 4.86 mmol), DMF-DMA (10 mL), and t-BuOK (54 mg, 0.486 mmol) was degassed and purged three times with nitrogen, then stirred at 120 °C for 20 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by neutral alumina chromatography (PE / EtOAc = 10 / 1) to give the title compound (656 mg, 39%). LCMS (M+H) + = 344.2.

[0235] Step 5: 1-(4-((dimethylamino)methyl)-1-oxo-1,2-dihydrophthalazine-6-yl)cyclobutane-1-carboxylic acid tert-butyl ester At 25 °C, hydrazine monohydrate (237 mg, 3.8 mmol) was added to a mixture of 1-(4-((dimethylamino)methyl)-1-oxo-1,2-dihydrophthalazin-6-yl)cyclobutane-1-carboxylic acid tert-butyl ester (656 mg, 1.9 mmol) and EtOH (10 mL). The mixture was degassed with nitrogen and then stirred at 70 °C for 12 h. The mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by silica gel chromatography (PE / EtOAc = 1 / 1) to give the title compound (500 mg, 74%). LCMS (M+H)+ = 358.3.

[0236] Step 6: 1-(4-(chloromethyl)-1-oxo-1,2-dihydrophthalazine-6-yl)cyclobutane-1-carboxylic acid tert-butyl ester A solution of tert-butyl 1-(4-((dimethylamino)methyl)-1-oxo-1,2-dihydrophthalazin-6-yl)cyclobutane-1-carboxylate (400 mg, 1.4 mmol) in THF (10 mL) was degassed three times with nitrogen and cooled to 0 °C. A solution of isobutyl chloroformate (286 mg, 2.1 mmol) in THF (2 mL) was added dropwise. The mixture was stirred at 25 °C for 6 hours, then concentrated under vacuum to give the title compound (240 mg, 60%). LCMS (M+H) + = 349.2.

[0237] Step 7: 1-(4-((1,3-dioxoisoindoline-2-yl)methyl)-1-oxo-1,2-dihydrophthalazine-6-yl) tert-butyl cyclobutane-1-carboxylate Potassium phthalate (233 mg, 1.26 mmol) was added to a mixture of 1-(4-(chloromethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)cyclobutane-1-carboxylic acid tert-butyl ester (240 mg, 0.84 mmol) in DMF (10 mL), and the mixture was stirred at 25 °C for 1 hour. The mixture was diluted with water (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were 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 (220 mg, 57%). LCMS (M+H) + = 460.3.

[0238] Step 8: 1-(4-((1,3-dioxoisoindoline-2-yl)methyl)-1-oxo-1,2-dihydrophthalazine-6-yl) Cyclobutane-1-carboxylic acid A solution of 1-(4-((1,3-dioxoisoindoline-2-yl)methyl)-1-oxo-1,2-dihydrophthalazin-6-yl)cyclobutane-1-carboxylic acid tert-butyl ester (120 mg, 0.26 mmol) in DCM (4 mL) and TFA (2 mL) was stirred at room temperature for 8 hours. The mixture was concentrated under reduced pressure to give the title compound (100 mg, 95%). LCMS (M+H) + = 404.2.

[0239] Step 9: 1-(4-((1,3-dioxoisoindoline-2-yl)methyl)-1-oxo-1,2-dihydrophthalazine-6-yl)- N-(5,6,7,8-tetrahydroquinolin-8-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)cyclobutane-1-carboxamide A solution of 1-(4-((1,3-dioxoisoindoline-2-yl)methyl)-1-oxo-1,2-dihydrophthalazin-6-yl)cyclobutane-1-carboxylic acid (100 mg, 0.25 mmol) in SOCl2 (3 mL) was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in DCM (5 mL), and the solution was added dropwise at 0 °C to a mixture of Et3N (242 mg, 2.4 mmol) and N-((5-(trifluoromethyl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinoline-8-amine (74 mg, 0.24 mmol) in DCM (10 mL). After 15 min, the mixture was concentrated under reduced pressure. The residue was purified by preparative TLC to give the title compound (120 mg, 69%). LCMS (M+H) + = 693.4.

[0240] Step 10: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazine-6-yl)-N-(5,6,7,8-tetrahydroquinoline- 8-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)cyclobutane-1-carboxamide A mixture of 1-(4-((1,3-dioxoisoindoline-2-yl)methyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-(5,6,7,8-tetrahydroquinoline-8-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)cyclobutane-1-carboxamide (120 mg, 0.17 mmol) and hydrazine monohydrate (80%, 32 mg, 0.51 mmol) in EtOH (4 mL) was stirred at 80 °C for 3 hours. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to give Example 35 (20 mg, 20%). 1H NMR (500 MHz, DMSO) δ = 12.45 (s, 1H), 8.79 – 8.56 (m, 1H), 8.38 -8.36 (m, 2H), 8.15 - 7.65 (m, 3H), 7.55 - 7.47 (m, 1H), 7.31 – 7.18 (m, 2H),4.82 - 4.51 (m, 2H), 4.10 - 3.90 (m, 2H), 3.78 - 3.58 (m, 1H), 3.22 - 3.00(m, 3H), 2.64 - 2.56 (m, 2H), 2.21 - 1.70 (m, 4H), 1.52 - 0.73 (m, 3H). LCMS(M+H)+ = 563.4.

[0241] Compounds in gene pairs such as HCT116 kill cells. The HCT116 cell line (ATCC, CCL-247) was isolated from the colon of an adult male with colon cancer. It contains a mutation at codon 13 of the ras proto-oncogene and was used as a positive control for PCR assays of this codon mutation. HCT116-MTAP-KO is a knockout MTAP gene based on HCT116, and a single clone passed the assay. HCT116-mock-RNA-KO is a knockout mock gene based on HCT116 with the MTAP wild-type genotype. The basal medium for the HCT116 gene pair was RPMI 1640, HEPES (Gibco, 22400105). To prepare a complete growth medium, the following component was added to the basal medium: fetal bovine serum, final concentration 10% (Gibco, 10099-141C). The cell line was grown at 37°C in a humid 5% CO2 atmosphere, and the presence of mycoplasma was tested periodically using the MycoAlert™ PLUS Mycoplasma Detection Kit (Lonza, LT07-710).

[0242] experiment • Seed HCT116-mock-RNA-KO (4E2 / well) or HCT116-MTAP-KO (4E2 / well) cells into 96-well plates (Greiner: 655090), 100 μL / well.

[0243] • Incubate overnight at 37°C and 5% CO2.

[0244] • Add 50 μL of fresh growth medium containing serial dilutions of the compound to each well, so that the final compound concentration is 0-10 μM.

[0245] • Incubate at 37°C and 5% CO2 for 6 days.

[0246] • Assess cell viability using Cell Titer-Glo (Promega, G7573). Add 70 μL CellTiter-Glo® reagent to each well.

[0247] • Incubate at room temperature for 10 minutes to stabilize the luminescence signal.

[0248] • Analyze using a microplate reader (TECAN, SPARK) and fit the IC using Prism® 9. 50 .

[0249] The compounds disclosed in this paper exhibit cytotoxic activity values ​​as shown in Table 1. Table 1: Cell-killing IC50 of the compounds disclosed in this paper 50 (nM) The foregoing description of the embodiments and certain implementations should be considered illustrative and not limiting of the invention as defined by the claims. It will be readily understood that various variations and combinations of the above features may be utilized without departing from the invention as set forth in the claims. All such variations are intended to be included within the scope of the invention. All cited references are incorporated herein by reference in their entirety.

[0250] It should be understood that if any prior art publications are mentioned in this document, such mentions do not constitute an acknowledgment that such publications constitute common general knowledge in the field in any country.

Claims

1. A compound of formula (I): (I) Or its N-oxide, or its pharmaceutically acceptable salt, or its stereoisomer, or its tautomer, or its deuterated analogue, wherein: n is 1, 2, 3 or 4; m can be 1, 2, 3, or 4; R 1 and R 2 Each is independently selected from hydrogen, halogen, -C 1-8 Alkyl, -C3-C8 cycloalkyl, -CN, -OR 1a -NR 1a R 1b -COR 1a -CO2R 1a -CONR 1a R 1b or -NR 1a COR 1b , where -C 1-8 Each of the alkyl group and the -C3-C8 cycloalkyl group is optionally substituted by at least one substituent selected from the following: halogen, -C 1-8 Alkoxy, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, C6-C 12 aryl, 5- to 12-membered heteroaryl, oxoyl, -CN, -OR 1c -SO2R 1c -SO2NR 1c R 1d -COR 1c -CO2R 1c -CONR 1c R 1d -NR 1c R 1d -NR 1c COR 1d -NR 1c CO2R 1d Or –NR 1c SO2R 1d ; R 1a and R 1b Each is independently hydrogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, -C6-C 12 aryl or 5 to 12-membered heteroaryl; the -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, -C6-C 12 Each of the aryl group or the 5- to 12-membered heteroaryl group is optionally bonded by at least one halogen, -OH, or -C. 1-8 Alkyl, -C 1-8 Alkoxy, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 alkenyl, -C 2-8 Alkyne, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, -C6-C 12 Aryl or 5 to 12 heteroaryl substituents; R 1c and R 1d Each is independently hydrogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, -C6-C 12 aryl or 5 to 12-membered heteroaryl; the -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, -C6-C 12 Each of the aryl group or the 5- to 12-membered heteroaryl group is optionally bonded by at least one halogen, -OH, or -C. 1-8 Alkyl, -C 1-8 Alkoxy, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 alkenyl, -C 2-8 Alkyne, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, -C6-C 12 Aryl or 5 to 12 heteroaryl substituents; R 3 R 4 R 5 and R 6 Each is independently selected from hydrogen, halogen, -C 1-8 Alkyl, -C3-C8 cycloalkyl, -CN, -OR 3a -NR 3a R 3b -COR 3a -CO2R 3a -CONR 3a R 3b or -NR 3a COR 3b , where -C 1-8 Each of the alkyl group and the -C3-C8 cycloalkyl group is optionally substituted by at least one substituent selected from the following: 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, oxoyl, -CN, -OR 3c -SO2R 3c -SO2NR 3c R 3d -COR 3c -CO2R 3c -CONR 3c R 3d -NR 3c R 3d -NR 3c COR 3d -NR 3c CO2R 3d Or –NR 3c SO2R 3d ; R 3a R 3b R 3c and R 3d Each is independently hydrogen, -C 1-8 Alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, -C6-C 12 aryl or 5 to 12-membered heteroaryl; the -C 1-8 Alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, -C6-C 12 Each of the aryl group or the 5- to 12-membered heteroaryl group is optionally bonded by at least one halogen, -OH, or -C. 1-8 Alkyl, -C 1-8 Alkoxy, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 alkenyl, -C 2-8 Alkyne, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, -C6-C 12 Aryl or 5 to 12 heteroaryl substituents; R 7 and R 8 Each is independently selected from hydrogen and -C 1-8 Alkyl, -C3-C8 cycloalkyl or -C6-C 12 Aryl, where -C 1-8 Alkyl, -C3-C8 cycloalkyl and -C6-C 12 Each of the aryl groups may optionally be substituted by at least one substituent selected from the following: hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl group, -NR 7a R 7b -OR 7a , oxoyl group, -C3-C8 cycloalkyl group, 3 to 8 membered heterocyclic group, -C6-C 12 aryl, 5 to 12-membered heteroaryl or -CN; R 7a and R 7b Each is independently selected from hydrogen and -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkyne, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, -C6-C 12 aryl or 5 to 12-membered heteroaryl, wherein the -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, C6-C 12 Each of the aryl or 5 to 12 heteroaryl groups is optionally substituent R. 7c replace; R 7c Independently halogen, hydroxyl, -C 1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 alkenyl, -C 2-8 Alkyne, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, -C6-C 12 aryl, 5 to 12-membered heteroaryl, or -CN, wherein the -C 1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 alkenyl, -C 2-8 Alkyne, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, -C6-C 12 Each of the aryl group and the 5- to 12-membered heteroaryl group is optionally bound by at least one hydrogen, halogen, hydroxyl group, or -C group. 1-8 Alkyl, -C 1-8 Alkoxy, -CN, -NH2, or oxo groups are substituted; R 9 and R 10 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 group and the 5 to 12 heteroaryl groups is optionally substituent R. 9a Replace; or R 9 and R 10 Together with the nitrogen atom to which it is attached, it forms a 3- to 8-membered unsaturated or saturated ring, the ring containing 0-3 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the ring is optionally substituented by at least one R. 9a replace; R 9a Independently 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 9b -SO2R 9b -SO2NR 9b R 9c -COR 9b -CO2R 9b -CONR 9b R 9c -NR 9b R 9c -NR 9b COR 9c -NR 9b CO2R 9c –NR 9b SO2R 9c , oxo group 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 group and the 5 to 12 heteroaryl groups is optionally substituent R. 9d Replace; or Two Rs 9a Together with the atoms to which it is attached, it forms a 3- to 8-membered unsaturated or saturated ring, the ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the ring optionally being substituented by at least one R. 9d replace; R 9b and R 9c 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 group and the 5 to 12 heteroaryl groups is optionally substituent R. 9e replace; R 9d and R 9e 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 9f -SO2R 9f -SO2NR 9f R 9g -COR 9f -CO2R 9f -CONR 9f R 9g -NR 9f R 9g -NR 9f COR 9g -NR 9f CO2R 9g –NR 9f SO2R 9g , oxo group, -SF5 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 group and the 5 to 12 heteroaryl groups is optionally substituent R. 9h replace; R 9f and R 9g 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 group and the 5 to 12 heteroaryl groups is optionally substituent R. 9i replace; R 9h and R 9i 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 9j -SO2R 9j -SO2NR 9j R 9k -COR 9j -CO2R 9j -CONR 9j R 9k -NR 9j R 9k -NR 9j COR 9k -NR 9j CO2R 9k –NR 9j SO2R 9k , oxo group 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 heteroaryl groups may optionally be substituted by 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, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, -C6-C 12 Aryl, 5 to 12-membered heteroaryl, -CN, -OH, -NH2 or oxo group; R 9j and R 9k 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 heteroaryl groups may optionally be substituted by 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, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, -C6-C 12 Aryl, 5 to 12 heteroaryl, -CN, -OH, -NH2 or oxo group.

2. The compound of claim 1, wherein the compound is of formula (IIa) or (IIb): (IIa); (IIb); Preferably, the compound is selected from formula (IIc) or (IId): (IIc); (IId)。 3. The compound of claim 1, wherein the compound is of formula (IIIa): (IIIa); Preferably, the compound is selected from formula (IIIb): (IIIb); More preferably, the compound is selected from formula (IIIc): (IIIc); More preferably, the compound is selected from formula (IIId): (IIId).

4. The compound of claim 1, wherein the compound is of formula (IVa) or (IVb): (IVa), (IVb); Preferably, the compound is selected from formula (IVc) or (IVd): (IVc); (IVd); More preferably, the compound is selected from formula (IVe) or (IVf): (IVe); (IVf); Even more preferably, the compound is selected from formula (IVg) or (IVh): (IVd); (IVh); Even more preferably, the compound is selected from formula (IVi) or (IVj): (iv); (IVj)。 5. The compound of claim 1, wherein the compound is of formula (Va): (And) Preferably, the compound is selected from formula (Vb) or (Vc): (Vb); (You); More preferably, the compound is selected from formula (Vd) or (Ve): (Vd); (And); Even more preferably, the compound is selected from formula (Vf) or (Vg): (Vf); (Vg); Even more preferably, the compound is selected from formula (Vh) or (Vi): (Vh); (V); in, R 9a As defined in claim 1.

6. The compound as claimed in any one of the preceding claims, wherein R 1 and R 2 Each is independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -CN, -OR 1a -NR 1a R 1b -COR 1a -CO2R 1a -CONR 1a R 1b or -NR 1a COR 1b Each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, 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, heptoxy, octyloxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -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 groups, oxoyl groups, -CN, -OR 1c -SO2R 1c -SO2NR 1c R 1d -COR 1c -CO2R 1c -CONR 1c R 1d -NR 1c R 1d -NR 1c COR 1d -NR 1c CO2R 1d Or –NR 1c SO2R 1d ; R 1a and R 1b Each of the following is independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 Alkyne, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclic, phenyl, or 5 to 12-membered heteroaryl; wherein methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 Each of the following groups is optionally surrounded by at least one of the following: alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclic, phenyl, or 5 to 12-membered heteroaryl, and is further distinguished by at least one of the following: -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, phenyl or 5 to 12-membered heteroaryl substitution; R 1c and R 1d Each of the following is independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 Alkyne, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclic, phenyl, or 5 to 12-membered heteroaryl; wherein methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 Each of the following groups is optionally surrounded by at least one of the following: alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclic, phenyl, or 5 to 12-membered heteroaryl, and is further distinguished by at least one of the following: -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, phenyl or 5 to 12-membered heteroaryl substitution.

7. The compound as claimed in any one of the preceding claims, wherein R 1 and R 2 Each is independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -CN, -OR 1a -NR 1a R 1b -COR 1a -CO2R 1a -CONR 1a R 1b or -NR 1a COR 1b ; R 1a and R 1b Each of the following is independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 Alkyne, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclic, phenyl, or 5 to 12-membered heteroaryl; wherein methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 Each of the following groups is optionally surrounded by at least one of the following: alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclic, phenyl, or 5 to 12-membered heteroaryl, and is further distinguished by at least one of the following: -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, phenyl or 5 to 12-membered heteroaryl substitution; Preferably, R 1 and R 2 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, cyclooctyl, -CN; More preferably, R 1 and R 2 Each is independently selected from hydrogen, -F, -Cl, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), cyclopropyl, cyclobutyl; Even more preferably, R 1 and R 2 Each is independently selected from hydrogen or methyl.

8. The compound as claimed in any one of the preceding claims, wherein R 3 R 4 R 5 and R 6 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, cyclooctyl, -CN, -OR 3a -NR 3a R 3b -COR 3a -CO2R 3a -CONR 3a R 3b or -NR 3a COR 3b Each of the following groups is optionally substituted by at least one substituent selected from: -F, -Cl, -Br, -I, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexyloxy, heptoxy, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl: -F, -Cl, -Br, -I, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, 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 group, oxo group, -CN, -OR 3c -SO2R 3c -SO2NR 3c R 3d -COR 3c -CO2R 3c -CONR 3c R 3d -NR 3c R 3d -NR 3c COR 3d -NR 3c CO2R 3d Or –NR 3c SO2R 3d ; R 3a R 3b R 3c and R 3d 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, cyclo Each of propyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclic, phenyl, or 5 to 12-membered heteroaryl is optionally bounded by at least one of -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 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 alkenyl, -C 2-8 Alkyne, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclic, phenyl or 5 to 12-membered heteroaryl substitution; Preferably, R 3 R 4 R 5 and R 6 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, cyclooctyl, -CN, -OR 3a -NR 3a R 3b -COR 3a -CO2R 3a -CONR 3a R 3b or -NR 3a COR 3b ; R 3a and R 3b 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, cyclo Each of propyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclic, phenyl, or 5 to 12-membered heteroaryl is optionally bounded by at least one of -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 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 alkenyl, -C 2-8 Alkyne, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclic, phenyl or 5 to 12-membered heteroaryl substitution; More preferably, R 3 R 4 R 5 and R 6 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, cyclooctyl, -CN, -OH, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy; Even more preferably, R 3 R 4 R 5 and R 6 Each is independently 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 R 4 R 5 and R 6 Each is independently selected from hydrogen.

9. The compound as claimed in any one of the preceding claims, wherein R 7 and R 8 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, or phenyl, wherein each of the following groups is optionally substituted by at least one substituent 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, or phenyl, and is optionally substituted by at least one substituent 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, -C 2-8 alkenyl, -C 2-8 alkynyl, -NR 7a R 7b -OR 7a Oxyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl (3 to 8 membered heterocyclic groups), phenyl, (5 to 12 membered heteroaryl groups) or -CN; R 7a and R 7b 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, -C 2-8 alkenyl, -C 2-8 Alkyne, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclic, 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, -C 2-8 alkenyl, -C 2-8 Each of the following groups is optionally substituent R: alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclic, phenyl, or 5 to 12-membered heteroaryl. 7c replace; R 7c Independently, -F, -Cl, -Br, -I, hydroxyl, 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, 3 to 8-membered heterocyclic, phenyl, 5 to 12-membered heteroaryl, or -CN, wherein the hydroxyl, 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 Each of the following groups is optionally separated by at least one hydrogen, halogen, hydroxyl, -C: alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclic group, phenyl, or 5 to 12-membered heteroaryl. 1-8 Alkyl, -C 1-8 Alkoxy, -CN, -NH2, or oxo groups are substituted; Preferably, R 7 and R 8 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, or phenyl, wherein each of the following groups is optionally substituted by at least one substituent 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, or phenyl, and is optionally substituted by at least one substituent 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, -C 2-8 alkenyl, -C 2-8 alkynyl, -NR 7a R 7b -OR 7a Oxyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl (3 to 8 membered heterocyclic groups), phenyl, (5 to 12 membered heteroaryl groups) or -CN; R 7a and R 7b 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, -C 2-8 alkenyl, -C 2-8 Alkyne, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclic, phenyl or 5 to 12-membered heteroaryl; More preferably, R 7 and R 8 Each is independently selected from hydrogen, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), cyclopropyl, cyclobutyl, and cyclopentyl; Even more preferably, R 7 and R 8 Each is independently selected from hydrogen.

10. The compound as claimed in any one of the preceding claims, wherein R 9 and R 10 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 12 Cycloalkenyl, 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. 9a Replace; or R 9 and R 10 Together with the nitrogen atom to which it is attached, it forms a 3, 4, 5, 6, 7, or 8-membered unsaturated or saturated ring, the ring containing 0, 1, 2, or 3 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the ring is optionally substituented by at least one R. 9a replace; R 9a Independently, it can be hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl, or tert-butyl), pentyl, naphthyl, 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 9b -SO2R 9b -SO2NR 9b R 9c -COR 9b -CO2R 9b -CONR 9b R 9c -NR 9b R 9c -NR 9b COR 9c -NR 9b CO2R 9c –NR 9b SO2R 9c , oxo group 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 following groups—cycloalkenyl, 3- to 12-membered heterocyclic, phenyl, or 5- to 12-membered heteroaryl—is optionally substituent for at least one R group. 9d Replace; or Two Rs 9a Together with the atoms to which it is attached, it forms a 3, 4, 5, 6, 7, or 8-membered unsaturated or saturated ring, the ring containing 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the ring is optionally substituented by at least one R. 9d replace; R 9b and R 9c 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, phenyl, or 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, or 5 to 12-membered heteroaryl is optionally substituent R. 9e replace; R 9d and R 9e Each of the following can be independently represented as 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 9f -SO2R 9f -SO2NR 9f R 9g -COR 9f -CO2R 9f -CONR 9f R 9g -NR 9f R 9g -NR 9f COR 9g -NR 9f CO2R 9g –NR 9f SO2R 9g Oxoyl group, -SF5 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. 9h replace; R 9f and R 9g 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, phenyl, naphthyl, or 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, naphthyl, or 5 to 12-membered heteroaryl is optionally substituent R. 9i replace; R 9h and R 9i Each of the following can be independently represented as 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 9j -SO2R 9j -SO2NR 9j R 9k -COR 9j -CO2R 9j -CONR 9j R 9k -NR 9j R 9k -NR 9j COR 9k -NR 9j CO2R 9k –NR 9j SO2R 9k , oxo group 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 following groups is optionally substituents: cycloalkenyl, 3- to 12-membered heterocyclic, phenyl, and 5- to 12-membered heteroaryl: -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, 3 to 8-membered heterocyclic group, phenyl, 5 to 12-membered heteroaryl, -CN, -OH, -NH2 or oxo-substituted; R 9j and R 9k 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. 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 are optionally substituents of at least one of the following: -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 group, phenyl, 5 to 12-membered heteroaryl, -CN, -OH, -NH2 or oxo-substituted.

11. The compound as claimed in any one of the preceding claims, wherein R 9 and R 10 Each 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, chromoalkyl, isochromoalkyl, 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), 6,7-dihydro-5H-cyclopento[b]pyridyl, pyrimidinyl Tetrahydro-2H-pyranyl, pyridazinyl, pyrazinyl, dihydrofuranopyridyl (preferably 2,3-dihydrofurano[2,3-b]pyridyl), tetrahydronaphthyl (preferably 1,2,3,4-tetrahydronaphthyl), 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, chromoalkyl, isochromoalkyl, 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), 6,7-dihydro-5H-cyclopentano[b]pyridyl, pyrimidinyl, tetrahydro-2H-pyranyl Each of the following groups is optionally substituent R: pyrazinyl, pyrazinyl, dihydrofuranopyridyl (preferably 2,3-dihydrofurano[2,3-b]pyridyl), tetrahydronaphthyl (preferably 1,2,3,4-tetrahydronaphthyl), 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. 9a Replace; or R 9 and R 10 Together with the nitrogen atom to which it is attached, it forms a 3, 4, 5, 6, 7, or 8-membered unsaturated or saturated ring, the ring containing 0, 1, 2, or 3 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur; the ring is optionally substituented by at least one R. 9a replace; R 9a 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, naphthyl, chromoalkyl, isochromoalkyl, 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]pyridine). ), pyrimidinyl, tetrahydro-2H-pyranyl, pyridazinyl, pyrazinyl, dihydrofuranopyridyl (preferably, 2,3-dihydrofurano[2,3-b]pyridyl), tetrahydronaphthyl (preferably, 1,2,3,4-tetrahydronaphthyl), 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 9b -SO2R 9b -SO2NR 9b R 9c -COR 9b -CO2R 9b -CONR 9b R 9c -NR 9b R 9c -NR 9b COR 9c -NR 9b CO2R 9c –NR 9b SO2R 9c , oxo 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, naphthyl, chromoalkyl, isochromoalkyl, 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-pyran The following groups are optionally substituents: pyrazinyl, pyrazinyl, dihydrofuranopyridyl (preferably 2,3-dihydrofurano[2,3-b]pyridyl), tetrahydronaphthyl (preferably 1,2,3,4-tetrahydronaphthyl), 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 of which is optionally substituented by at least one R. 9d Replace; or Two Rs 9a Together with the atoms to which it is attached, it forms a 3, 4, 5, or 6-membered unsaturated or saturated ring, the ring containing 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the ring is optionally substituented by at least one R. 9d replace; R 9b and R 9c 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, phenyl, chromoalkyl, isochromoalkyl, 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, pyrazinyl, dihydrofuranopyridyl (preferably 2,3-dihydrofurano[2,3-b]pyridyl), tetrahydronaphthyl (preferably 1,2,3,4-tetrahydronaphthyl), 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, chromoalkyl, isochromoalkyl, 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 Each of the following groups is optionally substituent R: pyrazinyl, pyrazinyl, dihydrofuranopyridyl (preferably 2,3-dihydrofurano[2,3-b]pyridyl), tetrahydronaphthyl (preferably 1,2,3,4-tetrahydronaphthyl), 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. 9e replace; R 9d and R 9e 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, chromoalkyl, isochromoalkyl, 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), pyrimidine Tetrahydro-2H-pyranyl, pyridazinyl, pyrazinyl, dihydrofuranopyridyl (preferably 2,3-dihydrofurano[2,3-b]pyridyl), tetrahydronaphthyl (preferably 1,2,3,4-tetrahydronaphthyl), 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 9f -SO2R 9f -COR 9f -CO2R 9f -CONR 9f R 9g -NR 9f R 9g -NR 9f COR 9g -NR 9f CO2R 9g , oxo, -SF5 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, chromoalkyl, isochromoalkyl, 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-pyridyl The following groups are optionally substituents: uranyl, pyrazinyl, dihydrofuranopyridyl (preferably 2,3-dihydrofurano[2,3-b]pyridyl), tetrahydronaphthyl (preferably 1,2,3,4-tetrahydronaphthyl), 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 of which is optionally substituented by at least one substituent R. 9h replace; R 9f and R 9g 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, phenyl, chromoalkyl, isochromoalkyl, 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, pyrazinyl, dihydrofuranopyridyl (preferably 2,3-dihydrofurano[2,3-b]pyridyl), tetrahydronaphthyl (preferably 1,2,3,4-tetrahydronaphthyl), 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, chromoalkyl, isochromoalkyl, 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 Each of the following groups is optionally substituent R: pyrazinyl, pyrazinyl, dihydrofuranopyridyl (preferably 2,3-dihydrofurano[2,3-b]pyridyl), tetrahydronaphthyl (preferably 1,2,3,4-tetrahydronaphthyl), 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. 9i replace; R 9h and R 9i 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, phenyl, chromogenic alkyl, isochromogenic alkyl, 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, pyrazinyl, pyrazinyl, dihydrofuranopyridyl (preferably 2,3-dihydrofurano[2,3-b]pyridyl), tetrahydronaphthyl (preferably 1,2,3,4-tetrahydronaphthyl), 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 9j -COR 9j -CO2R 9j -CONR 9j R 9k -NR 9j R 9k -NR 9j COR 9k -NR 9j CO2R 9k Oxoyl 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, chromoalkyl, isochromoalkyl, 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 substituented by at least one of the following groups: tetrahydronaphthyl (preferably 1,2,3,4-tetrahydronaphthyl), 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: -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-substituted groups; R 9j and R 9k Each is independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, chromoalkyl, isochromoalkyl, 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, pyrazinyl, dihydrofuranopyridyl (preferably) , 2,3-dihydrofurano[2,3-b]pyridyl), tetrahydronaphthyl (preferably, 1,2,3,4-tetrahydronaphthyl), 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, cyclo Hexyl, cycloheptyl, cyclooctyl, phenyl, chromoalkyl, isochromoalkyl, 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 (preferably 1,2,3,4-tetrahydronaphthyl), benzene Each of the following groups is optionally substituents: 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 substituented by at least one of the following: -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-substituted groups; Preferably, R 9 and R 10 Each 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, chromoalkyl, isochromoalkyl, 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), 6,7-dihydro-5H-cyclopento[b]pyridyl, pyrimidinyl Tetrahydro-2H-pyranyl, pyridazinyl, pyrazinyl, dihydrofuranopyridyl (preferably 2,3-dihydrofurano[2,3-b]pyridyl), tetrahydronaphthyl (preferably 1,2,3,4-tetrahydronaphthyl), 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, chromoalkyl, isochromoalkyl, 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), 6,7-dihydro-5H-cyclopentano[b]pyridyl, pyrimidinyl, tetrahydro-2H-pyranyl Each of the following groups is optionally substituent R: pyrazinyl, pyrazinyl, dihydrofuranopyridyl (preferably 2,3-dihydrofurano[2,3-b]pyridyl), tetrahydronaphthyl (preferably 1,2,3,4-tetrahydronaphthyl), 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. 9a Replace; or R 9 and R 10 Together with the nitrogen atom to which it is attached, it forms a 3, 4, 5, 6, 7, or 8-membered unsaturated or saturated ring, the ring containing 0, 1, 2, or 3 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur; the ring is optionally substituented by at least one R. 9a replace; R 9a Independently, it 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, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, chromoalkyl, isochromoalkyl, 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 (preferably 1,2,3,4-tetrahydronaphthyl), 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 9b 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, naphthyl, chromoalkyl, isochromoalkyl, 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 (preferably 1,2,3,4-tetrahydronaphthyl), 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 are optionally substituents R. 9d Replace; or Two Rs 9a Together with the atoms to which it is attached, it forms a 3, 4, 5, or 6-membered unsaturated or saturated ring, the ring containing 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the ring is optionally substituented by at least one R. 9d replace; R 9b Each can be independently hydrogen, methyl, ethyl, propyl (isopropyl or n-propyl), cyclopropyl or cyclobutyl; R 9d 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, chromoalkyl, isochromoalkyl, 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), pyrimidine Tetrahydro-2H-pyranyl, pyridazinyl, pyrazinyl, dihydrofuranopyridyl (preferably 2,3-dihydrofurano[2,3-b]pyridyl), tetrahydronaphthyl (preferably 1,2,3,4-tetrahydronaphthyl), 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 9f -NR 9f R 9g -NR 9f COR 9g , Oxide group, -SO2R 9f -SF5 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, chromoalkyl, isochromoalkyl, 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 Each of the following groups is optionally substituent R: pyrazinyl, pyrazinyl, dihydrofuranopyridyl (preferably 2,3-dihydrofurano[2,3-b]pyridyl), tetrahydronaphthyl (preferably 1,2,3,4-tetrahydronaphthyl), 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. 9h replace; R 9f and R 9g Each 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, chromoalkyl, isochromoalkyl, 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, pyrazinyl, dihydrofuranopyridyl (preferably, 2,3-dihydrofurano[2,3-b]pyridyl), tetrahydronaphthyl (preferably, 1,2,3,4-tetrahydronaphthyl), 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, chromoalkyl, isochromoalkyl, 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, pyrazine The group consisting of pyridyl, dihydrofuranopyridyl (preferably 2,3-dihydrofurano[2,3-b]pyridyl), tetrahydronaphthyl (preferably 1,2,3,4-tetrahydronaphthyl), 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 substituented by at least one substituent R. 9i replace; R 9h and R 9i 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, chromogenic alkyl, isochromogenic alkyl, 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, tetra Hydrogen-2H-pyranyl, pyridazinyl, pyrazinyl, dihydrofuranopyridyl (preferably, 2,3-dihydrofurano[2,3-b]pyridyl), tetrahydronaphthyl (preferably, 1,2,3,4-tetrahydronaphthyl), 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 9 and R 10 Each is independently selected from hydrogen, methyl, ethyl, propyl (isopropyl or n-propyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, chromoalkyl, isochromoalkyl, 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), 6,7-dihydro-5H-cyclo Pento[b]pyridyl, pyrimidinyl, tetrahydro-2H-pyranyl, pyrazinyl, pyrazinyl, dihydrofuranopyridyl (preferably 2,3-dihydrofurano[2,3-b]pyridyl), tetrahydronaphthyl (preferably 1,2,3,4-tetrahydronaphthyl), benzo[d]thiazolyl, pyridyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl or tetrahydrofuranopyridyl pyridyl, wherein the methyl, ethyl, propyl (isopropyl or n-propyl), phenyl, chromoalkyl, isochromoalkyl, 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), 6,7-dihydro-5H-cyclopentano[b]pyridyl, pyrimidinyl, tetrahydro-2H- Pyranyl, pyridazinyl, pyrazinyl, dihydrofuranopyridyl (preferably 2,3-dihydrofurano[2,3-b]pyridyl), tetrahydronaphthyl (preferably 1,2,3,4-tetrahydronaphthyl), benzo[d]thiazolyl, pyridyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl, or tetrahydrofuranopyridyl are optionally substituents R. 9a Replace; or R 9 and R 10 Together with the nitrogen atom to which it is attached, it forms a 6-membered unsaturated or saturated ring, which is optionally substituent R. 9a replace; R 9a Independently, it can be hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (isopropyl or n-propyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyrimidinyl, pyridazinyl, pyrazinyl, dihydrofuranopyridyl (preferably 2,3-dihydrofurano[2,3-b]pyridyl), benzo[d]thiazolyl, pyridyl, quinolinyl, isoquinolinyl, thiazolyl, -OR 9b or -CN, wherein each of the following groups—methyl, ethyl, propyl (isopropyl or n-propyl), phenyl, naphthyl, pyrimidinyl, pyridazinyl, pyrazinyl, dihydrofuranopyridinyl (preferably 2,3-dihydrofurano[2,3-b]pyridinyl), benzo[d]thiazolyl, pyridinyl, quinolinyl, isoquinolinyl, or thiazolyl—is optionally substituent R. 9d replace; R 9b Each can be independently hydrogen, methyl, ethyl, propyl (isopropyl or n-propyl), cyclopropyl or cyclobutyl; R 9d Each of the following groups 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 9f -SO2R 9f -SF5 or -CN, wherein each of the following groups—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 substituented by at least one substituent R. 9h replace; R 9f 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. 9i replace; R 9h and R 9i 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.

12. The compound as claimed in any of the preceding claims, wherein R 9 and R 10 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. 9a Replace; or R 9 and R 10 Together with the nitrogen atom to which it is attached, it forms a 3- to 8-membered unsaturated or saturated ring, the ring containing 0-3 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the ring is optionally substituented by at least one R. 9a replace; R 9a Independently hydrogen, halogen, deuterium, -C 1-8 Alkyl, -C3-C8 cycloalkyl, -C6-C 12 aryl, 5- to 12-membered heteroaryl, -OR 9b Or -CN, where -C 1-8 Alkyl, -C3-C8 cycloalkyl, -C6-C 12 Each of the aryl group and the 5 to 12 heteroaryl groups is optionally substituent R. 9d Replace; or Two Rs 9a Together with the atoms to which it is attached, it forms a 3- to 8-membered unsaturated or saturated ring, the ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the ring optionally being substituented by at least one R. 9d replace; R 9b 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. 9e replace; R 9d and R 9e Each is independently hydrogen, halogen, -C 1-8 Alkyl, -C3-C8 cycloalkyl, -C6-C 12 aryl, 5- to 12-membered heteroaryl, -OR 9f -SO2R 9f -SF5 or -CN, wherein -C 1-8 Alkyl, -C6-C 12 Each of the aryl group and the 5 to 12 heteroaryl groups is optionally substituent R. 9h replace; R 9f Each is independently selected from hydrogen and -C 1-8 Alkyl and -C3-C8 cycloalkyl, -C6-C 12 Aryl, wherein the -C 1-8 Alkyl, -C6-C 12 Each of the aryl and -C3-C8 cycloalkyl groups is optionally substituent R. 9i replace; R 9h and R 9i Each is independently hydrogen, halogen, -C 1-8 Alkyl or -CN; Preferably, R 9 and R 10 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, chromoalkyl, isochromoalkyl, 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, chromoalkyl, isochromoalkyl, pyridyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydronaphthyl, dihydrofuranopyridyl, or tetrahydrofuranopyridyl. 9a Replace; or R 9 and R 10 Together with the nitrogen atom to which it is attached, it forms a 3, 4, 5, 6, 7, or 8-membered unsaturated or saturated ring, the ring containing 0, 1, 2, or 3 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur; the ring is optionally substituented by at least one R. 9a replace; R 9a 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 9b or -CN, wherein each of the following groups—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. 9d Replace; or Two Rs 9a Together with the atoms to which it is attached, it forms a 3, 4, 5, or 6-membered unsaturated or saturated ring, the ring containing 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the ring is optionally substituented by at least one R. 9d replace; R 9b 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. 9e replace; R 9d and R 9e Each of the following can be independently represented as 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 9f -SO2R 9f -SF5 or -CN, wherein each of the following groups—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. 9h replace; R 9f 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, phenyl, or naphthyl, 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, phenyl, or naphthyl groups is optionally substituent R. 9i replace; R 9h and R 9i 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, heptyl, octyl or -CN.

13. The compound as claimed in any one of the preceding claims, wherein R 9 and R 10 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 R 9 and R 10 Together with the nitrogen atom it is attached to, it forms ( , , or ), ( , , or ), ( , , or ), ( , , or ).

14. The compound of any one of the preceding claims, wherein the compound is selected from... 。 15. A pharmaceutical composition comprising the compound of any one of claims 1-14 or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof, and a pharmaceutically acceptable excipient.

16. A method for reducing PRMT5 activity by inhibition, the method comprising administering to an individual a compound of any one of claims 1-14 or a pharmaceutically acceptable salt thereof, including a compound of formula (I) or a specific compound illustrated herein.

17. The method of claim 16, wherein the disease is selected from cancer.

18. Use of any compound of claims 1-14 or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof in the preparation of a medicament for treating a disease regulated by PRMT5.

19. The use as claimed in claim 18, wherein the disease is cancer.

20. The use as described in claim 18, wherein the disease is a solid tumor lacking MTAP, including but not limited to lung cancer, bladder cancer, melanoma, pancreatic cancer, esophageal cancer, gastric adenocarcinoma, breast cancer, or glioblastoma.

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