Intermediates and methods of synthesis of 1-(1-oxo-1, 2-dihydrophthalazin-6-yl) cycloalkyl-1-carboxamide derivatives as MTA synergistic inhibitors of PRMT5

Abstract

The present disclosure provides intermediates of 1-(1-oxo-1, 2-dihydrophthalazin-6-yl) cycloalkyl-1-carboxamide derivatives, and methods of synthesis thereof. The present invention relates to a 1-(1-oxo-1, 2-dihydrophthalazin-6-yl) cycloalkyl-1-carboxamide derivative compound, which can be used to selectively inhibit the synergistic activity of PRMT5 and MTA in a tumor carrying an MTAPDEL mutation, and a pharmaceutical composition comprising the compound as a therapeutic agent for various diseases, including cancer.

Description

Technical Field

[0001] The present disclosure provides an intermediate and a synthesis method of a 1-(1-oxo-1,2-dihydrophthalazine-6-yl)cycloalkyl-1-carboxamide derivative. The 1-(1-oxo-1,2-dihydrophthalazine-6-yl)cycloalkyl-1-carboxamide derivative compound can be used to selectively inhibit the interaction between PRMT5 and MTA in the presence of MTAP DEL The invention relates to synergistic activities in treating tumors with mutations thereof, and pharmaceutical compositions comprising the compounds as therapeutic agents for various diseases including cancer. Background Art

[0002] Epigenetic modification is a process that can modify genetic output and change the original DNA sequence. Epigenetic modification plays an important role in many aspects such as gene expression and regulation, protein production and cell differentiation. Generally, the process is reversible and selective to DNA, its regulatory proteins such as histones and other proteins such as transcription factors [Bradbury, EM, BioEssays, 1992, 14 (1): pp. 9-16]. PMT (protein methyltransferase) is the main participant of epigenetic modification, consisting of two subfamilies, i.e. PKMT (protein lysine methyltransferase) and PRMT (protein arginine methyltransferase) [Copel and RA et al., Oncogene, 2012.32 (8): pp. 939-46]. PMT is related to various human diseases and is considered to be a potential therapeutic target [Copel and RA et al., Oncogene, 2012, 32 (8): pp. 939-46].

[0003] As the name implies, PRMT catalyzes the methylation of protein arginine residues. In addition to its main function of methylating histone tails, PRMT also targets other cellular proteins, such as NAB2p, FOXO1, PABP1, Sm D1, etc. [Bedford, MT et al., Molecular Cell, 2005, 18 (3): p. 263-72]. According to the product classification, 9 mammalian PRMTs can be divided into 3 subtypes: type I (PRMT1, PRMT2, PRMT3, PRMT4, PRMT6 and PRMT8) catalyzes the formation of aDMA (asymmetric dimethylated arginine); type II (PRMT5, PRMT9) catalyzes sDMA (symmetric dimethylated arginine); and type III (PRMT7) catalyzes the formation of MMA (monomethylated arginine) [Yang, Y. et al., Nature Reviews Cancer, 2012, 13 (1): p. 37-50]. In addition, type I / II PRMTs can also catalyze the formation of MMA as intermediates of 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 proteins, namely the SAM pocket and the substrate pocket. The methylation process involves the transfer of an activated methyl group from the cofactor SAM to the guanidine group on the arginine residue. N 2. [Bedford, MT et al., Molecular Cell, 2005, 18(3): p. 263-72] The byproduct of this process is SAH (S-adenosyl-L-homocysteine).

[0004] For Arg: aDMA: MMA: sDMA, the total arginine level in the cell is roughly 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 main type I PRMT that acts on its own in the cell), PRMT5 binds to MEP50 (methyltransferase complex protein 50) to form a heterocomplex that is often elevated in cancer cells and associated with poor patient survival [Gao, G. et al., Nucleic Acids Research, 2019, 47 (10): 5038-48]. PRMT5 promotes tumorigenesis by multiple mechanisms. PRMT5 is a strong repressor of many genes; when PRMT5 methylates histone H2a and H4 on Arg3 and histone H3 on Arg8, it inhibits gene transcripts involved in differentiation, transformation, cell cycle progression, and tumor suppression [Karkhanis, V. et al., Trends in Biochemical Sciences, 2011, 36 (12): p. 633-41]. In addition to its epigenetic effects, PRMT5 may also regulate RNA binding proteins, such as splicing factors. For example, reproducible events were observed in PRMT5 knockout mice, in which exon 6 skipping of MDM4 (mouse double minute 4) occurred and p53 was released to upregulate the p53 pathway [Gerhart, SV et al., Scientific Reports, 2018, 8: 9711]. In addition, PRMT5 can be activated through p53 [Jansson, M. et al., Nature Cell Biology, 2008, 10(12): pp. 1431-9], EGFR [Hsu, J.-M. et al., Nature Cell Biology, 2011, 13(2): pp. 174-81], PI3K [Wei, T.-YW, et al., Cellular Signaling, 2014, 26(12): pp. 2940-50], etc. Therefore, PRMT5 is likely to become a clinically relevant target.

[0005] On the other hand, PRMT5 is an essential gene in normal tissues, and systemic inhibition of PRMT5 may lead to significant adverse consequences, especially hematological toxicity [Ahnert, JR et al., Journal of Clinical Oncology, 2021, 39(15 Supplement): p. 3019]. Therefore, for safer treatment, strategies to selectively block PRMT5 activity in tumor cells are needed.

[0006] Homozygous deletion of the tumor suppressor CDKN2A (cyclin-dependent kinase inhibitor 2A) occurs in about 15% of all tumor types. Interestingly, this mutation often involves co-deletion of neighboring genes present in 9p21, including the gene encoding MTAP (methylthioadenosine phosphorylase) [Firestone, RS et al., Journal of American Chemical Society, 2017, 139 (39): p. 13754-60]. Due to MTAP deletion, MTAP substrate MTA (methylthioadenosine) accumulates. MTA is structurally related to SAM and is a weak ligand / inhibitor of PRMT5 that occupies the same pocket as SAM. The formation of the MTA-PRMT5 complex provides an opportunity to further inhibit PRMT5 by forming a tertiary complex. In this way, the correlation between the MTAP ineffective state and PRMT5 dependence is established by the MTA concentration level to provide precise tumor treatment.

[0007] Currently, most clinical-stage PRMT5 inhibitors cannot distinguish between normal cells and cancer cells based on SAM / MTA competition mechanisms (JNJ64619178, PF06939999, PRT543, and PRT811) or non-MTA synergistic mechanisms (GSK3326595). Therefore, there is still an unmet and ongoing medical need for potent and selective MTA-synergistic PRMT5 inhibitors. Summary of the invention

[0008] One object of the present invention is to provide an intermediate of a compound used as a PRMT5 inhibitor, and a preparation method and use thereof.

[0009] Aspect 1. A compound of formula (I):

[0010]

[0011] n is 1, 2, 3 or 4;

[0012] m is 1, 2, 3 or 4;

[0013] R 1 and R 2 are each 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 -C3-C8 alkyl and -C3-C8 cycloalkyl is optionally substituted with at least one substituent selected from the group consisting of 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 group, C6-C 12 Aryl, 5- to 12-membered heteroaryl, oxo, -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 S02R 1d ;

[0014] R 1a and R 1b are independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, -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 group, -C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted with at least one halogen, -OH, -C 1-8 Alkyl, -C 1-8 Alkoxy, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, -C6-C 12 aryl or 5- to 12-membered heteroaryl substituted;

[0015] R 1c and R 1d are independently hydrogen, -C 1-8 Alkyl, -C 2-8Alkenyl, -C 2-8 Alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, -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 group, -C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted with at least one halogen, -OH, -C 1-8 Alkyl, -C 1-8 Alkoxy, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, -C6-C 12 aryl or 5- to 12-membered heteroaryl substituted;

[0016] R 3 , R 4 , R 5 and R 6 are each 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 -C3-C8 alkyl and -C3-C8 cycloalkyl is optionally substituted with at least one substituent selected from the group consisting of halogen, -C 1-8 Alkoxy, -C 1-8 Alkyl, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, C6-C 12 Aryl, 5- to 12-membered heteroaryl, oxo, -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 CO2R3d or –NR 3c S02R 3d ;

[0017] R 3a , R 3b , R 3c and R 3d are independently hydrogen, -C 1-8 Alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, -C6-C 12 Aryl or 5 to 12 membered heteroaryl; the -C 1-8 Alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, -C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted with at least one halogen, -OH, -C 1-8 Alkyl, -C 1-8 Alkoxy, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, -C6-C 12 aryl or 5- to 12-membered heteroaryl substituted;

[0018] R 7 Selected from hydrogen;

[0019] R 8 Selected from -COR 8a 、-CO2R 8a or-CONR 8a R 8b ;

[0020] R 8a and R 8b Each independently is -C 1-8 Alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, -C6-C 12 Aryl or 5 to 12 membered heteroaryl; the -C 1-8 Alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, -C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted with at least one halogen, -OH, -C 1-8 Alkyl, -C 1-8 Alkoxy, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, -C6-C 12 aryl or 5- to 12-membered heteroaryl.

[0021] Aspect 2. The compound according to Aspect 1, wherein the compound is of formula (IIa):

[0022]

[0023] Preferably, the compound is selected from formula (IIb):

[0024]

[0025] More preferably, the compound is selected from formula (IIc):

[0026]

[0027] Even more preferably, the compound is selected from formula (IId):

[0028]

[0029] Even more preferably, the compound is selected from formula (IIe):

[0030]

[0031] Aspect 3. A compound as described in any one of the preceding 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 , wherein each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl is optionally substituted with at least one substituent selected from: -F, -Cl, -Br, -I, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, oxo, -CN, -OR 1c 、-SO2R 1c 、-SO2NR 1c R1d 、-COR 1c 、-CO2R 1c 、-CONR 1c R 1d 、-NR 1c R 1d 、-NR 1c COR 1d 、-NR 1c CO2R 1d or –NR 1c S02R 1d ;

[0032] R 1a and R 1b are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8 membered heterocyclyl, phenyl or 5 to 12 membered heteroaryl; the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl is optionally substituted with at least one -F, -Cl, -Br, -I, -OH, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, C 1-8 Alkoxy-C 1-8 Alkyl-, C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl;

[0033] R 1c and R 1d are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8 membered heterocyclyl, phenyl or 5 to 12 membered heteroaryl; the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl is optionally substituted with at least one -F, -Cl, -Br, -I, -OH, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, C 1-8 Alkoxy-C 1-8 Alkyl-, C 2-8 Alkenyl, -C 2-8 The cyclohexyl group may be substituted with an alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a 3- to 8-membered heterocyclyl, a phenyl group, or a 5- to 12-membered heteroaryl group.

[0034] Aspect 4. A compound as described in any one of the preceding 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 ;

[0035] R 1a and R 1b are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8 membered heterocyclyl, phenyl or 5 to 12 membered heteroaryl; the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl is optionally substituted with at least one -F, -Cl, -Br, -I, -OH, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, C 1-8 Alkoxy-C 1-8 Alkyl-, C 2-8 Alkenyl, -C 2-8The cyclohexyl group may be substituted with an alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a 3- to 8-membered heterocyclyl, a phenyl group, or a 5- to 12-membered heteroaryl group.

[0036] 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;

[0037] 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.

[0038] Even more preferably, R 1 and R 2 are each independently selected from hydrogen.

[0039] Aspect 5. A compound as described in any one of the preceding aspects, 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, wherein each of methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl is optionally substituted with at least one substituent selected from -F, -Cl, -Br, -I, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, 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 heterocyclyl, phenyl, 5 to 12 membered heteroaryl, oxo, -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 S02R 3d ;

[0040] 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 heterocyclyl, phenyl or 5- to 12-membered heteroaryl; 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 8-membered heterocyclyl, phenyl or 5- to 12-membered heteroaryl; Each of propyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl is optionally substituted with at least one -F, -Cl, -Br, -I, -OH, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 Alkenyl, -C 2-8Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl;

[0041] 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 ;

[0042] 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 heterocyclyl, phenyl or 5- to 12-membered heteroaryl; 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 8-membered heterocyclyl, phenyl or 5- to 12-membered heteroaryl; Each of propyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl is optionally substituted with at least one -F, -Cl, -Br, -I, -OH, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl;

[0043] More preferably, R 3 , R 4 , R 5 and R 6each 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, pentyloxy, hexyloxy, heptyloxy, octyloxy;

[0044] 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);

[0045] Even more preferably, R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen.

[0046] Aspect 6. A compound as described in any one of the preceding aspects, wherein R 8 Selected from -COR 8a 、-CO2R 8a or-CONR 8a R 8b ;

[0047] R 8a and R 8b Each of the above groups is independently a methyl group, an ethyl group, a propyl group (isopropyl or n-propyl), a butyl group (n-butyl, sec-butyl, isobutyl or tert-butyl), a pentyl group, a hexyl group, a heptyl group, an octyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a 3- to 8-membered heterocyclyl group, a phenyl group, or a 5- to 12-membered heteroaryl group; the methyl group, the ethyl group, the propyl group (isopropyl or n-propyl), the butyl group (n-butyl, sec-butyl, isobutyl or tert-butyl), the pentyl group, the hexyl group, the heptyl group, the octyl group , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8 membered heterocyclyl, phenyl or 5 to 12 membered heteroaryl are each optionally substituted with at least one -F, -Cl, -Br, -I, -OH, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C 1-8 Alkoxy, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 Alkenyl, -C 2-8 substituted with alkynyl, 3- to 8-membered heterocyclyl, phenyl or 5- to 12-membered heteroaryl;

[0048] Preferably, R 8 Selected from -Cbz or -Boc.

[0049] Aspect 7. A compound as described in any one of the preceding aspects, wherein the compound is

[0050]

[0051] Aspect 8. A method for synthesizing the compound according to aspects 1 to 7, wherein the method comprises step A:

[0052]

[0053] R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 11 , m and n are as defined in any one of aspects 1 to 7;

[0054] The alkyl group is selected from methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl or octyl; preferably, the alkyl group is ethyl;

[0055] The base is selected from LiOH, NaOH, KOH, MeONa or EtONa; preferably, the base is LiOH.

[0056] Aspect 9. The synthesis method according to aspect 8, wherein the solvent of step A is THF, DMF, DMSO, MeOH, EtOH, water and a combination thereof;

[0057] Preferably, the solvent of step A is a combination of THF, MeOH and water.

[0058] Aspect 10. The synthesis method according to any one of aspects 8 to 9, wherein the temperature of step A is 10°C-80°C; preferably, the temperature of step A is 40°C-70°C; more preferably, the temperature of step A is 60°C;

[0059] The reaction time of step A is 2 hours to 24 hours; preferably, the reaction time of step A is 8 hours to 18 hours; more preferably, the reaction time of step A is 16 hours.

[0060] Aspect 11. The synthesis method according to any one of aspects 8 to 10, wherein the method further comprises step B:

[0061]

[0062] R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 11 , alkyl, m and n are as defined in any one of aspects 1 to 7 and aspect 8;

[0063] The Pd catalyst is selected from Pd2(dba)3.

[0064] Aspect 12. The synthesis method according to aspect 11, wherein the zinc powder is activated zinc powder;

[0065] Preferably, the zinc powder is activated by 1,2-dibromoethane and / or trimethylsilyl chloride;

[0066] More preferably, the zinc powder is activated by 1,2-dibromoethane and trimethylchlorosilane.

[0067] Aspect 13. The synthesis method according to aspect 11, wherein the temperature of step B is 10°C-80°C; preferably, the temperature of step A is 30°C-60°C; more preferably, the temperature of step A is 40°C;

[0068] Aspect 14. The synthesis method as described in Aspect 11, wherein the reaction time of step A is 2 hours to 24 hours; preferably, the reaction time of step A is 8 hours to 18 hours; more preferably, the reaction time of step A is 16 hours. DETAILED DESCRIPTION

[0069] The following terms have the indicated meanings throughout the specification:

[0070] Unless specifically defined elsewhere in this document, all other technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0071] The following terms have the indicated meanings throughout the specification:

[0072] As used herein, including the appended claims, singular forms of words such as "a," "an," and "the" include their corresponding plural referents unless the context clearly dictates otherwise.

[0073] Unless the context clearly dictates otherwise, the term "or" is used to mean, and is used interchangeably with, the term "and / or."

[0074] The term "alkyl" includes hydrocarbon groups selected from straight and branched chain saturated hydrocarbon groups containing 1 to 18 (such as 1 to 12, further such as 1 to 10, further such as 1 to 8, or 1 to 6, or 1 to 4) carbon atoms. 1-6 Examples of alkyl) include, but are not limited to, methyl, ethyl, 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr"), 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or 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.

[0075] The term "propyl" includes 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr").

[0076] 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"), 1,1-dimethylethyl or tert-butyl ("t-Bu").

[0077] The term "pentyl" includes 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl.

[0078] 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.

[0079] The term "alkylene" refers to a divalent alkyl group produced by removing two hydrogens from an alkane. Alkylene includes, but is not limited to, methylene, ethylene, propylene, and the like.

[0080] The term "halogen" includes fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0081] The term "alkenyl" includes hydrocarbon groups selected from straight and branched hydrocarbon groups containing at least one C=C double bond and 2 to 18 (such as 2 to 8, further such as 2 to 6) carbon atoms. 2-6 Examples of alkenyl groups include, but are not limited to, ethenyl or vinyl, prop-1-enyl, prop-2-enyl, 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-dienyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, and hex-1,3-dienyl.

[0082] The term "alkenylene" refers to a divalent alkenyl group generated by removing two hydrogens from an alkene. Alkenylene includes, but is not limited to, vinylene, butenylene, and the like.

[0083] The term "alkynyl" includes hydrocarbon groups selected from straight and branched hydrocarbon groups containing at least one C≡C triple bond and 2 to 18 (such as 2 to 8, further such as 2 to 6) carbon atoms. 2-6 Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl, and 3-butynyl.

[0084] The term "alkynylene" refers to a divalent alkynyl group generated by removing two hydrogen atoms from an alkyne. Alkynylenes include, but are not limited to, ethynylene and the like.

[0085] The term "cycloalkyl" includes hydrocarbon groups selected from saturated cyclic hydrocarbon groups, including monocyclic and polycyclic (eg, bicyclic and tricyclic) groups, including fused, bridged or spiro-connected cycloalkyl groups.

[0086] For example, cycloalkyl can contain 3 to 12 (such as 3 to 10, further such as 3 to 8, further such as 3 to 6, 3 to 5 or 3 to 4) carbon atoms. Even further for example, cycloalkyl can be selected from the monocyclic group containing 3 to 12 (such as 3 to 10, further such as 3 to 8, 3 to 6) carbon atoms. The example of monocyclic cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl. In particular, saturated monocyclic cycloalkyl (for example, C 3-8 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In a preferred embodiment, cycloalkyl is a monocyclic ring (abbreviated as C 3-6Examples of bicyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Examples of bicyclic cycloalkyls include those with 7 to 12 ring atoms, arranged as fused bicyclics selected from [4,4], [4,5], [5,5], [5,6] and [6,6] ring systems, or arranged as bridged bicyclics selected from bicyclic [2.2.1] heptane, bicyclic [2.2.2] octane and bicyclic [3.2.2] nonane. Other examples of bicyclic cycloalkyls include those arranged as bicyclics selected from [5,6] and [6,6] ring systems.

[0087] The term "spirocycloalkyl" includes cyclic structures containing carbon atoms and formed by at least two rings that share one atom.

[0088] The term "fused cycloalkyl" includes bicyclic cycloalkyls as defined herein which are saturated and formed by two or more rings sharing two adjacent atoms.

[0089] The term "bridged cycloalkyl" includes a cyclic structure containing carbon atoms and formed by two rings, and the two rings share two atoms that are not adjacent to each other. The term "7-10 membered bridged cycloalkyl" includes a cyclic structure containing 7 to 12 carbon atoms and formed by two rings, and the two rings share two atoms that are not adjacent to each other.

[0090] 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, decalin, and benzo 3 to 8 membered cycloalkyl, benzo C 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, which in the above examples refers to a cyclic structure containing 8 to 9 ring atoms.

[0091] The term "aryl" used alone or in combination with other terms includes groups selected from:

[0092] 5- and 6-membered carbocyclic aromatic rings, e.g., phenyl;

[0093] Bicyclic ring systems, such as 7- to 12-membered bicyclic ring systems in which at least one ring is carbocyclic and aromatic, for example, naphthyl and indanyl; and

[0094] A tricyclic ring system, such as a 10 to 15 membered tricyclic ring system, wherein at least one ring is carbocyclic and aromatic, for example, fluorenyl.

[0095] The terms "aromatic hydrocarbon ring" and "aryl" are used interchangeably throughout the disclosure herein. In some embodiments, the monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 ring carbon atoms (i.e., C 5-10 Examples of monocyclic or bicyclic aromatic hydrocarbon rings include, but are not limited to, phenyl, naphthalene-1-yl, naphthalene-2-yl, anthracenyl, phenanthryl, etc. In some embodiments, the aromatic hydrocarbon ring is a naphthalene ring (naphthalene-1-yl or naphthalene-2-yl) or a phenyl ring. In some embodiments, the aromatic hydrocarbon ring is a phenyl ring.

[0096] Specifically, the term "bicyclic fused aryl" embraces bicyclic aryl rings as defined herein. A typical bicyclic fused aryl is naphthalene.

[0097] The term "heteroaryl" includes groups selected from:

[0098] 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, the remaining ring atoms being carbon;

[0099] 7- to 12-membered bicyclic rings comprising at least one heteroatom selected from N, O and S, e.g., 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 an aromatic ring; and

[0100] An 11- to 14-membered tricyclic ring comprising at least one heteroatom selected from N, O and S, e.g., 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 an aromatic ring.

[0101] When the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in the heteroaryl group does not exceed 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle does not exceed 1. When the heteroaryl group contains more than one heteroatom ring member, the heteroatoms can be the same or different. The nitrogen atoms in one or more rings of the heteroaryl group can be oxidized to form N-oxides.

[0102] Specifically, the term "bicyclic fused heteroaryl" includes 7 to 12 members, preferably 7 to 10 members, more preferably 9 or 10 members, of fused bicyclic heteroaryl rings as defined herein. Typically, the bicyclic fused heteroaryl is a 5 / 5-membered, 5 / 6-membered, 6 / 6-membered or 6 / 7-membered bicyclic ring. The group may be attached to the rest of the molecule via either ring.

[0103] "Heterocyclyl", "heterocycle" 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, the remaining ring members being carbon, including monocyclic, fused, bridged and spirocyclic rings, i.e., containing monocyclic heterocyclyls, bridged heterocyclyls, spiro heterocyclyls and fused heterocyclyls.

[0104] 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 it conforms to the valence theory. 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.

[0105] The term "divalent" refers to a linking group that is capable of forming a covalent bond with two other moieties. For example, a "divalent cycloalkyl" refers to a cycloalkyl obtained by removing two hydrogens from the corresponding cycloalkane to form a linking group. The terms "divalent aryl", "divalent heterocyclyl" or "divalent heteroaryl" should be understood in a similar manner.

[0106] The compounds disclosed herein may contain asymmetric centers and therefore may exist as enantiomers. "Enantiomers" refer to two stereoisomers of a compound that are non-superimposable mirror images of each other. In the case where the compounds disclosed herein have two or more asymmetric centers, they may additionally exist as diastereomers. Enantiomers and diastereomers belong to a wider class of stereoisomers. It is intended to include all such possible stereoisomers in the form of substantially pure resolved 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 noted, a reference to an isomer is applicable to any possible isomer. As long as the isomer composition is not specified, all possible isomers are included.

[0107] Unless stated otherwise, when compounds disclosed herein contain olefinic double bonds, such double bonds are intended to include both E and Z geometric isomers.

[0108] When the compounds disclosed herein contain a disubstituted cyclic ring system, the substituents found on such ring systems can take cis and trans forms. The cis form means that both substituents are located above the two substituent positions on the carbon, while the trans form means that they are located on opposite sides. For example, the disubstituted cyclic ring system can be a cyclohexyl ring or a cyclobutyl ring.

[0109] It may be advantageous to separate the reaction products from each other and / or from the starting materials. The desired product of each step or series of steps is separated and / or purified (hereinafter separated) to a desired degree of homogeneity by techniques commonly used in the art. Typically, such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography may involve any number of methods, including, for example: reverse 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 or thick layer chromatography, as well as small scale thin layer and flash chromatography techniques. Those skilled in the art may select and apply the technique most likely to achieve the desired separation.

[0110] "Diastereoisomers" refer to stereoisomers of compounds that have two or more chiral centers but are not mirror images of each other. Diastereomeric mixtures can be separated into their individual diastereomers based on their physicochemical differences by methods well known to those skilled in the art, such as by chromatography and / or fractional crystallization. Enantiomers can be separated by reacting the enantiomeric mixture with an appropriate optically active compound (e.g., a chiral auxiliary, such as a chiral alcohol or Mosher's acid chloride), converting the enantiomer mixture into a diastereomeric mixture, separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers into the corresponding pure enantiomers. Enantiomers can also be separated by using a chiral HPLC column.

[0111] Single stereoisomers (e.g., substantially pure enantiomers) can be obtained by resolving racemic mixtures using a method such as using an optically active resolving agent to form diastereomers (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): p. 283-302). Racemic mixtures of chiral compounds of the present invention can be separated and isolated by any suitable method, including: (1) forming ionic diastereomeric salts with chiral compounds and separating them by fractional crystallization or other methods, (2) forming diastereomeric compounds with chiral derivatizing agents, separating the diastereomers and converting them to pure stereoisomers, and (3) separating substantially pure or enriched stereoisomers directly under chiral conditions. See: Wainer, Irving W., ed., Drug Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker, Inc., 1993.

[0112] Some of the compounds disclosed herein may exist with different points of hydrogen attachment, known as tautomers. For example, a compound comprising a carbonyl -CH2C(O)- group (keto form) may undergo tautomerism to form a hydroxyl -CH=C(OH)- group (enol form). Where applicable, both the individual keto and enol forms as well as mixtures thereof are also intended to be included.

[0113] In some embodiments, the structure " "Transformable structure

[0114] "Prodrug" refers to a derivative of an active agent that requires conversion in vivo to release the active agent. In some embodiments, the conversion is an enzymatic conversion. Prodrugs are usually (but not necessarily) pharmacologically inactive prior to conversion to the active agent.

[0115] "Pharmaceutically acceptable salts" refers to those salts which are suitable, within the scope of sound medical judgment, for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, and the like, and commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compounds disclosed herein, or separately by reacting 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 invention.

[0116] In addition, 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, an addition salt, such as a pharmaceutically acceptable addition salt, can be prepared according to conventional methods for preparing acid addition salts from base compounds by dissolving the free base in a suitable organic solvent and treating the solution with an acid. Those skilled in the art will recognize various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts without undue experimentation.

[0117] As used herein, the terms "administration," "administering," "treating," and "treatment" refer to the contact of an exogenous drug, therapeutic agent, diagnostic agent, or composition with an animal, a human, a subject, a cell, a tissue, an organ, or a biological fluid. Treatment of cells encompasses contact of an agent with a cell, and contact of an agent with a fluid, wherein the fluid is in contact with the cell. The terms "administering" and "treatment" also refer to in vitro and ex vivo treatment of a cell, for example, by an agent, a diagnostic agent, a binding compound, or by another cell. The term "subject" herein includes any organism, preferably an animal, more preferably a mammal (e.g., rats, mice, dogs, cats, and rabbits), and most preferably a human.

[0118] The term "effective amount" or "therapeutically effective amount" refers to an amount of an active ingredient (such as a compound) that is sufficient to affect the treatment of a disease, disorder or symptom when administered to a subject to treat a disease, or at least one clinical symptom of a disease or condition. The term "therapeutically effective amount" may vary with the compound, the disease, disorder, and / or the symptoms of the disease or condition, the severity of the disease, disorder and / or the symptoms of the disease or condition, the age of the subject to be treated, and / or the weight of the subject to be treated. In any given case, the appropriate amount may be obvious to those skilled in the art, or may be determined by routine experimentation. In some embodiments, a "therapeutically effective amount" is an amount of at least one compound disclosed herein and / or at least one stereoisomer, tautomer or prodrug thereof and / or at least one pharmaceutically acceptable salt thereof that is effective to "treat" a disease or condition of a subject as defined herein. In the case of combination therapy, the term "therapeutically effective amount" refers to the total amount of a combination object used to effectively treat a disease, disorder or illness.

[0119] The term "disease" refers to any illness, ailment, ailment, symptom, or indication, and is interchangeable with the terms "disorder" or "condition."

[0120] Throughout the specification and the appended claims, unless the context requires otherwise, the term "comprise" and variations such as "comprises" and "comprising" are intended to specify the presence of the following features, but do not preclude the presence or addition of one or more other features. When used herein, the term "comprises" may be replaced by the terms "contains", "includes" or sometimes "has".

[0121] Throughout the specification and the appended claims, the term “C n-m " indicates a range including the endpoints, where n and m are integers and indicate the number of carbons. Examples include C 1-8 , C 1-6 wait.

[0122] Unless specifically defined elsewhere in this document, all other technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0123] Example

[0124] General Synthesis

[0125] The compounds disclosed herein, including salts thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of a number of possible synthetic routes.

[0126] The reaction for preparing the compounds disclosed herein can be carried out in a suitable solvent, which can be easily selected by a technician in the field of organic synthesis. Suitable solvents can be substantially free from reaction with starting materials, intermediates or products at a temperature that is within the boiling temperature range of the solvent, for example. A given reaction can be carried out in a solvent or a mixture of solvents.

[0127] The selection of suitable protecting groups can be easily determined by those skilled in the art. In the synthesis scheme, some protection / deprotection steps are not shown and can be introduced before, after or between any steps. Based on reaction conditions, the protecting groups shown in the synthesis scheme may or may not be used. The order of reactions can vary and provide similar results.

[0128] The reaction can be monitored according to 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 PE / EtOAc or DCM / MeOH systems as mobile phases. Use Bruker or Varian instrument recording NMR spectra with a preset pulse sequence.

[0129] abbreviation

[0130] NMR Nuclear Magnetic Resonance

[0131] UV

[0132] HPLC High Performance Liquid Chromatography

[0133] prep preparation / preparative

[0134] LC-MS Liquid Chromatography Mass Spectrometry

[0135] TLC Thin Layer Chromatography

[0136] PE Petroleum Ether

[0137] Et Ethyl

[0138] Ac Acetyl

[0139] dppf 1,1'-Bis(diphenylphosphino)ferrocene

[0140] Me Methyl

[0141] DCM Dichloromethane

[0142] Boc tert-Butyloxycarbonyl

[0143] NBS N-Bromosuccinimide

[0144] Bu Butyl

[0145] Tf trifluoromethanesulfonyl

[0146] dba dibenzylideneacetone

[0147] BPD Bis(pinacol)diboron

[0148] DMSO Dimethyl sulfoxide

[0149] XPhos 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

[0150] THF Tetrahydrofuran

[0151] Ph Phenyl

[0152] DMF N,N-Dimethylformamide

[0153] DIPEA Diisopropylethylamine

[0154] HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0155] BOPCl Bis(2-oxo-3-oxazolidinyl)phosphinyl chloride

[0156] DMAP 4-dimethylaminopyridine

[0157] MTBE Methyl tert-butyl ether

[0158] Example 1: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-(5,6,7,8-tetrahydroquinolin-8-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)cyclopropane-1-carboxamide

[0159]

[0160] Step 1: 5-Bromo-3-((dimethylamino)methylene)isobenzofuran-1(3H)-one

[0161]

[0162] To a solution of 5-bromo-3H-isobenzofuran-1-one (100 g, 469 mmol) in toluene (600 mL) was added 1-tert-butoxy-N,N,N',N'-tetramethyl-methanediamine (98.1 g, 563 mmol). The mixture was stirred at 90 ° C for 12 hours. The mixture was cooled to room temperature and the solid was collected by filtration. The solid was rinsed with EtOAc (100 mL) and dried in vacuo to give the title compound (80.0 g, 64%). 1 H NMR (400MHz, DMSO-d6) δ7.97 (d, J = 0.8 Hz, 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).

[0163] Step 2: 6-Bromo-4-((dimethylamino)methyl)phthalazin-1(2H)-one

[0164]

[0165] To a solution of 5-bromo-3-((dimethylamino)methylene)isobenzofuran-1(3H)-one (80.0 g, 298 mmol) in EtOH (480 mL) was added hydrazine monohydrate (29.0 g, 579 mmol). The mixture was stirred at 80 °C for 12 hours. The mixture was cooled to room temperature and the solid was collected by filtration. The solid was dried in vacuo to give the title compound (70.0 g, 83%). LC-MS (M+H) + =282.0.

[0166] Step 3: 6-Bromo-4-(chloromethyl)phthalazin-1(2H)-one

[0167]

[0168] To a solution of 6-bromo-4-((dimethylamino)methyl)phthalazin-1(2H)-one (60.0 g, 212 mmol) in anhydrous THF (360 mL) was added isobutyl chloroformate (116 g, 850 mmol) dropwise under nitrogen at 0-5° C. The solid was collected by filtration and dried in vacuo to give the title compound (36.0 g, 62%).

[0169] Step 4: 2-((7-bromo-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)isoindoline-1,3-dione

[0170]

[0171] To a solution of 6-bromo-4-(chloromethyl)phthalazin-1(2H)-one (31.0 g, 113 mmol) in DMF (180 mL) was added potassium phthalate (31.4 g, 154 mmol). The mixture was stirred at 25°C for 12 hours. The solid was collected by filtration and dried in vacuo to give the title compound (40.0 g, 92%).

[0172] Step 5: 4-(Aminomethyl)-6-bromophthalazin-1(2H)-one

[0173]

[0174] 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) was added hydrazine monohydrate (53.1 g, 1.04 mol). The mixture was stirred at 80° C. for 12 hours. The mixture was cooled to room temperature and the solid was collected by filtration. The solid was dried in vacuo to give the title compound (20.0 g, 76%). 1 H NMR (400MHz, DMSO-d6) δ8.37(d,J=1.6Hz,1H),8.18(d,J=8.4Hz,1H),8.12-8.06(m,2H),8.03(dd,J=1.8,8.6Hz,1H),7.88-7.81(m,2H),4.00(s,2H).

[0175] Step 6: tert-Butyl ((7-bromo-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate

[0176]

[0177] To a solution of 4-(aminomethyl)-6-bromophthalazin-1(2H)-one (20.0 g, 78.7 mmol) in DCM (144 mL) was added Boc2O (34.3 g, 157 mmol) and triethylamine (23.9 g, 236 mmol). The mixture was stirred at 20°C for 12 hours. The solid was collected by filtration and dried in vacuo to give the title compound (20.0 g, 72%). 1 H NMR (400MHz, DMSO-d6) δ12.7(br s,1H),8.28(s,1H),8.18(d,J=8.2Hz,1H),8.04(d,J=8.2Hz,1H),7.48(br s,1H),5.78(s,1H),4.53-4.31(m,2H),1.42(s,10H).

[0178] Step 7: 1-(4-(((tert-Butyloxycarbonyl)amino)methyl)-1-oxo-1,2-dihydrophthalazin-6-yl)cyclopropane Ethyl 1-oxanecarboxylate

[0179]

[0180] Under nitrogen, at room temperature, 1,2-dibromoethane (1.94g, 10.3mmol) was added to a suspension of zinc powder (9.9g, 154.6mmol) in anhydrous THF (70mL). The reaction mixture was stirred at 65°C for 5min and cooled to room temperature. The activation process was repeated 3 times. Trimethylchlorosilane (0.559g, 5.18mmol) was added, and the resulting suspension was stirred at room temperature for 15min. The mixture was warmed to 65°C, and a solution of 1-bromocyclopropane-1-ethyl formate (10.0g, 51.8mmol) in anhydrous THF (30mL) was added at a rate that kept reflux. The reaction mixture was refluxed for another 5 hours, and cooled to room temperature. Stirring was stopped to allow solid sedimentation. The supernatant was injected into a solution of tert-butyl ((7-bromo-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)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 under nitrogen for 16 hours. The mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo, and the filter cake was rinsed with EtOAc (200 mL). The combined filtrates were concentrated in vacuo. 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.

[0181] Step 8: 1-(4-(((tert-Butyloxycarbonyl)amino)methyl)-1-oxo-1,2-dihydrophthalazin-6-yl)cyclopropane 1-Hydroxy-1-oxo-1-ol

[0182]

[0183] 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) was added LiOH (2.6 g, 62 mol). The mixture was stirred at 60 °C for 16 hours and cooled to room temperature. The reaction mixture was cooled to room temperature, concentrated in vacuo, diluted into 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 in vacuo to give the title compound (4.0 g, 54%). 1H NMR(500MHz,DMSO-d6)δ12.53(s,2H),8.23-8.14(m,1H),7.99-7.76(m,2H),7.46-7.3 4(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.

[0184] Step 9: N-((5-(Trifluoromethyl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine

[0185]

[0186] To a solution of 5,6,7,8-tetrahydroquinolin-8-amine (0.30 g, 2.02 mmol) in MeOH (5 mL) was added 5-(trifluoromethyl)picolinaldehyde (354 mg, 2.02 mmol), AcOH (12 mg, 0.202 mmol) under stirring at 15° C. 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 (400MHz, CDCl3) δ8.84(s,1H),8.43(d,J=4.0Hz,1H),7.89(dd,J=8.4,2.2Hz,1H),7.63(d,J=8.0Hz,1H),7.40(d,J=8.0Hz,1H),7. 10(dd,J=8.4,4.8Hz,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.

[0187] Step 10: ((4-oxo-7-(1-((5,6,7,8-tetrahydroquinolin-8-yl)((5-(trifluoromethyl)pyridin-2-yl) tert-Butyl)methyl)carbamoyl)cyclopropyl)-3,4-dihydrophthalazin-1-yl)methyl)carbamate

[0188]

[0189] 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) was added HATU (64 mg, 0.17 mmol), N-((5-(trifluoromethyl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine (51.7 mg, 0.17 mmol) and DIPEA (39.5 mg, 0.31 mmol). 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 in vacuo. 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.

[0190] Step 11: 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

[0191] To a solution of tert-butyl ((4-oxo-7-(l-((5,6,7,8-tetrahydroquinolin-8-yl)((5-(trifluoromethyl)pyridin-2-yl)methyl)carbamoyl)cyclopropyl)-3,4-dihydrophthalazin-l-yl)methyl)carbamate (43 mg, 0.07 mmol) in DCM (4 mL) was added TFA (1 mL). The mixture was stirred at room temperature for 1 hour and then concentrated in vacuo. The residue was purified by preparative HPLC to give Example 1 (20 mg, 55%). 1 H NMR(500MHz,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,1 H),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.

[0192] Examples 2A and 2B: (R)-1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-(5,6,7,8-tetrahydroquinolin-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-tetrahydroquinolin-8-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)cyclopropane-1-carboxamide

[0193]

[0194] 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: 4.6X50 mm, 3 μm; Mobile phase: (hexane: DCM = 3: 1, containing 0.1% diethylamine): EtOH = 70: 30; Flow rate: 1 mL / min; Temperature: 25°C.

[0195] Example 2A: Chiral HPLC R =3.29min. 1 H NMR(500MHz,DMSO)δ12.79-12.42(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

[0196] Example 2B: Chiral HPLC R =4.05min. 1H NMR (500MHz, DMSO) δ12.55-12.33(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.

[0197] 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-tetrahydroquinolin-8-yl)cyclopropane-1-carboxamide

[0198]

[0199] Step 1: tert-Butyl ((5-(2,6-dichlorophenyl)pyridin-2-yl)methyl)carbamate

[0200]

[0201] Under nitrogen, K3PO4 (33.3 g, 157 mmol) and Pd(dppf)Cl2 (4.59 g, 6.27 mmol) were added to a solution of tert-butyl ((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 x 3). The combined organic layers were washed with brine (50 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE: EtOAc = 1: 0 to 5: 1) to give the title compound (9.0 g, 41%). LC-MS (M+H) + =353.1.

[0202] Step 2: (5-(2,6-dichlorophenyl)pyridin-2-yl)methanamine

[0203]

[0204] A mixture of tert-butyl ((5-(2,6-dichlorophenyl)pyridin-2-yl)methyl)carbamate (9.0 g, 25.5 mmol) in methanolic HCl (4 M, 90 mL) was stirred at 25 ° C for 1 hour, and then the mixture was neutralized to pH 7 with methanolic NaOH (1 M). The mixture was concentrated to dryness under reduced pressure, and the residue was triturated with DCM / MeOH (10 / 1, 10 mL). The filtrate was collected by filtration and concentrated in vacuo to give the title compound (6.0 g, 93%). 1 H NMR (400MHz, CDCl3) δ8.45 (s, 1H), 7.66-7.58 (m, 1H), 7.54 (d, J = 8.0Hz, 1H), 7.38 (d, J = 8.0Hz, 2H), 7.30-7.24 (m, 1H), 4.58 (s, 2H).

[0205] Step 3: N-((5-(2,6-dichlorophenyl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine

[0206]

[0207] To a solution of (5-(2,6-dichlorophenyl)pyridin-2-yl)methanamine (10.8 g, 42.8 mmol) and 6,7-dihydroquinolin-8(5H)-one (7.0 g, 47.6 mmol) in DCM (140 mL) and MeOH (1.4 mL) was added NaBH(OAc)3 (18.1 g, 85.6 mmol). 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 in vacuo. 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 (400MHz, CD3OD) δ8.43-8.35(m,2H),7.78-7.70(m,1H),7.66(d,J=8.0Hz,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=7.6,6.4Hz,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.

[0208] Step 4: ((7-(1-(((5-(2,6-dichlorophenyl)pyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinoline-8- tert-butyl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate

[0209]

[0210] 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) was added HATU (64 mg, 0.17 mmol), N-((5-(2,6-dichlorophenyl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine (64.3 mg, 0.17 mmol) and DIPEA (39.5 mg, 0.31 mmol). The mixture was stirred at 50 °C for 3 hours. The reaction 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 in vacuo. 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.

[0211] Step 5: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-((5-(2,6-dichlorophenyl) Pyridin-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinolin-8-yl)cyclopropane-1-carboxamide

[0212] To a solution of tert-butyl ((7-(1-(((5-(2,6-dichlorophenyl)pyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinolin-8-yl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate (30 mg, 0.04 mmol) in DCM (4 mL) was added TFA (1 mL). The mixture was stirred at room temperature for 1 hour and then concentrated in vacuo. The residue was purified by preparative HPLC to give Example 3. 1 H NMR(500MHz,DMSO-d6)δ12.55-12.33(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,2 H),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.

[0213] 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-tetrahydroquinolin-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-tetrahydroquinolin-8-yl)cyclopropane-1-carboxamide

[0214]

[0215] Example 3 (21 mg) was separated by chiral preparative HPLC to give 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: 4.6X50 mm, 3 μm; Mobile phase: (hexane:DCM=3:1, containing 0.1% diethylamine): EtOH=50:50; Flow rate: 1 mL / min; Temperature: 25°C.

[0216] Example 4A: Chiral HPLC R =3.32min. 1 H NMR(500MHz,DMSO-d6)δ12.54-12.30(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,2 H),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.

[0217] Example 4B: Chiral HPLC R =5.38min. 1H NMR(500MHz,DMSO-d6)δ12.55-12.34(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,2 H),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.

[0218] Example 5: 1-(4-(Aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-((3,3-dimethyl-2,3-dihydrofuro[2,3-b]pyridin-6-yl)methyl)-N-(5,6,7,8-tetrahydroquinolin-8-yl)cyclopropane-1-carboxamide

[0219]

[0220] Step 1: 3-iodo-2-((2-methylallyl)oxy)pyridine

[0221]

[0222] Under nitrogen, at 25°C, 2-methylprop-2-ene-1-ol (4.5 g, 62.41 mmol) was added dropwise to a mixture of NaH (60%, 4.99 g, 125 mmol) in THF (450 mL). The mixture was stirred at 25°C for 10 min, followed by the addition of 2-fluoro-3-iodo-pyridine (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 in vacuo. 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 (400MHz, CDCl3) δ8.10 (dd, J=4.8, 1.6Hz, 1H), 8.04 (dd, J=7.6, 1.6Hz, 1H), 6.66 (d d,J=7.6,4.8Hz,1H),5.19-5.15(m,1H),5.00-4.96(m,1H),4.79(s,2H),1.88(s,3H).

[0223] Step 2: 3,3-Dimethyl-2,3-dihydrofuro[2,3-b]pyridine

[0224]

[0225] To a solution of 3-iodo-2-((2-methylallyl)oxy)pyridine (9.3 g, 33.8 mmol) in DMF (90 mL) was added HCOONa (2.30 g, 33.8 mmol), TBAC (9.40 g, 33.8 mmol), KCO (14.0 g, 101 mmol) and Pd(OAc) (759 mg, 3.38 mmol) under nitrogen. The mixture was warmed 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 in vacuo. 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 (400MHz, CDCl3) δ8.01 (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).

[0226] Step 3: 3,3-Dimethyl-2,3-dihydrofuro[2,3-b]pyridine 7-oxide

[0227]

[0228] To a solution of 3,3-dimethyl-2,3-dihydrofuran [2,3-b] pyridine (2.5 g, 16.76 mmol) in DCM (50 mL) was added mCPBA (85%, 5.10 g, 25.1 mmol) at 0 ° C. The mixture was stirred at 25 ° C for 12 hours 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 HNMR (400MHz, CDCl3) δ7.95 (dd, J = 6.6, 5.0Hz, 1H), 7.39-7.25 (m, 1H), 6.97-6.91 (m, 1H), 4.47 (s, 2H), 1.34 (s, 6H).

[0229] Step 4: 3,3-Dimethyl-2,3-dihydrofuro[2,3-b]pyridine-6-carbonitrile

[0230]

[0231] To a solution of 3,3-dimethyl-2,3-dihydrofuran [2,3-b] pyridine 7-oxide (1.0 g, 6.05 mmol) in acetonitrile (10 mL) was added TMSCN (5.28 g, 53.3 mmol) and triethylamine (1.96 g, 19.4 mmol). The mixture was stirred at 100 ° C for 1 hour. The mixture was cooled to room temperature and concentrated in vacuo. 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 (400MHz, DMSO-d6) δ7.88 (d, J = 7.2Hz, 1H), 4.36 (s, 2H), 1.34 (s, 6H).

[0232] Step 5: (3,3-Dimethyl-2,3-dihydrofuro[2,3-b]pyridin-6-yl)methanamine

[0233]

[0234] At 0 ° C, NaBH4 (347 mg, 9.18 mmol) was added in batches to a mixture of 3,3-dimethyl-2,3-dihydrofuran [2,3-b] pyridine-6-carbonitrile (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 warmed to 25 ° C and stirred for 2 hours. Saturated NH4Cl (1 mL) was added dropwise to the reaction mixture. After stopping the gas evolution, the mixture was concentrated under reduced pressure. The residue was ground in EtOAc and filtered. The filtrate was concentrated under reduced pressure to give a crude product of tert-butyl ((3,3-dimethyl-2,3-dihydrofuran [2,3-b] pyridin-6-yl) methyl) carbamate (0.70 g). To the crude product was added methanolic HCl (4M, 1 mL) and the mixture was stirred at 25 °C for 0.5 h. The mixture was concentrated in vacuo and the residue was redissolved in MeOH (1 mL). The mixture was neutralized to pH 7 with methanolic NaOH (1 M). The mixture was triturated in DCM (10 mL). The filtrate was collected by filtration and concentrated in vacuo to give the title compound (160 mg, 39%). LC-MS (M+H) + =179.3.

[0235] Step 6: N-((3,3-dimethyl-2,3-dihydrofuro[2,3-b]pyridin-6-yl)methyl)-5,6,7,8-tetrahydrofuro[2,3-b]pyridin-6-yl)methyl Hydroquinolin-8-amine trifluoroacetate

[0236]

[0237] To a solution of (3,3-dimethyl-2,3-dihydrofuro[2,3-b]pyridin-6-yl)methanamine (0.15 g, 0.84 mmol) and 6,7-dihydroquinolin-8(5H)-one (83 mg, 0.56 mmol) in DCM (2 mL) and MeOH (0.2 mL) at 25°C was added NaBH(OAc)3 (238 mg, 1.12 mmol). 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 in vacuo. The residue was purified by preparative HPLC to give the title compound (105 mg, 60%). LC-MS (M+H) + =310.0.

[0238] Step 7: ((7-(1-(((3,3-dimethyl-2,3-dihydrofuro[2,3-b]pyridin-6-yl)methyl)(5,6, tert-(7,8-tetrahydroquinolin-8-yl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamic acid Butyl Ester

[0239]

[0240] 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) was added HATU (35 mg, 0.09 mmol), N-((3,3-dimethyl-2,3-dihydrofuro[2,3-b]pyridin-6-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine trifluoroacetate (28 mg, 0.065 mmol) and DIPEA (21 mg, 0.17 mmol). 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 in vacuo. 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.

[0241] Step 8: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-((3,3-dimethyl-2,3-dihydrophthalazin-6-yl)- 6-Hydrofuro[2,3-b]pyridin-6-yl)methyl)-N-(5,6,7,8-tetrahydroquinolin-8-yl)

[0242] Cyclopropane-1-carboxamide

[0243] To a solution of tert-butyl ((7-(1-(((3,3-dimethyl-2,3-dihydrofuro[2,3-b]pyridin-6-yl)methyl)(5,6,7,8-tetrahydroquinolin-8-yl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate (20 mg, 0.03 mmol) in DCM (4 mL) was added TFA (1 mL). The mixture was stirred at room temperature for 1 hour and then concentrated in vacuo. The residue was purified by preparative HPLC to give Example 5 (10 mg, 60%); 1 HNMR(500MHz,DMSO-d6)δ12.65-12.20(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.

[0244] Example 6: 1-(4-(Aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-((5-(2-hydroxypropan-2-yl)pyridin-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinolin-8-yl)cyclopropane-1-carboxamide

[0245]

[0246] Step 1: 6-(((tert-Butyloxycarbonyl)amino)methyl)nicotinate

[0247]

[0248] To a solution of methyl 6-cyanonicotinate (5.0 g, 30.8 mmol) in MeOH (100 mL) was added Boc2O (13.5 g, 61.7 mmol) and Pd / C (10%, 0.50 g) under nitrogen at 25°C. The mixture was purged with hydrogen three times and stirred at 25°C for 12 hours under 15 psi of hydrogen. The mixture was filtered and the residue was rinsed 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 in vacuo. 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.

[0249] Step 2: tert-Butyl ((5-(2-hydroxypropan-2-yl)pyridin-2-yl)methyl)carbamate

[0250]

[0251] Under nitrogen, at 0°C, to a solution of MeMgBr in THF (3.0 M, 1.88 mL, 5.6 mmol) in THF (6 mL) was slowly added a solution of methyl 6-(((tert-butoxycarbonyl)amino)methyl)nicotinate (0.50 g, 1.88 mmol) in THF (4 mL). The mixture was stirred at 25°C for 12 hours, and aqueous 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 in vacuo. 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 (400MHz, DMSO-d6) δ8.58-8.55(m,1H),7.79(dd,J=8.0,2.4Hz,1H),7.17(d,J=8.0Hz 1H),5.16(s,1H),4.19(d,J=6.0Hz 1H),1.43(s,6H),1.40(s,9H).

[0252] Step 3: 2-(6-(((5,6,7,8-tetrahydroquinolin-8-yl)amino)methyl)pyridin-3-yl)propan-2-ol

[0253]

[0254] A solution of tert-butyl ((5-(2-hydroxypropan-2-yl)pyridin-2-yl)methyl)carbamate (0.30 g, 1.13 mmol) in methanolic HCl (4M, 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-dihydroquinolin-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 in vacuo. The residue was purified by preparative HPLC to give the title compound (72 mg, 40%). LC-MS (M+H) + =298.2.

[0255] Step 4: ((7-(1-(((5-(2-hydroxypropan-2-yl)pyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinoline-8- tert-butyl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate

[0256]

[0257] 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) was added HATU (35 mg, 0.09 mmol), 2-(6-(((5,6,7,8-tetrahydroquinolin-8-yl)amino)methyl)pyridin-3-yl)propan-2-ol (27.3 mg, 0.09 mmol) and DIPEA (21.5 mg, 0.17 mmol). 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 in vacuo. 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.

[0258] Step 5: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-((5-(2-hydroxypropan-2-yl) Pyridin-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinolin-8-yl)cyclopropane-1-carboxamide

[0259] To a solution of tert-butyl ((7-(1-(((5-(2-hydroxypropan-2-yl)pyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinolin-8-yl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate (20 mg, 0.03 mmol) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred at room temperature for 1 hour and then concentrated in vacuo. The residue was purified by preparative HPLC to give Example 6 (9 mg, 53%). 1 H NMR(500MHz,DMSO-d6)δ12.77-12.16(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.

[0260] 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-tetrahydroquinolin-8-yl)cyclopropane-1-carboxamide

[0261]

[0262] Step 1: 4-Methyl-5-(trifluoromethyl)picolinonitrile

[0263]

[0264] To a solution of 2-chloro-4-methyl-5-(trifluoromethyl)pyridine (500 mg, 2.56 mmol) in DMF (5 mL) was added Zn(CN)2 (1.20 g, 10.23 mmol) and Pd(PPh3)4 (295 mg, 0.26 mmol). The mixture was degassed and purged with nitrogen 3 times, then warmed to 80 ° C. After 3 hours, the mixture was cooled to room temperature, diluted with water (20 mL) and extracted with EtOAc (10 mL x3). 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%) LC-MS (M + H) + =187.2.

[0265] Step 2: tert-Butyl ((4-methyl-5-(trifluoromethyl)pyridin-2-yl)methyl)carbamate

[0266]

[0267] At 0 ° C, to 4-methyl-5-(trifluoromethyl) pyridine carbonitrile (300mg, 1.61mmol), NiCl2(62mg, 0.48mmol) and Boc2O(704mg, 3.22mmol) in a mixture of MeOH (4.5mL) was added NaBH4(122mg, 3.22mmol). The mixture was warmed to 25 ° C and stirred for 2 hours. Water (10mL) was added, and the mixture was extracted with EtOAc (5mLx3). The combined organic layer was washed with brine (10mL), 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 obtain the title compound (300mg, 1.03mmol, 64% yield). 1H NMR (400MHz, CDCl3) δ8.71 (s, 1H), 7.22 (s, 1H), 5.53 (br s, 1H), 4.46 (d, J = 5.6Hz, 2H), 2.50 (s, 3H), 1.47 (s, 9H).

[0268] Step 3: N-((4-methyl-5-(trifluoromethyl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine

[0269]

[0270] The title compound (130 mg, 37%) was prepared in a manner analogous to Example 6, Step 3, from tert-butyl ((4-methyl-5-(trifluoromethyl)pyridin-2-yl)methyl)carbamate and 6,7-dihydroquinolin-8(5H)-one. LCMS (M+H) + =322.1.

[0271] Step 4: ((7-(1-(((4-methyl-5-(trifluoromethyl)pyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinoline- tert-butyl (8-yl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate

[0272]

[0273] The title compound (30 mg, 41%) was prepared in a manner analogous to step 4 of example 6 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-tetrahydroquinolin-8-amine. LCMS (M+H) + =663.4.

[0274] Step 5: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-((4-methyl-5-(trifluoromethyl)- 1-(4-(4-(5-(2-((4-((2-( ...

[0275] Example 7 (10 mg, 39%) was prepared in a manner analogous to Example 6, Step 5, from tert-butyl ((7-(1-(((4-methyl-5-(trifluoromethyl)pyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinolin-8-yl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate. 1H NMR(500MHz,DMSO-d6)δ12.54-12.34(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.

[0276] 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-tetrahydroquinolin-8-yl)cyclopropane-1-carboxamide

[0277]

[0278] Step 1: tert-Butyl ((6-methyl-5-phenylpyridin-2-yl)methyl)carbamate

[0279]

[0280] The title compound was prepared in a manner similar to step 2 of Example 7 from 6-methyl-5-phenylpyridinecarbonitrile (0.60 g, 49%). LCMS (M+H) + =299.2.

[0281] Step 2: N-((6-methyl-5-phenylpyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine

[0282]

[0283] The title compound (65 mg, 39%) was prepared in a manner similar to Example 6, step 3, from tert-butyl ((6-methyl-5-phenylpyridin-2-yl)methyl)carbamate and 6,7-dihydroquinolin-8(5H)-one. LCMS (M+H) + =330.2.

[0284] Step 3: ((7-(1-(((6-methyl-5-phenylpyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinolin-8-yl)amino tert-Butyl (4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate

[0285]

[0286] The title compound (20 mg, 35%) was prepared in a manner analogous to Example 6, Step 4, 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-tetrahydroquinolin-8-amine. LC-MS (M+H) + =671.4.

[0287] Step 4: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-((6-methyl-5-phenylpyrrolidone ... (2-pyridin-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinolin-8-yl)cyclopropane-1-carboxamide

[0288] Example 8 (8 mg, 47%) was prepared in a manner analogous to Example 6, Step 5, from tert-butyl ((7-(1-(((6-methyl-5-phenylpyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinolin-8-yl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate. 1 HNMR(400MHz,DMSO-d6)δ12.6-12.2(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,1 H),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.

[0289] 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

[0290]

[0291] Step 1: N-(2-chloro-6-fluorobenzyl)-1-(5-(trifluoromethyl)pyridin-2-yl)methanamine

[0292]

[0293] The title compound (90 mg, 43%) was prepared in a manner similar to Example 3, Step 3, from (5-(trifluoromethyl)pyridin-2-yl)methanamine and 2-chloro-6-fluorobenzaldehyde. LC-MS (M+H) + =319.1.

[0294] Step 2: ((7-(1-((2-chloro-6-fluorobenzyl)((5-(trifluoromethyl)pyridin-2-yl)methyl)carbamoyl) tert-Butyl (cyclopropyl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate

[0295]

[0296] The title compound (15 mg, 23%) was prepared in a manner similar to Example 6, step 4, 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)methanamine. LC-MS (M+H) + =660.4.

[0297] 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

[0298] Example 9 (6 mg, 47%) was prepared in a manner analogous to Example 6, Step 5, from tert-butyl ((7-(1-((2-chloro-6-fluorobenzyl)((5-(trifluoromethyl)pyridin-2-yl)methyl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate. 1 H NMR (400MHz, DMSO-d6) δ12.41(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.

[0299] Example 10: 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

[0300]

[0301] Step 1: tert-Butyl ((5-phenylpyridin-2-yl)methyl)carbamate

[0302]

[0303] The title compound (170 mg, 86%) was prepared in a manner similar to Example 3, Step 1, from tert-butyl ((5-bromopyridin-2-yl)methyl)carbamate and phenylboronic acid. LC-MS (M+H) + =285.1.

[0304] Step 2: N-((5-phenylpyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine

[0305]

[0306] The title compound (188 mg, 78%) was prepared in a manner similar to Example 6, Step 3 from tert-butyl ((5-phenylpyridin-2-yl)methyl)carbamate and 6,7-dihydroquinolin-8(5H)-one. LCMS (M+H) + =316.2.

[0307] Step 3: ((4-oxo-7-(1-(((5-phenylpyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinolin-8-yl)amino tert-Butyl (methyl)-(formyl)cyclopropyl)-3,4-dihydrophthalazin-1-yl)methyl)carbamate

[0308]

[0309] The title compound (30 mg, 46%) was prepared from N-((5-phenylpyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine and 1-(4-(((tert-butoxycarbonyl)amino)methyl)-1-oxo-1,2-dihydrophthalazin-6-yl)cyclopropane-1-carboxylic acid in a manner analogous to Example 6, Step 4. LC-MS (M+H)+=657.5.

[0310] 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

[0311] Example 10 (15 mg, 59%) was prepared in a manner analogous to Example 6, Step 5, from tert-butyl ((4-oxo-7-(1-(((5-phenylpyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinolin-8-yl)carbamoyl)cyclopropyl)-3,4-dihydrophthalazin-1-yl)methyl)amino. 1 H NMR (400MHz, DMSO-d6) δ12.55-12.32(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.

[0312] 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-tetrahydroquinolin-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-tetrahydroquinolin-8-yl)cyclopropane-1-carboxamide

[0313]

[0314] Example 10 (38 mg) was separated by chiral preparative HPLC to give 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: 4.6X50 mm, 3 μm; Mobile phase: (hexane:DCM=1:1, containing 0.1% diethylamine): EtOH=50:50; Flow rate: 1 mL / min; Temperature: 25°C.

[0315] Example 11A: Chiral HPLC R =2.71min. 1 H NMR(400MHz,DMSO-d6)δ12.55-12.30(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.

[0316] Example 11B: Chiral HPLC R =5.90min. 1 H NMR(400MHz,DMSO-d6)δ12.55-12.30(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.

[0317] Example 12: 1-(4-(Aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-((5-iodo-4-methylthiazol-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinolin-8-yl)cyclopropane-1-carboxamide

[0318]

[0319] Step 1: 2-(1,3-dioxolan-2-yl)-4-methylthiazole

[0320]

[0321] To a solution of 4-methylthiazole-2-carboxaldehyde (1.0 g, 7.86 mmol) in toluene (10 mL) was added ethylene glycol (1.46 g, 23.6 mmol) and TsOH monohydrate (449 mg, 2.36 mmol), and the mixture was stirred at 110 ° C for 12 hours. 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 (400MHz, CDCl3) δ6.92(s,1H),6.12(s,1H),4.20-4.03(m,4H),2.47(s,3H).

[0322] Step 2: 2-(1,3-dioxolan-2-yl)-5-iodo-4-methylthiazole

[0323]

[0324] At -78 ° C, n-BuLi (2.5M, 2.34mL, 4.58mmol) was added dropwise to a solution of 2-(1,3-dioxolane-2-yl)-4-methylthiazole (1.0g, 5.84mmol) in anhydrous THF (30mL), followed by I2 (1.48g, 5.84mmol). The mixture was stirred at -78 ° C for 2 hours, then quenched with saturated NH4Cl (30mL), warmed to room temperature, and then extracted with EtOAc (20mL x 3). The combined organic layers were washed with brine (10mL 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 (1.0g, 58%). 1 H NMR (400MHz, CDCl3) δ6.09 (s, 1H), 4.15-4.05 (m, 4H), 2.47 (s, 3H).

[0325] Step 3: 5-iodo-4-methylthiazole-2-carbaldehyde

[0326]

[0327] 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 hours. The mixture was cooled to room temperature and neutralized with saturated NaHCO3 solution until its pH value became 7. The mixture was extracted with DCM (5 mL x 5). The combined organic layer was washed with brine (10 mL) and concentrated in vacuo. The residue was purified by silica gel chromatography (PE / EtOAc=1 / 0 to 10 / 1) to obtain the title compound (0.50 g, 59%). 1 H NMR (400MHz, CDCl3) δ9.85 (s, 1H), 2.58 (s, 3H).

[0328] Step 4: N-((5-iodo-4-methylthiazol-2-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine

[0329]

[0330] To a solution of 5,6,7,8-tetrahydroquinolin-8-amine (150 mg, 1.01 mmol) and 5-iodo-4-methylthiazole-2-carbaldehyde (171 mg, 0.67 mmol) in DCM (2 mL) and MeOH (0.2 mL) at 25°C was added NaBH(OAc)3 (286 mg, 1.35 mmol). The mixture was stirred at 25°C for 0.5 h and then washed with aqueous NaHCO3 solution (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 in vacuo. The residue was purified by preparative HPLC to give the title compound (31 mg, 12%). LC-MS (M+H) + =386.0.

[0331] Step 5: ((7-(1-(((5-iodo-4-methylthiazol-2-yl)methyl)(5,6,7,8-tetrahydroquinolin-8-yl)amino tert-Butyl (4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate

[0332]

[0333] The title compound (30 mg, 51%) was prepared in a manner analogous to Example 6, Step 4, from 1-(4-(((tert-butoxycarbonyl)amino)methyl)-1-oxo-1,2-dihydrophthalazin-6-yl)cyclopropane-1-carboxylic acid and N-((5-iodo-4-methylthiazol-2-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine. LC-MS (M+H) + =727.1.

[0334] Step 6: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-((5-iodo-4-methylthiazole- 2-yl)methyl)-N-(5,6,7,8-tetrahydroquinolin-8-yl)cyclopropane-1-carboxamide

[0335] Example 12 (8 mg, 32%) was prepared in a manner analogous to Example 6, Step 5, from tert-butyl ((7-(1-(((5-iodo-4-methylthiazol-2-yl)methyl)(5,6,7,8-tetrahydroquinolin-8-yl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate. 1 HNMR(500MHz,DMSO-d6)δ12.60(s,1H),8.35(d,J=4.4Hz,1H),8.21(q,J=5.8Hz,2H),7.89– 7.82(m,2H),7.51(d,J=7.5Hz,1H),7.21(dd,J=7.6,4.7Hz,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=7.1Hz,1H),0.97-0.94(m,1H). LC-MS(M+H) + =627.1.

[0336] 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-tetrahydroquinolin-8-yl)cyclopropane-1-carboxamide

[0337]

[0338] Step 1: tert-Butyl ((5-(2-chloro-6-cyanophenyl)pyridin-2-yl)methyl)carbamate

[0339]

[0340] To a solution of tert-butyl ((5-bromopyridin-2-yl)methyl)carbamate (1.0 g, 3.48 mmol) in dioxane (10 mL) under nitrogen was added BPD (884 mg, 3.48 mmol), KOAc (854 mg, 8.71 mmol) and Pd(dppf)Cl2 (255 mg, 0.35 mmol). The mixture was stirred at 85°C for 16 hours, cooled to room temperature and filtered. The filtrate was concentrated to give a crude product (2.0 g). One quarter of the crude product (0.50 g), 3-chloro-2-iodobenzonitrile (418 mg, 1.59 mmol) were 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 in vacuo. 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.

[0341] Step 2: 3-Chloro-2-(6-(((5,6,7,8-tetrahydroquinolin-8-yl)amino)methyl)pyridin-3-yl)benzonitrile

[0342]

[0343] The title compound (90 mg, 53%) was prepared in a manner similar to Example 6, step 3, from tert-butyl ((5-(2-chloro-6-cyanophenyl)pyridin-2-yl)methyl)carbamate and 6,7-dihydroquinolin-8(5H)-one. LC-MS (M+H) + =375.1.

[0344] Step 3: ((7-(1-(((5-(2-chloro-6-cyanophenyl)pyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinoline- tert-butyl (8-yl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate

[0345]

[0346] The title compound (30 mg, 83%) was prepared in a manner analogous to Example 6, step 4, 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-tetrahydroquinolin-8-yl)amino)methyl)pyridin-3-yl)benzonitrile. LC-MS (M+H) + =716.2.

[0347] Step 4: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-((5-(2-chloro-6-cyanobenzene 1-(4-(4-(5-(2-((4-((2-( ...

[0348] Example 13 (8 mg, 32%) was prepared in a manner analogous to Example 6, Step 5, from tert-butyl ((7-(1-(((5-(2-chloro-6-cyanophenyl)pyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinolin-8-yl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate. 1 H NMR (500MHz, DMSO-d6) δ12.64(s,1H),8.59(d,J=1.6Hz,1H),8.43(d,J=4.2Hz,1H),8.28-8.22(m,1 H),8.03–7.87(m,5H),7.70–7.61(m,1H),7.50(t,J=8.4Hz,1H),7.39(d,J=8.1Hz,1H),7.24-7.19(m ,1H),5.56(dd,J=10.7,6.0Hz,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=4.8Hz,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.

[0349] 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-tetrahydroquinolin-8-yl)cyclopropane-1-carboxamide

[0350]

[0351] Step 1: 5-(tert-Butyl)-N-methoxy-N-methylpicolinamide

[0352]

[0353] A mixture of 5-tert-butylpyridine-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 under nitrogen for 12 hours. 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.

[0354] Step 2: 5-(tert-Butyl)pyridinecarboxaldehyde

[0355]

[0356] At -78 ° C, DIBAL-H (1.0M, 0.45mL, 0.45mmol) was added to a solution of 5-(tert-butyl)-N-methoxy-N-methylpicolinamide (100mg, 0.45mmol) in anhydrous THF (2mL). The mixture was stirred at -78 ° C for 2 hours, then quenched with saturated Rochelle salt (5mL), warmed to 20 ° C and stirred for 1 hour. The mixture was extracted with EtOAc (5mLx 3). The combined organic layer was washed with brine (10mL), 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 obtain the title compound (50mg, 68%). 1 H NMR (400MHz, CDCl3) δ10.08 (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).

[0357] Step 3: N-((5-(tert-butyl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine

[0358]

[0359] The title compound (84 mg, 71%) was prepared in a manner similar to Example 12, Step 4, from 5,6,7,8-tetrahydroquinolin-8-amine and 5-(tert-butyl)picolinaldehyde. LC-MS (M+H) + =296.3.

[0360] Step 4: ((7-(1-(((5-(tert-butyl)pyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinolin-8-yl)amino tert-Butyl (4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate

[0361]

[0362] 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-tetrahydroquinolin-8-amine in a manner analogous to Example 6, Step 4. LC-MS (M+H)+=637.2.

[0363] Step 5: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-((5-(tert-butyl)pyridine-2-yl)- 1-((5,6,7,8-tetrahydroquinolin-8-yl)methyl)cyclopropane-1-carboxamide

[0364] Example 14 (36 mg, 85%) was prepared in a manner analogous to Example 6, Step 5, from tert-butyl ((7-(1-(((5-(tert-butyl)pyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinolin-8-yl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate. 1 HNMR(500MHz,DMSO-d6)δ12.95-12.84(m,1H),8.58–8.32(m,5H),8.09-8.04(m,1H),7.87–7.76(m,1H),7.51(d,J=8.9Hz,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.

[0365] Example 15: 1-(4-(Aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-((4-bromoisoquinolin-1-yl)methyl)-N-(5,6,7,8-tetrahydroquinolin-8-yl)cyclopropane-1-carboxamide

[0366]

[0367] Step 1: 4-Bromoisoquinoline 2-oxide

[0368]

[0369] To a solution of 4-bromoisoquinoline (1.0 g, 4.81 mmol) in DCM (10 mL) at 0°C was added mCPBA (80%, 1.35 g, 6.25 mmol). The mixture was warmed to 25°C and stirred for 1 hour. The mixture was quenched by slowly adding 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 in vacuo. 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.

[0370] Step 2: 4-Bromoisoquinoline-1-carbonitrile

[0371]

[0372] To a solution of 4-bromoisoquinoline 2-oxide (900 mg, 4.02 mmol) and TMSCN (438 mg, 4.42 mmol) in THF (27 mL) was added DBU (1.37 g, 9.00 mmol). The mixture was stirred at 70 ° C for 0.5 hours, 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 (400MHz, CDCl3) δ8.86 (s, 1H), 8.38 (d, J = 8.4Hz, 1H), 8.29 (d, J = 8.4Hz, 1H), 7.97 (t, J = 8.4Hz, 1H), 7.89 (t, J = 8.4Hz, 1H).

[0373] Step 3: (4-bromoisoquinolin-1-yl)methanamine

[0374]

[0375] Under Ar, Raney Ni (4 mg, 0.05 mmol) was added to the reaction flask, and AcOH (3 mL) was added. A solution of 4-bromoisoquinoline-1-carbonitrile (100 mg, 0.43 mmol) in AcOH (2 mL) was added. The suspension was degassed in vacuo and purged with hydrogen three times. 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.

[0376] Step 4: N-((4-bromoisoquinolin-1-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine

[0377]

[0378] The title compound (107 mg, 41%) was prepared in a manner similar to Example 3, Step 3, from (4-bromoisoquinolin-1-yl)methanamine and 6,7-dihydroquinolin-8(5H)-one. LC-MS (M+H) + =367.9.

[0379] Step 5: ((7-(1-(((4-bromoisoquinolin-1-yl)methyl)(5,6,7,8-tetrahydroquinolin-8-yl)carbamoyl tert-Butyl)-4-oxo-3,4-dihydrophthalazin-1-yl)-cyclopropyl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate

[0380]

[0381] 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-bromoisoquinolin-1-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine in a manner analogous to Example 6, Step 4. LC-MS (M+H)+=709.4.

[0382] Step 6: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-((4-bromoisoquinolin-1-yl) Methyl)-N-(5,6,7,8-tetrahydroquinolin-8-yl)cyclopropane-1-carboxamide

[0383] In a manner similar to step 5 of Example 6, ((7-(1-(((4-bromoisoquinolin-1-yl)methyl)(5,6,7,8- tert-Butyl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate To prepare Example 15 (5 mg, 29%). 1 H NMR(400MHz,DMSO-d6)δ12.5(s,1H),8.83(s,1H),8.44-8.35(m,2H),8.19-8.13(m,2H),7.97-7.56(m,4H),7.4 9-7.12(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.

[0384] 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-tetrahydroquinolin-8-yl)cyclopropane-1-carboxamide

[0385]

[0386] Step 1: tert-Butyl ((5-(1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)methyl)carbamate

[0387]

[0388] The title compound (150 mg, 36%) was prepared in a manner similar to Example 3, Step 1, from tert-butyl ((5-bromopyridin-2-yl)methyl)carbamate and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. LC-MS (M+H) + =289.3.

[0389] Step 2: N-((5-(1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinoline-8-yl) amine

[0390]

[0391] The title compound (104 mg, 44%) was prepared in a manner similar to Example 6, step 3, from tert-butyl ((5-(1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)methyl)carbamate and 6,7-dihydroquinolin-8(5H)-one. LC-MS (M+H) + =320.2.

[0392] Step 3: ((7-(1-(((5-(1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinoline (4-oxo-3,4-dihydrophthalazin-1-yl)methyl)

[0393] Tert-Butyl Carbamate

[0394]

[0395] The title compound (30 mg, 65%) was prepared in a manner analogous to Example 6, Step 4, 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-tetrahydroquinolin-8-amine. LC-MS (M+H) + =661.3.

[0396] Step 4: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-((5-(1-methyl-1H-pyrrolidone)- (5-oxazol-5-yl)pyridin-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinolin-8-yl)cyclopropane-1-carboxamide

[0397] Example 16 (8 mg, 17%) was prepared in a manner analogous to Example 6, Step 5, from tert-butyl ((7-(1-(((5-(1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinolin-8-yl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate. 1H NMR(500MHz,DMSO-d6)δ12.72(s,1H),8.68(d,J=1.9Hz,1H),8.43(d,J=3.0Hz,1H),8.33-8.25(m,2H),8.0 0–7.89(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.

[0398] Example 17: 1-(4-(Aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-(4-methoxy-5,6,7,8-tetrahydroquinolin-8-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)cyclopropane-1-carboxamide

[0399]

[0400] Step 1: 4-methoxy-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine

[0401]

[0402] The title compound (60 mg, 29%) was prepared in a manner similar to Example 3, Step 3, from (5-(trifluoromethyl)pyridin-2-yl)methanamine and 4-methoxy-6,7-dihydroquinolin-8(5H)-one. LC-MS (M+H) + =338.1.

[0403] Step 2: ((7-(1-((4-methoxy-5,6,7,8-tetrahydroquinolin-8-yl)((5-(trifluoromethyl)pyridine-2- 1-yl)methyl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)

[0404] Tert-Butyl Carbamate

[0405]

[0406] The title compound (30 mg, 71%) was prepared in a manner analogous to Example 6, Step 4, 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-tetrahydroquinolin-8-amine. LC-MS (M+H) + =679.3.

[0407] Step 3: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-(4-methoxy-5,6,7,8- Tetrahydroquinolin-8-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)cyclopropane-1-carboxamide

[0408] Example 17 (13 mg, 51%) was prepared in a manner analogous to Example 6, Step 5, from tert-butyl ((7-(1-((4-methoxy-5,6,7,8-tetrahydroquinolin-8-yl)((5-(trifluoromethyl)pyridin-2-yl)methyl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate. 1 H NMR (500MHz, DMSO-d6) δ12.98–12.58(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,1 H),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).

[0409] 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-tetrahydroquinolin-8-yl)cyclopropane-1-carboxamide

[0410]

[0411] Step 1: tert-Butyl ((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)carbamate

[0412]

[0413] To a solution of tert-butyl ((5-bromopyridin-2-yl)methyl)carbamate (5.0 g, 17.4 mmol) in dioxane (50 mL) was added BPD (5.31 g, 20.9 mmol), Pd(dppf)Cl2 (1.27 g, 1.74 mmol) and KOAc (4.27 g, 43.5 mmol). 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 product 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 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 5: 1) to give the title compound (3.0 g, 54%). 1 H NMR (400MHz, CDCl3) δ8.64(s,1H),7.78(d,J=8.4Hz,1H),7.39(d,J=8.4Hz,1H),7.36-7.28(m,1H),7.06-6.96(m,1H),5.62(br s, 1H), 4.50 (d, J = 5.6Hz, 2H), 7.47 (s, 9H). LC-MS(M+H) + =321.1.

[0414] Step 2: (5-(2,6-difluorophenyl)pyridin-2-yl)methanamine

[0415]

[0416] A mixture of tert-butyl ((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)carbamate (3.0 g, 9.37 mmol) in methanolic HCl (4 M, 50 mL) was stirred at 25 ° C for 2 hours, and then the mixture was neutralized to pH 7 with methanolic NaOH (1 M). The mixture was concentrated to dryness under reduced pressure, and the residue was triturated with DCM / MeOH (10 / 1, 10 mL). The filtrate was collected by filtration and concentrated in vacuo to give the title compound (1.5 g, 73%). 1H NMR (400MHz, CD3OD) δ8.72(s,1H),7.97(d,J=6.0Hz,1H),7.60(d,J=6.0Hz,1H),7.54-7.45(m,1H),7.20-7.10(m,1H),4.37(s,2H). LC-MS(M+H) + =221.1.

[0417] Step 3: N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine

[0418]

[0419] To a solution of 6,7-dihydroquinolin-8(5H)-one (0.25 g, 1.70 mmol) and (5-(2,6-difluorophenyl)pyridin-2-yl)methanamine (449 mg, 2.04 mmol) in DCM (4 mL) and MeOH (0.4 mL) was added NaBH(OAc)3 (720 mg, 3.40 mmol). The mixture was stirred at 25 °C for 2 hours and 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 in vacuo. The residue was purified by preparative HPLC to give the title compound (176 mg, 30%). LC-MS (M+H) + =352.1.

[0420] Step 4: ((7-(1-(((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinoline-8- tert-butyl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate

[0421]

[0422] 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) was added HATU (180 mg, 0.47 mmol), N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine (166 mg, 0.47 mmol) and DIPEA (111 mg, 0.86 mmol). The solution was stirred at 50 °C for 6 hours. The mixture was cooled to room temperature, poured into 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 in vacuo. 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.

[0423] Step 5: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-((5-(2,6-difluorophenyl) Pyridin-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinolin-8-yl)cyclopropane-1-carboxamide

[0424] To a solution of tert-butyl ((7-(1-(((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinolin-8-yl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate (200 mg, 0.29 mmol) in DCM (4 mL) was added TFA (1 mL). The mixture was stirred at room temperature for 1 hour and then concentrated in vacuo. The residue was purified by preparative HPLC to give Example 18 (149 mg, 87%). 1 H NMR(500MHz,DMSO-d6)δ13.05–12.73(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).

[0425] 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-tetrahydroquinolin-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-tetrahydroquinolin-8-yl)cyclopropane-1-carboxamide

[0426]

[0427] Example 18 (146 mg) was separated by chiral preparative HPLC to give 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: 4.6X50 mm, 3 μm; Mobile phase: (hexane:DCM=1:1, containing 0.1% diethylamine): EtOH=75:25; Flow rate: 1 mL / min; Temperature: 25°C.

[0428] Example 19A: Chiral HPLC R =2.97min. 1H NMR(500MHz,DMSO-d6)δ12.83-12.42(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,4 H),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;

[0429] Example 19B: Chiral HPLC R =4.13min. 1 H NMR(500MHz,DMSO-d6)δ12.83-12.42(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,4 H),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.

[0430] Example 20: 1-(4-(Aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-((5-phenoxypyridin-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinolin-8-yl)cyclopropane-1-carboxamide

[0431]

[0432] Step 1: 5-Phenoxypyridinecarboxaldehyde

[0433]

[0434] To a solution of 5-fluoropyridinecarboxaldehyde (0.20 g, 1.60 mmol) in DMF (2 mL) at room temperature, phenol (181 mg, 1.92 mmol) and K2CO3 (663 mg, 4.80 mmol) were added. The mixture was heated to 110 ° C and stirred for 1 hour. The mixture was cooled to room temperature and distributed between EtOAc (80 mL) and water (40 mL). The organic phase was separated, dried over Na2SO4, filtered and concentrated in vacuo. 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.

[0435] Step 2: N-((5-phenoxypyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine

[0436]

[0437] The title compound (316 mg, 70%) was prepared in a manner similar to Example 12, Step 4, from 5,6,7,8-tetrahydroquinolin-8-amine and 5-phenoxypicolinaldehyde. LC-MS (M+H) + =332.2.

[0438] Step 3: ((4-oxo-7-(1-(((5-phenoxypyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinolin-8-yl) tert-Butyl)carbamoyl)cyclopropyl)-3,4-dihydrophthalazin-1-yl)methyl)carbamate

[0439]

[0440] The title compound (10 mg, 24%) was prepared in a manner analogous to Example 6, Step 4, 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-tetrahydroquinolin-8-amine. LC-MS (M+H) + =673.4.

[0441] Step 4: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-((5-phenoxypyridine-2-yl)- 1-((5,6,7,8-tetrahydroquinolin-8-yl)methyl)cyclopropane-1-carboxamide

[0442] Example 20 (2 mg, 23%) was prepared in a manner analogous to Example 6, Step 4, from tert-butyl ((4-oxo-7-(1-(((5-phenoxypyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinolin-8-yl)carbamoyl)cyclopropyl)-3,4-dihydrophthalazin-1-yl)methyl)carbamate. 1H NMR(500MHz,DMSO-d6)δ12.60–12.37(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,3 H),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.

[0443] 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-tetrahydronaphthalen-1-yl)cyclopropane-1-carboxamide

[0444]

[0445] Step 1: N-((5-bromopyridin-2-yl)methyl)-8-fluoro-1,2,3,4-tetrahydronaphthalen-1-amine

[0446]

[0447] To a solution of 8-fluoro-3,4-dihydronaphthalen-1(2H)-one (100 mg, 0.61 mmol) and (5-bromopyridin-2-yl)methanamine (125 mg, 0.67 mmol) in dioxane (3 mL) was added Ti(OEt)4 (695 mg, 3.05 mmol). The mixture was warmed 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.

[0448] Step 2: N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-8-fluoro-1,2,3,4-tetrahydronaphthalen-1-amine

[0449]

[0450] The title compound (26 mg, 47%) was prepared in a manner similar to Example 3, Step 1, from N-((5-bromopyridin-2-yl)methyl)-8-fluoro-1,2,3,4-tetrahydronaphthalen-1-amine and (2,6-difluorophenyl)boronic acid. LC-MS (M+H) + =369.1.

[0451] Step 3: ((7-(1-(((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)(8-fluoro-1,2,3,4-tetrahydronaphthalene- tert-butyl tert-butyl ester

[0452]

[0453] The title compound (7 mg, 18%) was prepared in a manner analogous to step 4 of Example 6 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-tetrahydronaphthalen-1-amine. LC-MS (M+H) + =710.4.

[0454] Step 4: 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-tetrahydronaphthalen-1-yl)cyclopropane-1-carboxamide

[0455] Example 21 (1 mg, 17%) was prepared in a manner analogous to Example 6, Step 4, from tert-butyl ((7-(1-(((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)(8-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate. 1 H NMR(500MHz,DMSO-d6)δ12.77–12.30(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.

[0456] Example 22: 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

[0457]

[0458] Step 1: N-(4-bromo-2-fluorobenzyl)-5,6,7,8-tetrahydroquinolin-8-amine

[0459]

[0460] The title compound (74 mg, 33%) was prepared in a manner similar to Example 12, Step 4, from 5,6,7,8-tetrahydroquinolin-8-amine and 4-bromo-2-fluorobenzaldehyde. LC-MS (M+H) + =335.0.

[0461] Step 2: ((7-(1-((4-bromo-2-fluorobenzyl)(5,6,7,8-tetrahydroquinolin-8-yl)carbamoyl)cyclopropane tert-Butyl (4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate

[0462]

[0463] The title compound (30 mg, 44%) was prepared in a manner analogous to Example 6, Step 4, 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-tetrahydroquinolin-8-amine. LC-MS (M+H) + =676.4.

[0464] 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

[0465] Example 22 (8 mg, 31%) was prepared in a manner analogous to Example 6, Step 4, from tert-butyl ((7-(1-((4-bromo-2-fluorobenzyl)(5,6,7,8-tetrahydroquinolin-8-yl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate. 1 H NMR(400MHz,DMSO-d6)δ12.45(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.

[0466] 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-tetrahydroquinolin-8-yl)cyclopropane-1-carboxamide

[0467]

[0468] Step 1: N-((5-bromopyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine

[0469]

[0470] The title compound (3.0 g, 50%) was prepared in a manner similar to Example 18, Step 3, from 6,7-dihydroquinolin-8(5H)-one and (5-bromopyridin-2-yl)methanamine. LC-MS (M+H) + =318.1.

[0471] 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-tetrahydroquinolin-8-amine

[0472]

[0473] The title compound (104 mg, 26%) was prepared in a manner similar to Example 3, Step 1 from N-((5-bromopyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine and 3,5-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. LC-MS (M+H) + =418.2.

[0474] Step 3: ((7-(1-(((5-(3,5-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyrrolidone (2-pyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinolin-8-yl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazine-1- tert-Butyl)methyl)carbamate

[0475]

[0476] The title compound (30 mg, 48%) was prepared in a manner analogous to step 4 of Example 6 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-tetrahydroquinolin-8-amine. LC-MS (M+H) + =759.1.

[0477] Step 4: 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-tetrahydroquinolin-8-yl)cyclopropane-1-carboxamide

[0478] Example 23 (16 mg, 70%) was prepared in a manner analogous to Example 6, Step 4, from tert-butyl ((7-(1-(((5-(3,5-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinolin-8-yl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate. 1 H NMR(500MHz,DMSO-d6)δ12.58-12.26(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,2 H),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.

[0479] Example 24: (±)-4-(aminomethyl)-6-(1-((2S,6S)-2-methyl-6-(5-(trifluoromethyl)pyridin-2-yl)piperidine-1-carbonyl)cyclopropyl)phthalazin-1(2H)-one

[0480]

[0481] Step 1: tert-Butyl 2-methyl-6-(5-(trifluoromethyl)pyridin-2-yl)piperidine-1-carboxylate

[0482]

[0483] Four identical reactions as described below were set up in parallel. A mixture of 2-chloro-5-(trifluoromethyl)pyridine (75 mg, 0.41 mmol), 1-(tert-butoxycarbonyl)-6-methylpiperidine-2-carboxylic acid (100 mg, 0.41 mmol), nickel(II) chloride glycol dimethyl ether complex (9 mg, 0.041 mmol), Cs2CO3 (335 mg, 1.0 mmol), dtbbpy (17 mg, 0.062 mmol), bis[2-(2,4-difluorophenyl)-5-methylpyridine-N,C20]-4,40-di-tert-butyl-2,20-bipyridyliridium(III)hexafluorophosphate (4.2 mg, 0.004 mmol) in DMF (2 mL) was degassed and purged with nitrogen three times, and then the mixture was stirred under irradiation of a blue LED (34 W, 455 nm) for 12 h.

[0484] The mixtures from all four devices were combined, then 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.

[0485] Step 2: (±)-2-((2S,6S)-6-methylpiperidin-2-yl)-5-(trifluoromethyl)pyridine

[0486]

[0487] A solution of tert-butyl 2-methyl-6-(5-(trifluoromethyl)pyridin-2-yl)piperidine-1-carboxylate (100 mg, 0.29 mmol) in methanolic HCl (4M, 1 mL) was stirred at 25 °C for 0.5 h. The mixture was concentrated in vacuo and the residue was purified by preparative HPLC to give the title compound (12 mg, 17%). LC-MS (M+H) + =245.1.

[0488] Step 3: (±)-((7-(1-((2S,6S)-2-methyl-6-(5-(trifluoromethyl)pyridin-2-yl)piperidine-1-carbonyl)- tert-Butyl)-4-oxo-3,4-dihydrophthalazin-1-yl)-cyclopropyl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate

[0489]

[0490] The title compound (4 mg, 14%) was prepared in a manner analogous to step 4 of Example 6 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. LC-MS (M+H) + =586.2.

[0491] Step 4: (±)-4-(aminomethyl)-6-(1-((2S,6S)-2-methyl-6-(5-(trifluoromethyl)pyridine-2-yl)- (2H)-1-piperidine-1-carbonyl)cyclopropyl)phthalazin-1(2H)-one

[0492] Example 24 (0.7 mg, 21%) was prepared in a manner analogous to Example 6, Step 4, from tert-butyl (±)-((7-(1-((2S,6S)-2-methyl-6-(5-(trifluoromethyl)pyridin-2-yl)piperidine-1-carbonyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate. 1H NMR(500MHz,DMSO-d6)δ12.75–12.33(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,1 H),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.

[0493] 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

[0494]

[0495] Step 1: 5-(2,6-Difluorophenyl)picolinaldehyde

[0496]

[0497] Pd(dppf)Cl2(3.14g, 4.29mmol) and K3PO4(18.2g, 85.8mmol) were added to a mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridinecarboxaldehyde (20.0g, 85.8mmol) and 1,3-difluoro-2-iodobenzene (20.6g, 85.8mmol) in dioxane (100mL), toluene (50mL) and water (50mL). The mixture was stirred at 85°C for 16 hours. The mixture was cooled to room temperature and poured into water (100mL). The organic layer was separated and the aqueous phase was extracted with EtOAc (80mL x 2). The combined organic phase was washed with brine (50mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. 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.

[0498] Step 2: N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)cyclobutanamine

[0499]

[0500] The title compound (47 mg, 19%) was prepared in a manner similar to Example 12, Step 4 from 5-(2,6-difluorophenyl)picolinaldehyde and cyclobutylamine. LC-MS (M+H) + =275.1.

[0501] Step 3: ((7-(1-(cyclobutyl((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)carbamoyl)cyclopropane tert-Butyl (4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate

[0502]

[0503] The title compound (15 mg, 14%) was prepared in a manner similar to Example 6, step 4, 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)cyclobutanamine. LC-MS (M+H) + =615.3.

[0504] Step 4: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-cyclobutyl-N-((5-(2,6- difluorophenyl)pyridin-2-yl)methyl)cyclopropane-1-carboxamide

[0505] Example 25 (7 mg, 56%) was prepared in a manner similar to Example 6, Step 4, from tert-butyl ((7-(1-(cyclobutyl((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate. 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.

[0506] 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-tetrahydroquinolin-8-yl)cyclopropane-1-carboxamide

[0507]

[0508] Step 1: tert-Butyl ((5-(2-chloro-6-fluorophenyl)pyridin-2-yl)methyl)carbamate

[0509]

[0510] The title compound (180 mg, 69%) was prepared in a manner similar to Example 18, step 1, from tert-butyl ((5-bromopyridin-2-yl)methyl)carbamate and 1-chloro-3-fluoro-2-iodobenzene. LC-MS (M+H) + =337.2.

[0511] Step 2: N-((5-(2-chloro-6-fluorophenyl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine

[0512]

[0513] The title compound (60 mg, 29%) was prepared in a manner similar to Example 6, step 3, from tert-butyl ((5-(2-chloro-6-fluorophenyl)pyridin-2-yl)methyl)carbamate and 6,7-dihydroquinolin-8(5H)-one. LC-MS (M+H) + =368.1.

[0514] Step 3: ((7-(1-(((5-(2-chloro-6-fluorophenyl)pyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinoline-8- tert-butyl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate

[0515]

[0516] The title compound (30 mg, 38%) was prepared in a manner analogous to Example 6, Step 4, 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-tetrahydroquinolin-8-amine. LC-MS (M+H) + =709.4.

[0517] 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-tetrahydroquinolin-8-yl)cyclopropane-1-carboxamide

[0518] Example 26 (14 mg, 55%) was prepared in a manner analogous to Example 6, Step 5, from tert-butyl ((7-(1-(((5-(2-chloro-6-fluorophenyl)pyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinolin-8-yl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate. 1H NMR(400MHz,DMSO-d6)δ12.53-12.33(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.

[0519] Example 27: 1-(4-(Aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-((5-bromoquinolin-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinolin-8-yl)cyclopropane-1-carboxamide

[0520]

[0521] Step 1: tert-Butyl ((5-bromoquinolin-2-yl)methyl)carbamate

[0522]

[0523] The title compound (222 mg, 26%) was prepared in a manner similar to Example 7, Step 2, from 5-bromoquinoline-2-carbonitrile. LC-MS (M+H) + =337.2.

[0524] Step 2: N-((5-bromoquinolin-2-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine

[0525]

[0526] The title compound (50 mg, 16%) was prepared in a manner similar to Example 6, Step 3 from tert-butyl ((5-bromoquinolin-2-yl)methyl)carbamate and 6,7-dihydroquinolin-8(5H)-one. LC-MS (M+H) + =368.1.

[0527] Step 3: ((7-(1-(((5-bromoquinolin-2-yl)methyl)(5,6,7,8-tetrahydroquinolin-8-yl)carbamoyl) tert-Butyl (cyclopropyl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate

[0528]

[0529] The title compound (30 mg, 51%) was prepared in a manner analogous to step 4 of example 6 from 1-(4-(((tert-butoxycarbonyl)amino)methyl)-1-oxo-1,2-dihydrophthalazin-6-yl)cyclopropane-1-carboxylic acid and N-((5-bromoquinolin-2-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine. LC-MS (M+H) + =709.3.

[0530] Step 4: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-((5-bromoquinolin-2-yl)methyl yl)-N-(5,6,7,8-tetrahydroquinolin-8-yl)cyclopropane-1-carboxamide

[0531] Example 27 (7 mg, 27%) was prepared in a manner analogous to Example 6, Step 5, from tert-butyl ((7-(1-(((5-bromoquinolin-2-yl)methyl)(5,6,7,8-tetrahydroquinolin-8-yl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate. 1 H NMR(500MHz,DMSO-d6)δ12.55-12.2(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.

[0532] 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-tetrahydroquinolin-8-yl)cyclopropane-1-carboxamide

[0533]

[0534] Step 1: tert-Butyl ((5-(2-cyano-6-fluorophenyl)pyridin-2-yl)methyl)carbamate

[0535]

[0536] The title compound (308 mg, 77%) was prepared in a manner analogous to Example 18, step 1, from tert-butyl ((5-bromopyridin-2-yl)methyl)carbamate and 3-fluoro-2-iodobenzonitrile.1 HNMR(400MHz,DMSO-d6)δ8.65(s,1H),8.00(d,J=8.0Hz,1H),7.89(d,J=6.8Hz,1H),7.82-7.73(m,1H),7.73- 7.66(m,1H),7.56-7.50(m,1H),7.44(d,J=8.0Hz,1H),4.36-4.28(m,2H),4.50(d,J=5.6Hz,2H),1.40(s,9H).

[0537] Step 2: 3-Fluoro-2-(6-(((5,6,7,8-tetrahydroquinolin-8-yl)amino)methyl)pyridin-3-yl)benzonitrile

[0538]

[0539] The title compound (162 mg, 34%) was prepared in a manner similar to Example 6, step 3, from tert-butyl ((5-(2-cyano-6-fluorophenyl)pyridin-2-yl)methyl)carbamate and 6,7-dihydroquinolin-8(5H)-one. LC-MS (M+H) + =359.1.

[0540] Step 3: ((7-(1-(((5-(2-cyano-6-fluorophenyl)pyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinoline- tert-butyl (8-yl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate

[0541]

[0542] The title compound (30 mg, 38%) was prepared in a manner analogous to Example 6, step 4, 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-tetrahydroquinolin-8-yl)amino)methyl)pyridin-3-yl)benzonitrile. LC-MS (M+H) + =700.4.

[0543] Step 4: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-((5-(2-cyano-6-fluorophenyl)- 1-(4-(4-(5-(2-((4-((2-( ...

[0544] Example 28 (7 mg, 28%) was prepared in a manner analogous to Example 6, Step 5, from tert-butyl ((7-(1-(((5-(2-cyano-6-fluorophenyl)pyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinolin-8-yl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate and TFA. 1H NMR(500MHz,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=8.2Hz ,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.

[0545] 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

[0546]

[0547] Step 1: 1-(Pyrimidin-2-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)ethan-1-amine

[0548]

[0549] The title compound (5.0 g, 31%) was prepared in a manner similar to Example 3, Step 3, from (5-(trifluoromethyl)pyridin-2-yl)methanamine and 1-(pyrimidin-2-yl)ethan-1-one. LC-MS (M+H) + =283.1.

[0550] Step 2: ((4-oxo-7-(1-((1-(pyrimidin-2-yl)ethyl)((5-(trifluoromethyl)pyridin-2-yl)methyl) tert-Butyl)carbamoyl)cyclopropyl)-3,4-dihydrophthalazin-1-yl)methyl)carbamate

[0551]

[0552] The title compound (110 mg, 32%) was prepared in a manner similar to Example 6, Step 4, 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)ethan-1-amine. LC-MS (M+Na)+ =646.2.

[0553] Step 3: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-(1-(pyrimidin-2-yl)ethyl 1-((5-(trifluoromethyl)pyridin-2-yl)methyl)cyclopropane-1-carboxamide

[0554] Example 29 (31 mg, 37%) was prepared in a manner analogous to Example 6, Step 4, from tert-butyl ((4-oxo-7-(1-((1-(pyrimidin-2-yl)ethyl)((5-(trifluoromethyl)pyridin-2-yl)methyl)carbamoyl)cyclopropyl)-3,4-dihydrophthalazin-1-yl)methyl)carbamate. 1 HNMR(400MHz,DMSO-d6)δ12.89-12.76(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.

[0555] Example 30: 1-(4-(Aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-N-(1,3-dimethoxypropan-2-yl)cyclopropane-1-carboxamide

[0556]

[0557] Step 1: N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-1,3-dimethoxypropan-2-amine

[0558]

[0559] The title compound (0.20 g, 76%) was prepared in a manner analogous to Example 3, Step 3, from 1,3-dimethoxypropan-2-one and (5-(2,6-difluorophenyl)pyridin-2-yl)methanamine. 1 HNMR(400MHz,DMSO-d6)δ8.57(s,1H),7.87(d,J=8.4Hz,1H),7.60-7.48(m,2H),7.32-7 .22(m,2H),3.94(s,2H),3.34(d,J=5.6Hz,4H),3.24(s,6H),2.89(quin,J=5.6Hz,1H). LC-MS(M+H) + =323.2.

[0560] Step 2: ((7-(1-(((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)(1,3-dimethoxypropan-2-yl) tert-Butyl)-4-oxo-3,4-dihydrophthalazin-1-yl)-4-carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate

[0561]

[0562] The title compound (40 mg, 15%) was prepared in a manner similar to Example 6, step 4, 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-dimethoxypropan-2-amine. LC-MS (M+H) + =664.3.

[0563] Step 3: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-((5-(2,6-difluorophenyl) Pyridin-2-yl)methyl)-N-(1,3-dimethoxypropan-2-yl)cyclopropane-1-carboxamide

[0564] Example 30 (7 mg, 21%) was prepared in a manner analogous to Example 6, Step 5, from tert-butyl ((7-(1-(((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)(1,3-dimethoxypropan-2-yl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate. 1 H NMR (400MHz, CD3OD) δ8.70-8.40(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.

[0565] Example 31: (R)-1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-(4-(pentafluoro-λ 6 -sulfanyl)benzyl)-N-(5,6,7,8-tetrahydroquinolin-8-yl)cyclopropane-1-carboxamide

[0566]

[0567] Step 1: (R)-N-(4-(pentafluoro-λ 6 -sulfanyl)benzyl)-5,6,7,8-tetrahydroquinolin-8-amine

[0568]

[0569] In a manner similar to step 4 of Example 12, 4-(pentafluoro-λ 6The title compound (0.20 g, 55%) was prepared by mixing (R)-5,6,7,8-tetrahydroquinolin-8-amine with (R)-5,6,7,8-tetrahydroquinolin-8-amine. 1 H NMR (400MHz, DMSO-d6) δ8.36(d,J=4.4Hz,1H),7.84(d,J=8.8Hz,2H),7.62(d,J=8.8Hz,2H),7.50(d,J=7.6Hz,1H),7.18 (dd,J=7.6,4.4Hz,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.

[0570] Step 2: (R)-((4-oxo-7-(1-((4-(pentafluoro-λ 6 -sulfanyl)benzyl)(5,6,7,8-tetrahydroquinoline-8- tert-butyl)carbamoyl)cyclopropyl)-3,4-dihydrophthalazin-1-yl)methyl)carbamate

[0571]

[0572] In a manner similar to Example 6, Step 4, 1-(4-(((tert-butoxycarbonyl)amino)methyl)-1-oxo-1,2-dihydrophthalazin-6-yl)cyclopropane-1-carboxylic acid and (R)-N-(4-(pentafluoro-λ 6 The title compound (0.20 g, 57%) was prepared by adding 2-(4-(2-thio)-1-(4 ... + =706.2.

[0573] Step 3: (R)-1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-(4-(pentafluoro-λ 6 -sulfur alkyl)benzyl)-N-(5,6,7,8-tetrahydroquinolin-8-yl)cyclopropane-1-carboxamide

[0574] In a manner similar to that of Example 6, step 5, (R)-((4-oxo-7-(1-((4-(pentafluoro-λ 6 Example 31 (57 mg, 34%) was prepared from tert-butyl)(5,6,7,8-tetrahydroquinolin-8-yl)carbamoyl)cyclopropyl)-3,4-dihydrophthalazin-1-yl)methyl)carbamate. 1 HNMR(400MHz,CD3OD)δ8.47-8.18(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.

[0575] Example 32: 1-(4-(Aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-(4-cyclopropyl-5,6,7,8-tetrahydroquinolin-8-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)cyclopropane-1-carboxamide

[0576]

[0577] Step 1: 4-Methoxy-5,6,7,8-tetrahydroquinoline

[0578]

[0579] Under nitrogen, 4-methoxyquinoline (20g, 126mmol) was added to a solution of PtO2 (3.71g, 16.3mmol) in TFA (200mL). The suspension was degassed and purged with hydrogen 3 times. The mixture was stirred at 50°C for 3 hours under hydrogen (50psi). The filtrate was collected by filtration, concentrated to about 50mL, and diluted with water (100mL). The pH of the mixture was adjusted to 9 with an aqueous NaOH solution (1M). The mixture was extracted with DCM (50mL x 3). The combined organic layers were washed with brine (50mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the title compound (20g, 98%). 1 H NMR (400MHz, CD3OD) δ8.40(d,J=6.4Hz,1H),7.30(d,J=6.4Hz,1H),4.11(s,3H),2.96(t,J=6.2Hz,2H),2.71(t,J=6.2Hz,2H),1.96-1.83(m,4H). LCMS(M+H) + =164.2.

[0580] Step 2: 4-Bromo-5,6,7,8-tetrahydroquinoline

[0581]

[0582] To a solution of 4-methoxy-5,6,7,8-tetrahydroquinoline (17 g, 104 mmol) in DMF (170 mL) was added POBr3 (89.6 g, 312 mmol) at 0°C. 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 x 3). The combined organic layers were washed with brine (50 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE: EtOAc = 1: 0 to 5: 1) to give the title compound (15 g). LCMS (M+H)+ =212.1.

[0583] Step 3: 4-Bromo-5,6,7,8-tetrahydroquinoline 1-oxide

[0584]

[0585] To a solution of 4-bromo-5,6,7,8-tetrahydroquinoline (15 g, 70.7 mmol) in DCM (195 mL) was added mCPBA (80%, 30.5 g, 141 mmol). The mixture was stirred at 42 ° C for 2 hours and then cooled to room temperature. The mixture was washed with water (100 mL), and the aqueous phase was extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE: EtOAc = 1: 0 to 3: 1) to give the title compound (14 g, 87%). LCMS (M + H) + =228.2.

[0586] Step 4: 4-Bromo-5,6,7,8-tetrahydroquinolin-8-yl acetate

[0587]

[0588] 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 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.

[0589] Step 5: 4-Bromo-5,6,7,8-tetrahydroquinolin-8-ol

[0590]

[0591] Four identical reactions were set up in parallel as described below. To a solution of 4-bromo-5,6,7,8-tetrahydroquinolin-8-yl acetate (3.0 g, 11.1 mmol) in MeOH (15 mL) was added K2CO3 (5.8 g, 42.2 mmol). The mixture was stirred at 25°C for 2 hours.

[0592] The four batches of reaction mixture 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.

[0593] Step 6: 4-Bromo-6,7-dihydroquinolin-8(5H)-one

[0594]

[0595] To a solution of 4-bromo-5,6,7,8-tetrahydroquinolin-8-ol (5.0 g, 21.9 mmol) in DCM (260 mL) was added DMP (16.7 g, 39.5 mmol). 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.

[0596] Step 7: 4-Cyclopropyl-6,7-dihydroquinolin-8(5H)-one

[0597]

[0598] To a solution of 4-bromo-6,7-dihydroquinolin-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) was added SPhos (145 mg, 0.35 mmol), Pd(OAc)2 (99 mg, 0.44 mmol) and K3PO4 (2.35 g, 11.1 mmol). The mixture was stirred at 90 °C for 12 hours and cooled to room temperature. The mixture was diluted with water (10 mL) and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (15 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE:EtOAc=1:0 to 1:1) to give the title compound (0.20 g, 24%). LCMS (M+H) + =188.3.

[0599] Step 8: 4-Cyclopropyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine

[0600]

[0601] The title compound (0.20 g, 54%) was prepared in a manner similar to Example 3, Step 3, from 4-cyclopropyl-6,7-dihydroquinolin-8(5H)-one and (5-(trifluoromethyl)pyridin-2-yl)methanamine. LCMS (M+H) + =348.2.

[0602] Step 9: ((7-(1-((4-cyclopropyl-5,6,7,8-tetrahydroquinolin-8-yl)((5-(trifluoromethyl)pyridine-2- 1-yl)methyl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)

[0603] Tert-Butyl Carbamate

[0604]

[0605] The title compound (0.11 g, 50%) was prepared in a manner analogous to Example 6, Step 4, 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-tetrahydroquinolin-8-amine. LCMS (M+H) + =689.3.

[0606] Step 10: 1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-(4-cyclopropyl-5,6,7,8- Tetrahydroquinolin-8-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)cyclopropane-1-carboxamide

[0607] Example 32 (57 mg, 34%) was prepared in a manner analogous to Example 6, Step 5, from tert-butyl ((7-(1-((4-cyclopropyl-5,6,7,8-tetrahydroquinolin-8-yl)((5-(trifluoromethyl)pyridin-2-yl)methyl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate. 1 H NMR(400MHz,DMSO-d6)δ12.62-12.37(m,1H),8.95-8.56(m,1H),8.38-8.22(m,2H),8.2 0-7.77(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,1 H),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.

[0608] 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-cyclopenta[b]pyridin-7-yl)cyclopropane-1-carboxamide

[0609]

[0610] Step 1: N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine

[0611]

[0612] To a solution of 5-(2,6-difluorophenyl)picolinaldehyde (80 mg, 0.36 mmol) in DCM (10 mL) was added 6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine (49 mg, 0.36 mmol) and NaBH(OAc)3 (155 mg, 0.73 mmol). The solution was stirred at room temperature for 16 hours, poured into saturated NaHCO3 (50 mL), and then extracted with EtOAc (50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo. 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.

[0613] Step 2: tert-Butyl ((7-(1-(((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)(6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate

[0614]

[0615] 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-cyclopenta[b]pyridin-7-amine in a manner analogous to Example 6, Step 4. LC-MS (M+H)+=679.1.

[0616] Step 3: 1-(4-(Aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)-N-(6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl)cyclopropane-1-carboxamide

[0617] Example 33 (10 mg, 59%) was prepared in a manner analogous to Example 6, Step 5, from tert-butyl ((7-(1-(((5-(2,6-difluorophenyl)pyridin-2-yl)methyl)(6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate. 1H NMR(500MHz,DMSO-d6)δ12.68-12.28(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,4 H),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.

[0618] 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-tetrahydroquinolin-8-yl)cyclopropane-1-carboxamide

[0619]

[0620] Step 1: 5-(2,6-difluorophenoxy)picolinaldehyde

[0621]

[0622] The title compound (0.60 g, 64%) was prepared in a manner similar to Example 20, Step 1, from 5-fluoropicolinaldehyde and 2,6-difluorophenol. LCMS (M+H) + =236.2.

[0623] Step 2: (R)-N-((5-(2,6-difluorophenoxy)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine

[0624]

[0625] The title compound (0.13 g, 42%) was prepared in a manner similar to Example 12, Step 4, from (R)-5,6,7,8-tetrahydroquinolin-8-amine and 5-(2,6-difluorophenoxy)picolinaldehyde. LCMS (M+H) + =368.2.

[0626] Step 3: (R)-((7-(1-(((5-(2,6-difluorophenoxy)pyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinoline (4-oxo-3,4-dihydrophthalazin-1-yl)methyl)

[0627] Tert-Butyl Carbamate

[0628]

[0629] The title compound (0.10 g, 74%) was prepared in a manner analogous to Example 6, Step 4, 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-tetrahydroquinolin-8-amine. LCMS (M+H) + =709.4.

[0630] Step 4: (R)-1-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-((5-(2,6-difluorophenyl ... oxy)pyridin-2-yl)methyl)-N-(5,6,7,8-tetrahydroquinolin-8-yl)

[0631] Cyclopropane-1-carboxamide

[0632] Example 34 (25 mg, 29%) was prepared in a manner analogous to Example 6, Step 4, from (R)-tert-butyl ((7-(1-(((5-(2,6-difluorophenoxy)pyridin-2-yl)methyl)(5,6,7,8-tetrahydroquinolin-8-yl)carbamoyl)cyclopropyl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate. 1 H NMR(400MHz,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.

[0633] Example 35: 1-(4-(Aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-(5,6,7,8-tetrahydroquinolin-8-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)cyclobutane-1-carboxamide

[0634]

[0635] Step 1: 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)isobenzofuran-1(3H)-one

[0636]

[0637] A mixture of 5-bromoisobenzofuran-1(3H)-one (8.52 g, 40 mmol), BPD (13.2 g, 52.0 mmol), Pd(dppf)Cl2.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 then rinsed 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.

[0638] Step 2: tert-Butyl 2-(1-oxo-1,3-dihydroisobenzofuran-5-yl)acetate

[0639]

[0640] A mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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 the mixture was 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.

[0641] Step 3: tert-Butyl 1-(1-oxo-1,3-dihydroisobenzofuran-5-yl)cyclobutane-1-carboxylate

[0642]

[0643] 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) was added Cs2CO3 (10 g, 30.8 mmol), and the mixture was stirred at 0 ° C for 0.5 hours under nitrogen. 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 x3). 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.

[0644] Step 4: 1-(3-((dimethylamino)methylene)-1-oxo-1,3-dihydroisobenzofuran-5-yl)cyclobutane tert-Butyl 1-oxanecarboxylate

[0645]

[0646] 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 with nitrogen three times, then stirred at 120° C. for 20 hours. 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.

[0647] Step 5: 1-(4-((dimethylamino)methyl)-1-oxo-1,2-dihydrophthalazin-6-yl)cyclobutane-1-carboxylic acid Tert-butyl ester

[0648]

[0649] To a mixture of tert-butyl 1-(4-((dimethylamino)methyl)-1-oxo-1,2-dihydrophthalazin-6-yl)cyclobutane-1-carboxylate (656 mg, 1.9 mmol) in EtOH (10 mL) at 25°C was added hydrazine monohydrate (237 mg, 3.8 mmol). The mixture was degassed with nitrogen and then stirred at 70°C for 12 hours. The mixture was cooled to room temperature and concentrated in vacuo. 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.

[0650] Step 6: tert-Butyl 1-(4-(chloromethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)cyclobutane-1-carboxylate

[0651]

[0652] 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 3 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 and then concentrated in vacuo to give the title compound (240 mg, 60%). LCMS (M+H) + =349.2.

[0653] Step 7: 1-(4-((1,3-dioxoisoindolin-2-yl)methyl)-1-oxo-1,2-dihydrophthalazin-6-yl) tert-Butyl cyclobutane-1-carboxylate

[0654]

[0655] To a mixture of tert-butyl 1-(4-(chloromethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)cyclobutane-1-carboxylate (240 mg, 0.84 mmol) in DMF (10 mL) was added potassium phthalate (233 mg, 1.26 mmol) and 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.

[0656] Step 8: 1-(4-((1,3-dioxoisoindolin-2-yl)methyl)-1-oxo-1,2-dihydrophthalazin-6-yl) Cyclobutane-1-carboxylic acid

[0657]

[0658] A solution of tert-butyl 1-(4-((1,3-dioxoisoindolin-2-yl)methyl)-1-oxo-1,2-dihydrophthalazin-6-yl)cyclobutane-1-carboxylate (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.

[0659] Step 9: 1-(4-((1,3-dioxoisoindolin-2-yl)methyl)-1-oxo-1,2-dihydrophthalazin-6-yl)- N-(5,6,7,8-Tetrahydroquinolin-8-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)cyclobutane-1-carboxamide

[0660]

[0661] A solution of 1-(4-((1,3-dioxoisoindolin-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 to a mixture of Et3N (242 mg, 2.4 mmol) and N-((5-(trifluoromethyl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinolin-8-amine (74 mg, 0.24 mmol) in DCM (10 mL) at 0°C. 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.

[0662] Step 10: 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

[0663] A mixture of 1-(4-((1,3-dioxoisoindolin-2-yl)methyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N-(5,6,7,8-tetrahydroquinolin-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%). 1HNMR(500MHz,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.

[0664] Compound cell killing in HCT116 isogenic pairs

[0665] HCT116 cell line (ATCC, CCL-247) is isolated from the colon of an adult male suffering from colon cancer. It has a mutation in the 13th codon of the ras proto-oncogene, and can be used as a positive control for the PCR assay of the codon mutation. HCT116-MTAP-KO is a knockout MTAP gene based on HCT116, and a single clone has passed the assay. HCT116-mock-RNA-KO is a knockout mock gene based on HCT116 with a wild-type genotype of MTAP. The basal medium for HCT116 et al. is RPMI 1640, HEPES (Gibco, 22400105). In order to prepare complete growth medium, the following components are added to the basal medium: fetal bovine serum, a final concentration of 10% (Gibco, 10099-141C). The cell line was grown at 37°C in a humidified 5% CO2 atmosphere and regularly tested for the presence of mycoplasma using the MycoAlertTM PLUS Mycoplasma Detection Kit (Lonza, LT07-710).

[0666] experiment

[0667] HCT116-mock-RNA-KO (4E2 / well) or HCT116-MTAP-KO (4E2 / well) cells were seeded into 96-well plates (Greiner: 655090), 100 μL / well.

[0668] Incubate overnight at 37°C, 5% CO2.

[0669] • Add 50 μL of fresh growth medium containing serial dilutions of compound to each well, with a final compound concentration of 0-10 μM.

[0670] Incubate at 37°C, 5% CO2 for 6 days.

[0671] · Detect cell viability using Cell Titer-Glo (Promega, G7573). Add 70 μL of Reagents.

[0672] Incubate at room temperature for 10 minutes to stabilize the luminescent signal.

[0673] · Analyze with a microplate reader (TECAN, SPARK) and use 9 Fitting IC 50 .

[0674] The compounds disclosed herein exhibited cell killing activity values ​​as shown in Table 1

[0675] Table 1: Cell killing IC of compounds disclosed herein 50 (nM)

[0676]

[0677] The foregoing examples and descriptions of certain embodiments should be considered illustrative, rather than limiting, of the invention as defined by the claims. It will be readily appreciated that a variety of variations and combinations of the features described above 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.

[0678] It should be appreciated that, if any prior art publication is referred to herein, such reference does not constitute an admission that the publication forms part of the common general knowledge in the art in any country.

Claims

1. A compound of formula (I): in: n is 1, 2, 3 or 4; m is 1, 2, 3 or 4; R 1 and R 2 are each 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 -C3-C8 alkyl and -C3-C8 cycloalkyl is optionally substituted with at least one substituent selected from the group consisting of 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 group, C6-C 12 Aryl, 5- to 12-membered heteroaryl, oxo, -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 S02R 1d ; R 1a and R 1b are independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, -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 group, -C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted with at least one halogen, -OH, -C 1-8 Alkyl, -C 1-8 Alkoxy, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, -C6-C 12 aryl or 5- to 12-membered heteroaryl substituted; R 1c and R 1d are independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, -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 group, -C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted with at least one halogen, -OH, -C 1-8 Alkyl, -C 1-8 Alkoxy, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, -C6-C 12 aryl or 5- to 12-membered heteroaryl substituted; R 3 , R 4 , R 5 and R 6 are each 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 -C3-C8 alkyl and -C3-C8 cycloalkyl is optionally substituted with at least one substituent selected from the group consisting of halogen, -C 1-8 Alkoxy, -C 1-8 Alkyl, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, C6-C 12 Aryl, 5- to 12-membered heteroaryl, oxo, -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 S02R 3d ; R 3a , R 3b , R 3c and R 3d are independently hydrogen, -C 1-8 Alkyl, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, -C6-C 12 Aryl or 5 to 12 membered heteroaryl; the -C 1-8 Alkyl, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, -C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted with at least one halogen, -OH, -C 1-8 Alkyl, -C 1-8 Alkoxy, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, -C6-C 12 aryl or 5- to 12-membered heteroaryl substituted; R 7 Selected from hydrogen; R 8 Selected from -COR 8a 、-CO2R 8a or-CONR 8a R 8b ; R 8a and R 8b Each independently is -C 1-8 Alkyl, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, -C6-C 12 Aryl or 5 to 12 membered heteroaryl; the -C 1-8 Alkyl, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, -C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted with at least one halogen, -OH, -C 1-8 Alkyl, -C 1-8 Alkoxy, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, -C6-C 12 aryl or 5- to 12-membered heteroaryl.

2. The compound according to claim 1, wherein the compound is of formula (IIa): Preferably, the compound is selected from formula (IIb): More preferably, the compound is selected from formula (IIc): Even more preferably, the compound is selected from formula (IId): Even more preferably, the compound is selected from formula (IIe):

3. A 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 , wherein each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl is optionally substituted with at least one substituent selected from: -F, -Cl, -Br, -I, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, oxo, -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 S02R 1d ; R 1a and R 1b are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8 membered heterocyclyl, phenyl or 5 to 12 membered heteroaryl; the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl is optionally substituted with at least one -F, -Cl, -Br, -I, -OH, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, C 1-8 Alkoxy-C 1-8 Alkyl-, C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; R 1c and R 1d are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8 membered heterocyclyl, phenyl or 5 to 12 membered heteroaryl; the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl is optionally substituted with at least one -F, -Cl, -Br, -I, -OH, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, C 1-8 Alkoxy-C 1-8 Alkyl-, C 2-8 Alkenyl, -C 2-8 The cyclohexyl group may be substituted with an alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a 3- to 8-membered heterocyclyl, a phenyl group, or a 5- to 12-membered heteroaryl group.

4. A 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 are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8 membered heterocyclyl, phenyl or 5 to 12 membered heteroaryl; the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl is optionally substituted with at least one -F, -Cl, -Br, -I, -OH, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, C 1-8 Alkoxy-C 1-8 Alkyl-, C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; Preferably, R 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 are each independently selected from hydrogen.

5. A 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 , wherein each of methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl is optionally substituted with at least one substituent selected from -F, -Cl, -Br, -I, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, 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 heterocyclyl, phenyl, 5 to 12 membered heteroaryl, oxo, -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 S02R 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 heterocyclyl, phenyl or 5- to 12-membered heteroaryl; 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 8-membered heterocyclyl, phenyl or 5- to 12-membered heteroaryl; Each of propyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl is optionally substituted with at least one -F, -Cl, -Br, -I, -OH, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; Preferably, R 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 heterocyclyl, phenyl or 5- to 12-membered heteroaryl; 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 8-membered heterocyclyl, phenyl or 5- to 12-membered heteroaryl; Each of propyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl is optionally substituted with at least one -F, -Cl, -Br, -I, -OH, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; More preferably, R 3 , R 4 , R 5 and R 6 each 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, pentyloxy, hexyloxy, heptyloxy, 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 are each independently selected from hydrogen.

6. A compound as claimed in any one of the preceding claims, wherein R 8 Selected from -COR 8a 、-CO2R 8a or-CONR 8a R 8b ; R 8a and R 8b Each of the above groups is independently a methyl group, an ethyl group, a propyl group (isopropyl or n-propyl), a butyl group (n-butyl, sec-butyl, isobutyl or tert-butyl), a pentyl group, a hexyl group, a heptyl group, an octyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a 3- to 8-membered heterocyclyl group, a phenyl group, or a 5- to 12-membered heteroaryl group; the methyl group, the ethyl group, the propyl group (isopropyl or n-propyl), the butyl group (n-butyl, sec-butyl, isobutyl or tert-butyl), the pentyl group, the hexyl group, the heptyl group, the octyl group , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8 membered heterocyclyl, phenyl or 5 to 12 membered heteroaryl are each optionally substituted with at least one -F, -Cl, -Br, -I, -OH, methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C 1-8 Alkoxy, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 Alkenyl, -C 2-8 substituted with alkynyl, 3- to 8-membered heterocyclyl, phenyl or 5- to 12-membered heteroaryl; Preferably, R 8 Selected from -Cbz or -Boc.

7. A compound as claimed in any one of the preceding claims, wherein the compound is 8. The method for synthesizing the compound according to claims 1 to 7, wherein: The method comprises step A: R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 11 , m and n are as defined in any one of claims 1 to 6; The alkyl group is selected from methyl, ethyl, propyl (isopropyl or n-propyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl or octyl; preferably, the alkyl group is ethyl; The base is selected from LiOH, NaOH, KOH, MeONa or EtONa; preferably, the base is LiOH.

9. The synthesis method as claimed in claim 8, wherein the solvent of step A is THF, DMF, DMSO, MeOH, EtOH, water and a combination thereof; Preferably, the solvent of step A is a combination of THF, MeOH and water.

10. The synthesis method according to any one of claims 8 to 9, wherein the temperature of step A is 10°C-80°C; preferably, the temperature of step A is 40°C-70°C; more preferably, the temperature of step A is 60°C; The reaction time of step A is 2 hours to 24 hours; preferably, the reaction time of step A is 8 hours to 18 hours; more preferably, the reaction time of step A is 16 hours.

11. The synthesis method according to any one of claims 8 to 10, wherein the method further comprises step B: R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 11 , alkyl, m and n are as defined in any one of claims 1 to 6 and claim 8; The Pd catalyst is selected from Pd2(dba)3.

12. The synthesis method according to claim 11, wherein the zinc powder is activated zinc powder; Preferably, the zinc powder is activated by 1,2-dibromoethane and / or trimethylsilyl chloride; More preferably, the zinc powder is activated by 1,2-dibromoethane and trimethylchlorosilane.

13. The synthesis method according to claim 11, wherein the temperature of step B is 10°C-80°C; preferably, the temperature of step A is 30°C-60°C; more preferably, the temperature of step A is 40°C.

14. The synthesis method according to claim 11, wherein the reaction time of step A is 2 hours to 24 hours; preferably, the reaction time of step A is 8 hours to 18 hours; more preferably, the reaction time of step A is 16 hours.

Images