Amide compound as well as composition and application thereof

Abstract

The invention relates to a novel amide compound or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the amide compound or the pharmaceutically acceptable salt, and application of the amide compound or the pharmaceutically acceptable salt as a KIF18A inhibitor in prevention or treatment of related diseases. # imgabs0 #

Description

Amide compounds, compositions and uses thereof

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of and priority to the following four Chinese invention patent applications, the entire contents of which are hereby incorporated by reference in their entirety:

[0003] Patent application No. 202211103512.1 filed with the State Intellectual Property Office of China on September 9, 2022;

[0004] Patent application No. 202211481864.0 filed with the State Intellectual Property Office of China on November 24, 2022;

[0005] Patent application No. 202310395648.2 filed with the State Intellectual Property Office of China on April 13, 2023; and

[0006] Patent application No. 202310951733.2 submitted to the State Intellectual Property Office of China on July 28, 2023. Technical Field

[0007] The present disclosure relates to a novel amide compound or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the same, and use thereof as a KIF18A inhibitor in preventing or treating related diseases. Background Art

[0008] Cancer is often characterized by unregulated cell proliferation. Damage to one or more genes in the cell proliferation pathway can cause the loss of normal regulation of cell proliferation. These dysregulated genes can encode various tumor suppressors or oncogene proteins, leading to unchecked cell cycle progression and cell proliferation. Various kinases and kinesins have been identified as playing a key role in the cell cycle, mitosis regulation and progression of normal and cancer cells.

[0009] Kinesins are molecular motors that play a vital role in cell division and the transport of intracellular vesicles and organelles. Mitotic kinesins play a role in multiple processes, including spindle assembly, chromosome segregation, and centrosome separation. Human kinesins are classified into 14 subfamilies based on sequence homology within the so-called "motor domain," whose ATPase activity drives unidirectional movement along microtubules. The non-motor domains of these proteins are responsible for attaching to their "cargo," which can be a variety of membranous organelles, signal transduction scaffolds, and chromosomes. Kinesins utilize the energy from ATP hydrolysis to move their "cargo" along polarized microtubules. For this reason, kinesins are often referred to as "plus-end" or "minus-end"-directed motor proteins. The KIF18A gene belongs to the kinesin-8 subfamily and is a plus-end-directed motor protein. KIF18A is believed to influence the movement of the plus ends of centromeric microtubules to control correct chromosome positioning and maintain spindle tension. Ablation of human KIF18A in HeLa cervical cancer cells leads to longer spindles, increased chromosome oscillations during metaphase, and activation of the hammer assembly checkpoint. Therefore, KIF18A may be a viable target for cancer therapy, as KIF18A is overexpressed in many types of cancer. In addition, in cancer cells, KIF18A gene deletion, knockout, or inhibition affects the mitotic spindle. In particular, inhibition of KIF18A has been found to induce mitotic arrest, ultimately leading to mitotic catastrophe in cancer cells or mitotic slippage during interphase, which in turn causes cancer cell apoptosis.

[0010] Therefore, KIF18A inhibitors can be developed into promising anti-cancer drugs, and various research institutions have shown strong interest in finding inhibitors of KIF18A protein.

[0011] Summary of the Invention

[0012] The present disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof:

[0013] in,

[0014] Ring A is selected from 5-membered heteroaryl, pyridinone, azapyridinone, 10-16 membered tricyclic heterocyclyl, 12-20 membered tetracyclic heterocyclyl or 11-14 membered tricyclic heteroaryl;

[0015] The 5-membered heteroaryl group is optionally substituted by one or more R 1a Replace, each R 1a independently selected from halogen, CN, OH, NH2, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C5-C10 Cycloalkenyl, 4-10 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl, said OH, NH2, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C5-C 10 Cycloalkenyl, 4-10 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally substituted with one or more R 1b Replace, when two R 1a When located at the ortho position of a 5-membered heteroaryl group, the two R 1a They can also form, together with the atoms to which they are attached, a C5-C7 monocycloalkenyl, a 4-7 membered monoheterocyclic group, a phenyl group or a 5-6 membered monoheteroaryl group, wherein the C5-C7 monocycloalkenyl, the 4-7 membered monoheterocyclic group, the phenyl group or the 5-6 membered monoheteroaryl group is optionally substituted by one or more R 1b replace;

[0016] The pyridone group, azapyridone group, 10-16 membered tricyclic heterocyclic group, 12-20 membered tetracyclic heterocyclic group or 11-14 membered tricyclic heteroaryl group are optionally substituted by one or more R 2b replace;

[0017] The ring M is selected from C4-C7 monocycloalkenyl, 4-7 membered monoheterocyclic group, phenyl or 5-6 membered monoheteroaryl, and the structural unit By one or more R 3a Substituted, the R 3a Selected from C3-C 10 Cycloalkyl, C5-C 10 Cycloalkenyl, 4-10 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl; optionally, the 3a Replaced Can be further divided into one or more R 3b replace;

[0018] The X 1 、X 2 、X 3 、X 4 、X 5 、X 6 1, 2 or 3 of them are selected from N, and the rest are selected from CR 4 , or, the X 3 、X 4 、X 5 、X 6 One of them does not exist, and the other three are the same as X 1 、X2 Together constitute a 5-membered heteroaryl, the 5-membered heteroaryl is optionally substituted by one or more R 4b replace;

[0019] Every R 4 Each independently selected from absent, H or R 4b ;

[0020] The ring Q is selected from C5-C7 monocycloalkenyl, 4-7 membered monoheterocyclic group, phenyl or 5-6 membered monoheteroaryl, and the C5-C7 monocycloalkenyl, 4-7 membered monoheterocyclic group, phenyl or 5-6 membered monoheteroaryl is optionally substituted by one or more R 4b replace;

[0021] R 1 is selected from H or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more halogens;

[0022] R 2 Selected from described Optionally one or more R x Replace, each R x independently selected from halogen, CN, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl or 4-7 membered heterocyclic group, wherein the OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl or 4-7 membered heterocyclic group is optionally replaced by one or more R xb Replace, when The same carbon atom on the x When substituted, the two R x It can also form C3-C 10 Cycloalkyl, C3-C 10 Cycloalkenyl or 4-10 membered heterocyclic group, the C3-C 10 Cycloalkyl, C3-C 10 Cycloalkenyl or 4-10 membered heterocyclic group is optionally substituted by one or more R xb replace;

[0023] R 3 Selected from L 1 -L 2 -R y , L 1 Selected from-NR 5 -, -O-, -S-, -S(=O)-, -SO2-, -C(=O)-, -NR 5 SO2-、-NR 5 C(=O)-、-NR 5 -S(=O)(=NR 5 )-、-S(=O)(=NR 5)-、-S=N-、 Every R 5 Independently selected from H or C1-C4 alkyl, each R 5a 、R 5b Each is independently selected from C1-C4 alkyl, C3-C6 cycloalkyl or 4-7 membered heterocyclic group, or the R 5a 、R 5b and the atoms to which they are connected together form a 4-7 membered heterocyclic group, L 2 Selected from chemical bonds or C1-C4 alkylene, R y is selected from H, C3-C6 cycloalkyl or 4-7 membered heterocyclyl, each of which C1-C4 alkyl, C1-C4 alkylene, C3-C6 cycloalkyl or 4-7 membered heterocyclyl is optionally substituted with one or more halogen, CN, OH, NH2, O(C1-C4 alkyl), NH(C1-C4 alkyl) or N(C1-C4 alkyl)2;

[0024] X, Y, and Z are each independently selected from N or CR 6 , R 6 is selected from H, halogen, CN, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, O(C1-C4 alkyl), NH(C1-C4 alkyl) or N(C1-C4 alkyl)2, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, O(C1-C4 alkyl), NH(C1-C4 alkyl) or N(C1-C4 alkyl)2 is optionally substituted with one or more halogen or CN;

[0025] Every R 1b 、R 2b 、R 3b 、R 4b 、R xb independently selected from halogen, CN, OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C5-C 10 Cycloalkenyl, C(O)R d , C3-C6 cycloalkyl, 4-14 membered heterocyclyl, O(C1-C4 alkyl), NH(C1-C4 alkyl) or N(C1-C4 alkyl) 2, the C1-C6 alkyl, C2-C6 alkenyl, C5-C 10 Cycloalkenyl, C3-C6 cycloalkyl, 4-14 membered heterocyclyl, O(C1-C4 alkyl), NH(C1-C4 alkyl) or N(C1-C4 alkyl) 2 are optionally substituted by one or more R c replace;

[0026] Every R cIndependently selected from halogen, CN, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, O(C1-C4 alkyl), NH(C1-C4 alkyl) or N(C1-C4 alkyl)2;

[0027] R d Selected from OH, C1-C6 alkyl, O(C1-C4 alkyl), NH2, NH(C1-C4 alkyl) or N(C1-C4 alkyl)2.

[0028] In some embodiments, Ring A is selected from 5-membered heteroaryl, pyridonyl, azapyridonyl, 10-16 membered tricyclic heterocyclyl, 12-20 membered tetracyclic heterocyclyl or 11-14 membered tricyclic heteroaryl;

[0029] The 5-membered heteroaryl group is optionally substituted by one or more R 1a Replace, each R 1a independently selected from halogen, CN, OH, NH2, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C5-C 10 Cycloalkenyl, 4-10 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl, the OH, NH2, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C5-C 10 Cycloalkenyl, 4-10 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally substituted with one or more R 1b Replace, when two R 1a When located at the ortho position of a 5-membered heteroaryl group, the two R 1a They can also form, together with the atoms to which they are attached, a C5-C7 monocycloalkenyl, a 4-7 membered monoheterocyclic group, a phenyl group or a 5-6 membered monoheteroaryl group, wherein the C5-C7 monocycloalkenyl, the 4-7 membered monoheterocyclic group, the phenyl group or the 5-6 membered monoheteroaryl group is optionally substituted by one or more R 1b replace;

[0030] The pyridone group, azapyridone group, 10-16 membered tricyclic heterocyclic group, 12-20 membered tetracyclic heterocyclic group or 11-14 membered tricyclic heteroaryl group are optionally substituted by one or more R 2b replace;

[0031] The ring M is selected from C5-C7 monocycloalkenyl, 4-7 membered monoheterocyclic group, phenyl or 5-6 membered monoheteroaryl, and the structural unit By one or more R 3a Substituted, the R 3a Selected from C3-C 10 Cycloalkyl, C5-C 10 Cycloalkenyl, 4-10 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl; optionally, the 3a Replaced Can be further divided into one or more R 3b replace;

[0032] The X 1 、X 2 、X 3 、X 4 、X 5 、X 6 1, 2 or 3 of them are selected from N, and the rest are selected from CR 4 , or, the X 3 、X 4 、X 5 、X 6 One of them does not exist, and the other three are the same as X 1 、X 2 Together constitute a 5-membered heteroaryl, the 5-membered heteroaryl is optionally substituted by one or more R 4b replace;

[0033] Every R 4 Each independently selected from absent, H or R 4b ;

[0034] The ring Q is selected from C5-C7 monocycloalkenyl, 4-7 membered monoheterocyclic group, phenyl or 5-6 membered monoheteroaryl, and the C5-C7 monocycloalkenyl, 4-7 membered monoheterocyclic group, phenyl or 5-6 membered monoheteroaryl is optionally substituted by one or more R 4b replace;

[0035] R 1 is selected from H or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more halogens;

[0036] R 2 Selected from described Optionally one or more R x Replace, each R xindependently selected from halogen, CN, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl or 4-7 membered heterocyclic group, wherein the OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl or 4-7 membered heterocyclic group is optionally replaced by one or more R xb Replace, when The same carbon atom on the x When substituted, the two R x It can also form C3-C 10 Cycloalkyl, C3-C 10 Cycloalkenyl or 4-10 membered heterocyclic group, the C3-C 10 Cycloalkyl, C3-C 10 Cycloalkenyl or 4-10 membered heterocyclic group is optionally substituted by one or more R xb replace;

[0037] R 3 Selected from L 1 -L 2 -R y , L 1 Selected from-NR 5 -, -O-, -S-, -S(=O)-, -SO2-, -C(=O)-, -NR 5 SO2-、-NR 5 C(=O)-、-NR 5 -S(=O)(=NR 5 )-、-S(=O)(=NR 5 )-、-S=N-、 Every R 5 Independently selected from H or C1-C4 alkyl, each R 5a 、R 5b Each is independently selected from C1-C4 alkyl, C3-C6 cycloalkyl or 4-7 membered heterocyclic group, or the R 5a 、R 5b and the atoms to which they are connected together form a 4-7 membered heterocyclic group, L 2 Selected from chemical bonds or C1-C4 alkylene, R y is selected from H, C3-C6 cycloalkyl or 4-7 membered heterocyclyl, each of which C1-C4 alkyl, C1-C4 alkylene, C3-C6 cycloalkyl or 4-7 membered heterocyclyl is optionally substituted with one or more halogen, CN, OH, NH2, O(C1-C4 alkyl), NH(C1-C4 alkyl) or N(C1-C4 alkyl)2;

[0038] X, Y, and Z are each independently selected from N or CR 6 , R 6is selected from H, halogen, CN, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, O(C1-C4 alkyl), NH(C1-C4 alkyl) or N(C1-C4 alkyl)2, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, O(C1-C4 alkyl), NH(C1-C4 alkyl) or N(C1-C4 alkyl)2 is optionally substituted with one or more halogen or CN;

[0039] Every R 1b 、R 2b 、R 3b 、R 4b 、R xb independently selected from halogen, CN, OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, 4-14 membered heterocyclyl, O(C1-C4 alkyl), NH(C1-C4 alkyl) or N(C1-C4 alkyl)2, wherein the C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, 4-14 membered heterocyclyl, O(C1-C4 alkyl), NH(C1-C4 alkyl) or N(C1-C4 alkyl)2 is optionally replaced by one or more R c replace;

[0040] Every R c Independently selected from halogen, CN, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, O(C1-C4 alkyl), NH(C1-C4 alkyl) or N(C1-C4 alkyl)2.

[0041] In some embodiments, the X 1 、X 2 、X 3 、X 4 、X 5 、X 6 1, 2 or 3 of them are selected from N, and the rest are selected from CR 4 , each R 4 Each independently selected from absent, H or R 4b ; Each R 1b 、R 2b 、R 3b 、R 4b 、R xb independently selected from halogen, CN, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 4-14 membered heterocyclyl, O(C1-C4 alkyl), NH(C1-C4 alkyl) or N(C1-C4 alkyl)2, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, 4-14 membered heterocyclyl, O(C1-C4 alkyl), NH(C1-C4 alkyl) or N(C1-C4 alkyl)2 is optionally replaced by one or more Rc replace;

[0042] Every R c Independently selected from halogen, CN, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, O(C1-C4 alkyl), NH(C1-C4 alkyl) or N(C1-C4 alkyl)2.

[0043] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein the ring A is selected from 5-membered heteroaryl, pyridone, azapyridone, 10-16 membered tricyclic heterocyclyl or 11-14 membered tricyclic heteroaryl;

[0044] The 5-membered heteroaryl group is optionally substituted by one or more R 1a Replace, each R 1a independently selected from halogen, CN, OH, NH2, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C5-C 10 Cycloalkenyl, 4-10 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl, the OH, NH2, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C5-C 10 Cycloalkenyl, 4-10 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally substituted with one or more R 1b Replace, when two R 1a When located at the ortho position of a 5-membered heteroaryl group, the two R 1a They can also form, together with the atoms to which they are attached, a C5-C7 monocycloalkenyl, a 4-7 membered monoheterocyclic group, a phenyl group or a 5-6 membered monoheteroaryl group, wherein the C5-C7 monocycloalkenyl, the 4-7 membered monoheterocyclic group, the phenyl group or the 5-6 membered monoheteroaryl group is optionally substituted by one or more R 1b replace;

[0045] The pyridone group, azapyridone group, 10-16 membered tricyclic heterocyclic group or 11-14 membered tricyclic heteroaryl group is optionally substituted by one or more R 2b replace;

[0046] The ring M is selected from C5-C7 monocycloalkenyl, 4-7 membered monoheterocyclic group, phenyl or 5-6 membered monoheteroaryl, and the structural unit By one or more R3a Substituted, the R 3a Selected from C3-C 10 Cycloalkyl, C5-C 10 Cycloalkenyl, 4-10 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl; optionally, the 3a Replaced Can be further divided into one or more R 3b replace;

[0047] The X 1 、X 2 、X 3 、X 4 、X 5 、X 6 1, 2 or 3 of them are selected from N, and the rest are selected from CR 4 , each R 4 Each independently selected from absent, H or R 4b ;

[0048] The ring Q is selected from C5-C7 monocycloalkenyl, 4-7 membered monoheterocyclic group, phenyl or 5-6 membered monoheteroaryl, and the C5-C7 monocycloalkenyl, 4-7 membered monoheterocyclic group, phenyl or 5-6 membered monoheteroaryl is optionally substituted by one or more R 4b replace;

[0049] R 1 is selected from H or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more halogens;

[0050] R 2 Selected from described Optionally one or more R x Replace, each R x independently selected from halogen, CN, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl or 4-7 membered heterocyclic group, wherein the OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl or 4-7 membered heterocyclic group is optionally replaced by one or more R xb Replace, when The same carbon atom on the x When substituted, the two R x It can also form C3-C 10 Cycloalkyl, C3-C 10 Cycloalkenyl or 4-10 membered heterocyclic group, the C3-C 10 Cycloalkyl, C3-C 10 Cycloalkenyl or 4-10 membered heterocyclic group is optionally substituted by one or more R xb replace;

[0051] R 3 Selected from L 1 -L 2 -R y , L 1 Selected from-NR 5 -, -O-, -S-, -S(=O)-, -SO2-, -(C=O)-, -NR 5 SO2-、-NR 5 (C=O)-、-NR 5 -S(=O)(=NR 5 )-or-S(=O)(=NR 5 )-, each R 5 Independently selected from H or C1-C4 alkyl; L 2 Selected from chemical bonds or C1-C4 alkylene, R y Selected from H, C3-C6 cycloalkyl or 4-7 membered heterocyclyl, wherein the C1-C4 alkylene, C3-C6 cycloalkyl or 4-7 membered heterocyclyl is optionally substituted with one or more halogen, CN, OH, NH2, O(C1-C4 alkyl), NH(C1-C4 alkyl) or N(C1-C4 alkyl)2;

[0052] X, Y, and Z are each independently selected from N or CR 6 , R 6 is selected from H, halogen, CN, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, O(C1-C4 alkyl), NH(C1-C4 alkyl) or N(C1-C4 alkyl)2, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, O(C1-C4 alkyl), NH(C1-C4 alkyl) or N(C1-C4 alkyl)2 is optionally substituted with one or more halogen or CN;

[0053] Every R 1b 、R 2b 、R 3b 、R 4b 、R xb independently selected from halogen, CN, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, O(C1-C4 alkyl), NH(C1-C4 alkyl) or N(C1-C4 alkyl)2, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, O(C1-C4 alkyl), NH(C1-C4 alkyl) or N(C1-C4 alkyl)2 is optionally replaced by one or more R c replace;

[0054] Every R cIndependently selected from halogen, CN, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, O(C1-C4 alkyl), NH(C1-C4 alkyl) or N(C1-C4 alkyl)2.

[0055] In some embodiments, Ring A is selected from azapyridinone, 10-16 membered tricyclic heterocyclic group, 12-20 membered tetracyclic heterocyclic group or 11-14 membered tricyclic heteroaryl group, the azapyridone group, The 10-16 membered tricyclic heterocyclyl, 12-20 membered tetracyclic heterocyclyl or 11-14 membered tricyclic heteroaryl is as defined above.

[0056] In some embodiments, Ring A is selected from azapyridinone, 10-16 membered tricyclic heterocyclic group or 11-14 membered tricyclic heteroaryl group, the azapyridone group, The 10-16 membered tricyclic heterocyclyl or 11-14 membered tricyclic heteroaryl is as defined above.

[0057] In some embodiments, ring A is selected from azapyridonyl, 10-16 membered tricyclic heterocyclyl, 12-20 membered tetracyclic heterocyclyl or 11-14 membered tricyclic heteroaryl, wherein the azapyridonyl, 10-16 membered tricyclic heterocyclyl, 12-20 membered tetracyclic heterocyclyl or 11-14 membered tricyclic heteroaryl is selected from azapyridonyl, 10-16 membered tricyclic heterocyclyl, 12-20 membered tetracyclic heterocyclyl or 11-14 membered tricyclic heteroaryl, optionally substituted with one or more R 2b Substituted with the following groups:

[0058] In some embodiments, ring A is selected from azapyridonyl, 10-16 membered tricyclic heterocyclyl, 12-20 membered tetracyclic heterocyclyl or 11-14 membered tricyclic heteroaryl, wherein the azapyridonyl, 10-16 membered tricyclic heterocyclyl, 12-20 membered tetracyclic heterocyclyl or 11-14 membered tricyclic heteroaryl is selected from azapyridonyl, 10-16 membered tricyclic heterocyclyl, 12-20 membered tetracyclic heterocyclyl or 11-14 membered tricyclic heteroaryl, optionally substituted with one or more R 2b Substituted with the following groups:

[0059] In some embodiments, ring A is selected from azapyridonyl, 10-16 membered tricyclic heterocyclyl, 12-20 membered tetracyclic heterocyclyl or 11-14 membered tricyclic heteroaryl, wherein the azapyridonyl, 10-16 membered tricyclic heterocyclyl, 12-20 membered tetracyclic heterocyclyl or 11-14 membered tricyclic heteroaryl is selected from azapyridonyl, 10-16 membered tricyclic heterocyclyl, 12-20 membered tetracyclic heterocyclyl or 11-14 membered tricyclic heteroaryl, optionally substituted with one or more R 2b Substituted with the following groups:

[0060] In some embodiments, ring A is selected from azapyridonyl, 10-16 membered tricyclic heterocyclyl, 12-20 membered tetracyclic heterocyclyl or 11-14 membered tricyclic heteroaryl, wherein the azapyridonyl, 10-16 membered tricyclic heterocyclyl, 12-20 membered tetracyclic heterocyclyl or 11-14 membered tricyclic heteroaryl is selected from described Optionally one or more R 2b replace.

[0061] In some embodiments, the azapyridinone, 10-16 membered tricyclic heterocyclyl or 11-14 membered tricyclic heteroaryl is selected from described Optionally one or more R 2b replace.

[0062] In some embodiments, the structural unit The ring M is selected from C4-C7 monocycloalkenyl, 5-6 membered monoheteroaryl or 4-7 membered monoheterocyclic group, the structural unit By one or more R 3a substituted; optionally, by one or more R 3a Substituted structural units Can be further divided into one or more R 3b replace.

[0063] In some embodiments, the structural unit The ring M in is selected from a 5-6 membered monoheteroaryl or a 4-7 membered monoheterocyclic group, and the structural unit By one or more R 3a substituted; optionally, by one or more R 3a Substituted structural units Can be further divided into one or more R 3b replace.

[0064] In some embodiments, the structural unit The ring M in is selected from 5-6 membered heteroaryl groups, and the structural unit By one or more R 3a substituted; optionally, by one or more R 3a Substituted structural units Can be further divided into one or more R 3b replace.

[0065] In some embodiments, the structural unit Selected from one or more R 3a Substituted with the following groups: Optionally, one or more R 3a The above-mentioned substituted groups may be further substituted by one or more R 3b replace.

[0066] In some embodiments, the structural unit Selected from one or more R 3a Substituted with the following groups: Optionally, one or more R 3a The above-mentioned substituted groups may be further substituted by one or more R 3b replace.

[0067] In some embodiments, the structural unit Selected from one or more R 3a Substituted with the following groups: Optionally, one or more R 3a The above-mentioned substituted groups may be further substituted by one or more R 3b replace.

[0068] In some embodiments, the structural unit Selected from one or more R 3a Replaced Optionally, the one or more R 3a Replaced Can be further divided into one or more R 3b replace.

[0069] In some embodiments, the structural unit Selected from one or more R 3a Replaced Optionally, the one or more R 3a Replaced Can be further divided into one or more R 3b replace.

[0070] In some embodiments, the structural unit Selected from Ring atom Y 1 、Y 2 、Y 3 、Y 4 、Y 5 1, 2 or 3 of them are N, and the rest are C, R A6 、R A8 Any one of RA7 and the atoms to which they are attached together form a C5-C7 monocycloalkenyl, a 4-7 membered monoheterocyclic group, a phenyl group or a 5-6 membered monoheteroaryl group, wherein the C5-C7 monocycloalkenyl, the 4-7 membered monoheterocyclic group, the phenyl group or the 5-6 membered monoheteroaryl group is optionally substituted by one or more R 4b Substitution; R not involved in ring formation A6 、R A8 、R A9 、R A10 Each independently selected from absent, H or R 4b .

[0071] In some embodiments, the structural unit Selected from described Ring atom Y 1 、Y 2 、Y 3 、Y 4 、Y 5 One or two of them are N, and the rest are selected from C, R A6 、R A8 Any one of R A7 and the atoms to which they are attached together form a C5 monocycloalkenyl or a 5-6 membered monoheteroaryl, wherein the C5 monocycloalkenyl or the 5-6 membered monoheteroaryl is optionally substituted by one or more R 4b Substitution; R not involved in ring formation A6 、R A8 、R A9 、R A10 Each independently selected from absent, H or R 4b .

[0072] In some embodiments, the structural unit Selected from optionally one or more R 4b Substituted with the following groups:

[0073] In some embodiments, the structural unit Selected from optionally one or more R 4b Substituted with the following groups:

[0074] In some embodiments, the structural unit Selected from optionally one or more R 4b Substituted with the following groups:

[0075] In some embodiments, the structural unit Selected from described Optionally one or more R 4b replace.

[0076] In some embodiments, the structural unit Selected from described Optionally one or more R 4b replace.

[0077] In some embodiments, the structural unit Selected from described Optionally one or more R 4b replace.

[0078] In some embodiments, Ring A is selected from described Optionally one or more R 2b Replace, the By one or more R 3a Replace, the Optionally one or more R 4b replace.

[0079] In some embodiments, Ring A is selected from described Optionally one or more R 2b Replace, the By one or more R 3a Replace, the Optionally one or more R 4b replace.

[0080] In some embodiments, the R 3a Selected from C3-C6 cycloalkyl or 4-7 membered heterocyclic group.

[0081] In some embodiments, the R 3a Selected from C3-C6 cycloalkyl, such as cyclobutyl.

[0082] In some embodiments, the R 3ais selected from 4-7 membered heterocyclic groups, such as piperidinyl, morpholinyl or azabicyclo[3.1.0]hexyl. 3a is selected from cyclobutyl, piperidinyl or morpholinyl.

[0083] In some embodiments, the R 3a is selected from cyclobutyl or piperidinyl.

[0084] In some embodiments, the R 3a Selected from piperidinyl.

[0085] In some embodiments, the R 3b is selected from halogen or C1-C6 alkyl, such as F, Cl and methyl.

[0086] In some embodiments, the R 3b is selected from halogen, such as F.

[0087] In some embodiments, the R 2b and / or R 4b Each independently selected from halogen, CN, C1-C6 alkyl, C3-C6 cycloalkyl, 4-10 membered heterocyclyl, C2-C4 alkenyl, C5-C 10 Cycloalkenyl, C(O)R d , or O(C1-C4 alkyl), the C1-C6 alkyl, C3-C6 cycloalkyl, 4-10 membered heterocyclyl, C2-C4 alkenyl, C5-C 10 Cycloalkenyl or O(C1-C4 alkyl) optionally substituted by one or more R c replace.

[0088] In some embodiments, the R 2b and / or R 4b Each is independently selected from halogen, CN, C1-C6 alkyl, C3-C6 cycloalkyl, 4-10 membered heterocyclyl, C2-C4 alkenyl or O(C1-C4 alkyl), wherein the C1-C6 alkyl, C3-C6 cycloalkyl, 4-10 membered heterocyclyl, C2-C4 alkenyl or O(C1-C4 alkyl) is optionally replaced by one or more R c replace.

[0089] In some embodiments, the R 2b and / or R 4b Each independently selected from halogen, CN, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C4 alkenyl or 4-7 membered heterocyclyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, C2-C4 alkenyl or 4-7 membered heterocyclyl is optionally substituted by one or more R c replace.

[0090] In some embodiments, the R2b and / or R 4b Each is independently selected from halogen, CN, C1-C6 alkyl, C3-C6 cycloalkyl, 4-10 membered heterocyclyl or O(C1-C4 alkyl), wherein the C1-C6 alkyl, C3-C6 cycloalkyl, 4-10 membered heterocyclyl or O(C1-C4 alkyl) is optionally replaced by one or more R c replace.

[0091] In some embodiments, the R 2b and / or R 4b Each independently selected from halogen, CN, C1-C6 alkyl, C3-C6 cycloalkyl or 4-7 membered heterocyclic group, wherein the C1-C6 alkyl, C3-C6 cycloalkyl or 4-7 membered heterocyclic group is optionally replaced by one or more R c replace.

[0092] In some embodiments, each R c Independently selected from halogen, CN, OH, NH2, C1-C4 alkyl or O(C1-C4 alkyl).

[0093] In some embodiments, each R c Independently selected from halogen, CN, OH, NH2 or C1-C4 alkyl.

[0094] In some embodiments, each R c Independently selected from halogen or O(C1-C4 alkyl).

[0095] In some embodiments, each R c are independently selected from halogen.

[0096] In some embodiments, the R d Independently selected from O(C1-C4 alkyl), NH2, NH(C1-C4 alkyl) or N(C1-C4 alkyl)2.

[0097] In some embodiments, the R d Independently selected from O(C1-C4 alkyl) or NH(C1-C4 alkyl).

[0098] In some embodiments, the R d Independently selected from methoxy or NHCH2CH3.

[0099] In some embodiments, the R 2b independently selected from halogen, CN, C1-C6 alkyl, C3-C6 cycloalkyl, 4-10 membered heterocyclyl, C5-C 10 Cycloalkenyl, C(O)R dor O(C1-C4 alkyl), the C1-C6 alkyl, C3-C6 cycloalkyl, 4-10 membered heterocyclic group, C5-C 10 Cycloalkenyl or O(C1-C4 alkyl) optionally substituted by one or more R c substituted, and the R c Selected from halogen or O(C1-C4 alkyl).

[0100] In some embodiments, the R 2b independently selected from halogen, CN, C1-C6 alkyl, C3-C6 cycloalkyl, 4-10 membered heterocyclyl, C5-C 10 Cycloalkenyl, C(O)R d , or O(C1-C4 alkyl), the C1-C6 alkyl, 4-10 membered heterocyclic group and C5-C 10 The cycloalkenyl group is optionally substituted with one or more R c substituted, and the R c Selected from halogen.

[0101] In some embodiments, the R 2b Selected from cyano, halogen, C1-C4 alkyl, C5-C 10 Cycloalkenyl, C(O)R d , O(C1-C4 alkyl) or piperidinyl, wherein the C1-C4 alkyl, O(C1-C4 alkyl) or piperidinyl is optionally substituted with one or more F.

[0102] In some embodiments, the R 2b is selected from cyano, halogen, C1-C4 alkyl, O(C1-C4 alkyl) or piperidinyl, wherein the C1-C4 alkyl, O(C1-C4 alkyl) or piperidinyl is optionally substituted with one or more Fs.

[0103] In some embodiments, the R 2b is selected from halogen, C1-C4 alkyl or piperidinyl, wherein the C1-C4 alkyl or piperidinyl is optionally substituted with one or more F.

[0104] In some embodiments, the R 2b is selected from C1-C4 alkyl or piperidinyl, wherein the C1-C4 alkyl or piperidinyl is optionally substituted with one or more F.

[0105] In some embodiments, the R 2b Selected from CN, F, methyl, trifluoromethyl, methoxy, methoxymethyl, cyclopropyl, methoxycarbonyl or ethylaminocarbonyl.

[0106] In some embodiments, the R 2b Selected from CN, F, methyl, trifluoromethyl, methoxy, cyclopropyl, methoxycarbonyl or ethylaminocarbonyl.

[0107] In some embodiments, the R 2b Selected from CN, F, methyl, methoxy, methoxycarbonyl or ethylaminocarbonyl.

[0108] In some embodiments, the R 2b Selected from CN, F, methyl, methoxy or

[0109] In some embodiments, the R 2b Selected from F, methyl or

[0110] In some embodiments, the R 2b Selected from methyl or

[0111] In some embodiments, the R 4b is selected from C1-C4 alkyl, O(C1-C4 alkyl), 4-10 membered heterocyclyl or C2-C4 alkenyl, wherein the C1-C4 alkyl, O(C1-C4 alkyl), 4-10 membered heterocyclyl or C2-C4 alkenyl is optionally substituted with one or more F.

[0112] In some embodiments, the R 4b The group is selected from C1-C4 alkyl, O(C1-C4 alkyl) or 4-10 membered heterocyclyl, wherein the C1-C4 alkyl, O(C1-C4 alkyl) or 4-10 membered heterocyclyl is optionally substituted with one or more F.

[0113] In some embodiments, the R 4b is selected from C1-C4 alkyl, wherein the C1-C4 alkyl is optionally substituted with one or more F.

[0114] In some embodiments, the R 4b Selected from methyl, isopropyl, CF3CH2CH2, CF3CH2CH2O, Or vinyl.

[0115] In some embodiments, the R 4b Selected from methyl, isopropyl, CF3CH2CH2, CF3CH2CH2O,

[0116] In some embodiments, the R 4b Selected from methyl, isopropyl or CF3CH2CH2.

[0117] In some embodiments, Ring A is selected from

[0118] In some embodiments, Ring A is selected from

[0119] In some embodiments, Ring A is selected from

[0120] In some embodiments, Ring A is selected from

[0121] In some embodiments, Ring A is selected from

[0122] In some embodiments, R 1 Selected from H or C1-C4 alkyl.

[0123] In some embodiments, R 1 Selected from H.

[0124] In some embodiments, R 2 Selected from described The same carbon atom on the x Substitute, the two R x Together with the carbon atom, it forms a C3-C6 cycloalkyl, C3-C6 cycloalkenyl or 4-7 membered heterocyclic group, wherein the C3-C6 cycloalkyl, C3-C6 cycloalkenyl or 4-7 membered heterocyclic group is optionally substituted by one or more R xb replace.

[0125] In some embodiments, R 2 Selected from described The carbon atom in the x Substitute, the two R x Together with the carbon atom, it forms a C3-C6 cycloalkyl, C3-C6 cycloalkenyl or 4-7 membered heterocyclic group, wherein the C3-C6 cycloalkyl, C3-C6 cycloalkenyl or 4-7 membered heterocyclic group is optionally substituted by one or more R xb replace.

[0126] In some embodiments, R 2 Selected from described The carbon atom in the x Substitute, the two R x Together with the carbon atom, it forms a C3-C6 cycloalkyl group, wherein the C3-C6 cycloalkyl group is optionally substituted by one or more R xb replace.

[0127] In some embodiments, R 2 Selected from

[0128] In some embodiments, R 3 Selected from L 1 -L 2 -R y , L 1 Selected from -NH-, -O-, -S-, -S(=O)-, -SO2-, -C(=O)-, -NHSO2-, -NH(C=O)- or The R 5a 、R 5b Each independently selected from C1-C4 alkyl, or said R 5a 、R 5b and the atoms to which they are connected together form a 4-7 membered heterocyclic group, L 2 Selected from chemical bonds or C1-C4 alkylene, R y Selected from H, C3-C6 cycloalkyl or 4-7 membered heterocyclyl, each of the above C1-C4 alkyl, C1-C4 alkylene, C3-C6 cycloalkyl or 4-7 membered heterocyclyl is optionally substituted by one or more halogen, CN, OH or NH2.

[0129] In some embodiments, R 3 Selected from L 1 -L 2 -R y , L 1 is selected from -NH-, -O-, -S-, -S(=O)-, -SO2-, -C(=O)-, -NHSO2- or -NH(C=O)-, L 2 Selected from C1-C4 alkylene, R y is selected from H, said C1-C4 alkylene being optionally substituted with one or more halogen, CN, OH or NH2.

[0130] In some embodiments, R 3 Selected from L 1 -L 2 -R y , L 1 Selected from -NHSO2-, L 2 Selected from C1-C4 alkylene, R yis selected from H, said C1-C4 alkylene being optionally substituted with one or more halogen or OH.

[0131] In some embodiments, R 3 Selected from

[0132] In some embodiments, R 3 Selected from

[0133] In some embodiments, X, Y, and Z are all selected from CH.

[0134] In another aspect, the present disclosure provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof:

[0135] In formula (II):

[0136] A is a monocyclic or bicyclic ring selected from a 4-10 membered carbocyclic ring or a 4-10 membered heterocyclic ring, wherein the 4-10 membered carbocyclic ring or the 4-10 membered heterocyclic ring is optionally substituted by one or more R b Replace, each R b Independently selected from halogen, OH, C1-C6 alkyl, O(C1-C4 alkyl), NH2, NH(C1-C4 alkyl) or N(C1-C4 alkyl)2, the C1-C6 alkyl is optionally substituted by one or more groups independently selected from halogen, cyano, OH, NH2 or O(C1-C4 alkyl);

[0137] X1, X2, X3, X4 and X5 are each independently CR a or nitrogen; where R a are each independently selected from absent, H or halogen;

[0138] R 1 is absent, H, C1-C6 alkyl, cyano, C1-C6 alkoxy, (CH2) r -C(O)R d , halogen, (CH2) r -C3-C 10 Cycloalkyl, (CH2) r -C5-C 10 Cycloalkenyl, (CH2) r -4-10 membered heterocyclic group, (CH2) r -C6-C 10 Aryl or (CH2) r -5-10 membered heteroaryl, wherein r is 0, 1, 2 or 3, the C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C5-C 10 Cycloalkenyl, 4-10 membered heterocyclic group, C6-C10 Aryl or 5-10 membered heteroaryl is optionally substituted with one or more groups independently selected from halogen, CN, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, O(C1-C4 alkyl), NH(C1-C4 alkyl) or N(C1-C4 alkyl);

[0139] R 2 is H, C1-C6 alkyl, cyano, C1-C6 alkoxy, C(O)R d , halogen, C1-C6 haloalkyl or C1-C6 haloalkoxy; R d is selected from OH, C1-C6 alkyl, O(C1-C4 alkyl), NH2, NH(C1-C4 alkyl) or N(C1-C4 alkyl)2; and

[0140] R 3 is selected from C1-C6 alkyl groups optionally substituted by one or more halogen or OH.

[0141] In some embodiments, the compound represented by formula (II) and its sub-formula (III) does not include the following compounds:

[0142] In some embodiments, the compound represented by formula (II) and its sub-formula (III) does not include the following compounds:

[0143] In some embodiments, the compound represented by formula (II) and its sub-formula (III) does not include the following compounds:

[0144] In some embodiments, the compound represented by formula (II) and its sub-formula (III) does not include the following compounds:

[0145] In some embodiments, R 1 and R 2 When one of is H, the other is not H, methyl, CN or halogen.

[0146] In some embodiments, A is a monocyclic or bicyclic ring selected from a 4-10 membered carbocyclic ring or a 4-10 membered heterocyclic ring, wherein the 4-10 membered carbocyclic ring or the 4-10 membered heterocyclic ring is optionally substituted by one or more R b Replace, each R bindependently selected from F or C1-C4 alkyl, said C1-C4 alkyl being optionally substituted with one or more groups independently selected from F or O(C1-C4 alkyl).

[0147] In some embodiments, the structural unit Selected from optionally one or more R b Substituted with the following groups:

[0148] In some embodiments, the structural unit Selected from

[0149] In some embodiments, X1, X2, X3, X4 and X5 are each independently CR a or N; where R a Each is independently selected from absent, H or F.

[0150] In some embodiments, X5 is N.

[0151] In some embodiments, at least one of X1, X2, X3, X4, and X5 is N.

[0152] In some embodiments, one, two, or three of X1, X2, X3, X4, and X5 are N.

[0153] In some embodiments, X2 and X5 are both N; in some embodiments, X3 and X5 are both N; in some embodiments, X4 and X5 are both N.

[0154] In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof is selected from the compound of formula (III) or a pharmaceutically acceptable salt thereof:

[0155] In formula (III):

[0156] A is a monocyclic or bicyclic ring selected from a 4-10 membered carbocyclic ring or a 4-10 membered heterocyclic ring, wherein the 4-10 membered carbocyclic ring or the 4-10 membered heterocyclic ring is optionally substituted by one or more R b Replace, each R b Independently selected from halogen, OH, C1-C6 alkyl, O(C1-C4 alkyl), NH2, NH(C1-C4 alkyl) or N(C1-C4 alkyl)2, the C1-C6 alkyl is optionally substituted by one or more groups independently selected from halogen, cyano, OH, NH2 or O(C1-C4 alkyl);

[0157] X1, X2, and X3 are each independently C or N;

[0158] R 1 is absent, H, C1-C6 alkyl, cyano, C1-C6 alkoxy, (CH2) r -C(O)R d , halogen, (CH2) r -C3-C 10 Cycloalkyl, (CH2) r -C5-C 10 Cycloalkenyl, (CH2) r -4-10 membered heterocyclic group, (CH2) r -C6-C 10 Aryl or (CH2) r -5-10 membered heteroaryl, wherein r is 0, 1, 2 or 3, the C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C5-C 10 Cycloalkenyl, 4-10 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally substituted with one or more groups independently selected from halogen, CN, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, O(C1-C4 alkyl), NH(C1-C4 alkyl) or N(C1-C4 alkyl);

[0159] R 2 is H, C1-C6 alkyl, cyano, C1-C6 alkoxy, C(O)R d , halogen, C1-C6 haloalkyl or C1-C6 haloalkoxy;

[0160] R d is selected from OH, C1-C6 alkyl, O(C1-C4 alkyl), NH2, NH(C1-C4 alkyl) or N(C1-C4 alkyl)2, and when R 1 and R 2 When one of is H, the other is not H, cyano or halogen; and

[0161] R 3 is selected from C1-C6 alkyl groups optionally substituted by one or more halogen or OH.

[0162] In some embodiments, R in Formula (II) or Formula (III) 1 is absent, H, C1-C6 alkyl, cyano, C1-C6 alkoxy or C(O)R d .

[0163] In some embodiments, R in Formula (II) or Formula (III) 1is absent, H, cyano, C1-C6 alkoxy or C(O)R d .

[0164] In some embodiments, R in Formula (II) or Formula (III) 1 is absent, H, cyano, methoxy, C(O)NHCH2CH3 or C(O)OCH3.

[0165] In some embodiments, R in Formula (II) or Formula (III) 2 is H, C1-C6 alkyl, cyano, C1-C6 alkoxy or C(O)R d .

[0166] In some embodiments, R in Formula (II) or Formula (III) 2 is H or C1-C6 alkyl.

[0167] In some embodiments, R in Formula (II) or Formula (III) 2 is H or methyl.

[0168] In some embodiments, R in Formula (II) or Formula (III) d Selected from O(C1-C4 alkyl), NH2, NH(C1-C4 alkyl) or N(C1-C4 alkyl)2.

[0169] In some embodiments, R in Formula (II) or Formula (III) d Selected from O(C1-C4 alkyl) or NH(C1-C4 alkyl).

[0170] In some embodiments, R in Formula (II) or Formula (III) d Selected from methoxy or NHCH2CH3.

[0171] In some embodiments, R in Formula (II) or Formula (III) 3 is selected from C1-C4 alkyl groups optionally substituted by one or more halogen or OH.

[0172] In some embodiments, R in Formula (II) or Formula (III) 3 is selected from C1-C4 alkyl groups optionally substituted by one or more OH groups.

[0173] In some embodiments, R in Formula (II) or Formula (III) 3 Selected from

[0174] In some embodiments, R in Formula (II) or Formula (III) 3 Selected from

[0175] It is understood that any embodiment of the compounds of formula (I), formula (II) and formula (III) disclosed herein as described above and the specific rings A, M, Q, R, and R in the compounds disclosed herein as described above are not limited to the embodiments of the compounds of formula (I), formula (II) and formula (III) disclosed herein. a 、R b 、R 1a 、R 1b 、R 2b 、R 3a 、R 3b 、X 1 To X 6 、R 4b 、R 1 to R 5 、R x 、R xb , L 1 , L 2 、R y 、R 5a 、R 5b , X, Y, Z, R c and R d Any specific substituent described above for a substituent such as a substituent may be independently combined with other embodiments of the invention and / or substituents of compounds to form embodiments of the invention not specifically described above. In addition, any specific substituents described in the specific embodiments and / or claims with respect to any specific ring A, ring M, ring Q, R a 、R 1a 、R 1b 、R 2b 、R 3a 、R 3b 、X 1 To X 6 、R 4b 、R 1 to R 5 、R x 、R xb , L 1 , L 2 、R y 、R 5a 、R 5b , X, Y, Z, R c and R d Where a list of substituents is disclosed, it is understood that one or more substituents may be deleted from the list and the remaining list of substituents will be considered an embodiment of the invention.

[0176] In another aspect, the present disclosure further provides the following compound or a pharmaceutically acceptable salt thereof:

[0177] The present disclosure also provides a pharmaceutical composition comprising a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0178] Furthermore, the present disclosure relates to the use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for preventing or treating KIF18A-related diseases.

[0179] Furthermore, the present disclosure relates to the use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for preventing or treating tumors.

[0180] Furthermore, the present disclosure relates to the use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in preventing or treating KIF18A-related diseases.

[0181] Furthermore, the present disclosure relates to the use of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in preventing or treating tumors.

[0182] Furthermore, the present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for preventing or treating a KIF18A-related disease.

[0183] Furthermore, the present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preventing or treating tumors.

[0184] The present disclosure also relates to a method for treating a KIF18A-related disease, which comprises administering to a patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, or a pharmaceutical preparation comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0185] The present disclosure also relates to a method for treating tumors, which comprises administering to a patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, or a pharmaceutical preparation comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0186] In some embodiments, the KIF18A-related disease is selected from tumors.

[0187] In some embodiments, the KIF18A-related disease is selected from ovarian cancer.

[0188] Definitions and Explanations of Terms

[0189] Unless otherwise indicated, the terms used in this disclosure have the following meanings. The definitions of groups and terms described in this disclosure, including their exemplary definitions, preferred definitions, definitions described in tables, and definitions of specific compounds in the Examples, may be combined and coupled with each other in any manner. A particular term should not be considered undefined or unclear unless specifically defined, but should be understood according to its common meaning in the art. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0190] In this article Indicates the attachment site.

[0191] Structural units such as The dotted circle inside the ring represents the aromatic delocalized bond.

[0192] The term "tautomer" refers to functional group isomers resulting from the rapid shift of an atom between two positions in a molecule. Compounds of the present disclosure may exhibit tautomerism. Tautomeric compounds may exist as two or more interconvertible species. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer typically produce a mixture whose physical and chemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates, while in phenols, the enol form predominates. The present disclosure encompasses all tautomeric forms of the compounds.

[0193] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and diastereomers.

[0194] The compounds of the present disclosure may have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms or asymmetric double bonds, so that the compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. Specific geometric or stereoisomeric forms may be cis and trans isomers, E and Z geometric isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures or other mixtures thereof, such as mixtures enriched in enantiomers or diastereomers, all of which are within the definition of compounds of the present disclosure and mixtures thereof. Substituents such as alkyl groups may have additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms or asymmetric phosphorus atoms, and all of which are within the definition of compounds of the present disclosure and mixtures thereof. Compounds of the present disclosure containing an asymmetric atom can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or reagents.

[0195] The term "substituted" refers to the replacement of any one or more (e.g., 1, 2, 3, 4, 5, 6) hydrogen atoms on a particular atom by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced. Oxo does not occur on aromatic groups.

[0196] The term "optionally" or "optionally" refers to that the event or situation described subsequently may or may not occur, and the description includes that the event or situation occurs and that the event or situation does not occur. For example, ethyl is "optionally" substituted by one or more halogens, meaning that ethyl can be unsubstituted (CH2CH3), monosubstituted (CH2CH2F, CH2CH2Cl etc.), polysubstituted (CHFCH2F, CH2CHF2, CHFCH2Cl, CH2CHCl2 etc.) or fully substituted (CF2CF3, CF2CCl3, CCl2CCl3 etc.). It will be appreciated by those skilled in the art that for any group comprising one or more substituents, any sterically impossible existence and / or incomposable replacement or substitution pattern will not be introduced.

[0197] When any variable (such as R a 、R b ) appears more than once in the composition or structure of a compound, its definition is independent in each case. For example, if a group is represented by two R b is replaced, then each R b There are independent options.

[0198] When the number of a linking group is 0, such as -(CH2)0-, it means that the linking group is a bond.

[0199] When one of the variables is selected from a chemical bond or does not exist, it means that the two groups it connects are directly connected. For example, when L in ALZ represents a bond, it means that the structure is actually AZ.

[0200] When the linking group mentioned in this article does not specify its connection direction, its connection direction is arbitrary. 1 -L 2 -R y L in 1 Selected from "-NR 5 SO2-", at this time L 1 You can connect L in the direction from left to right 2 -R y Composition "-NR 5 SO2-L 2 -R y ", you can also connect L from right to left 2 -R y Composition "-SO2NR 5 -L 2 -R y ”.

[0201] When a chemical bond crosses two atoms in a ring, it means that the chemical bond can be bonded to any atom in the ring. This means that the chemical bond can be bonded to any position on the benzene ring.

[0202] In this article, C m -C n It means having an integer number of carbon atoms in the range mn. For example, "C1-C 10 ” means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, or 10 carbon atoms.

[0203] The term "azapyridinone" refers to a pyridinone group (e.g. ) is replaced by 1 or 2 N atoms (including but not limited to ).

[0204] The term "alkyl" refers to a group of the formula C n H 2n+1 The term "C1-C 10The term "alkyl" is understood to mean a straight-chain or branched saturated hydrocarbon radical having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Specific examples of the alkyl radical include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2- dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc.; the term "C1-C6 alkyl" can be understood to mean an alkyl group having 1 to 6 carbon atoms, and specific examples include but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc. The term "C1-C4 alkyl" can be understood to mean a straight-chain or branched saturated alkyl group having 1 to 4 carbon atoms. The "C1-C 10 The term "alkyl" may include "C1-C6 alkyl" or "C1-C4 alkyl" and the like, and the "C1-C6 alkyl" may further include "C1-C4 alkyl".

[0205] The term "alkylene" may be understood to mean a linear or branched saturated divalent hydrocarbon group. The term "C1-C4 alkylene" may be understood to mean a linear or branched saturated divalent hydrocarbon group having 1, 2, 3, or 4 carbon atoms. The "C1-C4 alkylene" may include "C1-C3 alkylene."

[0206] The term "alkoxy" refers to a group generated by the loss of a hydrogen atom from a hydroxyl group of a straight-chain or branched alcohol, and can be understood as "alkyloxy" or "alkyl-O-". The term "C1-C 10 "Alkoxy" can be understood as "C1-C 10 Alkyloxy" or "C1-C 10 Alkyl-O-"; the term "C1-C6 alkoxy" can be understood as "C1-C6 alkyloxy" or "C1-C6 alkyl-O-". The "C1-C 10 The term "alkoxy" may include "C1-C6 alkoxy" and "C1-C3 alkoxy", and the "C1-C6 alkoxy" may further include "C1-C3 alkoxy".

[0207] The term "haloalkyl" refers to an alkyl group as defined above in which one, two, or more hydrogen atoms, or all of the hydrogen atoms, are replaced by halogen. "Haloalkyl" may be a C1-C8 haloalkyl, a C1-C6 haloalkyl, or a C1-C4 haloalkyl. The term "haloalkoxy" refers to an alkoxy group as defined above in which one, two, or more hydrogen atoms, or all of the hydrogen atoms, are replaced by halogen. "Haloalkoxy" may be a C1-C8 haloalkoxy, a C1-C6 haloalkoxy, or a C1-C4 haloalkoxy.

[0208] The term "alkenyl" refers to a linear or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one double bond. 10 "Alkenyl" is understood to mean a linear or branched unsaturated hydrocarbon radical containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, "C2-C 10 The term "alkenyl" may include "C2-C6 alkenyl", "C2-C4 alkenyl", C2 or C3 alkenyl. It will be understood that when the alkenyl contains more than one double bond, the double bonds may be separated or conjugated with each other. Specific examples of the alkenyl include, but are not limited to, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl or (Z)-1-methylprop-1-enyl, etc.

[0209] The term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one triple bond. 10 "Alkynyl" is understood to mean a linear or branched unsaturated hydrocarbon radical containing one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. "C2-C 10 Examples of "alkynyl" include, but are not limited to, ethynyl (-C≡CH), propynyl (-C≡CCH 3、 -CH2C≡CH), but-1-ynyl, but-2-ynyl or but-3-ynyl. "C2-C 10 The term "alkynyl" may include "C2-C3 alkynyl". Examples of "C2-C3 alkynyl" include ethynyl (-C≡CH), prop-1-ynyl (-C≡CCH3), and prop-2-ynyl (-CH2C≡CH).

[0210] The term "cycloalkyl" refers to a fully saturated carbocyclic group that exists in the form of a monocyclic, fused, bridged, or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically a 3- to 20-membered ring. The term "C3-C 12"Cycloalkyl" refers to a cycloalkyl group having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ring carbon atoms, and specific examples of the cycloalkyl group include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, spiro[4.5]decyl, etc. The term "C3-C 12 The cycloalkyl group may contain C5-C 12 Cycloalkyl", "C3-C 10 The term "C5-C6 cycloalkyl" and "C3-C6 cycloalkyl" are also included. 12 "Cycloalkyl" refers to a cycloalkyl group having 5, 6, 7, 8, 9, 10, 11 or 12 ring carbon atoms. The term "C3-C 10 The term "cycloalkyl" refers to a cycloalkyl group having 3, 4, 5, 6, 7, 8, 9 or 10 ring carbon atoms. The term "C3-C6 cycloalkyl" refers to a cycloalkyl group having 3, 4, 5 or 6 ring carbon atoms.

[0211] The term "cycloalkyloxy" may be understood as "cycloalkyl-O-".

[0212] The term "C3-C 10 "Cycloalkenyl" refers to an incompletely saturated non-aromatic carbocyclic group having at least one carbon-carbon double bond and existing in the form of a monocyclic, condensed, bridged or spirocyclic ring, which has 3 to 10 ring carbon atoms. The term "C5-C 10 "Cycloalkenyl" refers to a cycloalkenyl group having 5, 6, 7, 8, 9, or 10 ring carbon atoms. The term "C5-C7 monocycloalkenyl" refers to a monocycloalkenyl group having 5, 6, or 7 ring carbon atoms. Specific examples of the cycloalkenyl group include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, or cycloheptadienyl.

[0213] The term "heterocyclyl" refers to a fully saturated or partially saturated (not aromatic as a whole) monocyclic, fused, spiro or bridged ring group, the ring atoms of which contain 1-5 (e.g., 1-3 or 1-2) heteroatoms or heteroatom groups (i.e., atomic groups containing heteroatoms), wherein the "heteroatoms or heteroatom groups" include but are not limited to nitrogen atom (N), oxygen atom (O), sulfur atom (S), phosphorus atom (P), boron atom (B), -S(=O)2-, -S(=O)-, -P(=O)2-, -P(=O)-, -NH-, -S(=O)(=NH)-, -C(=O)NH- or -NHC(=O)NH-, etc. The fused, spiro or bridged ring may be bicyclic, tricyclic, tetracyclic or pentacyclic. The term "12-20 membered tetracyclic heterocyclyl" refers to a tetracyclic heterocyclyl having 12, 13, 14, 15, 16, 17, 18, 19 or 20 ring atoms, wherein the ring atoms contain 1, 2, 3, 4 or 5 heteroatoms or heteroatom groups independently selected from the above, wherein the tetracyclic ring exists in the form of a fused ring, a spiro ring, a bridged ring or a combination thereof. The term "10-16 membered tricyclic heterocyclyl" refers to a tricyclic heterocyclyl having 10, 11, 12, 13, 14, 15 or 16 ring atoms, wherein the ring atoms contain 1, 2, 3, 4 or 5 heteroatoms or heteroatom groups independently selected from the above, wherein the tricyclic ring exists in the form of a fused ring, a spiro ring, a bridged ring or a combination thereof. The "10-16 membered tricyclic heterocyclyl" may include a "12-15 membered tricyclic heterocyclyl". The term "4-14 membered heterocyclyl" refers to a heterocyclyl group having 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, and containing 1, 2, 3, 4 or 5 heteroatoms or heteroatom groups independently selected from the above-mentioned heteroatoms. The term "4-10 membered heterocyclyl" refers to a heterocyclyl group having 4, 5, 6, 7, 8, 9 or 10 ring atoms, and containing 1, 2, 3, 4 or 5 heteroatoms or heteroatom groups independently selected from the above-mentioned heteroatoms. "4-14 membered heterocyclyl" may include "4-10 membered heterocyclyl" and "4-7 membered heterocyclyl". "4-10 membered heterocyclyl" may include "4-7 membered heterocyclyl". The term "4-7 membered heterocyclyl" refers to a heterocyclyl having 4, 5, 6 or 7 ring atoms, and containing 1, 2, 3, 4 or 5 heteroatoms or heteroatom groups independently selected from the above-mentioned heteroatoms. The term "4-7 membered monoheterocyclyl" refers to a 4-7 membered heterocyclyl in the form of a monocyclic ring.Specific examples of 4-membered heterocyclic groups include, but are not limited to, azetidinyl or oxetanyl; specific examples of 5-membered heterocyclic groups include, but are not limited to, tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, 4,5-dihydrooxazolyl or 2,5-dihydro-1H-pyrrolyl; specific examples of 6-membered heterocyclic groups include, but are not limited to, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, tetrahydropyridinyl or 4H-[1,3,4]thiadiazinyl; specific examples of 7-membered heterocyclic groups include, but are not limited to, diazepanyl. The heterocyclic group may also be a bicyclic group, wherein specific examples of 5,5-membered bicyclic groups include but are not limited to hexahydrocyclopenta[c]pyrrol-2(1H)-yl; specific examples of 5,6-membered bicyclic groups include but are not limited to hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl or 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazinyl. Optionally, the heterocyclic group may be a benzo-fused ring group of the above-mentioned 4-7-membered heterocyclic groups, specific examples of which include but are not limited to dihydroisoquinolinyl and the like. "4-10 membered heterocyclyl" may include "5-10 membered heterocyclyl", "4-7 membered heterocyclyl", "5-6 membered heterocyclyl", "6-8 membered heterocyclyl", "4-10 membered heterocycloalkyl", "5-10 membered heterocycloalkyl", "4-7 membered heterocycloalkyl", "5-6 membered heterocycloalkyl", "6-8 membered heterocycloalkyl", etc., and "4-7 membered heterocyclyl" may further include "4-6 membered heterocyclyl", "5-6 membered heterocyclyl", "4-7 membered heterocycloalkyl", "4-6 membered heterocycloalkyl", "5-6 membered heterocycloalkyl", etc. In the present disclosure, although some bicyclic heterocyclyl groups partially contain a benzene ring or a heteroaromatic ring, the heterocyclyl group as a whole is still non-aromatic.

[0214] The term "heterocyclyloxy" may be understood as "heterocyclyl-O-".

[0215] The term "heterocycloalkyl" refers to a fully saturated cyclic group in the form of a monocyclic, fused, bridged or spirocyclic ring, wherein the ring atoms of the ring contain 1 to 5 heteroatoms or heteroatomic groups (i.e., heteroatomic groups containing heteroatoms), wherein the "heteroatoms or heteroatomic groups" include, but are not limited to, nitrogen atom (N), oxygen atom (O), sulfur atom (S), phosphorus atom (P), boron atom (B), -S(=O)2-, -S(=O)-, -NH-, -S(=O)(=NH)-, -C(=O)NH- or -NHC(=O)NH-. The term "4-10 membered heterocycloalkyl" refers to a heterocycloalkyl group having 4, 5, 6, 7, 8, 9 or 10 ring atoms, wherein the ring atoms of the heterocycloalkyl group contain 1 to 5 heteroatoms or heteroatomic groups independently selected from the above-mentioned heteroatoms or heteroatomic groups. “4-10 membered heterocycloalkyl” includes “4-7 membered heterocycloalkyl”, wherein specific examples of 4 membered heterocycloalkyl include but are not limited to azetidinyl, oxetanyl or thietanyl; specific examples of 5 membered heterocycloalkyl include but are not limited to tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl or tetrahydropyrazolyl; specific examples of 6 membered heterocycloalkyl include but are not limited to piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl or 1,4-dithianyl; specific examples of 7 membered heterocycloalkyl include but are not limited to azepanyl, oxetanyl or thiepanyl.

[0216] The term "heterocycloalkyloxy" may be understood as "heterocycloalkyl-O-".

[0217] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π electron system. The aryl group may have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms. The term "C6-C 20 "Aryl" is understood to mean an aromatic group having 6 to 20 carbon atoms. For example, a ring having 6 carbon atoms ("C6 aryl"), such as phenyl; or a ring having 9 carbon atoms ("C9 aryl"), such as indanyl or indenyl; or a ring having 10 carbon atoms ("C 10 or a ring having 13 carbon atoms ("C 13 aryl) such as fluorenyl; or a ring having 14 carbon atoms ("C 14 The term "C6-C 10 "Aryl" is understood to mean an aromatic group having 6 to 10 carbon atoms. For example, a ring having 6 carbon atoms ("C6 aryl"), such as phenyl; or a ring having 9 carbon atoms ("C9 aryl"), such as indanyl or indenyl; or a ring having 10 carbon atoms ("C 10"aryl"), for example tetrahydronaphthyl, dihydronaphthyl or naphthyl.

[0218] The term "aryloxy" may be understood as "aryl-O-".

[0219] The term "heteroaryl" refers to an aromatic monocyclic or fused polycyclic ring system containing at least one ring atom selected from N, O, and S, with the remaining ring atoms being C. It typically has 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms and contains 1 to 8, preferably 1 to 5, heteroatoms independently selected from N, O, and S. The term "11-14 membered tricyclic heteroaryl" refers to an aromatic fused tricyclic ring system having 11, 12, 13, or 14 ring atoms, containing at least one ring atom selected from N, O, and S, with the remaining ring atoms being C. The term "5-10 membered heteroaryl" is understood to include monocyclic or bicyclic aromatic ring systems having 5, 6, 7, 8, 9, or 10 ring atoms, for example, 5, 6, 9, or 10 ring atoms, and containing 1 to 5, for example, 1 to 3, heteroatoms independently selected from N, O, and S. In particular, the heteroaryl group is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl or thiadiazolyl, and the like, and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl or isoindolyl, and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl, and the like, and benzo derivatives thereof, such as quinolyl, quinazolinyl or isoquinolyl, and the like; or acinyl, indolizinyl, purinyl, and the like, and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl or phenoxazinyl, and the like. The term "5-6 membered heteroaryl" or "5-6 membered monoheteroaryl" refers to an aromatic ring system having 5 or 6 ring atoms, and which contains 1 to 3, for example, 1 to 2, heteroatoms independently selected from N, O and S. The term "5-membered heteroaryl" refers to an aromatic ring system having 5 ring atoms, and which contains 1 to 3, for example, 1 or 2, heteroatoms independently selected from N, O and S.

[0220] The term "heteroaryloxy" may be understood as "heteroaryl-O-".

[0221] The term "halo" or "halogen" refers to fluorine, chlorine, bromine or iodine.

[0222] The term "hydroxy" refers to an -OH group.

[0223] The term "cyano" refers to a -CN group.

[0224] The term "mercapto" refers to a -SH group.

[0225] The term "amino" refers to a -NH2 group.

[0226] The term "nitro" refers to a -NO2 group.

[0227] The term "therapeutically effective amount" means an amount of a Compound of the Disclosure that (i) treats a particular disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) delays the onset of one or more symptoms of a particular disease, condition, or disorder as described herein. The amount of a Compound of the Disclosure that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art based on their knowledge and this disclosure.

[0228] The term "prevention" means administering a compound or formulation described herein to prevent a disease or one or more symptoms associated with the disease, and includes preventing the disease or disease state from occurring in an individual (e.g., a mammal), particularly when such individual (e.g., a mammal) is susceptible to the disease state but has not yet been diagnosed as having the disease state.

[0229] The term "subject" includes mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates (e.g., chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, and pigs; domestic animals, such as rabbits, dogs, and cats; and laboratory animals, including rodents, such as rats, mice, and guinea pigs. Examples of non-human mammals include, but are not limited to, birds and fish. In one embodiment of the methods and compositions provided herein, the mammal is a human. The terms "patient" and "subject" are used interchangeably.

[0230] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0231] The term "pharmaceutically acceptable salt" refers to a salt of a pharmaceutically acceptable acid or base, including a salt formed between a compound and an inorganic acid or organic acid, and a salt formed between a compound and an inorganic base or an organic base.

[0232] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure or their salts and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present disclosure to an organism.

[0233] The term "pharmaceutically acceptable excipient" refers to an excipient that is non-irritating to organisms and does not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

[0234] The word "comprise" or "comprises" and its English variations such as comprises or comprising are to be understood as having an open and non-exclusive meaning, ie, "including but not limited to".

[0235] The present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but where one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 123 I. 125 I and 36 Cl et al.

[0236] Certain isotopically labeled compounds of the present disclosure (e.g., 3 H and 14 C-labeled) can be used in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron emitting isotopes, such as 15 O. 13 N. 11 C and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically-labeled compounds of the disclosure can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or Examples below, by substituting an isotopically-labeled reagent for a non-isotopically-labeled reagent.

[0237] The pharmaceutical compositions of the present disclosure can be prepared by combining the compounds of the present disclosure with suitable pharmaceutically acceptable excipients, and can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.

[0238] Typical routes of administration of the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0239] The pharmaceutical composition of the present disclosure can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, emulsification methods, freeze-drying methods, and the like.

[0240] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present disclosure to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, and the like for oral administration to a patient.

[0241] Solid oral compositions can be prepared by conventional mixing, filling, or tableting methods. For example, they can be prepared by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients as needed, and then granulating the mixture to obtain a tablet or dragee core. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, or flavoring agents.

[0242] The pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.

[0243] In all administration methods of the compound of formula (I) described herein, the daily dosage is 0.01 mg / kg to 200 mg / kg body weight, preferably 0.05 mg / kg to 50 mg / kg body weight, more preferably 0.1 mg / kg to 30 mg / kg body weight, in the form of single or divided doses.

[0244] The compounds of the present disclosure can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present disclosure.

[0245] The chemical reactions of the specific embodiments of the present disclosure are carried out in a suitable solvent, which must be compatible with the chemical transformations of the present disclosure and the reagents and materials required. In order to obtain the compounds of the present disclosure, it is sometimes necessary for those skilled in the art to modify or select the synthetic steps or reaction schemes based on the existing embodiments.

[0246] This disclosure uses the following abbreviations: DETAILED DESCRIPTION

[0247] The invention is described in detail below by way of examples, but this is not intended to limit the present disclosure in any way. While the present disclosure has been described in detail herein, including specific embodiments thereof, it will be apparent to those skilled in the art that various changes and modifications can be made to the embodiments without departing from the spirit and scope of the present disclosure. All reagents used in the present disclosure are commercially available and used without further purification.

[0248] Unless otherwise specified, the ratios expressed for mixed solvents are volume ratios.

[0249] Unless otherwise specified, % refers to weight %.

[0250] Compounds are manually or Software naming, commercially available compounds use supplier catalog names.

[0251] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The units of NMR shifts are 10 -6 (ppm). The solvents for NMR determination are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS); "IC 50 ” refers to the half-maximal inhibitory concentration, which is the concentration at which half of the maximum inhibitory effect is achieved.

[0252] The eluent or mobile phase may be a mixed eluent or mobile phase composed of two or more solvents, and the ratio is the volume ratio of each solvent. For example, "0-10% methanol / dichloromethane" means that the volume ratio of methanol to dichloromethane in the mixed eluent or mobile phase is 0:100 to 10:100.

[0253] Example 1 Synthesis of Compound 1

[0254] Step 1: Synthesis of compound 1c

[0255] Compound 1a (2.00 g, 7.52 mmol) and potassium carbonate (3.12 g, 22.5 mmol) were added to DMSO (20 mL). Compound 1b hydrochloride (1.22 g, 8.27 mmol) was then added at 25°C. The reaction mixture was heated to 140°C for complete reaction. The reaction mixture was cooled, and water (60 mL) was added to the reaction system. The aqueous phase was washed with petroleum ether (30 mL x 2) and adjusted to pH 3 with hydrochloric acid (1 N). The mixture was filtered, and the filter cake was dried to obtain compound 1c (1.80 g).

[0256] Step 2: Synthesis of compound 1e

[0257] Compound 1c (30.0 mg, 83.9 μmol), diisopropylethylamine (54.2 mg, 419 μmol), and HATU (47.5 mg, 125 μmol) were added to DMF (1 mL). After sonication for 1 minute, compound 1d (13.5 mg, 100 μmol) was added and the reaction mixture was allowed to react fully at room temperature. Water (3 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (2 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was spin-dried. Compound 1e (32 mg) was purified by flash column chromatography (petroleum ether:ethyl acetate = 6:1) to afford compound 1e.

[0258] Step 3: Synthesis of compound 1

[0259] Compound 1e (20.0 mg, 42.2 μmol), compound 1f (10.5 mg, 84.5 μmol), potassium phosphate (26.9 mg, 126 μmol), and (1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (6.01 mg, 42.25 μmol) were added to DMF (0.5 mL), followed by cuprous iodide (16.0 mg, 84.5 μmol). The reaction mixture was allowed to react at 95°C under nitrogen. After completion of the reaction, the reaction mixture was cooled and directly purified by flash reverse-phase column chromatography (acetonitrile:water, 10-85%) to obtain compound 1 (8 mg).

[0260] MS m / z(ESI):471.4[M+H] + .

[0261] 1H NMR: (400MHz, DMSO-d6) δ12.63(s,1H),8.05(d,J=8.3Hz,1H),8.00(d,J=8.7Hz,1H),7.63(d,J=8.3Hz,1H),7.23(s,1H),7.08(d ,J=8.6Hz,1H),3.75(t,J=6.4Hz,2H),2.97(t,J=4.5Hz,6H),2.86(q,J=7.0Hz,4H),2.12–1.99(m,2H),1.67(s,4H),0.37(s,4H).

[0262] Example 2 Synthesis of Compound 2

[0263] Step 1: Synthesis of compound 2c

[0264] Compound 2a (1.0 g, 7.1 mmol) and PyBOP (11.3 g, 21.6 mmol) were dissolved in DMF (30 mL). DBU (11.2 g, 73.8 mmol) and the hydrochloride salt of compound 2b (1.6 g, 10.1 mmol) were added to the reaction solution. The reaction mixture was stirred at room temperature for sufficient reaction. The reaction mixture was dissolved in a mixed solvent of ethyl acetate and water and extracted with ethyl acetate (5 x 100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and purified by flash column chromatography (petroleum ether:ethyl acetate = 100:0 to 0:100) to obtain compound 2c (820 mg).

[0265] 1 H NMR (400MHz, DMSO-d6) δ6.22(s,2H),4.86(s,1H),3.24(s,3H),3.21(t,J=5.7Hz,4H),2.17 –2.03(m,4H).

[0266] Step 2: Synthesis of compound 2d

[0267] Oxalyl chloride (0.8 mL) and DMF (0.01 mL) were added separately to a solution of compound 1c (300 mg, 839.9 μmol) in dichloromethane (10 mL) at 0°C. The reaction mixture was stirred at room temperature. After completion, the reaction solution was spun down to dryness, and the residue was dissolved in dioxane (10 mL). A solution of compound 2c (204.8 mg, 838.6 μmol) and triethylamine (424.3 mg, 4.2 mmol, 584.8 μL) in 1,4-dioxane (15 mL) was slowly added dropwise at 0°C. The reaction mixture was allowed to react fully at room temperature. After completion, the reaction was quenched with water (25 mL) and extracted with ethyl acetate (3 x 30 mL). The organic phases were combined, concentrated, and purified by flash column chromatography (petroleum ether:ethyl acetate = 100:0 to 50:50) to afford compound 2d (180 mg).

[0268] MS m / z(ESI):584.0[M+H] + .

[0269] Step 3: Synthesis of compound 2

[0270] Compound 2 (20 mg) was synthesized and purified using the same method as in step 3 of Example 1 using compound 2d (50.0 mg, 85.7 μmol) and compound 1f (21.5 mg, 171.4 μmol) as starting materials.

[0271] MS m / z(ESI):581.1[M+H] + .

[0272] 1 H NMR (400MHz, DMSO-d6) δ13.13(s,1H),8.03(d,J=8.7Hz,1H),7.24(d,J=2.2Hz,1H),7.10(dd,J=8.7,2.1Hz,1H),6. 83(s,1H),3.75(t,J=6.5Hz,2H),3.38–3.32(m,9H),2.95(t,J=5.3Hz,4H),2.15(m,4H),1.71(m,4H),0.38(s,4H).

[0273] Example 3 Synthesis of Compound 3

[0274] Step 1: Synthesis of compound 3b

[0275] Compound 3b (33 mg) was synthesized and purified using the same method as in Step 2 of Example 1 using compound 1c (30.0 mg, 83.9 μmol) and compound 3a (14.9 mg, 100 μmol) as starting materials.

[0276] Step 2: Synthesis of compound 3

[0277] Compound 3 (8.1 mg) was synthesized and purified using the same method as in step 3 of Example 1 using compound 3b (33.0 mg, 67.7 μmol) and compound 1f (16.9 mg, 135 μmol) as starting materials.

[0278] MS m / z(ESI):485.3[M+H] + .

[0279] 1 H NMR (400MHz, DMSO-d6) δ12.94(s,1H),8.59(d,J=7.8Hz,1H),8.54(d,J=6.7Hz,1H),8.06(d,J=8.6Hz,1H),7.30(d,J=2 .2Hz,1H),7.15–7.07(m,2H),3.75(t,J=6.5Hz,2H),3.35(s,4H),2.98(s,4H),2.52(s,3H),1.85(s,2H),0.34(s,4H).

[0280] Example 4 Synthesis of Compound 4

[0281] Step 1: Synthesis of compound 4a

[0282] Compound 1f (2.00 g, 15.9 mmol) and imidazole (1.31 g, 19.1 mmol) were added to DMF (20 mL), followed by the addition of tert-butyldimethylsilyl chloride (2.89 g, 19.1 mmol) at 0°C. The reaction mixture was allowed to fully react at room temperature. Saturated ammonium chloride solution (50 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and slurried with petroleum ether to afford compound 4a (3.20 g).

[0283] Step 2: Synthesis of compound 4c

[0284] Compound 4b (200 mg, 1.23 mmol) and cesium carbonate (603 mg, 1.85 mmol) were added to DMF (20 mL), followed by cyclobutane bromide (333 mg, 2.46 mmol). The reaction mixture was allowed to react at 80°C. After cooling, water (30 mL) was added and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and dried. Compound 4c (212 mg) was then purified by flash column chromatography (petroleum ether:ethyl acetate = 9:1) to afford compound 4c.

[0285] Step 3: Synthesis of compound 4d

[0286] Compound 4c (100 mg, 0.46 mmol) and ammonium chloride (196 mg, 3.70 mmol) were added to ethanol (2 mL) and water (0.5 mL), followed by the addition of iron powder (103 mg, 1.85 mmol). The reaction mixture was allowed to react at 80°C. Aqueous sodium hydroxide solution (1N, 5 mL) was added, and the mixture was extracted with ethyl acetate (3 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was spin-dried to afford compound 4d (59.9 mg).

[0287] MS m / z(ESI):187.2[M+H] + .

[0288] Step 4: Synthesis of compound 4e

[0289] Compound 1c (1.00 g, 2.80 mmol) and potassium carbonate (464 mg, 3.36 mmol) were added to DMF (20 mL), followed by the addition of benzyl bromide (526 mg, 3.08 mmol) at 0°C. The reaction mixture was allowed to react fully at room temperature. Water (50 mL) was added to the system, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine, dried over magnesium sulfate, filtered, and the filtrate was spin-dried and purified by flash column chromatography (petroleum ether:ethyl acetate = 8:1) to afford compound 4e (1.0 g).

[0290] MS m / z(ESI):448.2[M+H] + .

[0291] Step 5: Synthesis of compound 4f

[0292] Compound 4f (0.51 g) was synthesized and purified using the same method as in step 3 of Example 1 using compound 4e (0.50 g, 1.12 mmol) and compound 4a (401 mg, 1.68 mmol) as starting materials.

[0293] MS m / z(ESI):559.3[M+H] + .

[0294] Step 6: Synthesis of compound 4g

[0295] Compound 4f (0.50 g, 1.12 mmol) was added to methanol (6 mL) and ethyl acetate (4 mL), and palladium on carbon (0.20 g, 10%) was added, and the mixture was fully reacted under a hydrogen atmosphere at 25°C. The reaction solution was filtered and dried, and slurried with petroleum ether (5 mL) to obtain compound 4g (314 mg).

[0296] MS m / z(ESI):469.3[M+H] + .

[0297] Step 7: Synthesis of compound 4h

[0298] Compound 4h (20.0 mg) was synthesized and purified using the same method as in step 2 of Example 1 using compound 4g (20.0 mg, 42.7 μmol) and compound 4d (11.9 mg, 64.1 μmol) as starting materials.

[0299] MS m / z(ESI):637.5[M+H] + .

[0300] Step 8: Synthesis of compound 4

[0301] Compound 4h (20.0 mg, 31.4 μmol) and pyridine hydrofluoride (9.32 mg, 94.2 μmol) were added to DMF and the reaction mixture was allowed to react at room temperature. The product was directly purified by flash reverse phase column chromatography (acetonitrile:water, 80%) to obtain compound 4 (7.2 mg).

[0302] MS m / z(ESI):523.3[M+H] + .

[0303] 1H NMR (400MHz, DMSO-d6) δ11.22(s,1H),7.94(d,J=7.6Hz,1H),7.86(d,J=8.4Hz,1H),7.60(d,J=3 .3Hz,1H),7.26(d,J=8.2Hz,1H),7.17(s,1H),7.11(t,J=8.0Hz,1H),7.01(d,J=8.5Hz,1H),6.7 0(d,J=3.3Hz,1H),5.04–4.90(m,1H),3.76(t,J=6.6Hz,2H),3.02(t,J=5.0Hz,4H),2.90–2.74( m,1H),2.49–2.40(m,4H),1.92–1.79(m,2H),1.46(s,4H),1.26–1.08(m,1H),0.32–0.22(s,4H).

[0304] Example 5 Synthesis of Compound 5

[0305] Step 1: Synthesis of compound 5b

[0306] Compound 5b (0.19 g) was synthesized and purified using the same method as in step 2 of Example 4 using compound 5a (0.20 g, 1.22 mmol) and 1-iodo-3,3,3-trifluoropropane (1.37 g, 6.13 mmol) as starting materials.

[0307] MS m / z(ESI):260.2[M+H] + .

[0308] Step 2: Synthesis of compound 5c

[0309] Compound 5c (0.12 g) was synthesized and purified using compound 5b (0.19 g, 0.73 mmol) as starting material in the same manner as in step 3 of Example 4.

[0310] MS m / z(ESI):230.1[M+H] + .

[0311] Step 3: Synthesis of compound 5d

[0312] Compound 4g (20.0 mg, 42.7 μmol), compound 5c (14.7 mg, 64.1 μmol), NMI (35.0 mg, 427 μmol), and TCFH (35.9 mg, 128 μmol) were added to acetonitrile (0.5 mL), and the reaction mixture was fully reacted at 80°C. Water (3 mL) was added to the system, and the mixture was extracted with ethyl acetate (2 mL*3). The combined organic phases were washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was spin-dried and purified by flash column chromatography (petroleum ether:ethyl acetate = 9:1) to obtain compound 5d (20.0 mg).

[0313] MS m / z(ESI):680.4[M+H] + .

[0314] Step 4: Synthesis of compound 5

[0315] Compound 5 (7.1 mg) was synthesized and purified using compound 5d (20.0 mg, 29.4 μmol) as starting material in the same manner as in step eight of Example 4.

[0316] MS m / z(ESI):566.3[M+H] + .

[0317] Example 6 Synthesis of Compound 6

[0318] Step 1: Synthesis of compound 6a

[0319] Compound 6a (0.21 g) was synthesized and purified using the same method as in step 2 of Example 4 using compound 5a (0.20 g, 1.22 mmol) and 2-iodopropane (0.31 g, 1.83 mmol) as starting materials.

[0320] MS m / z(ESI):206.4[M+H] + .

[0321] Step 2: Synthesis of compound 6b

[0322] Compound 6b (0.13 g) was synthesized and purified using compound 6a (0.21 g, 0.99 mmol) as a starting material in the same manner as in step 3 of Example 4.

[0323] MS m / z(ESI):176.2[M+H] + .

[0324] Step 3: Synthesis of compound 6c

[0325] Compound 6c (20.6 mg) was synthesized and purified using the same method as in step 3 of Example 5 using compound 4g (20.0 mg, 42.7 μmol) and 6b (11.3 mg, 64.1 mmol) as starting materials.

[0326] MS m / z(ESI):626.3[M+H] + .

[0327] Step 4: Synthesis of compound 6

[0328] Compound 6 (8.8 mg) was synthesized and purified using compound 6c (20.0 mg, 32.0 μmol) as starting material in the same manner as in step eight of Example 4.

[0329] MS m / z(ESI):512.3[M+H] + .

[0330] 1 H NMR(400MHz,Methanol-d4)δ8.21(d,J=5.5Hz,1H),8.09(d,J=5.4Hz,1H),8.0 0(d,J=8.5Hz,1H),7.55(d,J=4.4Hz,1H),7.30(s,1H),7.11(d,J=8.5Hz,1H),6 .78(d,J=3.7Hz,1H),5.18–5.08(m,1H),3.97(t,J=6.3Hz,2H),3.39(t,J=6.3H z,2H),3.13(d,J=5.7Hz,4H),1.59(s,4H),1.56(d,J=6.8Hz,6H),0.35(s,4H).

[0331] Example 7 Synthesis of Compound 7

[0332] Step 1: Synthesis of compound 7a

[0333] Compound 4g (30.0 mg, 64.1 μmol), diisopropylethylamine (54.2 mg, 321 μmol), and HATU (36.5 mg, 96.1 μmol) were added to DMF (1 mL). After sonication for 1 minute, ammonium chloride (10.1 mg, 192 μmol) was added, and the reaction mixture was allowed to react fully at room temperature. Water (3 mL) was added to the system, and the mixture was extracted with ethyl acetate (2 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was spin-dried. Compound 7a (24.9 mg) was purified by flash column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain compound 7a.

[0334] MS m / z(ESI):468.4[M+H] + .

[0335] Step 2: Synthesis of compound 7c

[0336] Compound 7a (10.0 mg, 21.4 μmol), compound 7b (5.71 mg, 32.1 μmol), and potassium phosphate (9.07 mg, 42.8 μmol) were added to DMF (0.3 mL), followed by the addition of X-Phos (2.03 mg, 4.28 μmol) and Pd2(dba)3 (1.96 mg, 2.14 μmol). The reaction mixture was allowed to react fully at room temperature. Water (2 mL) was added to the system, and the mixture was extracted with ethyl acetate (1 mL*3). The combined organic phases were washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was spin-dried. Compound 7c (9.07 mg) was obtained by flash column chromatography (petroleum ether:ethyl acetate = 6:1).

[0337] MS m / z(ESI):610.4[M+H] + .

[0338] Step 3: Synthesis of compound 7

[0339] Compound 7 (5.6 mg) was synthesized and purified using compound 7c (9.07 mg, 14.9 μmol) as starting material in the same manner as in step eight of Example 4.

[0340] MS m / z(ESI):496.3[M+H] + .

[0341] Example 8 Synthesis of Compound 8

[0342] Step 1: Synthesis of compound 8b

[0343] Compound 8b (25.0 mg) was synthesized and purified using the same method as in step 2 of Example 1 using compound 4g (20.0 mg, 42.7 μmol) and compound 8a (11.7 mg, 64.1 μmol) as starting materials.

[0344] MS m / z(ESI):634.1[M+H] + .

[0345] Step 2: Synthesis of compound 8

[0346] Compound 8 (9.6 mg) was synthesized and purified using compound 8b (20.0 mg, 31.6 μmol) as starting material in the same manner as in step eight of Example 4.

[0347] MS m / z(ESI):520.1[M+H] + .

[0348] Example 9 Synthesis of Compound 9

[0349] Step 1: Synthesis of compound 9b

[0350] Compound 9b (21.0 mg) was synthesized and purified using the same method as in step 2 of Example 1 using compound 4g (20.0 mg, 42.7 μmol) and compound 9a (10.3 mg, 64.1 μmol) as starting materials.

[0351] MS m / z(ESI):612.3[M+H] + .

[0352] Step 2: Synthesis of compound 9

[0353] Compound 9 (8.30 mg) was synthesized and purified using compound 9b (20.0 mg, 32.7 μmol) as starting material in the same manner as in step eight of Example 4.

[0354] MS m / z(ESI):498.4[M+H] + .

[0355] 1 H NMR (400MHz, Methanol-d4) δ8.25(d,J=7.5Hz,1H),8.04(d,J=8.2Hz,1H),7.87(d,J=6.8Hz,1H),7.30(s,1H),7.12(d,J=8.4Hz,1H),6.92( t,J=7.1Hz,1H),3.97(t,J=6.3Hz,2H),3.38(t,J=6.3Hz,2H),3.10(s,4H),2.45(d,J=16.2Hz,6H),1.73(s,2H),1.29(s,2H),0.32(s,4H).

[0356] Example 10 Synthesis of Compound 10

[0357] Step 1: Synthesis of compound 10c

[0358] Compound 10a (1.0 g, 5.66 mmol), compound 10b (1.22 g, 5.66 mmol), and triethylamine (1.14 g, 11.3 mmol) were added to DMF (10 mL), and the reaction mixture was allowed to react fully at room temperature. Water (20 mL) was added to the system, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was spin-dried. Compound 10c (960 mg) was purified by flash column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain compound 10c.

[0359] MS m / z(ESI):372.4[M+H] + .

[0360] Step 2: Synthesis of compound 10d

[0361] Compound 10c (742 mg, 2 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (1 mL) was added. The reaction mixture was allowed to react fully at room temperature. Volatiles were removed under vacuum, and the residue was redissolved in dichloromethane (5 mL). Triethylamine (1 mL) was added, and the reaction mixture was allowed to react fully at room temperature. Water (10 mL) was added to the system, and extraction was performed with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was spin-dried. Compound 10d (60 mg) was obtained by flash column chromatography (petroleum ether:ethyl acetate = 8:1).

[0362] MS m / z(ESI):236.3[M+H] + .

[0363] Step 3: Synthesis of compound 10e

[0364] Compound 10e (18 mg) was synthesized and purified using compound 10d (30 mg, 0.13 mmol) as starting material in the same manner as in step 3 of Example 4.

[0365] MS m / z(ESI):206.1[M+H] + .

[0366] Step 4: Synthesis of compound 10f

[0367] Compound 10f (24 mg) was synthesized and purified using the same method as in step 2 of Example 1 using compound 10e (15 mg, 73 μmol) and compound 4g (34 mg, 73 μmol) as starting materials.

[0368] MS m / z(ESI):656.5[M+H] + .

[0369] Step 5: Synthesis of compound 10

[0370] Compound 10 (6.3 mg) was synthesized and purified using compound 10f (20.0 mg, 30.5 μmol) as starting material in the same manner as in step eight of Example 4.

[0371] MS m / z(ESI):542.3[M+H] + .

[0372] 1 H NMR (400MHz, CDCl3) δ11.74(s,1H),8.11(d,J=8.5Hz,1H),7.98(d,J=5.7Hz,1H ),7.78(d,J=5.8Hz,1H),6.97(d,J=8.2Hz,1H),4.68(d,J=13.1Hz,1H),4.29(d ,J=10.0Hz,1H),4.13(t,J=5.2Hz,2H),4.02(t,J=9.2Hz,1H),3.41–3.19(m,3H ),3.13–2.95(m,4H),2.63(t,J=12.1Hz,1H),2.02–1.18(m,11H),0.37(s,4H).

[0373] Synthesis of Compounds 11 and 12 in Example 11 and Example 12

[0374] Step 1: Synthesis of compound 11b

[0375] Compound 11a (1.0 g, 6.54 mmol) and 5-valerolactone (0.65 g, 6.54 mmol) were added to 4N hydrochloric acid (20 mL), and the reaction mixture was fully reacted under reflux. After cooling to room temperature, the mixture was neutralized to a pH of 7-8 by adding 4N sodium hydroxide solution. The mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was spin-dried. Compound 11b (680 mg) was obtained by purification via flash column chromatography (petroleum ether:ethyl acetate = 1:1).

[0376] MS m / z(ESI):236.2[M+H] + .

[0377] Step 2: Synthesis of compound 11c

[0378] Compound 11c (500 mg, 2.13 mmol) was added to thionyl chloride (10 mL), and the reaction mixture was fully reacted under reflux. Volatiles were removed under vacuum, and saturated sodium bicarbonate solution (10 mL) was added. The mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was spin-dried. Compound 11c (460 mg) was purified by flash column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain compound 11c.

[0379] MS m / z(ESI):254.2[M+H] + .

[0380] Step 3: Synthesis of Compound 11d and Compound 11e

[0381] Compound 11c (400 mg, 1.57 mmol) was dissolved in anhydrous ethanol (10 mL), and sodium ethoxide (129 mg, 1.89 mmol) was added. The reaction mixture was allowed to react at room temperature. Volatiles were removed under vacuum, and saturated ammonium chloride solution (10 mL) was added. The mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was spin-dried. The mixture was purified by flash column chromatography (petroleum ether:ethyl acetate = 4:1) to afford a mixture of compound 11d and compound 11e (275 mg).

[0382] MS m / z(ESI):218.2[M+H] + .

[0383] Step 4: Synthesis of Compound 11f and Compound 11g

[0384] By the same method as in step 3 of Example 4, a mixture of compound 11d and compound 11e (217 mg, 1.0 mmol) was used as starting material to synthesize and purify a mixture of compound 11f and compound 11g (118 mg).

[0385] MS m / z(ESI):188.1[M+H] + .

[0386] Step 5: Synthesis of Compound 11h and Compound 11i

[0387] By the same method as in step 2 of Example 1, a mixture of compound 11f and compound 11g (40 mg, 214 μmol) and compound 4g (100 mg, 214 μmol) were used as raw materials to synthesize and purify a mixture of compound 11h and compound 11i (89 mg).

[0388] MS m / z(ESI):638.5[M+H] + .

[0389] Step 6: Synthesis of Compounds 11 and 12

[0390] By the same method as in Step 8 of Example 4, using a mixture of Compound 11h and Compound 11i (80.0 mg, 125 μmol) as starting material, Compound 11 (23 mg) and Compound 12 (26 mg) were synthesized and purified.

[0391] MS m / z(ESI):524.3[M+H] + .

[0392] Compound 11

[0393] 1 H NMR (400MHz, Methanol-d4) δ8.10(d,J=8.6Hz,1H),7.54(d,J=8.0Hz,1H),7.37(s,1H),7.27(t,J=7.8Hz,1H),7.19–7.11(m,2H),4.28(t,J=5.9 Hz,2H),3.96(t,J=6.1Hz,2H),3.38(t,J=6.4Hz,2H),3.15(t,J=5.4Hz, 4H), 3.06 (t, J = 6.2Hz, 2H), 2.04–1.96 (m, 4H), 1.61 (s, 2H), 0.40 (s, 4H).

[0394] Compound 12

[0395] 1 H NMR (400MHz, CDCl3) δ12.33(s,1H),8.32(d,J=8.0Hz,1H),8.04(d,J=8.4Hz,1H),7.08(d,J=8.0Hz,1H),6.94(d,J=8.5Hz, 1H),4.13(s,2H),4.04(s,2H),3.27(s,2H),3.15-3.03(m,6H),2.17(s,2H),2.05(s,2H),1.98–1.65(m,4H),0.28(s,4H).

[0396] Example 13 Synthesis of Compound 13

[0397] Step 1: Synthesis of compound 13b

[0398] Trifluoropropanol (328 mg), compound 13a (270 mg), and potassium carbonate (437 mg) were mixed in DMF (20 mL), and the mixture was stirred at 90°C for thorough reaction. After cooling to room temperature, water (100 mL) was added, and the mixture was extracted with dichloromethane (3 x 20 mL). The organic phases were combined and concentrated, and purified by flash column chromatography (petroleum ether:ethyl acetate = 100:0 to 80:20) to provide compound 13b (200 mg).

[0399] MS m / z(ESI):266.0[M+H] + .

[0400] Step 2: Synthesis of compound 13d

[0401] Under nitrogen, Pd2(dba)3 (65 mg), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (Xantphos, 83 mg), and cesium carbonate (0.6 g) were added to a dioxane (5 mL) solution of 13b (190 mg) and 13c (170 mg), and the reaction mixture was fully reacted in a microwave at 120°C. After the reaction solution was cooled to room temperature, water (25 mL) was added, and the mixture was extracted with dichloromethane (3 x 10 mL). The organic phases were combined and concentrated, and purified by flash column chromatography (petroleum ether:ethyl acetate = 100:0-55:45) to give compound 13d (160 mg).

[0402] MS m / z(ESI):347.1[M+H] + .

[0403] Step 3: Synthesis of compound 13e

[0404] Trifluoroacetic acid (2 mL) was added to a solution of 13d (150 mg) in dichloromethane (5 mL) at 0°C, and the reaction mixture was allowed to react fully at room temperature. The volatiles were removed under vacuum, and the residue was mixed with dichloromethane (5 mL) and saturated sodium bicarbonate solution (5 mL). The mixture was extracted with dichloromethane (3 x 5 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried to give 13e (100 mg).

[0405] MS m / z(ESI):247.1[M+H] + .

[0406] Step 4: Synthesis of compound 13f

[0407] Compound 13f (80 mg) was synthesized and purified using the same method as in Step 2 of Example 1 using Compound 1c (42 mg) and Compound 13e (60 mg) as starting materials.

[0408] MS m / z(ESI):586.1[M+H] + .

[0409] Step 5: Synthesis of compound 13

[0410] Compound 13 (25 mg) was synthesized and purified using the same method as in Step 3 of Example 1 using Compound 13f (50 mg) and Compound 1f (54 mg) as starting materials.

[0411] MS m / z(ESI):583.2[M+H] + .

[0412] 1 H-NMR (600MHz, DMSO-d6) δ13.47(s,1H),10.34(m,1H),8.10(d,J=8.7Hz,1H),7.94(s,1H),7.66(s,1H),7.52(s,1H),7.29(d,J=2.2Hz,1H) ,7.14(dd,J=8.5,2.2Hz,1H),4.85(t,J=5.9Hz,2H),3.77(t,J=6.5Hz,2H),3.38–3.34(m,2H),3.10–2.96(m,6H),1.76(m,4H),0.41(s,4H).

[0413] Example 14 Synthesis of Compound 14

[0414] Step 1: Synthesis of compound 14a

[0415] Compound 14a (650 mg) was synthesized and purified using the same method as in Step 1 of Example 13, using Compound 13a (500 mg) and Compound 2b (838 mg) as starting materials.

[0416] MS m / z(ESI):273.1[M+H] + .

[0417] Step 2: Synthesis of compound 14b

[0418] Compound 14b (600 mg) was synthesized and purified using the same method as in Step 2 of Example 13, using compound 14a (500 mg) and p-methoxybenzylamine (PMBNH2, 503 mg) as starting materials.

[0419] Step 3: Synthesis of compound 14c

[0420] Compound 14c (230 mg) was synthesized and purified using compound 14b (600 mg) as starting material in the same manner as in step 3 of Example 13.

[0421] MS m / z(ESI):254.1[M+H] + .

[0422] Step 4: Synthesis of compound 14d

[0423] Compound 14d (120 mg) was synthesized and purified using compound 14c (100 mg) and compound 1c (141 mg) as starting materials in the same manner as in step 2 of Example 1.

[0424] MS m / z(ESI):586.1[M+H] + .

[0425] Step 5: Synthesis of compound 14

[0426] Compound 14 (20 mg) was synthesized and purified using the same method as in Step 3 of Example 1 using Compound 14d (50 mg) and Compound 1f (50 mg) as starting materials.

[0427] MS m / z(ESI):590.2[M+H] + .

[0428] 1 H NMR(400MHz,DMSO-d6)δ13.30(s,1H),10.47–10.02(m,1H),8.10(d,J=8.7 Hz,1H),7.94(s,1H),7.82(s,1H),7.55(s,1H),7.29(d,J=2.1Hz,1H),7.1 4(dd,J=8.7,2.1Hz,1H),4.95(m,1H),3.77(t,J=6.5Hz,2H),3.61(d,J=6. 4Hz,4H),3.33(m,2H),3.00(s,4H),2.29(m,4H),1.76(m,4H),0.41(s,4H).

[0429] Example 15 Synthesis of Compound 15

[0430] Step 1: Synthesis of compound 15b

[0431] Compound 15b (60 mg) was synthesized and purified using compound 15a (40 mg) and compound 1c (100 mg) as starting materials in the same manner as in step 2 of Example 1.

[0432] MS m / z(ESI):487.1[M+H] + .

[0433] Step 2: Synthesis of compound 15

[0434] Compound 15 (23 mg) was synthesized and purified using the same method as in Step 3 of Example 1 using Compound 15b (60 mg) and Compound 1f (40 mg) as starting materials.

[0435] MS m / z(ESI):484.1[M+H] + .

[0436] 1 H NMR (400MHz, DMSO-d6) δ13.40 (s, 1H), 10.20 (br, 1H), 8.09 (d, J = 8.7Hz, 2H), 7. 99(d,J=8.4Hz,1H),7.40(d,J=3.5Hz,1H),7.29(d,J=2.2Hz,1H),7.14(dd,J=8. 6,2.1Hz,1H),6.43(d,J=3.4Hz,1H),4.96(br,1H),3.79(s,3H),3.77(t,J=6.4 Hz,2H),3.36(t,J=6.6Hz,2H),3.02(t,J=5.3Hz,4H),1.85(m,4H),0.41(s,4H).

[0437] Example 16 Synthesis of Compound 16

[0438] Step 1: Synthesis of compound 16a

[0439] Under H2 protection, 15a (350 mg) and palladium carbon (35.0 mg, palladium content 10%) were added to methanol (10 mL), and the reaction mixture was stirred at room temperature for sufficient reaction, filtered, and concentrated under vacuum to obtain 16a (340 mg).

[0440] MS m / z(ESI):150.1[M+H] +

[0441] Step 2: Synthesis of compound 16b

[0442] Compound 16b (450 mg) was synthesized and purified using compound 16a (300 mg) and compound 1c (700 mg) as starting materials in the same manner as in step 2 of Example 1.

[0443] MS m / z(ESI):489.1[M+H]+ .

[0444] Step 3: Synthesis of compound 16

[0445] Compound 16 (110 mg) was synthesized and purified using the same method as in Step 3 of Example 1 using compound 16b (200 mg) and compound 1f (80 mg) as starting materials.

[0446] MS m / z(ESI):486.2[M+H] + .

[0447] 1 H NMR(400MHz,DMSO-d6)δ12.98(s,1H),10.15(br,1H),8.04(d,J=8.6Hz,1H),7.3 8(d,J=7.6Hz,1H),7.26(dd,J=7.8,1.6Hz,2H),7.11(dd,J=8.6,2.1Hz,1H),5.02 (br,1H),3.76(t,J=6.5Hz,2H),3.42(t,J=8.2Hz,2H),3.35(d,J=6.5Hz,2H),2.9 7(t,J=5.3Hz,4H),2.89(t,J=8.2Hz,2H),2.85(s,3H),1.77(m,4H),0.37(s,4H).

[0448] Example 17 Synthesis of Compound 17

[0449] Step 1: Synthesis of compound 17c

[0450] Compound 17a (100 mg), compound 17b (98 mg), and sodium carbonate (120 mg) were added to ethanol (2 mL), and the reaction mixture was fully reacted at 80°C. The reaction solution was cooled to room temperature and filtered, and the filtrate was purified by reverse phase column chromatography (acetonitrile:water = 10-85%) to obtain compound 17c (49.7 mg).

[0451] MS m / z(ESI):251.2[M+H] + .

[0452] Step 2: Synthesis of compound 17d

[0453] Compound 17d (6.00 mg) was synthesized and purified using the same method as in Step 2 of Example 7 using compounds 17c (12.9 mg) and 7a (20.0 mg) as starting materials.

[0454] MS m / z(ESI):638.3[M+H]+ .

[0455] Step 3: Synthesis of compound 17

[0456] Compound 17 (2.96 mg) was synthesized and purified using compound 17d (6.00 mg) as starting material in the same manner as in step 8 of example 4.

[0457] MS m / z(ESI):524.5[M+H] + .

[0458] 1 H NMR (400MHz, DMSO-d6) δ11.92(s,1H),7.72(d,J=8.5Hz,1H),7.65(s,1H),7.44(d,J=9.0Hz,2H),7.27(t,J=8.9Hz,1H),6.91(s,1H),6.78 (d,J=8.2Hz,2H),4.26(t,J=5.9Hz,2H),3.71(t,J=6.5Hz,2H),3.35(t,J=7.1Hz,2H),3.06(s,2H),2.80(m,8H),1.53(s,4H),0.32(s,4H).

[0459] Example 18 Synthesis of Compound 18

[0460] Step 1: Synthesis of compound 18b

[0461] Compound 18b (42.0 mg) was synthesized and purified using compound 17a (100 mg) and compound 18a (106 mg) as starting materials in the same manner as in step 1 of example 17.

[0462] MS m / z(ESI):265.2[M+H] + .

[0463] Step 2: Synthesis of compound 18c

[0464] Compound 18c (8.95 mg) was synthesized and purified using the same method as in Step 2 of Example 7 using compounds 18b (12.9 mg) and 7a (20.0 mg) as starting materials.

[0465] MS m / z(ESI):652.2[M+H] + .

[0466] Step 3: Synthesis of compound 18

[0467] Compound 18 (5.30 mg) was synthesized and purified using compound 18c (8.95 mg) as starting material in the same manner as in step 8 of example 4.

[0468] MS m / z(ESI):538.3[M+H] + .

[0469] Example 19 Synthesis of Compound 19

[0470] Step 1: Synthesis of compound 19b

[0471] Compound 19b (220 mg) was synthesized and purified using the same method as in Step 2 of Example 1 using Compound 19a (165 mg) and Compound 1c (357 mg) as starting materials.

[0472] MS m / z(ESI):505.2[M+H] + .

[0473] Step 2: Synthesis of compound 19

[0474] Compound 19 (15 mg) was synthesized and purified using the same method as in Step 3 of Example 1 using Compound 19b (50 mg) and Compound 1f (50 mg) as starting materials.

[0475] MS m / z(ESI):502.2[M+H] + .

[0476] 1 H NMR (400MHz, DMSO-d6) δ12.90(s,1H),8.04(d,J=8.5Hz,1H),7.42(d,J=8.2Hz,1H),7.23(s,1H),7.08(d,J=8.9Hz,1H),6.96(d,J=8.2 Hz,1H),4.96(s,1H),4.19(s,2H),3.76(d,J=6.8Hz,2H),3.47–3.41(m,4H),3.06(s,3H),2.96(s,4H),2.16–1.39(m,4H),0.37(s,4H).

[0477] Example 20 Synthesis of Compound 20

[0478] Step 1: Synthesis of compound 20a

[0479] Compound 20a (270 mg) was synthesized and purified using the same method as in Step 1 of Example 13, using Compound 13a (200 mg) and Compound 1b (130 mg) as starting materials.

[0480] MS m / z(ESI):263.1[M+H] + .

[0481] Step 2: Synthesis of compound 20b

[0482] Compound 20b (280 mg) was synthesized and purified using the same method as in Step 2 of Example 13 using compound 20a (262 mg) and p-methoxybenzylamine (150 mg) as starting materials.

[0483] Step 3: Synthesis of compound 20c

[0484] Compound 20c (125 mg) was synthesized and purified using compound 20b (240 mg) as starting material in the same manner as in step 3 of Example 13.

[0485] MS m / z(ESI):244.2[M+H] + .

[0486] Step 4: Synthesis of compound 20d

[0487] Compound 20d (70 mg) was synthesized and purified using compound 20c (100 mg) and compound 1c (120 mg) as starting materials in the same manner as in step 2 of Example 1.

[0488] MS m / z(ESI):583.3[M+H] + .

[0489] Step 5: Synthesis of compound 20

[0490] Compound 20 (12 mg) was synthesized and purified using the same method as in Step 3 of Example 1 using Compound 20d (50 mg) and Compound 1f (50 mg) as starting materials.

[0491] MS m / z(ESI):580.3[M+H] + .

[0492] 1H NMR (400MHz, DMSO-d6) δ13.34(s,1H),10.27(s,1H),8.11(d,J=8.6Hz,1H),7.88(s,1H),7.71(s,1H),7.52(s,1H),7.29(d,J=2.1Hz,1H),7. 15(dd,J=8.5,2.0Hz,1H),4.97(m,1H),3.76(m,2H),3.50(d,J=6.3Hz,4H),3.33(s,3H),2.99(s,4H),1.60(s,4H),0.41(s,4H),0.38(s,4H).

[0493] Example 21 Synthesis of Compound 21

[0494] Step 1: Synthesis of compound 21b

[0495] Compound 21b (43 mg) was synthesized and purified using the same method as in Step 2 of Example 1 using Compound 4g (47 mg) and Compound 21a (20 mg) as raw materials.

[0496] MS m / z(ESI):634.2[M+H] + .

[0497] Step 2: Synthesis of compound 21

[0498] Compound 21 (28 mg) was synthesized and purified using compound 21b (40.0 mg) as starting material in the same manner as in step eight of Example 4.

[0499] MS m / z(ESI):520.2[M+H] + .

[0500] 1 H NMR (400MHz, DMSO-d6) δ11.60(s,1H),10.11(s,1H),8.74(d,J=2.1Hz,1H),8.13( d,J=7.6Hz,1H),7.85(d,J=8.4Hz,1H),7.73(m,2H),7.65(dd,J=8.8,2.2Hz,1H), 7.57–7.51(m,1H),7.42(m,1H),7.18(d,J=2.0Hz,1H),7.05(dd,J=8.5,1.9Hz,1H ),4.99(m,1H),3.77(m,2H),3.35(s,2H),3.02(m,4H),1.54(s,4H),0.34(s,4H).

[0501] Example 22 Synthesis of Compound 22

[0502] Step 1: Synthesis of compound 22b

[0503] Compound 22a (4.0 g, 21.3 mmol) and chloroacetaldehyde (2.5 g, 31.9 mmol) were added to a mixed solution of ethanol (84 mL) and water (6 mL), and the mixture was fully reacted under reflux. The mixture was concentrated under reduced pressure to remove most of the organic solvent, and saturated sodium bicarbonate solution (40 mL) was added. The aqueous phase was extracted with ethyl acetate (40 mL x 2), and the organic phase was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain compound 22b (3 g).

[0504] MS m / z(ESI):212.0[M+H] + .

[0505] Step 2: Synthesis of compound 22c

[0506] At 0°C, tert-butyl nitrite (2.9 g, 28.3 mmol) and copper chloride (3.8 g, 28.3 mmol) were added to acetonitrile (60 mL). Compound 22b (3.0 g, 14.2 mmol) was added portionwise. The reaction mixture was then allowed to warm to room temperature and stirred for sufficient reaction. Saturated sodium bicarbonate solution (60 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (60 mL x 3). The organic phases were combined and concentrated to obtain compound 22c (1.5 g).

[0507] MS m / z(ESI):231.0[M+H] + .

[0508] Step 3: Synthesis of compound 22d

[0509] Under nitrogen, compound 22c (1.5 g, 6.5 mmol), benzophenone imine (1.8 g, 9.7 mmol), Pd2dba3 (593.4 mg, 648.0 μmol), RuPhos (604.8 mg, 1.3 mmol), and cesium carbonate (6.3 g, 19.4 mmol) were added to DMF (10 mL), and the mixture was reacted at 110°C. After cooling, water (50 mL) was added, and the aqueous phase was extracted with ethyl acetate (50 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by flash column chromatography (petroleum ether:ethyl acetate = 100:0 to 75:25) to give compound 22d (0.3 g).

[0510] Step 4: Synthesis of compound 22e

[0511] Under nitrogen, compound 22d (150 mg, 452 μmol), compound 2b (hydrochloride, 85.5 mg, 542 μmol), Pd2dba3 (41.4 mg, 45 μmol), RuPhos (42.2 mg, 90 μmol), and cesium carbonate (442 mg, 1.4 mmol) were added to DMF (3 mL), and the mixture was reacted at 110°C. After cooling, water (15 mL) was added, and the aqueous phase was extracted with ethyl acetate (15 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by flash column chromatography (petroleum ether:ethyl acetate = 100:0 to 75:25) to give compound 22e (150 mg).

[0512] Step 5: Synthesis of compound 22f

[0513] A solution of hydrogen chloride in dioxane (4N, 3.5 mL) was added dropwise to a solution of compound 22e (100 mg, 240 μmol) in dioxane (7 mL), and the mixture was allowed to react at room temperature. Water (10 mL) was added to the reaction solution, which was washed with ethyl acetate (10 mL x 2). The organic phase was discarded, and the aqueous phase was adjusted to pH 8 with saturated sodium bicarbonate solution and extracted with ethyl acetate (10 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 22f (55 mg).

[0514] MS m / z(ESI):253.1[M+H] + .

[0515] Step 6: Synthesis of compound 22g

[0516] Compound 22g (16 mg) was synthesized and purified using the same method as in Step 2 of Example 1 using Compound 1c (86 mg, 0.24 mmol) and Compound 22f (55 mg, 0.22 mmol) as starting materials.

[0517] MS m / z(ESI):592.1[M+H] + .

[0518] Step 7: Synthesis of compound 22

[0519] Compound 22 (3 mg) was synthesized and purified using the same method as in step 3 of Example 1 using compound 22f (16 mg, 27 μmol) and compound 1f (6.4 mg, 54 μmol) as starting materials.

[0520] MS m / z(ESI):589.2[M+H] + .

[0521] 1 H NMR (400MHz, DMSO-d6) δ11.80(s,1H),7.86(s,1H),7.79(d,J=8.5Hz,1H),7.73(s,1H),7.53(s,1H),7.13(s,1H),7.01(d,J=8.3Hz,1H),6.8 1(s,1H),3.76(t,J=6.5Hz,3H),3.58–3.51(m,2H),3.24–3.21(m,4H), 2.99–2.95(m,4H),2.31–2.23(m,4H),2.04–1.93(m,4H),0.34(s,4H).

[0522] Example 23 Synthesis of Compound 23

[0523] Step 1: Synthesis of compound 23a

[0524] Compound 23a (570 mg) was synthesized and purified using the same method as in Step 1 of Example 12 using compound 11a (800 mg, 5.23 mmol) and 4-butyrolactone (860 mg, 10.0 mmol) as starting materials.

[0525] MS m / z(ESI):222.0[M+H] + .

[0526] Step 2: Synthesis of compound 23b

[0527] Compound 23b (450 mg) was synthesized and purified using compound 23a (500 mg, 2.25 mmol) as starting material in the same manner as in step 2 of Example 12.

[0528] MS m / z(ESI):240.0[M+H] + .

[0529] Step 3: Synthesis of compound 23c

[0530] Compound 23c (35 mg) was synthesized and purified using compound 23b (400 mg, 1.67 mmol) as starting material in the same manner as in step 3 of Example 12.

[0531] MS m / z(ESI):204.0[M+H] + .

[0532] Step 4: Synthesis of compound 23c

[0533] Compound 23d (27 mg) was synthesized and purified using compound 23c (35 mg, 0.17 mmol) as starting material in the same manner as in step 3 of Example 4.

[0534] MS m / z(ESI):174.1[M+H] + .

[0535] Step 5: Synthesis of compound 23

[0536] Compound 4g (46.8 mg, 100 μmol), diisopropylethylamine (38.7 mg, 300 μmol), and HATU (45.6 mg, 120 μmol) were added to DMF (0.5 mL). After stirring for 1 minute, compound 23d (17.3 mg, 100 μmol) was added, and the reaction mixture was allowed to react fully at room temperature. Pyridine hydrofluoride (14.9 mg, 150 μmol) was added, and the reaction mixture was allowed to react fully at room temperature. The product was directly purified by flash reverse-phase column chromatography (acetonitrile:water = 10:90 to 90:10) to provide compound 23 (10.7 mg).

[0537] MS m / z(ESI):510.2[M+H] + .

[0538] 1 H NMR (400MHz, DMSO-d6) δ12.70(s,1H),8.18(dd,J=12.9,2.4Hz,1H),8.05(d,J=8.6Hz,1H),7.29(d,J=2.1Hz,1H),7.12–7.06(m,2H),4.09(t ,J=5.9Hz,2H),3.76(t,J=6.5Hz,2H),3.37(t,J=6.4Hz,2H),3.05–2.97(m,4H),2.07(m,2H),1.98(m,2H),1.97–1.55(br,4H),0.32(s,4H).

[0539] Example 24 Synthesis of Compound 24

[0540] Step 1: Synthesis of compound 24a

[0541] Compound 24a (745 mg) was synthesized and purified using the same method as in Step 1 of Example 12 using compound 11a (1.0 g, 6.5 mmol) and 6-hexyllactone (1.48 g, 13.0 mmol) as starting materials.

[0542] MS m / z(ESI):250.0[M+H] +.

[0543] Step 2: Synthesis of compound 24b

[0544] Compound 24b (425 mg) was synthesized and purified using compound 24a (498 mg, 2.0 mmol) as starting material in the same manner as in step 2 of Example 12.

[0545] MS m / z(ESI):268.0[M+H] + .

[0546] Step 3: Synthesis of compound 24c

[0547] Compound 24c (136 mg) was synthesized and purified using compound 24b (400 mg, 1.5 mmol) as starting material in the same manner as in step 3 of Example 12.

[0548] MS m / z(ESI):232.1[M+H] + .

[0549] Step 4: Synthesis of compound 24d

[0550] Compound 24d (71 mg) was synthesized and purified using compound 24c (120 mg, 0.52 mmol) as starting material in the same manner as in step 3 of Example 4.

[0551] MS m / z(ESI):202.1[M+H] + .

[0552] Step 5: Synthesis of compound 24

[0553] Compound 24 (27.3 mg) was synthesized and purified using the same method as in Step 5 of Example 23 using compound 24d (40 mg, 0.2 mmol) and compound 4g (94 mg, 0.2 mmol) as starting materials.

[0554] MS m / z(ESI):538.2[M+H] + .

[0555] 1H NMR (400MHz, DMSO-d6) δ12.26(s,1H),8.00(d,J=8.6Hz,2H),8.05(d,J=8.6Hz,2H),7.26(br,3H),7.09(dd,J=8.6,2.1Hz,1H),4.3 9(br,2H),3.77(t,J=6.5Hz,2H),3.36(t,J=6.5Hz,2H),3.01(br,6H),1.91(m,2H),1.81(m,2H),1.79–1.45(br,6H),0.31(s,4H).

[0556] Example 25 Synthesis of Compound 25

[0557] Step 1: Synthesis of compound 25b

[0558] Compound 25a (1.0 g, 4.5 mmol) was added to a mixed solution of THF (10 mL) and ethanol (10 mL). Sodium borohydride (0.46 g, 13.5 mmol) was added at 0°C, and the mixture was stirred at room temperature for sufficient reaction. The mixture was quenched by the addition of saturated ammonium chloride solution (20 mL), and extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The solvent was removed from the filtrate under reduced pressure to obtain compound 25b (0.58 g).

[0559] Step 2: Synthesis of compound 25c

[0560] Compound 25c (320 mg) was synthesized and purified using the same method as in Step 1 of Example 12 using Compound 11a (0.41 g, 2.7 mmol) and Compound 25b (0.50 g, 2.7 mmol) as starting materials.

[0561] MS m / z(ESI):272.0[M+H] + .

[0562] Step 3: Synthesis of compound 25d

[0563] Compound 25c (0.30 g, 1.1 mmol) and triphenylphosphine (0.39 g, 1.5 mmol) were added to anhydrous THF (5 mL). Diethyl azodicarboxylate (0.23 g, 1.3 mmol) was added dropwise at 0°C. The mixture was stirred at room temperature for thorough reaction. The solvent was removed under reduced pressure, and the mixture was purified by flash column chromatography (petroleum ether:ethyl acetate = 1:1) to afford compound 25d (183 mg).

[0564] MS m / z(ESI):254.0[M+H] + .

[0565] Step 4: Synthesis of compound 25e

[0566] Compound 25e (90 mg) was synthesized and purified using compound 25d (165 mg, 0.65 mmol) as starting material in the same manner as in step 3 of Example 4.

[0567] MS m / z(ESI):224.0[M+H] + .

[0568] Step 5: Synthesis of compound 25

[0569] Compound 25 (23 mg) was synthesized and purified using the same method as in Step 5 of Example 23 using Compound 25e (45 mg, 0.2 mmol) and Compound 4g (94 mg, 0.2 mmol) as starting materials.

[0570] MS m / z(ESI):560.2[M+H] + .

[0571] 1 H NMR (400MHz, DMSO-d6) δ12.48 (s, 1H), 10.16 (s, 1H), 8.34 (d, J = 7.6Hz, 1H), 8. 04(d,J=8.6Hz,1H),7.33–7.22(m,3H),7.10(dd,J=8.6,2.1Hz,1H),4.70(t,J= 12.5Hz,2H),3.76(td,J=6.4,2.2Hz,2H),3.39–3.34(m,2H),3.22(t,J=6.9Hz ,2H),3.04–2.96(m,2H),1.91(m,2H),1.81(m,2H),1.80(br,4H),0.32(s,4H).

[0572] Example 26 Synthesis of Compound 26

[0573] Step 1: Synthesis of compound 26b

[0574] At 0°C, sodium hydride (2.2 g, 55.8 mmol, 60% dispersion in mineral oil) was added portionwise to a solution of compound 26a (10.0 g, 50.8 mmol) in THF (100 mL), and the mixture was stirred at 0°C for full reaction. Benzenesulfonyl chloride (9.9 g, 55.8 mmol) in THF (20 mL) was added dropwise to the reaction solution, and the mixture was fully reacted at room temperature. The reaction solution was poured into a mixture of ethyl acetate (50 mL) and saturated sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. Methyl tert-butyl ether (50 mL) was added for slurrying, and filtered to obtain compound 26b (14.5 g).

[0575] Step 2: Synthesis of compound 26c

[0576] At -78°C, lithium diisopropylamide (2M in THF, 9.6 mL) was slowly added dropwise to a solution of compound 26b (5.0 g, 14.8 mmol) and tetramethylethylenediamine (3.5 g, 29.7 mmol, 4.4 mL) in THF (100 mL). The mixture was maintained at -78°C and slowly added dropwise with 1,4-diiodobutane (5.1 g, 16.3 mmol). The mixture was allowed to react fully after warming to room temperature. The reaction mixture was quenched with saturated ammonium chloride solution (50 mL) and extracted with dichloromethane (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain crude compound 26c (9.0 g), which was used directly in the next step.

[0577] Step 3: Synthesis of compound 26d

[0578] Sodium tert-butoxide (3.3 g, 34.7 mmol) was added to a solution of compound 26c (9.0 g, 17.3 mmol) in 1,4-dioxane (150 mL). The mixture was stirred at 80°C for a thorough reaction, and the solvent was removed under reduced pressure. Flash column chromatography (petroleum ether:ethyl acetate = 100:0-85:15) afforded compound 26d (650 mg).

[0579] 1 H NMR (400MHz, DMSO-d6) δ7.79(d,J=8.1Hz,1H),7.20(d,J=8.1Hz,1H),6.22(d,J=1.3Hz ,1H),4.09(t,J=6.2Hz,2H),2.96–2.89(m,2H),2.04–1.96(m,2H),1.87–1.78(m,2H).

[0580] Step 4: Synthesis of compound 26e

[0581] Compound 26e (45 mg) was synthesized and purified using the same method as in step 2 of Example 7 using compound 26d (43 mg, 0.17 mmol) and 7a (80 mg, 0.17 mmol) as starting materials.

[0582] MS m / z(ESI):637.3[M+H] + .

[0583] Step 5: Synthesis of compound 26

[0584] Compound 26 (19 mg) was synthesized and purified using compound 26e (35 mg) as starting material in the same manner as in step 8 of example 4.

[0585] MS m / z(ESI):524.2[M+H] + .

[0586] 1 H NMR (400MHz, DMSO-d6) δ13.36(s,1H),10.19(s,1H),8.08(d,J=8.6Hz,1H),8.03(d,J= 8.4Hz,1H),7.85(d,J=8.4Hz,1H),7.30–7.24(m,1H),7.12(d,J=8.6Hz,1H),6.14(s,1H ),4.96(s,1H),4.09(t,J=6.1Hz,2H),3.76(t,J=6.5Hz,2H),3.38–3.35(m,2H),3.07– 2.95(m,4H),2.93(t,J=6.4Hz,2H),2.10–2.01(m,2H),2.00–1.62(m,6H),0.41(s,4H).

[0587] Example 27 Synthesis of Compound 27

[0588] Step 1: Synthesis of compound 27b

[0589] Compound 27a (200 mg, 0.72 mmol) and cesium carbonate (701 mg, 2.16 mmol) were added to DMF (2 mL). Methyl iodide (306 mg, 2.16 mmol) was added at 0°C, and the mixture was allowed to react fully at room temperature. Saturated sodium bicarbonate solution (5 mL) was added to the system, and the mixture was extracted with dichloromethane (3 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and dried by spin drying. Compound 27b (180 mg) was obtained by flash column chromatography (petroleum ether:ethyl acetate = 5:1).

[0590] MS m / z(ESI):293.2[M+H] + .

[0591] Step 2: Synthesis of compound 27c

[0592] Under an argon atmosphere, compound 27b (180 mg, 0.62 mmol), potassium vinyl tetrafluoroborate (165 mg, 1.24 mmol), and cesium carbonate (400 mg, 1.23 mmol) were added to dioxane (2 mL), followed by Pd(dppf)Cl2 (45.0 mg, 62 μmol), and the mixture was fully reacted at 50°C. After cooling to room temperature, the mixture was filtered and concentrated, and purified by flash column chromatography (petroleum ether:ethyl acetate = 3:1) to afford compound 27c (66 mg).

[0593] MS m / z(ESI):193.2[M+H] + .

[0594] Step 3: Synthesis of compound 27d

[0595] Compound 27d (6 mg) was synthesized and purified using the same method as in step 2 of Example 7 using compound 27c (12 mg, 64 μmol) and 7a (20 mg, 43 μmol) as starting materials.

[0596] MS m / z(ESI):624.3[M+H] + .

[0597] Step 4: Synthesis of compound 27

[0598] Compound 27 (2.6 mg) was synthesized and purified using compound 27d (6 mg) as starting material in the same manner as in step 8 of example 4.

[0599] MS m / z(ESI):510.2[M+H] + .

[0600] Example 28 Synthesis of Compound 28

[0601] Step 1: Synthesis of compound 28b

[0602] Compound 28a (1.0 g, 6 mmol) was dissolved in 1,4-dioxane (10 mL), and liquid bromine (3.2 g, 20 mmol) was added. The mixture was allowed to react at room temperature. Saturated sodium bicarbonate solution (10 mL) and sodium thiosulfate solution (10 mL) were added to the system, and the mixture was extracted with dichloromethane (10 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was spin-dried. Compound 28b (890 mg) was obtained by flash column chromatography (petroleum ether:ethyl acetate = 8:1).

[0603] Step 2: Synthesis of compound 28c

[0604] Compound 28c (278 mg) was synthesized and purified using the same method as in step 4 of Example 22 using compound 28b (600 mg, 2.5 mmol) and 2b (hydrochloride, 790 mg, 5 mmol) as starting materials.

[0605] Step 3: Synthesis of compound 28d

[0606] Compound 28d (110 mg) was synthesized and purified using compound 28c (200 mg, 0.70 mmol) as starting material in the same manner as in step 3 of Example 4.

[0607] MS m / z(ESI):255.1[M+H] + .

[0608] Step 4: Synthesis of compound 28

[0609] Compound 28 (27 mg) was synthesized and purified using the same method as in Step 5 of Example 23 using compound 28d (51 mg, 0.2 mmol) and compound 4g (94 mg, 0.2 mmol) as starting materials.

[0610] MS m / z(ESI):591.2[M+H] + .

[0611] 1 H NMR (400MHz, DMSO-d6) δ11.52(s,1H),10.06(s,1H),7.81(d,J=9.2Hz,1H),7.41(s,1H),7.15(s,1H),6.98–7.06(m,2H),4. 52(t,J=8.6Hz,2H),3.75(t,J=6.2Hz,2H),3.24–3.12(m,6H),2.95(br,4H),2.16–1.97(m,6H),1.54(br,4H),0.34(s,4H).

[0612] Example 29 Synthesis of Compound 29

[0613] Step 1: Synthesis of compound 29b

[0614] NBS (433 mg, 2.4 mmol) and p-toluenesulfonic acid monohydrate (35 mg, 0.20 mmol) were added to dichloromethane (2 mL), and compound 29a (200 mg, 2.0 mmol) was added at 0°C. The mixture was fully reacted at 0°C. Saturated sodium bicarbonate solution (3 mL) was added to the system, and extraction was performed with dichloromethane (2 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was spin-dried. Compound 29b (286 mg) was obtained by flash column chromatography (petroleum ether:ethyl acetate = 10:1).

[0615] Step 2: Synthesis of compound 29d

[0616] Compound 29b (100 mg, 0.57 mol) and compound 29c (98 mg, 0.57 mol) were added to ethanol (2 mL), and the mixture was fully reacted at 80°C. The reaction solution was filtered and purified by reverse-phase flash column chromatography (acetonitrile:water = 95:5 to 10:90) to obtain compound 29d (50 mg).

[0617] MS m / z(ESI):265.0[M+H] + .

[0618] Step 3: Synthesis of compound 29e

[0619] Compound 29e (9 mg) was synthesized and purified using the same method as in Step 2 of Example 7 using compounds 29d (10 mg, 38 μmol) and 7a (35 mg, 75 μmol) as starting materials.

[0620] MS m / z(ESI):652.3[M+H] + .

[0621] Step 4: Synthesis of compound 29

[0622] Compound 29 (4 mg) was synthesized and purified using compound 29e (9 mg) as starting material in the same manner as in step 8 of Example 4.

[0623] MS m / z(ESI):538.2[M+H] + .

[0624] Example 30 Synthesis of Compound 30

[0625] Step 1: Synthesis of compound 30c

[0626] Compound 30a (100 mg, 0.46 mmol), compound 30b (hydrochloride salt, 73 mg, 0.55 mmol), and cesium carbonate (371 mg, 1.14 mmol) were added to acetonitrile (1 mL), and the mixture was stirred at 60°C for thorough reaction. Water (5 mL) was added to the system, and the mixture was extracted with ethyl acetate (5 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and spin-dried. Compound 30c (125 mg) was then purified by flash column chromatography (petroleum ether:ethyl acetate = 5:1) to afford compound 30c.

[0627] MS m / z(ESI):297.2[M+H] + .

[0628] Step 2: Synthesis of compound 30d

[0629] Compound 30d (90 mg) was synthesized and purified using compound 30c (125 mg, 0.42 mmol) as starting material in the same manner as in step 3 of Example 4.

[0630] MS m / z(ESI):267.1[M+H] + .

[0631] Step 3: Synthesis of compound 30e

[0632] Compound 30d (90 mg, 0.34 mmol) was added to acetonitrile (1 mL) and water (0.1 mL). Iodine (430 mg, 1.69 mmol) was added at 80°C and stirred at this temperature for a thorough reaction. After cooling to room temperature, ethyl acetate (5 mL) was added to the system, and the mixture was washed with saturated aqueous sodium carbonate (5 mL) and sodium thiosulfate solution (5 mL). The organic phase was collected, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and dried. Compound 30e (76 mg) was purified by flash column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain the product.

[0633] MS m / z(ESI):263.2[M+H] + .

[0634] Step 4: Synthesis of compound 30f

[0635] Compound 30e (76 mg, 0.29 mmol), benzophenone imine (105 mg, 0.58 mmol), and cesium carbonate (291 mg, 0.87 mmol) were added to 1,4-dioxane (1 mL), followed by XantPhos (33.5 mg, 58 μmol) and Pd2(dba)3 (26.5 mg, 29 μmol), and the mixture was reacted at 100°C. The reaction mixture was filtered, dried, and purified by flash column chromatography (petroleum ether:ethyl acetate = 1:1) to afford compound 30f (80 mg).

[0636] MS m / z(ESI):364.3[M+H] + .

[0637] Step 5: Synthesis of compound 30g

[0638] Compound 30f (80 mg, 22 μmol) was dissolved in 1,4-dioxane (1 mL), and a solution of hydrogen chloride in dioxane (4N, 1.8 mL, 4.5 mmol) was added. The mixture was allowed to react at room temperature. The reaction mixture was filtered, and the filter cake was dried to obtain compound 30g (43 mg).

[0639] MS m / z(ESI):200.1[M+H] + .

[0640] Step 6: Synthesis of compound 30

[0641] Compound 30 (11 mg) was synthesized and purified using compound 30g (20 mg, 0.1 mmol) and compound 4g (47 mg, 0.1 mmol) as starting materials in the same manner as in step 5 of example 23.

[0642] MS m / z(ESI):536.2[M+H] + .

[0643] 1 H NMR (400MHz, DMSO-d6) δ10.16(s,1H),8.12(s,1H),8.00(d,J=8.5Hz,1H),7.41–7.19(m,3H),7.08(dd,J=8.5,2.0Hz,1H),4.37(s,2H),3.76 (t,J=6.5Hz,2H),3.35(t,J=6.5Hz,2H),3.11–2.87(m,6H),2.74(dt,J=8.3,5.4Hz,2H),1.85(s,2H),1.70(s,2H),1.24(s,2H),0.28(s,4H).

[0644] Example 31 Synthesis of Compound 31

[0645] Step 1: Synthesis of compound 31b

[0646] Compound 31b (470 mg) was synthesized and purified using the same method as in Step 1 of Example 12 using compound 31a (500 mg, 2.92 mmol) and 5-valerolactone (500 mg, 5 mmol) as starting materials.

[0647] MS m / z(ESI):254.0[M+H] + .

[0648] Step 2: Synthesis of compound 31c

[0649] Compound 31c (283 mg) was synthesized and purified using compound 31b (350 mg, 1.38 mmol) as starting material in the same manner as in step 2 of Example 12.

[0650] MS m / z(ESI):272.0[M+H] + .

[0651] Step 3: Synthesis of compound 31d

[0652] Compound 31d (135 mg) was synthesized and purified using compound 31c (200 mg, 0.74 mmol) as starting material in the same manner as in step 3 of Example 12.

[0653] MS m / z(ESI):237.0[M+H] + .

[0654] Step 4: Synthesis of compound 31e

[0655] Compound 31e (77 mg) was synthesized and purified using compound 31d (110 mg, 0.46 mmol) as starting material in the same manner as in step 3 of Example 4.

[0656] MS m / z(ESI):206.1[M+H] + .

[0657] Step 5: Synthesis of compound 31

[0658] Compound 31 (19 mg) was synthesized and purified using the same method as in Step 5 of Example 23 using compound 31e (41 mg, 0.2 mmol) and compound 4g (94 mg, 0.2 mmol) as starting materials.

[0659] MS m / z(ESI):542.2[M+H] + .

[0660] 1 H NMR (400MHz, DMSO-d6) δ12.08(s,1H),10.17(s,1H),7.95(d,J=8.5Hz,1H),7.85(br,1H),7.45(br,1H),7.24(d,J=2.1Hz,1H),7.08(dd,J=8.5,2 .1Hz,1H),4.31(br,2H),3.77(t,J=6.5Hz,2H),3.36(t,J=6.5Hz,2H),3.21(br,4H),3.03(br,4H),2.82–2.69(m,2H),1.57(br,4H),0.31(s,4H).

[0661] Example 32 Synthesis of Compound 32

[0662] Step 1: Synthesis of compound 32b

[0663] Compound 32a (500 mg, 3.31 mmol) was added to anhydrous ethanol (10 mL), and phosphorus pentasulfide (1.0 mL, 4.5 mmol) was added portionwise. The mixture was stirred at 80°C for a thorough reaction. After concentration, the mixture was purified by flash column chromatography (petroleum ether:ethyl acetate = 2:1) to afford compound 32b (320 mg).

[0664] MS m / z(ESI):168.1[M+H] + .

[0665] Step 2: Synthesis of compound 32c

[0666] Compound 32b (300 mg, 1.78 mmol) was dissolved in methanol (10 mL) and 30% hydrogen peroxide was slowly added dropwise. The reaction was monitored until complete. After concentration, the mixture was purified by flash column chromatography (petroleum ether:ethyl acetate = 3:1) to give compound 32c (93 mg).

[0667] MS m / z(ESI):166.0[M+H] + .

[0668] Step 3: Synthesis of compound 32

[0669] Compound 32 (3.5 mg) was synthesized and purified using the same method as in Step 5 of Example 23 using compound 32c (33 mg, 0.2 mmol) and compound 4g (94 mg, 0.2 mmol) as starting materials.

[0670] MS m / z(ESI):502.2[M+H] + .

[0671] Example 33 Synthesis of Compound 33

[0672] Step 1: Synthesis of compound 33b

[0673] Compound 33b (427 mg) was synthesized and purified using the same method as in Step 1 of Example 12 using compound 33a (500 mg, 2.45 mmol) and 5-valerolactone (500 mg, 5 mmol) as starting materials.

[0674] MS m / z(ESI):287.0[M+H] + .

[0675] Step 2: Synthesis of compound 33c

[0676] Compound 33c (190 mg) was synthesized and purified using compound 33b (300 mg, 1.05 mmol) as starting material in the same manner as in step 2 of Example 12.

[0677] MS m / z(ESI):305.0[M+H] + .

[0678] Step 3: Synthesis of compound 33d

[0679] Compound 33d (35 mg) was synthesized and purified using compound 33c (180 mg, 0.74 mmol) as starting material in the same manner as in step 3 of Example 12.

[0680] MS m / z(ESI):269.1[M+H] + .

[0681] Step 4: Synthesis of compound 33e

[0682] Compound 33e (29 mg) was synthesized and purified using the same method as in Step 2 of Example 7 using compound 33d (30 mg, 0.11 mmol) and 7a (52 mg, 0.11 mmol) as starting materials.

[0683] MS m / z(ESI):665.3[M+H] + .

[0684] Step 5: Synthesis of compound 33

[0685] Compound 33 (13 mg) was synthesized and purified using compound 33e (29 mg) as starting material in the same manner as in step 8 of Example 4.

[0686] MS m / z(ESI):542.2[M+H] + .

[0687] Example 34 Synthesis of Compound 34

[0688] Step 1: Synthesis of compound 34a

[0689] Compound 34a (200 mg) was synthesized and purified using the same method as in Step 1 of Example 30 using compound 30a (220 mg, 1.0 mmol) and morpholine as starting materials.

[0690] Step 2: Synthesis of compound 34b

[0691] Compound 34b (147 mg) was synthesized and purified using compound 34a (200 mg, 0.70 mmol) as starting material in the same manner as in step 3 of Example 4.

[0692] MS m / z(ESI):257.0[M+H] + .

[0693] Step 3: Synthesis of compound 34c

[0694] Compound 34c (65 mg) was synthesized and purified using compound 34b (100 mg, 0.39 mmol) as starting material in the same manner as in step 3 of Example 30.

[0695] MS m / z(ESI):253.0[M+H] + .

[0696] Step 4: Synthesis of compound 34d

[0697] Compound 34d (71 mg) was synthesized and purified using compound 34c (65 mg, 0.26 mmol) as starting material in the same manner as in step 4 of Example 30.

[0698] MS m / z(ESI):354.0[M+H] + .

[0699] Step 5: Synthesis of compound 34e

[0700] Compound 34e (32 mg) was synthesized and purified using compound 34d (71 mg, 0.20 mmol) as starting material in the same manner as in step 5 of Example 30.

[0701] MS m / z(ESI):190.0[M+H] + .

[0702] Step 6: Synthesis of compound 34

[0703] Compound 34 (17 mg) was synthesized and purified using the same method as in Step 5 of Example 23 using compound 34e (30 mg, 0.16 mmol) and compound 4g (75 mg, 0.16 mmol) as starting materials.

[0704] MS m / z(ESI):526.2[M+H] + .

[0705] Example 35 Synthesis of Compound 35

[0706] Step 1: Synthesis of compound 35b

[0707] Compound 35b (128 mg) was synthesized and purified using the same method as in Step 1 of Example 30 using compound 30a (100 mg, 0.46 mmol) and 35a (hydrochloride, 81 mg, 0.55 mmol) as starting materials.

[0708] Step 2: Synthesis of compound 35c

[0709] Compound 35c (95 mg) was synthesized and purified using compound 35b (122 mg, 0.39 mmol) as starting material in the same manner as in step 3 of Example 4.

[0710] MS m / z(ESI):281.0[M+H] + .

[0711] Step 3: Synthesis of compound 35d

[0712] Compound 35d (73 mg) was synthesized and purified using compound 35c (95 mg, 0.34 mmol) as starting material in the same manner as in step 3 of Example 30.

[0713] MS m / z(ESI):277.0[M+H] + .

[0714] Step 4: Synthesis of compound 35e

[0715] Compound 35e (66 mg) was synthesized and purified using compound 35d (73 mg, 0.26 mmol) as starting material in the same manner as in step 4 of Example 30.

[0716] MS m / z(ESI):378.1[M+H] + .

[0717] Step 5: Synthesis of compound 35f

[0718] Compound 35f (37 mg) was synthesized and purified using compound 35e (64 mg, 0.17 mmol) as starting material in the same manner as in step 5 of Example 30.

[0719] MS m / z(ESI):214.1[M+H] + .

[0720] Step 6: Synthesis of compound 35

[0721] Compound 35 (11 mg) was synthesized and purified using the same method as in Step 5 of Example 23 using compound 35f (32 mg, 0.15 mmol) and compound 4g (70 mg, 0.15 mmol) as starting materials.

[0722] MS m / z(ESI):550.3[M+H] + .

[0723] 1 H NMR (400MHz, DMSO-d6) δ12.45(s,1H),8.32(d,J=7.4Hz,1H),8.02(d,J=8.6Hz,1H),7 .25(d,J=2.1Hz,1H),7.18–7.02(m,3H),4.14(dd,J=11.5,3.7Hz,1H),3.96(d,J=11.5 Hz,1H),3.76(t,J=6.5Hz,2H),3.43(t,J=4.6Hz,2H),3.00(d,J=10.0Hz,4H),2.87(d ,J=8.0Hz,1H),2.15–1.96(m,4H),1.94–1.85(m,5H),1.68–1.53(m,2H),0.30(s,4H).

[0724] Example 36 Synthesis of Compound 36

[0725] Step 1: Synthesis of compound 36c

[0726] Compound 36b (217 mg, 1.59 mmol), DIEA (617 mg, 4.78 mmol), and HATU (1.21 g, 3.18 mmol) were added to THF (3 mL), followed by compound 36a (300 mg, 1.59 mmol). The mixture was allowed to react at room temperature. The reaction mixture was dried and purified by flash column chromatography (petroleum ether:ethyl acetate = 1:1) to afford compound 36c (425 mg).

[0727] MS m / z(ESI):306.2 / 308.2[M+H] + .

[0728] Step 2: Synthesis of compound 36d

[0729] Compound 36c (425 mg, 1.39 mmol) was added to anhydrous acetic acid (4 mL), and the mixture was fully reacted at 120° C. The reaction solution was spin-dried and purified by flash column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain compound 36d (181 mg).

[0730] MS m / z(ESI):252.3 / 254.3[M+H] + .

[0731] Step 3: Synthesis of compound 36e

[0732] Compound 36e (15 mg) was synthesized and purified using the same method as in Step 2 of Example 7 using compound 36d (16 mg, 0.064 mmol) and 7a (20 mg, 0.043 mmol) as starting materials.

[0733] MS m / z(ESI):639.0[M+H] + .

[0734] Step 4: Synthesis of compound 36

[0735] Compound 36 (3.6 mg) was synthesized and purified using compound 36e (15 mg) as starting material in the same manner as in step 8 of example 4.

[0736] MS m / z(ESI):525.3[M+H] + .

[0737] 1H NMR (400MHz, DMSO-d6) δ12.37(s,1H),10.15(s,1H),8.33(d,J=7.3Hz,1H),8.0 6(d,J=8.6Hz,1H),7.34(d,J=7.3Hz,1H),7.29(d,J=2.1Hz,1H),7.10(dd,J=8.6 ,2.1Hz,1H),4.94(s,1H),4.11(t,J=6.1Hz,2H),4.06(m,4H),3.76(t,J=6.5Hz, 2H),3.36(d,J=6.5Hz,2H),3.00(m,2H),2.62(m,4H),1.85(s,4H),0.35(s,4H).

[0738] Example 39 Synthesis of Compound 39

[0739] Step 1: Synthesis of compound 39a

[0740] Compound 39a (37 mg) was synthesized and purified using the same method as in Step 2 of Example 1 using compound 11f (30 mg, 0.16 mmol) and compound 1c (71 mg, 0.2 μmol) as starting materials.

[0741] Step 2: Synthesis of compound 39

[0742] Compound 39a (30 mg, 57 μmol), DBU sulfur trioxide complex (24 mg, 0.1 mmol), and triethylamine (15 mg, 0.15 mmol) were added to isopropanol (0.5 mL), followed by palladium acetate (2.2 mg, 10 μmol) and XantPhos (5.8 mg, 10 μmol). The reaction mixture was allowed to react under argon at 80°C. After cooling to room temperature, ethanolamine (12 mg, 0.2 mmol) and sodium hypochlorite (10% aqueous solution, 150 mg, 0.2 mmol) were added and allowed to react at room temperature. Compound 39 (4.5 mg) was directly purified by flash reverse-phase column chromatography (acetonitrile:water, 10-85%).

[0743] MS m / z(ESI):524.3[M+H] + .

[0744] Example 40 Synthesis of Compound 40

[0745] Step 1: Synthesis of compound 40b

[0746] Compound 40b (123 mg) was synthesized and purified using the same method as in Step 1 of Example 30 using compounds 30a (100 mg, 0.46 mmol) and 40a (hydrochloride, 82 mg, 0.55 mmol) as starting materials.

[0747] Step 2: Synthesis of compound 40c

[0748] Compound 40c (90 mg) was synthesized and purified using compound 40b (120 mg, 0.39 mmol) as starting material in the same manner as in step 3 of Example 4.

[0749] MS m / z(ESI):281.3 / 283.3[M+H] + .

[0750] Step 3: Synthesis of compound 40d

[0751] Compound 40d (72 mg) was synthesized and purified using compound 40c (90 mg, 0.34 mmol) as starting material in the same manner as in step 3 of Example 30.

[0752] MS m / z(ESI):277.2 / 279.2[M+H] + .

[0753] Step 4: Synthesis of compound 40e

[0754] Compound 40e (62 mg) was synthesized and purified using compound 40d (72 mg, 0.26 mmol) as starting material in the same manner as in step 4 of Example 30.

[0755] MS m / z(ESI):380.1[M+H] + .

[0756] Step 5: Synthesis of compound 40f

[0757] Compound 40f (35 mg) was synthesized and purified using compound 40e (62 mg, 0.16 mmol) as starting material in the same manner as in step 5 of Example 30.

[0758] MS m / z(ESI):216.2[M+H] + .

[0759] Step 6: Synthesis of compound 40

[0760] Compound 40 (10.5 mg) was synthesized and purified using the same method as in Step 5 of Example 23 using Compound 40f (25 mg, 0.12 mmol) and Compound 4g (55 mg, 0.12 mmol) as starting materials.

[0761] MS m / z(ESI):552.4[M+H] + .

[0762] 1 H NMR (400MHz, DMSO-d6) δ12.48(s,1H),8.36(dd,J=7.7,1.2Hz,1H),8.03(d,J=8.6Hz,1H),7.26(d,J=2. 1Hz,1H),7.23–7.13(m,2H),7.07(dd,J=8.6,2.0Hz,1H),5.33(d,J=5.9Hz,1H),5.02(d,J=5.7Hz,1H), 4.30(dd,J=11.9,4.2Hz,1H),4.05(d,J=11.9Hz,1H),3.76(t,J=6.5Hz,2H),3.31(t,J=6.5Hz,2H),2.9 9(m,6H),2.32–2.21(m,2H),2.10(t,J=10.7Hz,1H),1.93(t,J=10.8Hz,1H),1.24(s,2H),0.32(s,4H).

[0763] Example 41 Synthesis of Compound 41

[0764] Step 1: Synthesis of compound 41b

[0765] Compound 41a (0.5 g, 3.1 mmol) and NBS (573 mg, 3.2 mmol) were added to concentrated sulfuric acid (2 mL), and the mixture was fully reacted at 60°C. After cooling, the reaction solution was slowly poured into ice water (40 mL) and extracted with ethyl acetate (40 mL x 3). The layers were separated, and the combined organic phases were dried over anhydrous sodium sulfate, spin-dried, and purified by flash column chromatography (petroleum ether:ethyl acetate = 12:1) to provide compound 41b (500 mg).

[0766] Step 2: Synthesis of compound 41c

[0767] Compound 41c (99 mg) was synthesized and purified using the same method as in Step 4 of Example 22 using compound 41b (150 mg, 0.62 mmol) and 2b (hydrochloride salt, 146 mg, 0.93 mmol) as starting materials.

[0768] Step 3: Synthesis of compound 41d

[0769] Compound 41d (40 mg) was synthesized and purified using compound 41c (80 mg, 0.14 mmol) as starting material in the same manner as in step 3 of Example 4.

[0770] Step 4: Synthesis of compound 41

[0771] Compound 41 (6 mg) was synthesized and purified using the same method as in Step 5 of Example 23 using Compound 41d (36 mg, 0.14 mmol) and Compound 4g (62 mg, 0.14 mmol) as starting materials.

[0772] MS m / z(ESI):589.2[M+H] + .

[0773] 1 H NMR (400MHz, DMSO-d6) δ11.52(s,1H),10.06(s,1H),7.81(d,J=9.2Hz,1H),7.41(s,1H),7.15(s,1H),6.98–7.06(m,2H),4. 52(t,J=8.6Hz,2H),3.75(t,J=6.2Hz,2H),3.24–3.12(m,6H),2.95(br,4H),2.16–1.97(m,6H),1.54(br,4H),0.34(s,4H).

[0774] Example 42 Synthesis of Compound 42

[0775] Step 1: Synthesis of compound 42b

[0776] Compound 42a (300 mg, 1.66 mmol), tert-butyl nitrite (206 mg, 2.00 mmol), and cuprous bromide (357 mg, 2.50 mmol) were added to acetonitrile (3 mL), and the mixture was reacted at 70°C. Water (6 mL) was added to the system, and the mixture was extracted with ethyl acetate (2 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and dried by spin drying. Compound 42b (320 mg) was obtained by flash column chromatography (petroleum ether:ethyl acetate = 5:1).

[0777] Step 2: Synthesis of compound 42c

[0778] Compound 42b (150 mg, 0.62 mmol) was added to concentrated sulfuric acid (1 mL), followed by concentrated nitric acid (0.2 mL) at 0°C and allowed to react fully at room temperature. The reaction solution was poured into ice water (10 mL), filtered, and the filter cake was purified by flash column chromatography (petroleum ether:ethyl acetate = 4:1) to obtain compound 42c (68.0 mg).

[0779] Step 3: Synthesis of compound 42d

[0780] Compound 42d (43 mg) was synthesized and purified using compound 42c (68 mg, 0.24 mmol) as starting material in the same manner as in step 3 of Example 4.

[0781] MS m / z(ESI):229.3 / 231.3[M+H] + .

[0782] Step 4: Synthesis of compound 42e

[0783] Compound 42e (57 mg) was synthesized and purified using the same method as in Step 1 of Example 36 using compounds 42d (43 mg, 0.19 mmol) and 36b (26 mg, 0.19 mmol) as starting materials.

[0784] Step 5: Synthesis of compound 42f

[0785] Compound 42f (38 mg) was synthesized and purified using compound 42e (55 mg, 0.16 mmol) as starting material in the same manner as in step 2 of Example 36.

[0786] MS m / z(ESI):293.4 / 295.4[M+H] + .

[0787] Step 6: Synthesis of compound 42g

[0788] Compound 42g (39 mg) was synthesized and purified using compound 42f (38 mg, 0.13 mmol) as starting material in the same manner as in step 4 of Example 30.

[0789] MS m / z(ESI):394.3[M+H] + .

[0790] Step 7: Synthesis of compound 42h

[0791] Compound 42h (22 mg) was synthesized and purified using compound 42g (39 mg, 0.1 mmol) as starting material in the same manner as in step 5 of Example 30.

[0792] MS m / z(ESI):230.2[M+H] + .

[0793] Step 8: Synthesis of compound 42

[0794] Compound 42 (3.9 mg) was synthesized and purified using the same method as in Step 5 of Example 23 using compound 42h (20 mg, 87 mol) and compound 4g (47 mg, 0.1 mmol) as starting materials.

[0795] MS m / z(ESI):566.3[M+H] + .

[0796] 1 H NMR(400MHz,DMSO-d6)δ12.24(s,1H),8.23(s,1H),8.00(d,J=8.6Hz,1H),7 .23(d,J=2.1Hz,1H),7.05(dd,J=8.6,2.1Hz,1H),4.92(s,1H),4.66(t,J=8 .7Hz,2H),4.27(t,J=5.8Hz,2H),3.75(t,J=6.5Hz,2H),3.24(t,J=6.5Hz,2 H),2.97(m,6H),2.09–1.89(m,4H),1.78(m,4H),1.24(m,2H),0.30(s,4H).

[0797] Example 43 Synthesis of Compound 43

[0798] Step 1: Synthesis of compound 43b

[0799] Compound 43b (425 mg) was synthesized and purified using the same method as in Step 1 of Example 36 using compounds 43a (217 mg, 1.59 mmol) and 36b (300 mg, 1.59 mmol) as starting materials.

[0800] Step 2: Synthesis of compound 43c

[0801] Compound 43c (143 mg) was synthesized and purified using compound 43b (425 mg, 1.39 mmol) as starting material in the same manner as in step 2 of Example 36.

[0802] MS m / z(ESI):252.2 / 254.2[M+H] + .

[0803] Step 3: Synthesis of compound 43d

[0804] Compound 43d (140 mg) was synthesized and purified using compound 43c (143 mg, 57 μmol) as starting material in the same manner as in step 4 of Example 30.

[0805] MS m / z(ESI):353.2[M+H] + .

[0806] Step 4: Synthesis of compound 43e

[0807] Compound 43e (62 mg) was synthesized and purified using compound 43d (140 mg, 41.5 μmol) as starting material in the same manner as in step 5 of Example 30.

[0808] MS m / z(ESI):189.2[M+H] + .

[0809] Step 5: Synthesis of compound 43

[0810] Compound 43 (3.7 mg) was synthesized and purified using the same method as in Step 5 of Example 23 using compound 43e (19 mg, 0.1 mmol) and compound 4g (47 mg, 0.1 mmol) as starting materials.

[0811] MS m / z(ESI):525.2[M+H] + .

[0812] 1 H NMR (400MHz, DMSO-d6) δ12.68(s,1H),9.47(s,1H),8.59(s,1H),8.08(d,J=8.6Hz,1H),7.30(s,1H),7.11(d,J=8.6Hz,1H),4.93(s,1H),4.25( t,J=5.9Hz,2H),3.76(t,J=6.5Hz,2H),3.28(t,J=6.5Hz,2H),3.05(t,J =6.5Hz,2H),2.99(m,4H),2.13–1.95(m,4H),1.84(s,4H),0.33(s,4H).

[0813] Example 44 Synthesis of Compound 44

[0814] Step 1: Synthesis of compound 44b

[0815] Compound 44a (300 mg, 1.08 mmol), compound 2b (hydrochloride, 189 mg, 1.2 mmol), and triethylamine (300 mg, 3 mmol) were added to acetonitrile (3 mL), and the mixture was reacted at 40°C. Water (20 mL) was added to the system, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and dried by spin drying. The product was purified by flash column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain compound 44b (305 mg).

[0816] MS m / z(ESI):317.1 / 319.1[M+H] + .

[0817] Step 2: Synthesis of compound 44c

[0818] Compound 44c (40 mg) was synthesized and purified using the same method as in Step 2 of Example 7 using compounds 44b (32 mg, 0.1 mmol) and 7a (47 mg, 0.1 mmol) as starting materials.

[0819] Step 3: Synthesis of compound 44

[0820] Compound 44 (28 mg) was synthesized and purified using compound 44c (40 mg, 0.058 mmol) as starting material in the same manner as in step 8 of Example 4.

[0821] MS m / z(ESI):590.3[M+H] + .

[0822] 1 H NMR(400MHz,DMSO-d6)δ10.63(s,1H),9.72(s,1H),7.27(s,1H),7.16(d,J =8.1Hz,1H),6.66–6.39(m,2H),4.95(s,1H),3.84(s,4H),3.74(t,J=6.8H z,2H),3.51–3.37(m,2H),3.26(t,J=6.8Hz,2H),3.14(d,J=10.0Hz,2H),2 .29(s,3H),1.93(d,J=14.5Hz,4H),1.48(m,2H),0.99(s,2H),0.80(s,2H).

[0823] Example 45 Synthesis of Compound 45

[0824] Step 1: Synthesis of compound 45c

[0825] Compound 45a (1.0 g, 4.06 mmol), compound 45b (1.17 g, 4.88 mmol), and potassium carbonate (1.69 g, 12.2 mmol) were added to acetone (20 mL), and the mixture was heated to 80°C for complete reaction. After cooling to room temperature, the mixture was poured into water (100 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried. The mixture was purified by flash column chromatography (petroleum ether:ethyl acetate = 4:1) to obtain compound 45c (520 mg).

[0826] Step 2: Synthesis of compound 45d

[0827] Sodium hydroxide (132 mg, 3.31 mmol) was added to a mixed solution of compound 45c (0.52 g, 1.66 mmol) in methanol (4 mL), tetrahydrofuran (8 mL), and water (2 mL), and the mixture was allowed to react at room temperature. The reaction solution was poured into water (50 mL), the pH was adjusted to 3 with dilute hydrochloric acid, and extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and dried by spin drying. Compound 45d (350 mg) was purified by flash column chromatography (ethyl acetate).

[0828] Step 3: Synthesis of compound 45e

[0829] Copper powder (133 mg, 2.10 mmol) was added to a solution of compound 45d (300 mg, 1.05 mmol) in quinoline (3 mL), and the mixture was heated to 200°C for complete reaction. After cooling, the mixture was poured into water (50 mL), and the pH was adjusted to 6-7 with dilute hydrochloric acid. The mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The mixture was then purified by flash column chromatography (petroleum ether:ethyl acetate = 10:1) to afford compound 45e (120 mg).

[0830] Step 4: Synthesis of compound 45f

[0831] Compound 45f (278 mg) was synthesized and purified using the same method as in Step 4 of Example 22 using compound 45e (150 mg, 0.62 mmol) and 2b (hydrochloride salt, 127 mg, 0.8 mmol) as starting materials.

[0832] Step 5: Synthesis of compound 45g

[0833] Compound 45g (70 mg) was synthesized and purified using compound 45f (120 mg, 0.42 mmol) as starting material in the same manner as in step 3 of Example 4.

[0834] MS m / z(ESI):253.1[M+H] + .

[0835] Step 6: Synthesis of compound 45

[0836] Compound 45 (12 mg) was synthesized and purified using the same method as in Step 5 of Example 23 using Compound 45g (70 mg, 0.28 mmol) and Compound 4g (130 mg, 0.28 mmol) as starting materials.

[0837] MS m / z(ESI):589.1[M+H] + .

[0838] 1 H NMR (400MHz, DMSO-d6) δ11.71(s,1H),7.96(d,J=2.1Hz,1H),7.87–7.82(m,2H),7.17(d,J=2.1Hz,1H),7.09(d,J=1.9Hz,1H),7.04(dd,J=8.5,2. 1Hz,1H),6.95(d,J=2.2Hz,1H),3.76(t,J=6.6Hz,2H),3.46(t,J=5.7Hz, 4H), 2.98 (t, J = 5.2Hz, 4H), 2.26–2.09 (m, 4H), 1.57 (s, 4H), 0.35 (s, 4H).

[0839] Example 46 Synthesis of Compound 46

[0840] Step 1: Synthesis of compound 46b

[0841] Compound 46b (640 mg) was synthesized and purified using the same method as in Step 1 of Example 30 using compound 30a (500 mg, 2.27 mmol) and 46a (hydrochloride salt, 304 mg, 2.27 mmol) as starting materials.

[0842] Step 2: Synthesis of compound 46c

[0843] Compound 46c (490 mg) was synthesized and purified using compound 46b (540 mg, 2.15 mmol) as starting material in the same manner as in step 3 of Example 4.

[0844] Step 3: Synthesis of compound 46d

[0845] Compound 46d (230 mg) was synthesized and purified using compound 46c (470 mg, 1.76 mmol) as starting material in the same manner as in step 3 of Example 30.

[0846] Step 4: Synthesis of compound 46e

[0847] Compound 46e (80 mg) was synthesized and purified using the same method as in Step 4 of Example 30 using compound 46d (220 mg, 0.84 mmol) and tert-butyl carbamate (118 mg, 1.0 mmol) as starting materials.

[0848] Step 5: Synthesis of compound 46f

[0849] Compound 46f (45 mg) was synthesized and purified using compound 46e (75 mg, 0.25 mmol) as starting material in the same manner as in step 5 of Example 30.

[0850] MS m / z(ESI):200.2[M+H] + .

[0851] Step 6: Synthesis of compound 46

[0852] Compound 46 (4.5 mg) was synthesized and purified using the same method as in Step 5 of Example 23 using compound 46f (40 mg, 0.2 mmol) and compound 4g (94 mg, 0.2 mmol) as starting materials.

[0853] MS m / z(ESI):536.2[M+H] + .

[0854] 1 H NMR (400MHz, DMSO-d6) δ12.64(s,1H),8.30(d,J=7.8Hz,1H),7.92(d,J=8.6Hz,1H),7.20 (d,J=8.0Hz,1H),7.11(t,J=8.0Hz,1H),7.06(d,J=2.2Hz,1H),6.87(dd,J=8.7,2.1Hz,1H ),4.96(q,J=4.7Hz,1H),3.73(t,J=6.6Hz,2H),3.14(t,J=6.6Hz,2H),3.03–2.93(m,4H), 2.75–2.71(m,2H),2.11–1.76(m,5H),1.68–1.62(m,2H),1.49–1.42(m,1H),0.32(s,4H).

[0855] Example 47 Synthesis of Compound 47

[0856] Step 1: Synthesis of compound 47b

[0857] Compound 47b (1.8 g) was synthesized and purified using the same method as in Step 1 of Example 30 using compound 30a (1.34 g, 6.1 mmol) and 47a (hydrochloride, 857 mg, 5.8 mmol) as starting materials.

[0858] Step 2: Synthesis of compound 47c

[0859] Compound 47c (1.54 g) was synthesized and purified using compound 47b (1.8 g, 5.78 mmol) as starting material in the same manner as in step 3 of Example 4.

[0860] Step 3: Synthesis of compound 47d

[0861] Compound 47d (500 mg) was synthesized and purified using compound 47c (1.53 g, 5.44 mmol) as starting material in the same manner as in step 3 of Example 30.

[0862] Step 4: Synthesis of compound 47e

[0863] Compound 47e (500 mg) was synthesized and purified using compound 47d (500 mg, 1.80 mmol) as starting material in the same manner as in step 4 of Example 30.

[0864] Step 5: Synthesis of compound 47f

[0865] Compound 47f (100 mg) was synthesized and purified using compound 47e (500 mg, 1.32 mmol) as starting material in the same manner as in step 5 of Example 30.

[0866] MS m / z(ESI):214.2[M+H] + .

[0867] Step 6: Synthesis of compound 47

[0868] Compound 47 (31 mg) was synthesized and purified using the same method as in Step 5 of Example 23 using compound 47f (89 mg, 0.4 mmol) and compound 4g (188 mg, 0.4 mmol) as starting materials.

[0869] MS m / z(ESI):550.1[M+H] + .

[0870] 1H NMR (400MHz, DMSO-d6) δ12.45(s,1H),8.30(dd,J=8.0,0.9Hz,1H),8.03(d,J=8 .6Hz,1H),7.31(dd,J=8.1,1.0Hz,1H),7.26(d,J=2.2Hz,1H),7.14(t,J=8.0Hz, 1H),7.08(dd,J=8.6,2.1Hz,1H),5.02(s,1H),3.77(t,J=6.5Hz,2H),3.38–3.3 6(m,2H),3.04–2.91(m,4H),2.18–1.68(m,8H),1.68–1.55(m,4H),0.28(s,4H).

[0871] Example 48 Synthesis of Compound 48

[0872] Step 1: Synthesis of compound 48b

[0873] Compound 48b (3.5 g) was synthesized and purified using the same method as in Step 1 of Example 30 using compound 30a (3.00 g, 13.6 mmol) and 48a (hydrochloride, 1.96 g, 16.4 mmol) as starting materials.

[0874] Step 2: Synthesis of compound 48c

[0875] Compound 48c (2.00 g) was synthesized and purified using compound 48b (2.26 g, 8.0 mmol) as starting material in the same manner as in step 3 of Example 4.

[0876] Step 3: Synthesis of compound 48d

[0877] Compound 48d (850 mg) was synthesized and purified using compound 48c (2.00 g, 7.90 mmol) as starting material in the same manner as in step 3 of Example 30.

[0878] Step 4: Synthesis of compound 48e

[0879] Compound 48e (300 mg) was synthesized and purified using compound 48d (300 mg, 1.20 mmol) as starting material in the same manner as in step 4 of Example 30.

[0880] Step 5: Synthesis of compound 48f

[0881] Compound 48f (222 mg) was synthesized and purified using compound 48e (300 mg, 0.86 mmol) as starting material in the same manner as in step 5 of Example 30.

[0882] MS m / z(ESI):186.1[M+H] + .

[0883] Step 6: Synthesis of compound 48

[0884] Compound 48 (26 mg) was synthesized and purified using the same method as in Step 5 of Example 23 using compound 48f (118 mg, 0.64 mmol) and compound 4g (200 mg, 0.43 mmol) as starting materials.

[0885] MS m / z(ESI):522.1[M+H] + .

[0886] 1 H NMR (400MHz, DMSO-d6) δ12.30(s,1H),10.16(s,1H),8.26(d,J=7.7Hz,1H),8.00(d,J=8.5Hz ,1H),7.26(d,J=2.1Hz,1H),7.15–7.04(m,3H),4.95(s,1H),4.25(dd,J=11.2,5.7Hz,1H),4. 16(d,J=11.2Hz,1H),3.76(t,J=6.5Hz,2H),3.38–3.36(m,2H),3.06–2.93(m,4H),2.64–2.5 7(m,1H),2.47–2.43(m,1H),1.79(s,4H),1.46–1.38(m,1H),0.80–0.74(m,1H),0.31(s,4H).

[0887] Example 49 Synthesis of Compound 49

[0888] Step 1: Synthesis of compound 49b

[0889] Compound 49b (1.1 g) was synthesized and purified using the same method as in Step 1 of Example 30 using compound 30a (1.0 g, 4.5 mmol) and 49a (hydrochloride, 0.86 g, 5.0 mmol) as starting materials.

[0890] Step 2: Synthesis of compound 49c

[0891] Compound 49c (0.9 g) was synthesized and purified using compound 49b (1.1 g, 3.3 mmol) as starting material in the same manner as in step 3 of Example 4.

[0892] Step 3: Synthesis of compound 49d

[0893] Compound 49d (270 mg) was synthesized and purified using compound 49c (0.9 g, 3.0 mmol) as starting material in the same manner as in step 3 of Example 30.

[0894] Step 4: Synthesis of compound 49e

[0895] Compound 49e (280 mg) was synthesized and purified using compound 49d (270 mg, 0.90 mmol) as starting material in the same manner as in step 4 of Example 30.

[0896] Step 5: Synthesis of compound 49f

[0897] Compound 49f (121 mg) was synthesized and purified using compound 49e (280 mg, 0.70 mmol) as starting material in the same manner as in step 5 of Example 30.

[0898] MS m / z(ESI):238.1[M+H] + .

[0899] Step 6: Synthesis of compound 49

[0900] Compound 49 (16 mg) was synthesized and purified using the same method as in Step 5 of Example 23 using compound 49f (80 mg, 0.34 mmol) and compound 4g (158 mg, 0.34 mmol) as starting materials.

[0901] MS m / z(ESI):574.2[M+H] + .

[0902] Example 50 Synthesis of Compound 50

[0903] Step 1: Synthesis of compound 50c

[0904] Compound 50a (200 mg, 1.08 mmol) and compound 50b (235 mg, 1.08 mmol) were dissolved in DMF (4 mL), and sodium hydride (86.4 mg, 2.16 mmol, 60%) was added. The mixture was allowed to react at room temperature. Water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and dried by spin drying. Compound 50c (244 mg) was obtained by flash column chromatography (petroleum ether:ethyl acetate = 5:1).

[0905] Step 2: Synthesis of compound 50d

[0906] Compound 50d (121 mg) was synthesized and purified using the same method as in Step 1 of Example 30 using compound 50c (122 mg, 0.32 mmol) and piperidine (43 mg, 0.5 mmol) as starting materials.

[0907] Step 3: Synthesis of compound 50e

[0908] Compound 50e (87 mg) was synthesized and purified using compound 50d (120 mg, 0.27 mmol) as starting material in the same manner as in step 3 of Example 4.

[0909] Step 4: Synthesis of compound 50f

[0910] Compound 50f (62 mg) was synthesized and purified using compound 50e (83 mg, 0.21 mmol) as starting material in the same manner as in step 3 of Example 30.

[0911] Step 5: Synthesis of compound 50g

[0912] Compound 50f (62 mg, 0.15 mmol) was added to anhydrous dioxane (1 mL), followed by dioxane hydrochloride (4N, 0.2 mL), and the mixture was allowed to react at room temperature. The reaction mixture was filtered, and the filter cake was dried to obtain compound 50g (30 mg, crude product).

[0913] MS m / z(ESI):213.1[M+H] + .

[0914] Step 6: Synthesis of compound 50h

[0915] Compound 50h (13.9 mg) was synthesized and purified using the same method as in step 3 of Example 5 using compounds 4g (70 mg, 0.15 mmol) and 50g (21 mg, 0.1 mmol) as starting materials.

[0916] Step 7: Synthesis of Compound 50

[0917] Compound 50 (5.6 mg) was synthesized and purified using compound 50h (13.9 mg, 21 μmol) as starting material in the same manner as in step 8 of Example 4.

[0918] MS m / z(ESI):549.2[M+H] + .

[0919] 1H NMR (400MHz, DMSO-d6) δ12.88(s,1H),8.46(d,J=8.5Hz,1H),8.03(d,J=8.6Hz,1 H),7.65(d,J=8.5Hz,1H),7.26(s,1H),7.06(d,J=8.7Hz,1H),4.45(t,J=6.1Hz,2 H),3.75(t,J=6.5Hz,2H),3.30(t,J=6.5Hz,2H),3.05(t,J=6.3Hz,2H),2.98(t,J =5.4Hz,4H),2.20–2.06(m,2H),1.97(t,J=5.7Hz,2H),1.84(s,4H),0.33(s,4H).

[0920] Example 51 Synthesis of Compound 51

[0921] Step 1: Synthesis of compound 51a

[0922] Compound 51a (80 mg) was synthesized and purified using the same method as in Step 4 of Example 22 using compound 28b (100 mg, 0.41 mmol) and morpholine (36 mg, 0.41 mmol) as starting materials.

[0923] Step 2: Synthesis of compound 51b

[0924] Compound 51b (41 mg) was synthesized and purified using compound 51a (60 mg, 0.24 mmol) as starting material in the same manner as in step 3 of Example 4.

[0925] MS m / z(ESI):221.1[M+H] + .

[0926] Step 3: Synthesis of compound 51

[0927] Compound 51 (13 mg) was synthesized and purified using the same method as in Step 5 of Example 23 using Compound 51b (11 mg, 0.05 mmol) and Compound 4g (28 mg, 0.06 mmol) as starting materials.

[0928] MS m / z(ESI):557.2[M+H] + .

[0929] 1H NMR (400MHz, DMSO-d6) δ11.60(s,1H),7.83(d,J=8.4Hz,1H),7.39(s,1H),7.16(d,J=2.0Hz,1H),7.04-7.00(m,2H),4.52(t,J=8.8Hz,2H) ,3.77-3.72(m,6H),3.16(t,J=8.4Hz,2H),3.14(d,J=10.0Hz,2H),3.06-3.03(m,4H),2.98-2.95(m,4H),1.95-1.52(m,4H),0.36(s,4H).

[0930] Example 52 Synthesis of Compound 52

[0931] Step 1: Synthesis of compound 52b

[0932] Compound 52b (45 mg) was synthesized and purified using compound 52a (45 mg, 0.26 mmol) as starting material in the same manner as in step 1 of Example 32.

[0933] Step 2: Synthesis of compound 52c

[0934] Compound 52c (42 mg) was synthesized and purified using compound 52b (45 mg, 0.22 mmol) as starting material in the same manner as in step 2 of Example 32.

[0935] MS m / z(ESI):206.1[M+H] + .

[0936] Step 3: Synthesis of compound 52d

[0937] Compound 52d (100 mg) was synthesized and purified using the same method as in step 3 of Example 5 using compounds 4g (93 mg, 0.2 mmol) and 52c (41 mg, 0.2 mmol) as starting materials.

[0938] Step 4: Synthesis of compound 52

[0939] Compound 52 (8.0 mg) was synthesized and purified using compound 52d (100 mg, 15 μmol) as starting material in the same manner as in step 8 of Example 4.

[0940] MS m / z(ESI):542.2[M+H] + .

[0941] 1H NMR (400MHz, DMSO-d6) δ14.92(s,1H),10.37(s,1H),8.19(d,J=8.7Hz,1H),7.73(s,1H),7.42(d,J=2.1Hz,1H),7.23(dd,J=8.7,2.1Hz,1H),4.97 (t,J=5.2Hz,1H),3.78(q,J=6.0Hz,2H),3.40(t,J=6.4Hz,2H),3.09(t,J =6.6Hz,2H),3.04(s,4H),2.94(t,J=6.3Hz,2H),2.28–1.38(m,8H),0.43 (s,4H).

[0942] Example 53 and Example 54 Synthesis of Compound 53 and Compound 54

[0943] Step 1: Synthesis of compound 53b

[0944] Compound 53b (5.1 g) was synthesized and purified using the same method as in Step 1 of Example 30 using compound 30a (4.0 g, 18.2 mmol) and 53a (hydrochloride salt, 2.5 g, 18.2 mmol) as starting materials.

[0945] Step 2: Synthesis of compound 53c

[0946] Compound 53c (3.1 g) was synthesized and purified using compound 53b (5.1 g, 17 mmol) as starting material in the same manner as in step 3 of Example 4.

[0947] Step 3: Synthesis of Compound 53d and Compound 53e

[0948] By the same method as in Step 3 of Example 30, using Compound 53c (3.0 g, 11 mmol) as starting material, a mixture of Compound 53d and Compound 53e (1.2 g) was synthesized and purified.

[0949] Step 4: Synthesis of Compound 53f and Compound 53g

[0950] A mixture of Compound 53f and Compound 53g (0.24 g) was synthesized and purified using a mixture of Compound 53d and Compound 53e (276 mg, 1.0 mmol) and tert-butyl carbamate (140 mg, 1.2 mmol) as starting materials in the same manner as in Step 4 of Example 30.

[0951] Step 5: Synthesis of Compound 53h and Compound 53i

[0952] By the same method as in Step 5 of Example 30, a mixture of Compound 53f and Compound 53g (240 mg, 0.79 mmol) was used as starting material to synthesize and purify a mixture of Compound 53h and Compound 53i (110 mg).

[0953] MS m / z(ESI):204.1[M+H] + .

[0954] Step 6: Synthesis of Compound 53 and Compound 54

[0955] The final product was synthesized and purified using the same method as in Step 5 of Example 23 using a mixture of Compound 53h and Compound 53i (110 mg, 0.54 mmol) and Compound 4g (281 mg, 0.6 mmol) as starting materials.

[0956] Compound 53 (25 mg)

[0957] MS m / z(ESI):540.2[M+H] + .

[0958] 1 H NMR (400MHz, DMSO-d6) δ12.53(s,1H),8.34(dd,J=7.7,1.1Hz,1H),8.01(d,J=8.6Hz,1H),7.25–7.14(m,3H),7.03(dd,J=8.6,2.1Hz,1 H),4.45–4.33(m,2H),3.92–3.83(m,4H),3.75(t,J=6.5Hz,2H),3.31–3.26(m,4H),3.03–2.92(m,4H),2.07–1.54(m,4H),0.30(s,4H).

[0959] Compound 54 (34 mg)

[0960] MS m / z(ESI):540.2[M+H] + .

[0961] 1H NMR (400MHz, DMSO-d6) δ12.59(s,1H),8.36(d,J=7.8Hz,1H),8.04(d,J=8.6H z,1H),7.30(d,J=8.0Hz,1H),7.27–7.19(m,2H),7.05(dd,J=8.6,2.1Hz,1H) ,4.89(s,2H),4.47–4.38(m,2H),4.11–4.03(m,2H),3.75(t,J=6.5Hz,2H),3 .30(t,J=6.5Hz,2H),2.98(t,J=5.3Hz,4H),2.13–1.50(m,6H),0.32(s,4H).

[0962] Example 55 and Example 56 Synthesis of Compound 55 and Compound 56

[0963] Step 1: Synthesis of compound 55b

[0964] Compound 55b (2.8 g) was synthesized and purified using the same method as in Step 1 of Example 30 using compounds 30a (2.4 g, 10.9 mmol) and 55a (1.32 g, 13 mmol) as starting materials.

[0965] Step 2: Synthesis of compound 55c

[0966] Compound 55c (1.1 g) was synthesized and purified using compound 55b (2.8 g, 9.3 mmol) as starting material in the same manner as in step 3 of Example 4.

[0967] Step 3: Synthesis of Compound 55d and Compound 55e

[0968] By the same method as in Step 3 of Example 30, using Compound 55c (1.1 g, 4.1 mmol) as starting material, a mixture of Compound 55d and Compound 55e (0.3 g) was synthesized and purified.

[0969] Step 4: Synthesis of Compound 55f and Compound 55g

[0970] A mixture of Compound 55f and Compound 55g (0.13 g) was synthesized and purified using a mixture of Compound 55d and Compound 55e (150 mg, 0.56 mmol) and tert-butyl carbamate (132 mg, 1.1 mmol) as starting materials in the same manner as in Step 4 of Example 30.

[0971] Step 5: Synthesis of Compound 55h and Compound 55i

[0972] By the same method as in Step 5 of Example 30, a mixture of Compound 55f and Compound 55g (130 mg, 0.43 mmol) was used as starting material to synthesize and purify a mixture of Compound 55h and Compound 55i (50 mg).

[0973] MS m / z(ESI):204.1[M+H] + .

[0974] Step 6: Synthesis of Compound 55 and Compound 56

[0975] The final product was synthesized and purified using the same method as in Step 5 of Example 23 using a mixture of Compound 55h and Compound 55i (47 mg, 0.23 mmol) and Compound 4g (122 mg, 0.26 mmol) as starting materials.

[0976] Compound 55 (25 mg)

[0977] MS m / z(ESI):540.1[M+H] + .

[0978] 1 H NMR (400MHz, DMSO-d6) δ12.50(s,1H),8.38(dd,J=6.5,2.4Hz,1H),8.04(d,J=8.6Hz,1H),7.27 –7.18(m,3H),7.08(dd,J=8.6,2.1Hz,1H),5.02(d,J=15.8Hz,1H),4.97(d,J=15.7Hz,1H),4.36 (dd,J=12.0,3.3Hz,1H),4.25–4.16(m,1H),3.84(dd,J=12.0,10.4Hz,1H),3.76(t,J=6.5Hz,2H ),3.37–3.35(m,2H),3.03–2.92(m,4H),1.95–1.54(m,4H),1.39(d,J=6.1Hz,3H),0.31(s,4H).

[0979] Compound 56 (20 mg)

[0980] MS m / z(ESI):540.1[M+H] + .

[0981] 1H NMR(400MHz, DMSO-d6)δ12.15(s,1H),8.45(dd,J=6.2,2.7Hz,1H),8.00(d,J=8 .6Hz,1H),7.26–7.19(m,3H),7.05(dd,J=8.6,2.0Hz,1H),5.03(q,J=6.6Hz,1H ),4.39–4.31(m,1H),4.28–4.14(m,2H),4.10–4.01(m,1H),3.76(t,J=6.5Hz,2 H),3.32–3.30(m,2H),3.06–2.93(m,4H),1.96–1.56(m,7H),0.38–0.23(m,4H).

[0982] Example 57 Synthesis of Compound 57

[0983] Step 1: Synthesis of compound 57c

[0984] Compound 57c (1.3 g) was synthesized and purified using the same method as in Step 2 of Example 27 using Compound 57a (2.0 g, 10.1 mmol) and Compound 57b (3.4 g, 20.2 mmol) as starting materials.

[0985] Step 2: Synthesis of compound 57d

[0986] Palladium on carbon (130 mg) was added to a solution of compound 57c (1.3 g, 9.30 mmol) in methanol (20 mL), and the mixture was allowed to react under a hydrogen atmosphere at room temperature. The reaction solution was filtered, dried, and purified by column chromatography (petroleum ether:ethyl acetate = 100:0-70:30) to give compound 57d (1.0 g).

[0987] Step 3: Synthesis of compound 57e

[0988] Compound 57e (0.92 g) was synthesized and purified using compound 57d (1.0 mg, 6.2 mmol) as starting material in the same manner as in step 1 of Example 32.

[0989] Step 4: Synthesis of compound 57f

[0990] Compound 57f (0.60 g) was synthesized and purified using compound 57e (0.90 g, 4.6 mmol) as starting material in the same manner as in step 2 of Example 32.

[0991] MS m / z(ESI):194.1[M+H] + .

[0992] Step 5: Synthesis of compound 57g

[0993] Compound 57g (55 mg) was synthesized and purified using the same method as in step 3 of Example 5 using compound 4g (70 mg, 0.15 mmol) and 57f (29 mg, 0.15 mmol) as starting materials.

[0994] Step 6: Synthesis of compound 57

[0995] Compound 57 (13 mg) was synthesized and purified using compound 57g (50 mg, 78 μmol) as starting material in the same manner as in step 8 of Example 4.

[0996] MS m / z(ESI):530.1[M+H] + .

[0997] 1 H NMR(400MHz,DMSO-d6)δ15.00(s,1H),10.37(s,1H),8.60(d,J=1.9Hz,1H),8.18 (d,J=8.6Hz,1H),7.84(d,J=1.5Hz,1H),7.41(d,J=2.2Hz,1H),7.22(dd,J=8.7, 2.1Hz,1H),4.96(s,1H),3.83–3.73(m,2H),3.40(t,J=6.4Hz,2H),3.16(p,J=6. 9Hz, 1H), 3.04 (t, J = 5.4Hz, 4H), 1.87 (s, 4H), 1.33 (d, J = 6.9Hz, 6H), 0.43 (s, 4H).

[0998] Example 58 Synthesis of Compound 58

[0999] Step 1: Synthesis of compound 58b

[1000] Compound 58b (194 mg) was synthesized and purified using the same method as in Step 1 of Example 30 using compounds 58a (0.2 g, 0.75 mmol) and 2b (91 mg, 0.75 mmol) as starting materials.

[1001] Step 2: Synthesis of compound 58c

[1002] Compound 58c (12 mg) was synthesized and purified using the same method as in Step 2 of Example 7 using compounds 7a (31 mg, 0.065 mmol) and 58b (20 mg, 0.065 mmol) as starting materials.

[1003] Step 3: Synthesis of compound 58

[1004] Compound 58 (2.2 mg) was synthesized and purified using compound 58c (11 mg, 16 μmol) as starting material in the same manner as in step 8 of Example 4.

[1005] MS m / z(ESI):581.4[M+H] + .

[1006] 1 H NMR (400MHz, DMSO-d6) δ12.70(s,1H),10.15(s,1H),8.03(d,J=8.6Hz,1H),7.96(s,1H),7.25(d,J=2.2Hz,1H),7.12(dd,J=8.6,2.1Hz,1H),4 .94(s,1H),3.99(s,4H),3.75(t,J=6.5Hz,2H),3.45(s,3H),3.36(d,J =6.5Hz,2H),2.95(s,4H),2.16–1.99(m,4H),1.72(m,4H),0.39(s,4H).

[1007] Example 59 Synthesis of Compound 59

[1008] Step 1: Synthesis of compound 59b

[1009] Compound 59b (262 mg) was synthesized and purified using the same method as in Step 1 of Example 30 using compounds 30a (0.3 g, 1.36 mmol) and 59a (185 mg, 1.36 mmol) as starting materials.

[1010] Step 2: Synthesis of compound 59c

[1011] Compound 59c (188 mg) was synthesized and purified using compound 59b (262 mg, 0.88 mmol) as starting material in the same manner as in step 3 of Example 4.

[1012] Step 3: Synthesis of compound 59d

[1013] Compound 59d (60 mg) was synthesized and purified using compound 59c (188 mg, 0.7 mmol) as starting material in the same manner as in step 3 of Example 30.

[1014] Step 4: Synthesis of compound 59e

[1015] Compound 59e (44 mg) was synthesized and purified using compound 59d (59 mg, 0.22 mmol) as starting material in the same manner as in step 4 of Example 30.

[1016] Step 5: Synthesis of compound 59f

[1017] Compound 59f (18.6 mg) was synthesized and purified using compound 59e (44 mg, 0.12 mmol) as starting material in the same manner as in step 5 of Example 30.

[1018] MS m / z(ESI):202.1[M+H] + .

[1019] Step 6: Synthesis of compound 59

[1020] Compound 59 (3.6 mg) was synthesized and purified using the same method as in Step 5 of Example 23 using Compound 59f (12 mg, 0.06 mmol) and Compound 4g (28 mg, 0.06 mmol) as starting materials.

[1021] MS m / z(ESI):538.3[M+H] + .

[1022] Example 60 Synthesis of Compound 60

[1023] Step 1: Synthesis of compound 60b

[1024] Compound 60b (110 mg) was synthesized and purified using compound 60a (100 mg, 0.55 mmol) as starting material in the same manner as in step 1 of Example 28.

[1025] Step 2: Synthesis of compound 60c

[1026] Compound 60c (72 mg) was synthesized and purified using the same method as in step 4 of Example 22 using compound 60b (110 mg, 0.41 mmol) and 2b (hydrochloride salt, 60 mg, 0.41 mmol) as starting materials.

[1027] Step 3: Synthesis of compound 60d

[1028] Compound 60d (50 mg) was synthesized and purified using compound 60c (70 mg, 0.23 mmol) as starting material in the same manner as in step 3 of Example 4.

[1029] MS m / z(ESI):269.1[M+H] + .

[1030] Step 4: Synthesis of compound 60

[1031] Compound 60 (11 mg) was synthesized and purified using the same method as in Step 5 of Example 23 using compound 60d (14 mg, 0.05 mmol) and compound 4g (23 mg, 0.05 mmol) as starting materials.

[1032] MS m / z(ESI):605.3[M+H] + .

[1033] Example 61 Synthesis of Compound 61

[1034] Step 1: Synthesis of compound 61b

[1035] Compound 61b (0.7 g) was synthesized and purified using the same method as in Step 1 of Example 30 using compounds 30a (2.14 g, 9.7 mmol) and 61a (304 mg, 2.3 mmol) as starting materials.

[1036] Step 2: Synthesis of compound 61c

[1037] Compound 61c (520 mg) was synthesized and purified using compound 61b (616 mg, 2.0 mmol) as starting material in the same manner as in step 3 of Example 4.

[1038] Step 3: Synthesis of compound 61d

[1039] Compound 61d (360 mg) was synthesized and purified using compound 61c (520 mg, 1.8 mmol) as starting material in the same manner as in step 3 of Example 30.

[1040] Step 4: Synthesis of compound 61e

[1041] Compound 61e (234 mg) was synthesized and purified using compound 61d (210 mg, 1.0 mmol) as starting material in the same manner as in step 4 of Example 30.

[1042] Step 5: Synthesis of compound 61f

[1043] Compound 61f (116 mg) was synthesized and purified using compound 61e (230 mg, 0.6 mmol) as starting material in the same manner as in step 5 of Example 30.

[1044] MS m / z(ESI):216.1[M+H] + .

[1045] Step 6: Synthesis of compound 61

[1046] Compound 61 (26 mg) was synthesized and purified using the same method as in Step 5 of Example 23 using Compound 61f (22 mg, 0.1 mmol) and Compound 4g (47 mg, 0.1 mmol) as starting materials.

[1047] MS m / z(ESI):552.2[M+H] + .

[1048] 1 H NMR (400MHz, DMSO-d6) δ12.41(s,1H),10.14(s,1H),8.32(dd,J=7.9,1.0Hz,1H),8.04(d,J=8.6Hz,1H) ,7.28(d,J=2.2Hz,1H),7.24(dd,J=8.1,1.0Hz,1H),7.15(t,J=8.0Hz,1H),7.09(dd,J=8.6,2.1Hz,1H) ,4.93(s,1H),4.38(t,J=5.9Hz,2H),3.84–3.68(m,2H),3.36(t,J=6.5Hz,2H),3.09–3.02(m,2H),3.02 –2.96(m,4H),2.05–1.80(m,4H),1.80–1.59(m,4H),1.50–1.40(m,2H),1.17–1.08(m,2H),0.30(s,4H).

[1049] Example 62 and Example 63 Synthesis of Compound 62 and Compound 63

[1050] Step 1: Synthesis of compound 62b

[1051] Compound 62b (1.45 g) was synthesized and purified using the same method as in Step 1 of Example 30 using compounds 30a (1.08 g, 4.9 mmol) and 62a (0.5 g, 4.9 mmol) as starting materials.

[1052] Step 2: Synthesis of compound 62c

[1053] Compound 62c (1.2 g) was synthesized and purified using compound 62b (1.45 g, 4.5 mmol) as starting material in the same manner as in step 3 of Example 4.

[1054] Step 3: Synthesis of Compound 62d and Compound 62e

[1055] By the same method as in Step 3 of Example 30, using Compound 62c (1.2 g, 4.4 mmol) as starting material, a mixture of Compound 62d and Compound 62e (0.81 g) was synthesized and purified.

[1056] Step 4: Synthesis of Compound 62f and Compound 62g

[1057] A mixture of Compound 62f and Compound 62g (0.65 g) was synthesized and purified using a mixture of Compound 62d and Compound 62e (0.81 g, 3.0 mmol) and tert-butyl carbamate (0.39 g, 3.3 mmol) as starting materials in the same manner as in Step 4 of Example 30.

[1058] Step 5: Synthesis of Compound 62h and Compound 62i

[1059] By the same method as in Step 5 of Example 30, a mixture of Compound 62f and Compound 62g (0.64 g, 2.1 mmol) was used as starting material to synthesize and purify a mixture of Compound 62h and Compound 62i (130 mg).

[1060] MS m / z(ESI):204.1[M+H] + .

[1061] Step 6: Synthesis of Compound 62 and Compound 63

[1062] The final product was synthesized and purified using the same method as in Step 5 of Example 23 using a mixture of Compound 62h and Compound 62i (31 mg, 0.15 mmol) and Compound 4g (93 mg, 0.2 mmol) as starting materials.

[1063] Compound 62 (13 mg)

[1064] MS m / z(ESI):540.2[M+H] + .

[1065] 1H NMR (400MHz, DMSO-d6) δ12.37(s,1H),8.31(dd,J=6.9,2.1Hz,1H),7.99(d,J=8.5Hz, 1H),7.22(d,J=2.1Hz,1H),7.19–7.11(m,2H),7.04(dd,J=8.7,2.0Hz,1H),4.79–4.7 2(m,1H),4.36(dd,J=11.5,5.6Hz,1H),4.17(dd,J=11.4,2.2Hz,1H),3.76(t,J=6.5H z,2H),3.36(s,3H),3.32–3.28(m,3H),3.07–2.87(m,5H),1.78(s,4H),0.30(s,4H).

[1066] Compound 63(4mg)

[1067] MS m / z(ESI):540.2[M+H] + .

[1068] 1 H NMR (400MHz, DMSO-d6) δ12.25 (s, 1H), 8.42 (dd, J = 6.9, 2.1Hz, 1H), 7.96 (d, J=8.5Hz,1H),7.27–7.13(m,3H),6.99(d,J=8.7Hz,1H),4.86–4.77(m,1H),4 .27–4.13(m,2H),3.75(t,J=6.5Hz,2H),3.49(s,3H),3.28–3.23(m,2H),3.0 7–2.91(m,5H),2.62–2.56(m,1H),1.93–1.59(m,4H),0.29(d,J=6.4Hz,4H).

[1069] Example 64 Synthesis of Compound 64

[1070] Step 1: Synthesis of compound 64c

[1071] Compound 64a (300 mg, 1.9 mmol), compound 64b (214 mg, 1.9 mmol) and sodium tert-butoxide (366 mg, 3.8 mmol) were added to THF (10 mL). XPhos Pd G2 (73 mg, 95.5 μmol) was added under an argon atmosphere, and the mixture was fully reacted at room temperature. Water (20 mL) was added to the system, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and dried by spin drying. Compound 64c (180 mg) was obtained by flash column chromatography (petroleum ether: ethyl acetate = 5:1). Step 2: Synthesis of Compound 64d

[1072] Compound 64c (180 mg, 0.96 mmol), hydroxylamine hydrochloride (66 mg, 0.96 mmol), and sodium acetate (117 mg, 1.43 mmol) were added to anhydrous methanol (10 mL), and the mixture was fully reacted at 70°C. After cooling, saturated aqueous sodium bicarbonate solution (20 mL) was added to the system, and extraction was performed with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and spin-dried to obtain compound 64d (145 mg).

[1073] Step 3: Synthesis of compound 64e

[1074] Compound 64d (145 mg, 0.66 mmol) was added to dichloromethane (0.3 mL), and p-toluenesulfonyl chloride (125 mg, 66 mmol) and triethylamine (199 mg, 1.98 mmol) were added at 0°C. The mixture was allowed to react fully at room temperature. Water (5 mL) was added to the system, and the mixture was extracted with ethyl acetate (5 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and dried by spin drying. Compound 64e (44 mg) was then purified by flash column chromatography (petroleum ether:ethyl acetate = 4:1) to afford compound 64e.

[1075] Step 4: Synthesis of compound 64f

[1076] Compound 64e (44 mg, 0.22 mmol) was dissolved in anhydrous THF (0.3 mL). n-Butyl lithium (0.2 mL, 0.32 mmol, 1.6 M) was added at -60°C and allowed to react fully at this temperature. 1,2-Dibromotetrachloroethane (71 mg, 0.22 mmol) was then added and the mixture was allowed to react fully at room temperature. Saturated aqueous ammonium chloride (3 mL) was added to the system, and the mixture was extracted with ethyl acetate (3 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and dried by spin-drying. Compound 64f (45.8 mg) was obtained by purification by flash column chromatography (petroleum ether:ethyl acetate = 4:1).

[1077] MS m / z(ESI):265.2 / 267.2[M+H] + .

[1078] Step 5: Synthesis of compound 64g

[1079] Compound 64g (17.5 mg) was synthesized and purified using the same method as in Step 2 of Example 7 using compounds 7a (47 mg, 0.1 mmol) and 64f (27 mg, 0.1 mmol) as starting materials.

[1080] Step 6: Synthesis of compound 64

[1081] Compound 64 (8.0 mg) was synthesized and purified using compound 64g (17 mg, 26 μmol) as starting material in the same manner as in step 8 of Example 4.

[1082] MS m / z(ESI):538.3[M+H] + .

[1083] 1 H NMR (400MHz, DMSO-d6) δ12.95(s,1H),8.06(d,J=8.6Hz,1H),7.86–7.81(m,1H),7.30(dd,J=9.4,1.6Hz,2H),7.19(dd,J=8.8,7.4Hz,1H),7.12(dd, J=8.6,2.1Hz,1H),3.79(t,J=6.4Hz,2H),3.30(t,J=6.5Hz,2H),3.03(s,6 H),2.86–2.76(m,2H),1.92–1.74(m,6H),1.29–1.24(m,4H),0.34(s,4H).

[1084] Example 65 Synthesis of Compound 65

[1085] Step 1: Synthesis of compound 65b

[1086] Compound 65b (17.8 mg) was synthesized and purified using the same method as in Step 1 of Example 30 using compounds 65a (50 mg, 0.25 mmol) and 2b (242 mg, 2 mmol) as starting materials.

[1087] Step 2: Synthesis of compound 65c

[1088] Compound 65c (12 mg) was synthesized and purified using compound 65b (17 mg, 0.063 mmol) as starting material in the same manner as in step 3 of Example 4.

[1089] MS m / z(ESI):256.2[M+H] + .

[1090] Step 3: Synthesis of compound 65

[1091] Compound 65 (18 mg) was synthesized and purified using the same method as in Step 5 of Example 23 using compound 65c (12 mg, 0.05 mmol) and compound 4g (24 mg, 0.05 mmol) as starting materials.

[1092] MS m / z(ESI):592.5[M+H] + .

[1093] 1 H NMR (400MHz, DMSO-d6) δ12.70(s,1H),8.03(d,J=8.4Hz,1H),7.75(s,1H),7.22(s,1H),7.08(d,J=8.8Hz,1H),4.56(t,J=8.8Hz,2H),3.75( t,J=6.8Hz,2H),3.71-3.65(m,5H),3.19(t,J=8.8Hz,2H),2.96(t,J=8.4Hz,4H),2.09-1.97(m,4H),1.30-1.20(m,4H),0.38-0.34(m,4H).

[1094] Example 66 Synthesis of Compound 66

[1095] Step 1: Synthesis of compound 66b

[1096] Compound 66b (275 mg) was synthesized and purified using the same method as in Step 1 of Example 30 using compound 66a (200 mg, 1.06 mmol) and DMBNH2 (217 mg, 1.3 mmol) as starting materials.

[1097] Step 2: Synthesis of compound 66c

[1098] Compound 66c (110 mg) was synthesized and purified using the same method as in Step 4 of Example 22 using compound 66b (200 mg, 0.63 mmol) and compound 2b (121 mg, 1.0 mmol) as starting materials.

[1099] Step 3: Synthesis of compound 66d

[1100] Compound 66d (56 mg) was synthesized and purified using compound 66c (100 mg, 0.25 mmol) as starting material in the same manner as in step 5 of Example 30.

[1101] MS m / z(ESI):254.1[M+H] + .

[1102] Step 6: Synthesis of compound 66

[1103] Compound 66 (7.8 mg) was synthesized and purified using the same method as in Step 5 of Example 23 using compound 66d (25 mg, 0.1 mmol) and compound 4g (47 mg, 0.1 mmol) as starting materials.

[1104] MS m / z(ESI):590.3[M+H] + .

[1105] Example 67 Synthesis of Compound 67

[1106] Step 1: Synthesis of compound 67b

[1107] Compound 67b (255 mg) was synthesized and purified using the same method as in Step 1 of Example 30 using compound 67a (200 mg, 1.05 mmol) and DMBNH2 (217 mg, 1.3 mmol) as starting materials.

[1108] Step 2: Synthesis of compound 67c

[1109] Compound 67c (103 mg) was synthesized and purified using the same method as in Step 4 of Example 22 using compound 67b (200 mg, 0.62 mmol) and compound 2b (121 mg, 1.0 mmol) as starting materials.

[1110] Step 3: Synthesis of compound 67d

[1111] Compound 67d (38 mg) was synthesized and purified using compound 67c (99 mg, 0.24 mmol) as starting material in the same manner as in step 5 of Example 30.

[1112] MS m / z(ESI):256.1[M+H] + .

[1113] Step 6: Synthesis of compound 67

[1114] Compound 67 (6.7 mg) was synthesized and purified using the same method as in Step 5 of Example 23 using compound 67d (26 mg, 0.1 mmol) and compound 4g (47 mg, 0.1 mmol) as starting materials.

[1115] MS m / z(ESI):592.3[M+H] + .

[1116] Example 68 Synthesis of Compound 68

[1117] Step 1: Synthesis of compound 68b

[1118] Compound 68b (0.5 g) was synthesized and purified using the same method as in Step 1 of Example 30 using compound 30a (3.91 g, 17.8 mmol) and 68a (hydrochloride, 266 mg, 1.78 mmol) as starting materials.

[1119] Step 2: Synthesis of compound 68c

[1120] Compound 68c (0.32 g) was synthesized and purified using compound 68b (0.5 g, 1.6 mmol) as starting material in the same manner as in step 3 of Example 4.

[1121] Step 3: Synthesis of compound 68d

[1122] Compound 68d (220 mg) was synthesized and purified using compound 68c (300 mg, 1.06 mmol) as starting material in the same manner as in step 3 of Example 30.

[1123] Step 4: Synthesis of compound 68e

[1124] Compound 68e (180 mg) was synthesized and purified using the same method as in Step 4 of Example 30 using compound 68d (200 mg, 0.72 mmol) and tert-butyl carbamate (101 mg, 0.86 mmol) as starting materials.

[1125] Step 5: Synthesis of compound 68f

[1126] Compound 68f (90 mg) was synthesized and purified using compound 68e (170 mg, 0.54 mmol) as starting material in the same manner as in step 5 of Example 30.

[1127] MS m / z(ESI):216.1[M+H] + .

[1128] Step 6: Synthesis of compound 68

[1129] Compound 68 (10.0 mg) was synthesized and purified using the same method as in Step 5 of Example 23 using compound 68f (43 mg, 0.2 mmol) and compound 4g (94 mg, 0.2 mmol) as starting materials.

[1130] MS m / z(ESI):552.2[M+H] + .

[1131] 1 H NMR (400MHz, DMSO-d6) δ12.49(s,1H),8.32(d,J=7.8Hz,1H),8.05(d,J=8.6Hz,1H),7. 32–7.21(m,2H),7.16(t,J=8.0Hz,1H),7.09(dd,J=8.6,2.1Hz,1H),4.99–4.88(m,1H), 3.77(t,J=6.5Hz,2H),3.74–3.65(m,2H),3.61–3.57(m,1H),3.35–3.23(m,2H),3.00(d ,J=13.3Hz,5H),2.15–2.09(m,1H),2.06–1.75(m,7H),1.46–1.42(m,3H),0.31(s,4H).

[1132] Example 69 Synthesis of Compound 69

[1133] Step 1: Synthesis of compound 69b

[1134] Compound 69b (0.5 g) was synthesized and purified using the same method as in Step 1 of Example 30 using compound 30a (436 mg, 2.0 mmol) and 69a (hydrochloride, 240 mg, 1.8 mmol) as starting materials.

[1135] Step 2: Synthesis of compound 69c

[1136] Compound 69c (0.33 g) was synthesized and purified using compound 69b (0.5 g, 1.7 mmol) as starting material in the same manner as in step 3 of Example 4.

[1137] Step 3: Synthesis of compound 69d

[1138] Compound 69d (170 mg) was synthesized and purified using compound 69c (320 mg, 1.2 mmol) as starting material in the same manner as in step 3 of Example 30.

[1139] Step 4: Synthesis of compound 69e

[1140] Compound 69e (120 mg) was synthesized and purified using the same method as in step 4 of Example 30 using compound 69d (160 mg, 0.61 mmol) and tert-butyl carbamate (86 mg, 0.73 mmol) as starting materials.

[1141] Step 5: Synthesis of compound 69f

[1142] Compound 69f (70 mg) was synthesized and purified using compound 69e (110 mg, 0.37 mmol) as starting material in the same manner as in step 5 of Example 30.

[1143] MS m / z(ESI):200.1[M+H] + .

[1144] Step 6: Synthesis of compound 69

[1145] Compound 69 (18 mg) was synthesized and purified using the same method as in Step 5 of Example 23 using compound 69f (20 mg, 0.1 mmol) and compound 4g (60 mg, 0.13 mmol) as starting materials.

[1146] MS m / z(ESI):536.1[M+H] + .

[1147] 1 H NMR (400MHz, DMSO-d6) δ12.13(s,1H),8.43(dd,J=6.9,2.0Hz,1H),8.01(d,J=8.6Hz ,1H),7.27–7.18(m,3H),7.06(dd,J=8.6,2.1Hz,1H),6.29(d,J=1.9Hz,1H),5.35(d, J=1.9Hz,1H),4.23(t,J=5.9Hz,2H),3.76(t,J=6.5Hz,2H),3.46–3.36(m,2H),3.03( t,J=5.3Hz,4H),2.74(t,J=5.9Hz,2H),2.20–2.08(m,2H),1.77(s,4H),0.29(s,4H).

[1148] Example 70 and Example 71 Synthesis of Compound 70 and Compound 71

[1149] Step 1: Synthesis of compound 70b

[1150] Compound 70b (0.5 g) was synthesized and purified using the same method as in Step 1 of Example 30 using compounds 30a (436 mg, 2.0 mmol) and 70a (240 mg, 1.8 mmol) as starting materials.

[1151] Step 2: Synthesis of compound 70c

[1152] Compound 70c (0.39 g) was synthesized and purified using compound 70b (0.5 g, 1.7 mmol) as starting material in the same manner as in step 3 of Example 4.

[1153] Step 3: Synthesis of Compound 70d and Compound 70e

[1154] By the same method as in Step 3 of Example 30, using Compound 70c (380 mg, 1.4 mmol) as starting material, a mixture of Compound 70d and Compound 70e (280 mg) was synthesized and purified.

[1155] Step 4: Synthesis of Compound 70f and Compound 70g

[1156] A mixture of Compound 70f and Compound 70g (240 mg) was synthesized and purified using a mixture of Compound 70d and Compound 70e (260 mg, 1.0 mmol) and tert-butyl carbamate (140 mg, 1.2 mmol) as starting materials in the same manner as in Step 4 of Example 30.

[1157] Step 5: Synthesis of Compound 70h and Compound 70i

[1158] By the same method as in Step 5 of Example 30, a mixture of Compound 70f and Compound 70g (230 mg, 0.77 mmol) was used as starting material to synthesize and purify a mixture of Compound 70h and Compound 70i (95 mg).

[1159] MS m / z(ESI):200.1[M+H] + .

[1160] Step 6: Synthesis of Compound 70 and Compound 71

[1161] The final product was synthesized and purified using the same method as in Step 5 of Example 23 using a mixture of Compound 70h and Compound 70i (80 mg, 0.4 mmol) and Compound 4g (234 mg, 0.5 mmol) as starting materials.

[1162] Compound 70 (6.0 mg)

[1163] MS m / z(ESI):536.2[M+H] + .

[1164] 1 H NMR (400MHz, DMSO-d6) δ12.44(s,1H),9.94(s,1H),8.32(dd,J=7.7,1.2Hz,1H),8.03(d,J=8.6Hz,1H),7.2 6(d,J=2.1Hz,1H),7.20(dd,J=8.1,1.3Hz,1H),7.15(t,J=7.9Hz,1H),7.08(dd,J=8.6,2.1Hz,1H),4.96(s, 1H),4.59(d,J=12.8Hz,1H),4.30(dd,J=12.7,2.9Hz,1H),3.76(t,J=6.5Hz,2H),3.38–3.35(m,2H),2.97(t ,J=5.4Hz,4H),2.08–1.65(m,4H),1.61–1.52(m,2H),0.75–0.64(m,1H),0.30(s,4H),-0.03–-0.13(m,1H).

[1165] Compound 71 (40 mg)

[1166] MS m / z(ESI):536.2[M+H] + .

[1167] 1 H NMR (400MHz, DMSO-d6) δ12.46(s,1H),10.11(s,1H),8.30(dd,J=7.3,1.7Hz,1H),8.04(d,J=8 .6Hz,1H),7.28(d,J=2.2Hz,1H),7.18–7.05(m,3H),4.95(s,1H),4.31(dd,J=13.1,6.0Hz,1H) ,3.77(t,J=6.5Hz,2H),3.69(td,J=12.9,4.8Hz,1H),3.36(t,J=6.6Hz,2H),3.00(t,J=5.5Hz, 4H),2.37–2.22(m,2H),2.18–1.98(m,2H),1.98–1.62(m,4H),1.30–1.10(m,2H),0.32(s,4H).

[1168] Example 72 Synthesis of Compound 72

[1169] Step 1: Synthesis of compound 72b

[1170] Compound 72b (0.3 g) was synthesized and purified using the same method as in Step 1 of Example 30 using compounds 30a (224 mg, 1.0 mmol) and 72a (100 mg, 1.0 mmol) as starting materials.

[1171] Step 2: Synthesis of compound 72c

[1172] Compound 72c (0.26 g) was synthesized and purified using compound 72b (0.3 g, 1.0 mmol) as starting material in the same manner as in step 3 of Example 4.

[1173] Step 3: Synthesis of compound 72d

[1174] Compound 72d (110 mg) was synthesized and purified using compound 72c (0.26 g, 1.0 mmol) as starting material in the same manner as in step 3 of Example 30.

[1175] Step 4: Synthesis of compound 72e

[1176] Compound 72e (110 mg) was synthesized and purified using the same method as in Step 4 of Example 30 using compound 72d (100 mg, 0.38 mmol) and tert-butyl carbamate (89 mg, 0.76 mmol) as starting materials.

[1177] Step 5: Synthesis of compound 72f

[1178] Compound 72f (50 mg) was synthesized and purified using compound 72e (110 mg, 0.37 mmol) as starting material in the same manner as in step 5 of Example 30.

[1179] MS m / z(ESI):200.1[M+H] + .

[1180] Step 6: Synthesis of Compound 72

[1181] Compound 72 (12.5 mg) was synthesized and purified using the same method as in Step 5 of Example 23 using Compound 72f (20 mg, 0.1 mmol) and Compound 4g (47 mg, 0.1 mmol) as starting materials.

[1182] MS m / z(ESI):536.2[M+H] + .

[1183] 1H NMR (400MHz, DMSO-d6) δ12.33(s,1H),8.28(d,J=7.8Hz,1H),8.00(d,J=8.6Hz,1H),7.27 –7.21(m,2H),7.13(t,J=8.0Hz,1H),7.07(dd,J=8.6,2.1Hz,1H),5.15(s,1H),3.76(t,J =6.5Hz,2H),3.59(d,J=3.7Hz,1H),3.35–3.32(m,2H),3.05–2.91(m,4H),2.27–2.21(m, 1H),2.19–2.09(m,1H),2.03–1.95(m,2H),1.74(s,4H),1.20–1.09(m,2H),0.29(s,4H).

[1184] Example 73 Synthesis of Compound 73

[1185] Step 1: Synthesis of compound 73a

[1186] Compound 73a (27 mg) was synthesized and purified using the same method as in Step 2 of Example 1 using compound 41d (25 mg, 0.1 mmol) and compound 1c (36 mg, 0.1 mmol) as starting materials.

[1187] Step 2: Synthesis of compound 73

[1188] Compound 73 (7 mg) was synthesized and purified using the same method as in Step 3 of Example 1 using compound 73a (24 mg, 0.04 mmol) and ethanesulfonamide (11 mg, 0.1 mmol) as starting materials.

[1189] MS m / z(ESI):573.2[M+H] + .

[1190] 1H NMR(400MHz,DMSO-d6)δ11.65(s,1H),10.13(br,1H),7.83(d,J=8.5Hz,1H),7.46(s,1H) ,7.17(d,J=2.2Hz,1H),7.08(s,1H),7.04(dd,J=8.5Hz,J=2.1Hz,1H),3.19(q,J=7.3Hz, 2H),3.07(t,J=5.5Hz,4H),2.96(t,J=5.3Hz,4H),2.84(t,J=7.3Hz,2H),2.77(t,J=7.2H z,2H),2.12(m,4H),2.03–1.95(m,2H),1.56(br,4H),1.21(t,J=7.3Hz,2H),0.35(s,4H).

[1191] Example 74 Synthesis of Compound 74

[1192] Step 1: Synthesis of compound 74b

[1193] Compound 74b (453 mg) was synthesized and purified using the same method as in Step 1 of Example 30 using compounds 30a (414 mg, 1.88 mmol) and 74a (294 mg, 2.0 mmol) as starting materials.

[1194] Step 2: Synthesis of compound 74c

[1195] Compound 74c (150 mg) was synthesized and purified using compound 74b (347 mg, 1.0 mmol) as starting material in the same manner as in step 3 of Example 4.

[1196] Step 3: Synthesis of compound 74d

[1197] Compound 74d (90 mg) was synthesized and purified using compound 74c (150 mg, 0.47 mmol) as starting material in the same manner as in step 3 of Example 30.

[1198] Step 4: Synthesis of compound 74e

[1199] Compound 74e (77 mg) was synthesized and purified using the same method as in Step 4 of Example 30 using compound 74d (80 mg, 0.25 mmol) and tert-butyl carbamate (59 mg, 0.5 mmol) as starting materials.

[1200] Step 5: Synthesis of compound 74f

[1201] Compound 74f (50 mg) was synthesized and purified using compound 74e (77 mg, 0.22 mmol) as starting material in the same manner as in step 5 of Example 30.

[1202] MS m / z(ESI):200.1[M+H] + .

[1203] Step 6: Synthesis of Compound 74

[1204] Compound 74 (20 mg) was synthesized and purified using the same method as in Step 5 of Example 23 using compound 74f (40 mg, 0.16 mmol) and compound 4g (75 mg, 0.16 mmol) as starting materials.

[1205] MS m / z(ESI):586.2[M+H] + .

[1206] 1 H NMR (400MHz, DMSO-d6) δ12.51(s,1H),10.11(s,1H),8.38(dd,J=7.2,1.7Hz,1H),8.03(d,J=8.5Hz,1H),7.27–7.17(m,3H),7.07(dd,J=8.6,2.0Hz, 1H),4.92(s,1H),4.34(d,J=12.2Hz,1H),4.29–4.21(m,1H),3.76(t,J=6 .5Hz,2H),3.72–3.65(m,1H),3.37–3.33(m,2H),3.11–3.05(m,1H),3.04– 2.90(m,4H),2.30–2.21(m,2H),1.98–1.90(m,2H),1.90–1.58(m,4H),0.30(s,4H).

[1207] Example 75 Synthesis of Compound 75

[1208] Step 1: Synthesis of compound 75c

[1209] Copper acetate (11.4 mg, 57 μmol) and pyridine (45.2 mg, 571 μmol) were added to a solution of 75a (60.2 mg, 371 μmol) and 75b (50 mg, 285 μmol) in DMF (2 mL). The mixture was stirred at 100°C under an oxygen atmosphere and allowed to react thoroughly. The mixture was filtered, and the volatiles were removed under vacuum. The residue was purified by flash column chromatography (petroleum ether:ethyl acetate = 3:1) to provide compound 75c (61 mg).

[1210] Step 2: Synthesis of compound 75d

[1211] Compound 75d (9 mg) was synthesized and purified using the same method as in Step 2 of Example 7 using compounds 75c (25 mg, 86 μmol) and 7a (40 mg, 86 μmol) as starting materials.

[1212] Step 3: Synthesis of compound 75

[1213] Compound 75 (2.4 mg) was synthesized and purified using compound 75d (9 mg) as starting material in the same manner as in step 8 of Example 4.

[1214] MS m / z(ESI):564.2[M+H] + .

[1215] 1 H NMR (400MHz, DMSO-d6) δ13.63(s,1H),8.48–8.15(m,1H),7.98(d,J=8.6Hz,1H),7.20(s,1H),7.13–7.05(m,2H),6.09(s,1H),3.75(t,J=6 .4Hz,2H),3.30–3.29(m,2H),2.98–2.93(m,4H),2.80(t,J=14.7Hz,2H),2.71–2.66(m,2H),2.27–2.16(m,2H),1.65(s,4H),0.38(s,4H).

[1216] Example 76 Synthesis of Compound 76

[1217] Step 1: Synthesis of compound 76b

[1218] Compound 76b (585 mg) was synthesized and purified using the same method as in Step 1 of Example 30 using compounds 30a (760 mg, 3.45 mmol) and 76a (240 mg, 1.73 mmol) as starting materials.

[1219] Step 2: Synthesis of compound 76c

[1220] Compound 76c (349 mg) was synthesized and purified using compound 76b (400 mg, 1.18 mmol) as starting material in the same manner as in step 3 of Example 4.

[1221] Step 3: Synthesis of compound 76d

[1222] Compound 76d (250 mg) was synthesized and purified using compound 76c (330 mg, 1.07 mmol) as starting material in the same manner as in step 3 of Example 30.

[1223] Step 4: Synthesis of compound 76e

[1224] Compound 76e (240 mg) was synthesized and purified using the same method as in Step 4 of Example 30 using compound 76d (242 mg, 0.79 mmol) and tert-butyl carbamate (230 mg, 2.0 mmol) as starting materials.

[1225] Step 5: Synthesis of compound 76f

[1226] Compound 76f (70 mg) was synthesized and purified using compound 76e (240 mg, 0.70 mmol) as starting material in the same manner as in step 5 of Example 30.

[1227] MS m / z(ESI):242.1[M+H] + .

[1228] Step 6: Synthesis of Compound 76

[1229] Compound 76 (5 mg) was synthesized and purified using the same method as in Step 5 of Example 23 using compound 76f (62 mg, 0.26 mmol) and compound 4g (80 mg, 0.17 mmol) as starting materials.

[1230] MS m / z(ESI):578.1[M+H] + .

[1231] 1 H NMR(400MHz,DMSO-d6)ofδ12.38(s,1H),8.34(dd,J=7.7,1.3Hz,1H),8.00(d,J=8.6Hz,1H),7.25– 7.21(m,2H),7.18(t,J=7.9Hz,1H),7.05(dd,J=8.6,2.1Hz,1H),4.53(dd,J=11.2,8.8Hz,1H),4.33 (dd,J=11.2,4.8Hz,1H),4.28–4.17(m,1H),3.76(t,J=6.5Hz,2H),3.43(dd,J=17.1,9.6Hz,1H),3 .35–3.33(m,2H),3.08(dd,J=17.1,5.1Hz,1H),3.04–2.92(m,4H),1.98–1.54(m,4H),0.29(s,4H).

[1232] Example 77 Synthesis of Compound 77

[1233] Step 1: Synthesis of compound 77b

[1234] Compound 77b (358 mg) was synthesized and purified using the same method as in Step 1 of Example 30 using compounds 30a (440 mg, 2.0 mmol) and 77a (226 mg, 2.0 mmol) as starting materials.

[1235] Step 2: Synthesis of compound 77c

[1236] Compound 77c (219 mg) was synthesized and purified using compound 77b (310 mg, 1.0 mmol) as starting material in the same manner as in step 3 of Example 4.

[1237] Step 3: Synthesis of compound 77d

[1238] Compound 77d (150 mg) was synthesized and purified using compound 77c (200 mg, 0.71 mmol) as starting material in the same manner as in step 3 of Example 30.

[1239] Step 4: Synthesis of compound 77e

[1240] Compound 77e (105 mg) was synthesized and purified using the same method as in Step 4 of Example 30 using compound 77d (140 mg, 0.5 mmol) and tert-butyl carbamate (100 mg, 1.0 mmol) as starting materials.

[1241] Step 5: Synthesis of compound 77f

[1242] Compound 77f (70 mg) was synthesized and purified using compound 77e (100 mg, 0.32 mmol) as starting material in the same manner as in Step 5 of Example 30.

[1243] MS m / z(ESI):216.1[M+H] + .

[1244] Step 6: Synthesis of Compound 77

[1245] Compound 77 (8 mg) was synthesized and purified using the same method as in Step 5 of Example 23 using Compound 77f (22 mg, 0.1 mmol) and Compound 4g (47 mg, 0.1 mmol) as starting materials.

[1246] MS m / z(ESI):552.2[M+H]+ .

[1247] Example 78 Synthesis of Compound 78

[1248] Step 1: Synthesis of compound 78c

[1249] Compound 78a (300 mg, 1.53 mmol) and compound 78b (193 mg, 2.29 mmol) were added to dichloromethane (3 mL), and the mixture was allowed to react fully at room temperature. Water (5 mL) was added to the system, and the mixture was extracted with dichloromethane (3 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and dried by spin drying. The product was purified by flash column chromatography (petroleum ether:ethyl acetate = 8:1) to obtain compound 78c (373 mg).

[1250] Step 2: Synthesis of compound 78e

[1251] Compound 78c (373 mg, 1.33 mmol) was added to THF (6 mL), followed by the addition of lithium diisopropylamide (2 mL, 2.00 mmol, 1 N) at -60°C. The mixture was reacted at this temperature for 10 minutes, followed by the addition of 78d (655 mg, 2.00 mmol), and the mixture was allowed to react fully at room temperature. Saturated ammonium chloride solution (10 mL) was added to the system, and the mixture was extracted with ethyl acetate (5 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous magnesium sulfate, and purified by flash column chromatography (petroleum ether:ethyl acetate = 5:1) to afford compound 78e (331 mg).

[1252] Step 3: Synthesis of compound 78f

[1253] Compound 78e (331 mg, 678 μmol) was added to dioxane (1 mL), followed by a dioxane hydrochloride solution (1.70 mL, 6.78 mmol, 4N) and allowed to react at room temperature. Pyridine hydrofluoride (336 mg, 3.39 mmol) was then added and allowed to react at room temperature. Volatiles were removed under vacuum, and the residue was purified by flash reverse-phase column chromatography (acetonitrile:water) to afford compound 78f (173 mg).

[1254] Step 4: Synthesis of compound 78g

[1255] Compound 78f (173 mg, 603 μmol) was added to tetrahydrofuran (20 mL), followed by triphenylphosphine (474 ​​mg, 1.8 mmol) and diisopropyl azodicarboxylate (DIAD, 366 mg, 1.8 mmol). The mixture was allowed to react at room temperature. The reaction mixture was filtered, dried, and purified by flash column chromatography (petroleum ether:ethyl acetate = 2:1) to afford compound 78g (79.5 mg).

[1256] Step 5: Synthesis of compound 78h

[1257] Compound 78h (56.9 mg) was synthesized and purified using compound 78g (72.3 mg, 274 μmol) as starting material in the same manner as in step 4 of Example 30.

[1258] Step 6: Synthesis of compound 78i

[1259] Compound 78i (21 mg) was synthesized and purified using compound 78h (56.9 mg, 156 μmol) as starting material in the same manner as in step 5 of Example 30.

[1260] MS m / z(ESI):202.1[M+H] + .

[1261] Step 7: Synthesis of Compound 78

[1262] Compound 78 (4 mg) was synthesized and purified using the same method as in Step 5 of Example 23 using compound 78i (20 mg, 43 μmol) and compound 4g (31 mg, 67 μmol) as starting materials.

[1263] MS m / z(ESI):538.5[M+H] + .

[1264] Example 79 Synthesis of Compound 79

[1265] Step 1: Synthesis of compound 79b

[1266] Compound 79a (170 mg, 1.36 mmol) was added to methanol (2 mL) and acetic acid (0.2 mL), followed by the addition of bromide (260 mg, 1.63 mmol) and allowed to react at room temperature. Saturated aqueous sodium bicarbonate (6 mL) was added to the system, and the mixture was extracted with ethyl acetate (3 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and dried. Compound 79b (254 mg) was then purified by flash column chromatography (petroleum ether:ethyl acetate = 1:1) to afford compound 79b.

[1267] Step 2: Synthesis of compound 79d

[1268] Compound 79d (241 mg) was synthesized and purified using the same method as in Step 1 of Example 30 using Compound 79b (254 mg, 1.18 mmol) and Compound 79c (141 mg, 1.42 mmol) as starting materials.

[1269] Step 3: Synthesis of compound 79e

[1270] Compound 79e (93 mg) was synthesized and purified using compound 79d (241 mg, 0.85 mmol) as starting material in the same manner as in step 3 of Example 30.

[1271] Step 4: Synthesis of compound 79f

[1272] Compound 79f (26 mg) was synthesized and purified using the same method as in Step 2 of Example 7 using compounds 7a (48 mg, 0.1 mmol) and 79e (28 mg, 0.1 mmol) as starting materials.

[1273] Step 5: Synthesis of Compound 79

[1274] Compound 79 (5.4 mg) was synthesized and purified using compound 79f (26 mg, 39 μmol) as starting material in the same manner as in step 8 of Example 4.

[1275] MS m / z(ESI):553.4[M+H] + .

[1276] Example 80 Synthesis of Compound 80

[1277] Step 1: Synthesis of compound 80b

[1278] Compound 80b (273 mg) was synthesized and purified using the same method as in Step 1 of Example 30 using Compound 80a (220 mg, 1.0 mmol) and Compound 2b (242 mg, 2.0 mmol) as starting materials.

[1279] Step 2: Synthesis of compound 80c

[1280] Compound 80c (182 mg) was synthesized and purified using the same method as in Step 3 of Example 4 using compound 80b (257 mg, 0.8 mmol) as starting material.

[1281] Step 3: Synthesis of compound 80d

[1282] Compound 80d (117 mg) was synthesized and purified using compound 80c (145 mg, 0.5 mmol) as starting material in the same manner as in step 1 of Example 22.

[1283] Step 4: Synthesis of compound 80e

[1284] Compound 80e (39.4 mg) was synthesized and purified using the same method as in Step 4 of Example 30 using compound 80d (63 mg, 0.2 mmol) and benzophenone imine (40 mg, 0.22 mmol) as starting materials.

[1285] Step 5: Synthesis of compound 80f

[1286] Compound 80f (16.1 mg) was synthesized and purified using compound 80e (33 mg, 0.08 mmol) as starting material in the same manner as in step 5 of Example 30.

[1287] MS m / z(ESI):253.1[M+H] + .

[1288] Step 6: Synthesis of Compound 80

[1289] Compound 80 (9.4 mg) was synthesized and purified using the same method as in Step 5 of Example 23 using Compound 80f (12.6 mg, 0.05 mmol) and Compound 4g (47 mg, 0.1 mmol) as starting materials.

[1290] MS m / z(ESI):589.3[M+H] + .

[1291] Example 81 Synthesis of Compound 81

[1292] Step 1: Synthesis of compound 81b

[1293] Compound 81a (100 mg, 0.51 mmol) was added to THF (1 ml). After cooling to -78°C, n-butyllithium (0.48 ml, 1.6 M, 0.76 mmol) was slowly added dropwise. Hexachloroethane (0.15 g, 0.61 mmol) was then added. The mixture was allowed to warm to room temperature and allowed to react fully. Volatiles were removed under vacuum, and the residue was directly separated by flash column chromatography to afford compound 81b (76.2 mg).

[1294] Step 2: Synthesis of compound 81c

[1295] Compound 81c (76.2 mg) was synthesized and purified using the same method as in Step 1 of Example 30 using compound 81b (50 mg, 0.22 mmol) and compound 2b (266 mg, 2.2 mmol) as starting materials.

[1296] Step 3: Synthesis of compound 81d

[1297] Compound 81d (21 mg) was synthesized and purified using the same method as in Step 2 of Example 7 using compounds 7a (26 mg, 0.055 mmol) and 81c (16 mg, 0.05 mmol) as starting materials.

[1298] Step 4: Synthesis of compound 81

[1299] Compound 81 (7.6 mg) was synthesized and purified using compound 81d (21 mg, 30 μmol) as starting material in the same manner as in step 8 of Example 4.

[1300] MS m / z(ESI):589.3[M+H] + .

[1301] Example 82 Synthesis of Compound 82

[1302] Step 1: Synthesis of compound 82b

[1303] Compound 82a (1.1 g, 5.0 mmol) was added to THF (10 mL) and cooled to 0°C. Potassium tert-butoxide (678 mg, 6.0 mmol) was then added and allowed to react fully after warming to room temperature. Saturated aqueous ammonium chloride (20 mL) was added to the system, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and dried. Compound 82b (1.25 g) was then purified by flash column chromatography (petroleum ether:ethyl acetate = 12:1) to afford compound 82b.

[1304] Step 2: Synthesis of compound 82c

[1305] Compound 82b (1.0 g, 3.6 mmol), palladium acetate (250 mg, 0.8 mmol), tricyclohexylphosphine (238 mg, 1.0 mmol), pivalic acid (360 mg, 3.6 mmol), and potassium carbonate (0.69 g, 5 mmol) were added to mesitylene (15 mL) and allowed to react under a nitrogen atmosphere at 140°C. Saturated aqueous sodium bicarbonate solution (20 mL) was added to the system, and the mixture was extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and dried. Compound 82c (570 mg) was then purified by flash column chromatography (petroleum ether:ethyl acetate = 10:1) to afford compound 82c.

[1306] Step 3: Synthesis of compound 82d

[1307] Compound 82c (385 mg, 2.0 mmol) was added to dioxane (5 mL), followed by bromine (480 mg, 3.0 mmol), and the mixture was allowed to react at room temperature. Saturated aqueous sodium bicarbonate (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and dried. Compound 82d (401 mg) was then purified by flash column chromatography (petroleum ether:ethyl acetate = 10:1) to afford compound 82d.

[1308] Step 4: Synthesis of compound 82e

[1309] Compound 82e (199 mg) was synthesized and purified using the same method as in Step 4 of Example 22 using compound 82d (270 mg, 1.0 mmol) and compound 2b (132 mg, 1.1 mmol) as starting materials.

[1310] Step 5: Synthesis of compound 82f

[1311] Compound 82f (94 mg) was synthesized and purified using the same method as in Step 3 of Example 4 using compound 82e (190 mg, 0.61 mmol) as starting material.

[1312] MS m / z(ESI):282.2[M+H] + .

[1313] Step 6: Synthesis of Compound 82

[1314] Compound 82 (12 mg) was synthesized and purified using the same method as in Step 5 of Example 23 using compound 82f (28 mg, 0.1 mmol) and compound 4g (47 mg, 0.1 mmol) as starting materials.

[1315] MS m / z(ESI):619.3[M+H] + .

[1316] Example 83 Synthesis of Compound 83

[1317] Step 1: Synthesis of compound 83b

[1318] Compound 83b (1.0 g) was synthesized and purified using the same method as in Step 1 of Example 30 using compound 30a (820 mg, 3.7 mmol) and 83a (hydrochloride, 500 mg, 3.7 mmol) as starting materials.

[1319] Step 2: Synthesis of compound 83c

[1320] Compound 83c (499 mg) was synthesized and purified using compound 83b (1.0 g, 3.3 mmol) as starting material in the same manner as in step 3 of Example 4.

[1321] Step 3: Synthesis of compound 83d

[1322] Compound 83d (60 mg) was synthesized and purified using compound 83c (200 mg, 0.74 mmol) as starting material in the same manner as in step 3 of Example 30.

[1323] Step 4: Synthesis of compound 83e

[1324] Compound 83e (17 mg) was synthesized and purified using the same method as in Step 4 of Example 30 using compound 83d (30 mg, 0.11 mmol) and tert-butyl carbamate (40 mg, 0.34 mmol) as starting materials.

[1325] Step 5: Synthesis of compound 83f

[1326] Compound 83f (21 mg) was synthesized and purified using compound 83e (34 mg, 0.11 mmol) as starting material in the same manner as in step 5 of Example 30.

[1327] MS m / z(ESI):202.1[M+H] + .

[1328] Step 6: Synthesis of compound 83

[1329] Compound 83 (8 mg) was synthesized and purified using the same method as in Step 5 of Example 23 using compound 83f (20 mg, 0.1 mmol) and compound 4g (47 mg, 0.1 mmol) as starting materials.

[1330] MS m / z(ESI):538.2[M+H] + .

[1331] 1 H NMR(400MHz,DMSO-d6)δ12.39(s,1H),10.14(s,1H),8.37–8.30(m,1H),8.02(d,J=8.6Hz,1H),7.36 (dd,J=8.1,1.0Hz,1H),7.27(d,J=2.1Hz,1H),7.22(t,J=8.0Hz,1H),7.08(dd,J=8.6,2.1Hz,1H),5. 66(s,1H),5.44(d,J=2.3Hz,1H),4.93(s,1H),3.98(d,J=7.2Hz,1H),3.76(t,J=6.5Hz,2H),3.36–3. 35(m,2H),3.01–2.96(m,5H),2.46–2.42(m,1H),2.36–2.32(m,1H),1.88–1.69(m,4H),0.31(s,4H).

[1332] Example 84 and Example 85 Synthesis of Compound 84 and Compound 85

[1333] Step 1: Synthesis of compound 84b

[1334] Compound 84b (1.13 g) was synthesized and purified using the same method as in Step 1 of Example 30 using compound 30a (1.00 g, 4.55 mmol) and 84a (hydrochloride, 0.73 g, 5.45 mmol) as starting materials.

[1335] Step 2: Synthesis of compound 84c

[1336] Compound 84c (0.91 g) was synthesized and purified using the same method as in Step 3 of Example 4 using compound 84b (1.13 g, 3.8 mmol) as starting material.

[1337] Step 3: Synthesis of Compound 84d and Compound 84e

[1338] By the same method as in Step 3 of Example 30, using Compound 84c (0.91 g, 3.7 mmol) as starting material, a mixture of Compound 84d and Compound 84e (0.7 g) was synthesized and purified.

[1339] Step 4: Synthesis of Compound 84f and Compound 84g

[1340] A mixture of Compound 84f and Compound 84g (0.3 g) was synthesized and purified using a mixture of Compound 84d and Compound 84e (0.3 g, 1.14 mmol) and tert-butyl carbamate (0.2 g, 1.71 mmol) as starting materials in the same manner as in Step 4 of Example 30.

[1341] Step 5: Synthesis of Compound 84h and Compound 84i

[1342] By the same method as in Step 5 of Example 30, a mixture of Compound 84f and Compound 84g (0.3 g, 1.0 mmol) was used as starting material to synthesize and purify a mixture of Compound 84h and Compound 84i (182 mg).

[1343] MS m / z(ESI):200.1[M+H] + .

[1344] Step 6: Synthesis of Compound 84 and Compound 85

[1345] The final product was synthesized and purified using the same method as in Step 5 of Example 23 using a mixture of Compound 84h and Compound 84i (170 mg, 0.85 mmol) and Compound 4g (398 mg, 0.85 mmol) as starting materials.

[1346] Compound 84 (10.6 mg)

[1347] MS m / z(ESI):536.2[M+H] + .

[1348] 1 H NMR (400MHz, DMSO-d6) δ12.38(s,1H),8.35–8.30(m,1H),8.01(d,J=8.6Hz,1H),7.24(d,J=2.1Hz,1H),7.16(d,J=2.1Hz,1H),7.15(s,1H),7.09– 7.04(m,1H),4.11(s,2H),3.76(t,J=6.5Hz,2H),3.34–3.32(m,2H),3.02 (s,2H),3.01–2.93(m,4H),1.98–1.61(m,4H),0.88(s,4H),0.29(s,4H).

[1349] Compound 85(102mg)

[1350] MS m / z(ESI):536.2[M+H] + .

[1351] 1 H NMR (400MHz, DMSO-d6) δ12.22(s,1H),8.37(dd,J=7.6,1.5Hz,1H),8.02(d,J=8.6Hz,1H), 7.24(s,1H),7.16(dd,J=8.0,1.4Hz,1H),7.12(t,J=7.8Hz,1H),7.06(d,J=8.5Hz,1H),4. 28(t,J=7.2Hz,2H),3.76(t,J=6.5Hz,2H),3.35–3.35(m,2H),3.00(d,J=15.8Hz,4H),2.7 4(t,J=7.2Hz,2H),1.90–1.61(m,4H),1.34–1.29(m,2H),1.21–1.15(m,2H),0.34(s,4H).

[1352] Example 86 Synthesis of Compound 86

[1353] Step 1: Synthesis of compound 86b

[1354] Compound 86b (0.76 g) was synthesized and purified using the same method as in Step 1 of Example 30 using compound 30a (1.56 g, 7.07 mmol) and 86a (hydrochloride, 1.0 g, 6.43 mmol) as starting materials.

[1355] Step 2: Synthesis of compound 86c

[1356] Compound 86c (430 mg) was synthesized and purified using compound 86b (710 mg, 2.22 mmol) as starting material in the same manner as in step 3 of Example 4.

[1357] Step 3: Synthesis of compound 86d

[1358] Compound 86d (140 mg) was synthesized and purified using compound 86c (290 mg, 1.0 mmol) as starting material in the same manner as in step 3 of Example 30.

[1359] Step 4: Synthesis of compound 86e

[1360] Compound 86e (95 mg) was synthesized and purified using the same method as in Step 4 of Example 30 using compound 86d (100 mg, 0.35 mmol) and tert-butyl carbamate (164 mg, 1.4 mmol) as starting materials.

[1361] Step 5: Synthesis of compound 86f

[1362] Compound 86f (55 mg) was synthesized and purified using compound 86e (90 mg, 0.28 mmol) as starting material in the same manner as in step 5 of Example 30.

[1363] MS m / z(ESI):222.1[M+H] + .

[1364] Step 6: Synthesis of Compound 86

[1365] Compound 86 (7.9 mg) was synthesized and purified using the same method as in Step 5 of Example 23 using compound 86f (50 mg, 0.23 mmol) and compound 4g (104 mg, 0.23 mmol) as starting materials.

[1366] MS m / z(ESI):558.1[M+H] + .

[1367] 1 H NMR (400MHz, DMSO-d6) δ12.36 (s, 1H), 10.15 (s, 1H), 8.33 (dd, J = 6.8, 2.1Hz, 1H), 8.01 (d, J=8.6Hz,1H),7.26(d,J=2.1Hz,1H),7.23–7.16(m,2H),7.08(dd,J=8.6,2.0Hz,1H),4.57( dd,J=12.0,6.6Hz,1H),4.42(d,J=11.9Hz,1H),3.77(t,J=6.5Hz,2H),3.73(d,J=9.2Hz,1 H),3.59–3.51(m,1H),3.38–3.37(m,2H),2.99(t,J=5.4Hz,4H),1.76(s,4H),0.30(s,4H).

[1368] Example 87 Synthesis of Compound 87

[1369] Step 1: Synthesis of compound 87b

[1370] Compound 87b (0.4 g) was synthesized and purified using the same method as in Step 1 of Example 30 using compound 30a (0.3 g, 1.36 mmol) and 87a (172 mg, 1.49 mmol) as starting materials.

[1371] Step 2: Synthesis of compound 87c

[1372] Compound 87c (330 mg) was synthesized and purified using compound 87b (0.4 g, 1.27 mmol) as starting material in the same manner as in step 3 of Example 4.

[1373] Step 3: Synthesis of compound 87d

[1374] Compound 87d (130 mg) was synthesized and purified using compound 87c (330 mg, 1.16 mmol) as starting material in the same manner as in step 3 of Example 30.

[1375] Step 4: Synthesis of compound 87e

[1376] Compound 87e (95 mg) was synthesized and purified using the same method as in Step 4 of Example 30 using compound 87d (120 mg, 0.43 mmol) and tert-butyl carbamate (75 mg, 0.64 mmol) as starting materials.

[1377] Step 5: Synthesis of compound 87f

[1378] Compound 87f (60 mg) was synthesized and purified using compound 87e (90 mg, 0.28 mmol) as starting material in the same manner as in step 5 of Example 30.

[1379] MS m / z(ESI):218.1[M+H] + .

[1380] Step 6: Synthesis of Compound 87

[1381] Compound 87 (10.1 mg) was synthesized and purified using the same method as in Step 5 of Example 23 using compound 87f (46 mg, 0.21 mmol) and compound 4g (104 mg, 0.23 mmol) as starting materials.

[1382] MS m / z(ESI):554.2[M+H] + .

[1383] 1H NMR (400MHz, DMSO-d6) δ12.52(s,1H),8.42–8.34(m,1H),8.04(d,J=8.6Hz,1H),7.26(d,J=2.2Hz,1H),7.23–7.18(m,2H),7.08(dd,J=8.6,2.1H z,1H),4.98(s,2H),4.10(s,2H),3.77(t,J=6.5Hz,2H),3.34–3.32(m,2 H),2.97(t,J=5.4Hz,4H),2.01–1.53(m,4H),1.37(s,6H),0.31(s,4H).

[1384] Example 88 Synthesis of Compound 88

[1385] Step 1: Synthesis of compound 88b

[1386] Compound 88b (0.2 g) was synthesized and purified using the same method as in Step 1 of Example 30 using compounds 30a (824 mg, 3.75 mmol) and 88a (499 mg, 3.75 mmol) as starting materials.

[1387] Step 2: Synthesis of compound 88c

[1388] Compound 88c (80 mg) was synthesized and purified using the same method as in Step 3 of Example 4 using compound 88b (90 mg, 0.27 mmol) as starting material.

[1389] Step 3: Synthesis of compound 88d

[1390] Compound 88d (54 mg) was synthesized and purified using compound 88c (76 mg, 0.25 mmol) as starting material in the same manner as in step 3 of Example 30.

[1391] Step 4: Synthesis of compound 88e

[1392] Compound 88e (46 mg) was synthesized and purified using the same method as in Step 4 of Example 30 using compound 88d (50 mg, 0.17 mmol) and tert-butyl carbamate (40 mg, 0.34 mmol) as starting materials.

[1393] Step 5: Synthesis of compound 88f

[1394] Compound 88f (30 mg) was synthesized and purified using compound 88e (46 mg, 0.13 mmol) as starting material in the same manner as in step 5 of Example 30.

[1395] MS m / z(ESI):236.1[M+H] + .

[1396] Step 6: Synthesis of Compound 88

[1397] Compound 88 (10.0 mg) was synthesized and purified using the same method as in Step 5 of Example 23 using compound 88f (30 mg, 0.13 mmol) and compound 4g (61 mg, 0.13 mmol) as starting materials.

[1398] MS m / z(ESI):572.1[M+H] + .

[1399] 1 H NMR (400MHz, DMSO-d6) δ12.49(s,1H),8.38(dd,J=6.3,2.7Hz,1H),8.02(d,J=8.6Hz,1H ),7.26(d,J=2.2Hz,1H),7.25–7.20(m,2H),7.07(dd,J=8.7,2.1Hz,1H),4.41–4.34(m, 1H),4.32–4.24(m,2H),3.76(t,J=6.5Hz,2H),3.61–3.53(m,1H),3.35–3.34(m,2H),3. 14–3.07(m,1H),3.05–2.93(m,4H),2.80–2.72(m,1H),1.89–1.62(m,4H),0.28(s,4H).

[1400] Example 89 Synthesis of Compound 89

[1401] Step 1: Synthesis of compound 89b

[1402] Compound 89b (7.9 g) was synthesized and purified using the same method as in Step 1 of Example 30 using compounds 30a (5.0 mg, 22.7 mmol) and 89a (5.08 g, 27.3 mmol) as starting materials.

[1403] Step 2: Synthesis of compound 89c

[1404] Compound 89c (7.1 g) was synthesized and purified using compound 89b (7.9 g, 20.5 mmol) as starting material in the same manner as in step 3 of Example 4.

[1405] Step 3: Synthesis of compound 89d

[1406] Compound 89d (4.3 g) was synthesized and purified using compound 89c (7.1 g, 20 mmol) as starting material in the same manner as in step 3 of Example 30.

[1407] Step 4: Synthesis of compound 89e

[1408] Compound 89e (370 mg) was synthesized and purified using compound 89d (1.5 g, 4.26 mmol) as starting material in the same manner as in step 5 of Example 30.

[1409] Step 5: Synthesis of compound 89f

[1410] Compound 89e (360 mg, 1.43 mmol) and paraformaldehyde (471 mg, 1.43 mmol) were dissolved in methanol (2 mL). Acetic acid (0.1 mL) was added, and the mixture was stirred at 50°C for thorough reaction. After cooling to room temperature, sodium cyanoborohydride (180 mg, 2.86 mmol) was added, and the mixture was heated to 50°C for thorough reaction. After cooling to room temperature, the volatiles were removed under vacuum, and the residue was purified by flash column chromatography (petroleum ether:ethyl acetate = 80:20 to 66:34) to provide compound 89f (0.3 g).

[1411] Step 6: Synthesis of compound 89g

[1412] Compound 89g (203 mg) was synthesized and purified using the same method as in Step 4 of Example 30 using compound 89f (300 mg, 1.13 mmol) and tert-butyl carbamate (198 mg, 1.69 mmol) as starting materials.

[1413] Step 7: Synthesis of compound 89h

[1414] Compound 89h (97 mg) was synthesized and purified using compound 89g (198 mg, 0.66 mmol) as starting material in the same manner as in step 5 of Example 30.

[1415] MS m / z(ESI):203.1[M+H] + .

[1416] Step 8: Synthesis of Compound 89

[1417] Compound 89 (10.6 mg) was synthesized and purified using the same method as in Step 5 of Example 23 using compound 89h (34.5 mg, 0.17 mmol) and compound 4g (80 mg, 0.17 mmol) as starting materials.

[1418] MS m / z(ESI):539.2[M+H]+ .

[1419] 1 H NMR (400MHz, DMSO-d6) δ12.46(s,1H),10.17(s,1H),8.36(d,J=7.0Hz,1H),8.04(d,J=8.6Hz,1H),7.27(s,1H),7.24–7.15(m,2H ),7.09(d,J=8.6Hz,1H),4.96(s,1H),4.17(s,2H),3.86–3.72(m,4H),3.04–2.92(m,6H),2.47(s,3H),1.80(s,4H),0.32(s,4H).

[1420] Example 90 Synthesis of Compound 90

[1421] Step 1: Synthesis of compound 90b

[1422] Compound 90b (0.23 g) was synthesized and purified using the same method as in Step 1 of Example 30 using compounds 30a (184 mg, 0.84 mmol) and 90a (hydrochloride, 100 mg, 0.84 mmol) as starting materials.

[1423] Step 2: Synthesis of compound 90c

[1424] Compound 90c (197 mg) was synthesized and purified using compound 90b (0.23 g, 0.81 mmol) as starting material in the same manner as in step 3 of Example 4.

[1425] Step 3: Synthesis of compound 90d

[1426] Compound 90d (146 mg) was synthesized and purified using compound 90c (190 mg, 0.75 mmol) as starting material in the same manner as in step 3 of Example 30.

[1427] Step 4: Synthesis of compound 90e

[1428] Compound 90e (65 mg) was synthesized and purified using the same method as in step 4 of Example 30 using compound 90d (146 mg, 0.6 mmol) and tert-butyl carbamate (82 mg, 0.7 mmol) as starting materials.

[1429] Step 5: Synthesis of compound 90f

[1430] Compound 90f (37 mg) was synthesized and purified using compound 90e (65 mg, 0.23 mmol) as starting material in the same manner as in step 5 of Example 30.

[1431] MS m / z(ESI):186.1[M+H] + .

[1432] Step 6: Synthesis of Compound 90

[1433] Compound 90 (4.1 mg) was synthesized and purified using the same method as in Step 5 of Example 23 using Compound 90f (17 mg, 0.1 mmol) and Compound 4g (47 mg, 0.1 mmol) as starting materials.

[1434] MS m / z(ESI):522.2[M+H] + .

[1435] 1 H NMR (400MHz, DMSO-d6) δ12.49(s,1H),8.43(d,J=7.4Hz,1H),8.38(s,1H),8.03(d,J=8.6Hz,1H),7.33–7.15(m,3H),7.05(d,J=8.6Hz,1H),5.99( s,1H),5.43(s,1H),4.28(t,J=6.6Hz,2H),3.76(t,J=6.5Hz,2H),3.31– 3.29(m,4H),3.02(d,J=5.4Hz,4H),1.94(d,J=58.6Hz,4H),0.31(s,4H).

[1436] Example 91 Synthesis of Compound 91

[1437] Step 1: Synthesis of compound 91a

[1438] Compound 91a (1.27 g) was synthesized and purified using the same method as in Step 1 of Example 30 using compound 30a (1.0 g, 4.55 mmol) and compound 1b (hydrochloride, 805 mg, 5.45 mmol) as starting materials.

[1439] Step 2: Synthesis of compound 91b

[1440] Compound 91b (790 mg) was synthesized and purified using compound 91a (1.0 g, 3.2 mmol) as starting material in the same manner as in step 3 of Example 4.

[1441] Step 3: Synthesis of compound 91c

[1442] Compound 91c (465 mg) was synthesized and purified using compound 91b (785 mg, 2.8 mmol) as starting material in the same manner as in step 3 of Example 30.

[1443] Step 4: Synthesis of compound 91d

[1444] Compound 91d (279 mg) was synthesized and purified using the same method as in Step 4 of Example 30 using compound 91c (400 mg, 1.44 mmol) and tert-butyl carbamate (334 mg, 2 mmol) as starting materials.

[1445] Step 5: Synthesis of compound 91e

[1446] Compound 91e (127 mg) was synthesized and purified using compound 91d (279 mg, 0.89 mmol) as starting material in the same manner as in step 5 of Example 30.

[1447] MS m / z(ESI):214.1[M+H] + .

[1448] Step 6: Synthesis of Compound 91

[1449] Compound 91 (7.4 mg) was synthesized and purified using the same method as in Step 5 of Example 23 using Compound 91e (21 mg, 0.1 mmol) and Compound 4g (47 mg, 0.1 mmol) as starting materials.

[1450] MS m / z(ESI):550.1[M+H] + .

[1451] 1H NMR (400MHz, DMSO-d6) δ12.41(s,1H),10.14(s,1H),8.34(dd,J=7.5,1.3Hz,1H),8.03(d,J=8.6Hz,1H ),7.25(d,J=2.1Hz,1H),7.23–7.19(m,1H),7.17(t,J=7.8Hz,1H),7.08(dd,J=8.6,2.1Hz,1H),4.93( t,J=5.7Hz,1H),4.17(t,J=6.0Hz,2H),3.81–3.72(m,2H),3.37–3.34(m,2H),3.02–2.93(m,4H),2.90 (s,2H),1.95(t,J=6.0Hz,2H),1.91–1.53(m,4H),0.64–0.59(m,2H),0.53–0.48(m,2H),0.28(s,4H).

[1452] Example 92 Synthesis of Compound 92

[1453] Step 1: Synthesis of compound 92a

[1454] Compound 92a (129 mg) was synthesized and purified using the same method as in Step 1 of Example 30 using compound 50c (121 mg, 0.31 mmol) and compound 48a (hydrochloride, 60 mg, 0.5 mmol) as starting materials.

[1455] Step 3: Synthesis of compound 92b

[1456] Compound 92b (63 mg) was synthesized and purified using compound 92a (120 mg, 0.27 mmol) as starting material in the same manner as in step 3 of Example 4.

[1457] Step 4: Synthesis of compound 92c

[1458] Compound 92c (45 mg) was synthesized and purified using compound 92b (63 mg, 0.15 mmol) as starting material in the same manner as in step 3 of Example 30.

[1459] Step 5: Synthesis of compound 92d

[1460] Compound 92c (45 mg, 0.11 mmol) was added to anhydrous dioxane (1 mL), followed by dioxane hydrochloride (4N, 0.2 mL), and the mixture was allowed to react at room temperature. The reaction mixture was filtered, and the filter cake was dried to obtain compound 92d (21 mg).

[1461] MS m / z(ESI):211.1[M+H] + .

[1462] Step 6: Synthesis of compound 92

[1463] Compound 92 (5.0 mg) was synthesized and purified using the same method as in Step 5 of Example 23 using compounds 4g (47 mg, 0.1 mmol) and 92d (21 mg, 0.1 mmol) as starting materials.

[1464] MS m / z(ESI):547.3[M+H] + .

[1465] Example 93 Synthesis of Compound 93

[1466] Step 1: Synthesis of compound 93b

[1467] Compound 93b (54.1 mg) was synthesized and purified using the same method as in Step 1 of Example 30 using compound 93a (64 mg, 0.22 mmol) and compound 2b (266 mg, 2.2 mmol) as starting materials.

[1468] Step 2: Synthesis of compound 93c

[1469] Compound 93c (22 mg) was synthesized and purified using the same method as in Step 2 of Example 7 using compounds 7a (16 mg, 0.05 mmol) and 93b (16 mg, 0.05 mmol) as starting materials.

[1470] Step 3: Synthesis of compound 93

[1471] Compound 93 (13.7 mg) was synthesized and purified using compound 93c (22 mg, 30 μmol) as starting material in the same manner as in step 8 of Example 4.

[1472] MS m / z(ESI):607.3[M+H] + .

[1473] Example 95 Synthesis of Compound 95

[1474] Step 1: Synthesis of compound 95b

[1475] Compound 95b (8.9 g) was synthesized and purified using the same method as in Step 1 of Example 30 using compounds 30a (6.50 g, 29.6 mmol) and 95a (3.61 g, 32.5 mmol) as starting materials.

[1476] Step 2: Synthesis of compound 95c

[1477] Compound 95c (5.9 g) was synthesized and purified using compound 95b (8.9 g, 28.6 mmol) as starting material in the same manner as in step 3 of Example 4.

[1478] Step 3: Synthesis of compound 95d

[1479] Compound 95d (3.4 g) was synthesized and purified using compound 95c (5.7 g, 1.76 mmol) as starting material in the same manner as in step 3 of Example 30.

[1480] Step 4: Synthesis of compound 95e

[1481] Compound 95e (280 mg) was synthesized and purified using the same method as in Step 4 of Example 30 using compound 95d (300 mg, 1.1 mmol) and tert-butyl carbamate (507 mg, 4.3 mmol) as starting materials.

[1482] Step 5: Synthesis of compound 95f

[1483] Compound 95f (130 mg) was synthesized and purified using compound 95e (280 mg, 0.89 mmol) as starting material in the same manner as in step 5 of Example 30.

[1484] MS m / z(ESI):214.1[M+H] + .

[1485] Step 6: Synthesis of Compound 95

[1486] Compound 95 (30 mg) was synthesized and purified using the same method as in Step 5 of Example 23 using Compound 95f (92 mg, 0.43 mmol) and Compound 4g (100 mg, 0.21 mmol) as starting materials.

[1487] MS m / z(ESI):550.1[M+H] + .

[1488] 1H NMR (400MHz, DMSO-d6) δ12.32(s,1H),9.80(s,1H),8.26(dd,J=7.2,1.7Hz,1H),7.99(d, J=8.6Hz,1H),7.25(d,J=2.1Hz,1H),7.13–7.04(m,3H),5.03(s,1H),4.31(dd,J=11.8,5 .3Hz,1H),3.98(d,J=11.8Hz,1H),3.76(t,J=6.5Hz,2H),3.34(t,J=6.6Hz,2H),3.05–2. 92(m,4H),2.41–2.34(m,2H),1.98–1.53(m,4H),1.22(s,3H),0.64(s,3H),0.30(s,4H).

[1489] Example 96 Synthesis of Compound 96

[1490] Step 1: Synthesis of compound 96b

[1491] Compound 96a (1.00 g, 4.02 mmol) was added to compound 79c (5 mL), and the mixture was reacted at 100° C. After cooling, the volatiles were removed under vacuum, and the residue was purified by flash column chromatography (dichloromethane:methanol = 100:0-95:5) to give compound 96b (400 mg).

[1492] Step 2: Synthesis of compound 96c

[1493] Compound 96b (295 mg, 0.91 mmol), triethylamine (185 mg, 1.83 mmol), and diphenylphosphoryl azide (1.11 g, 4.57 mmol) were added to tert-butanol (5 mL) and water (1 mL), and the mixture was fully reacted at 100°C. After cooling, the reaction solution was poured into water and extracted with ethyl acetate (60 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and spin-dried. The mixture was then purified by flash column chromatography (petroleum ether:ethyl acetate = 100:0 to 90:10) to afford compound 96c (60.0 mg).

[1494] Step 3: Synthesis of compound 96d

[1495] Compound 96d (43 mg) was synthesized and purified using compound 96c (60 mg, 0.15 mmol) as starting material in the same manner as in step 3 of Example 30.

[1496] Step 4: Synthesis of compound 96e

[1497] Compound 96e (24 mg) was synthesized and purified using the same method as in Step 4 of Example 30 using compound 96d (25 mg, 0.085 mmol) and tert-butyl carbamate (40 mg, 0.34 mmol) as starting materials.

[1498] Step 5: Synthesis of compound 96f

[1499] Compound 96f (13 mg) was synthesized and purified using compound 96e (20 mg, 0.06 mmol) as starting material in the same manner as in step 5 of Example 30.

[1500] MS m / z(ESI):231.1[M+H] + .

[1501] Step 6: Synthesis of Compound 96

[1502] Compound 96 (1.1 mg) was synthesized and purified using the same method as in Step 5 of Example 23 using compound 96f (13 mg, 0.056 mmol) and compound 4g (26 mg, 0.056 mmol) as starting materials.

[1503] MS m / z(ESI):568.1[M+H] + .

[1504] 1 H NMR(400MHz, DMSO-d6)12.29(s,1H),10.10(s,1H),8.20(d,J=8.6Hz,1H),8.03(d,J=8.4Hz,1 H),7.26(d,J=2.1Hz,1H),7.08(dd,J=8.6,2.1Hz,1H),6.71(d,J=8.7Hz,1H),4.92(t,J=5.6H z,1H),4.68–4.60(m,2H),3.89(s,3H),3.78–3.72(m,2H),3.38–3.37(m,2H),3.10–3.05(m,2 H),3.00–2.94(m,4H),1.95–1.79(m,6H),1.78–1.74(m,2H),1.71–1.66(m,2H),0.30(s,4H).

[1505] Example 100 Synthesis of Compound 100

[1506] Step 1: Synthesis of compound 100b

[1507] Compound 45f (60 mg, 0.21 mmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (2 mL), and compound 100a (43 mg, 0.32 mmol) was added. The mixture was stirred at 50°C for a thorough reaction. Saturated sodium bicarbonate solution (20 mL) was added, and the mixture was extracted with dichloromethane (3 x 20 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography to afford compound 100b (30.0 mg). Step 2: Synthesis of compound 100c

[1508] Compound 100c (21 mg) was synthesized and purified using compound 100b (25 mg, 0.79 mmol) as starting material in the same manner as in step 3 of Example 4.

[1509] MS m / z(ESI):287.0[M+H] + .

[1510] Step 3: Synthesis of compound 100

[1511] Compound 100 (12 mg) was synthesized and purified using the same method as in Step 5 of Example 23 using compound 100c (15 mg, 0.52 mmol) and compound 4g (24.5 mg, 0.52 mmol) as starting materials.

[1512] MS m / z(ESI):623.1[M+H] + .

[1513] 1 H NMR(400MHz,DMSO-d6)δ11.52(s,1H),8.28(s,1H),8.06(d,J=2.1Hz,1H),7 .93(d,J=8.5Hz,1H),7.23(d,J=2.1Hz,1H),7.06(dd,J=8.5,2.1Hz,1H),7.0 2(d,J=2.2Hz,1H),3.77(t,J=6.5Hz,2H),3.40(t,J=5.6Hz,4H),3.36–3.34 (m,2H),3.02(t,J=5.3Hz,4H),2.23–2.10(m,4H),1.51(s,4H),0.33(s,4H).

[1514] Example 101 Synthesis of Compound 101

[1515] Step 1: Synthesis of compound 101b

[1516] Compound 101b (550 mg) was synthesized and purified using compound 101a (800 mg, 4.84 mmol) as starting material in the same manner as in step 1 of Example 41.

[1517] Step 2: Synthesis of compound 101c

[1518] Compound 101c (250 mg) was synthesized and purified using the same method as in Step 4 of Example 22 using compound 101b (300 mg, 1.23 mmol) and compound 2b (hydrochloride salt, 213 mg, 1.35 mmol) as starting materials.

[1519] Step 3: Synthesis of compound 101d

[1520] Compound 101d (70 mg) was synthesized and purified using compound 101c (100 mg, 0.35 mmol) as starting material in the same manner as in step 3 of Example 4.

[1521] MS m / z(ESI):255.1[M+H] + .

[1522] Step 4: Synthesis of compound 101

[1523] Compound 101 (15.0 mg) was synthesized and purified using the same method as in Step 5 of Example 23 using Compound 101d (23 mg, 0.09 mmol) and Compound 4g (30 mg, 0.064 mmol) as starting materials.

[1524] MS m / z(ESI):591.1[M+H] + .

[1525] 1 H NMR (400MHz, DMSO-d6) δ11.71(s,1H),7.82(d,J=8.5Hz,1H),7.51(d,J=1.5Hz,1H),7.16(d,J =2.1Hz,1H),7.13(d,J=1.7Hz,1H),7.03(dd,J=8.5,2.1Hz,1H),5.01–4.97(m,2H),4.97–4.94 (m,2H),3.76(t,J=6.6Hz,2H),3.34–3.33(m,2H),3.16–3.08(m,4H),3.01–2.93(m,4H),2.15–2.03(m,4H),1.60–1.49(m,4H),0.35(s,4H).

[1526] Example 103 Synthesis of Compound 103

[1527] Step 1: Synthesis of compound 103b

[1528] Compound 103b (610 mg) was synthesized and purified using compound 103a (1.0 g, 6.7 mmol) as starting material in the same manner as in step 1 of Example 41.

[1529] Step 2: Synthesis of compound 103c

[1530] Compound 103c (145 mg) was synthesized and purified using the same method as in Step 4 of Example 22 using compound 103b (600 mg, 2.63 mmol) and compound 2b (hydrochloride salt, 498 mg, 3.16 mmol) as starting materials.

[1531] Step 3: Synthesis of compound 103d

[1532] Compound 103d (71 mg) was synthesized and purified using compound 103c (100 mg, 0.37 mmol) as starting material in the same manner as in step 3 of Example 4.

[1533] MS m / z(ESI):239.1[M+H] + .

[1534] Step 4: Synthesis of compound 103

[1535] Compound 103 (5.0 mg) was synthesized and purified using the same method as in Step 5 of Example 23 using compound 103d (10 mg, 0.042 mmol) and compound 4g (19.6 mg, 0.042 mmol) as starting materials.

[1536] MS m / z(ESI):575.1[M+H] + .

[1537] 1H NMR(400MHz,DMSO-d6)δ11.54(s,1H),10.08(s,1H),7.84(d,J=8.5Hz,1H),7 .20–7.13(m,2H),7.04(dd,J=8.5,2.1Hz,1H),6.94(s,1H),3.76(t,J=6.5Hz ,2H),3.41–3.40(m,2H),3.33–3.31(m,4H),3.22–3.18(m,2H),3.07–3.02(m ,2H),2.99–2.93(m,4H),2.08–1.98(m,4H),1.60–1.51(m,4H),0.35(s,4H).

[1538] Example 105 Synthesis of Compound 105

[1539] Step 1: Synthesis of compound 105a

[1540] Compound 105a (485 mg) was synthesized and purified using the same method as in Step 3 of Example 1 using compound 1c (1.0 g, 2.8 mmol) and methanesulfonamide (0.54 g, 5.6 mmol) as starting materials.

[1541] Step 2: Synthesis of compound 105b

[1542] Compound 105b (135 mg) was synthesized and purified using compound 105a (0.32 g, 1.0 mmol) as starting material in the same manner as in step 1 of Example 7.

[1543] Step 3: Synthesis of compound 105

[1544] Compound 105 (18 mg) was synthesized and purified using the same method as in Step 2 of Example 7 using compound 105b (94 mg, 0.29 mmol) and compound 44b (138 mg, 0.44 mmol) as starting materials.

[1545] MS m / z(ESI):560.2[M+H] + .

[1546] 1H NMR(400MHz,DMSO-d6)δ12.88(s,1H),10.22(s,1H),8.84(s,1H),8.12–8.06(m,2H),7.55 (d,J=1.1Hz,1H),7.27(d,J=2.1Hz,1H),7.14(dd,J=8.6,2.1Hz,1H),4.51–4.35(m,4H ),3.12(s,3H),3.03–2.95(m,4H),2.16–2.05(m,4H),1.86–1.62(m,4H),0.41(s,4H).

[1547] Example 106 Synthesis of Compound 106

[1548] Step 1: Synthesis of compound 106c

[1549] Compound 106a (2.0 g, 6.0 mmol), compound 106b (1.02 ml, 7.2 mmol), cuprous iodide (110 mg, 0.6 mmol), and Pd(Ph3P)4 (420 mg, 0.6 mmol) were added to tetrahydrofuran (20 mL). Triethylamine (1.3 ml, 9.0 mmol) was added under ice-cooling and the mixture was allowed to react at room temperature. Volatiles were removed under vacuum, and the residue was purified by flash column chromatography to afford compound 106c (1.54 g).

[1550] Step 2: Synthesis of compound 106d

[1551] Compound 106c (1.5 g, 5.0 mmol) was added to ethanol (2 mL), followed by the addition of cuprous iodide (92 mg, 0.5 mmol) and triethylamine (2 mL), and the mixture was allowed to react at 70°C. Volatiles were removed under vacuum, and the residue was purified by flash column chromatography to afford compound 106d (0.87 g).

[1552] Step 3: Synthesis of compound 106e

[1553] Compound 106e (1.5 g) was synthesized and purified using the same method as in Step 1 of Example 96 using Compound 106d (0.8 g, 0.35 mmol) and Compound 2b (2 mL) as starting materials.

[1554] Step 4: Synthesis of compound 106

[1555] Compound 106 (13 mg) was synthesized and purified using the same method as in Step 2 of Example 7 using compound 106e (63 mg, 0.2 mmol) and compound 7a (103 mg, 0.22 mmol) as starting materials.

[1556] MS m / z(ESI):590.2[M+H] + .

[1557] 1 H NMR (400MHz, DMSO-d6) δ12.81(s,1H),10.17(br,1H),8.09(d,J=6.9Hz,1H),8.07(s,1H),7.27(d,J=2.2Hz,1H),7.13(dd,J=8.6,2.1Hz,1H ),6.99(d,J=2.1Hz,1H),3.97(t,J=5.5Hz,2H),3.76(t,J=6.5Hz,4H),2.99(t,J=5.4Hz,4H),2.19–2.05(m,4H),1.76(br,4H),0.39(s,4H).

[1558] Example 107 Synthesis of Compound 107

[1559] Step 1: Synthesis of compound 107c

[1560] Compound 107c (1.04 g) was synthesized and purified using the same method as in Step 1 of Example 64 using Compound 107a (1.36 g, 5.0 mmol) and Compound 107b (0.58 g, 6.0 mmol) as starting materials.

[1561] Step 2: Synthesis of compound 107d

[1562] Compound 107d (0.85 g) was synthesized and purified using compound 107c (1.0 g, 3.5 mmol) as starting material in the same manner as in step 2 of Example 64.

[1563] Step 3: Synthesis of compound 107e

[1564] Compound 107e (0.48 g) was synthesized and purified using compound 107d (0.84 g, 2.8 mmol) as starting material in the same manner as in step 3 of Example 64.

[1565] Step 4: Synthesis of compound 107f

[1566] Compound 107f (290 mg) was synthesized and purified using compound 107e (480 mg, 1.7 mmol) as starting material in the same manner as in step 5 of Example 30.

[1567] MS m / z(ESI):186.1[M+H] + .

[1568] Step 5: Synthesis of compound 107

[1569] Compound 107 (0.8 mg) was synthesized and purified using the same method as in Step 5 of Example 23 using Compound 107f (18.6 mg, 0.1 mmol) and Compound 4g (48 mg, 0.1 mmol) as starting materials.

[1570] MS m / z(ESI):522.2[M+H] + .

[1571] Example 109 Synthesis of Compound 109

[1572] Step 1: Synthesis of compound 109b

[1573] Compound 109b (224 mg) was synthesized and purified using the same method as in Step 1 of Example 30 using compound 109a (0.20 g, 0.82 mmol) and compound 2a (hydrochloride salt, 0.19 g, 1.23 mmol) as starting materials.

[1574] Step 2: Synthesis of compound 109d

[1575] Compound 109b (150 mg, 0.46 mmol) was added to compound 109c (1.5 mL) and the mixture was allowed to react at 120°C. Volatiles were removed under vacuum, and the residue was purified by flash reverse phase column chromatography (acetonitrile: water = 30:70) to give compound 109d (40 mg). Step 3: Synthesis of compound 109e

[1576] Compound 109e (41 mg) was synthesized and purified using compound 109d (40 mg, 0.1 mmol) as starting material in the same manner as in step 2 of Example 64.

[1577] Step 4: Synthesis of compound 109f

[1578] Compound 109f (7.8 mg) was synthesized and purified using compound 109e (41 g, 0.1 mmol) as starting material in the same manner as in step 3 of Example 64.

[1579] Step 5: Synthesis of compound 109g

[1580] Compound 109g (3 mg) was synthesized and purified using compound 109f (7.8 mg, 0.02 mmol) as starting material in the same manner as in step 5 of Example 30.

[1581] MS m / z(ESI):254.1[M+H] + .

[1582] Step 6: Synthesis of Compound 109

[1583] Compound 109 (1 mg) was synthesized and purified using the same method as in Step 5 of Example 23 using Compound 109g (3 mg, 0.01 mmol) and Compound 4g (9.6 mg, 0.2 mmol) as starting materials.

[1584] MS m / z(ESI):590.4[M+H] + .

[1585] Example 110 Synthesis of Compound 110

[1586] Step 1: Synthesis of compound 110a

[1587] Compound 110a (208 mg) was synthesized and purified using the same method as in Step 1 of Example 30 using Compound 50c (245 mg, 0.64 mmol) and Compound 86a (100 mg, 0.64 mmol) as starting materials.

[1588] Step 2: Synthesis of compound 110b

[1589] Compound 110b (155 mg) was synthesized and purified using compound 110a (200 mg, 0.42 mmol) as starting material in the same manner as in step 3 of Example 4.

[1590] Step 3: Synthesis of compound 110c

[1591] Compound 110c (90 mg) was synthesized and purified using compound 110b (155 mg, 0.44 mmol) as starting material in the same manner as in step 3 of Example 30.

[1592] Step 4: Synthesis of compound 110d

[1593] Compound 110d (43 mg) was synthesized and purified using compound 110c (90 mg, 0.26 mmol) as starting material in the same manner as in step 5 of Example 50.

[1594] MS m / z(ESI):247.2[M+H] + .

[1595] Step 5: Synthesis of compound 110e

[1596] Compound 110e (12 mg) was synthesized and purified using the same method as in step 3 of Example 5 using compound 4g (70 mg, 0.15 mmol) and 110d (25 mg, 0.1 mmol) as starting materials.

[1597] Step 6: Synthesis of compound 110

[1598] Compound 110 (7.8 mg) was synthesized and purified using compound 110e (11.8 mg, 17 μmol) as starting material in the same manner as in step 8 of Example 4.

[1599] MS m / z(ESI):583.4[M+H] + .

[1600] 1 H NMR (400MHz, DMSO-d6) δ12.78(s,1H),8.46(d,J=8.6Hz,1H),8.03(d,J=8.6Hz,1 H),7.72(d,J=8.5Hz,1H),7.26(dd,J=8.6,2.1Hz,1H),4.81(dd,J=11.8,6.6Hz,1 H),4.61(d,J=11.8Hz,1H),3.85(t,J=9.1Hz,1H),3.77(t,J=6.5Hz,2H),3.57–3 .70(m,1H),3.36(t,J=6.5Hz,2H),3.06–2.97(m,4H),1.76(br,4H),0.31(s,4H).

[1601] Example 112 Synthesis of Compound 112

[1602] Step 1: Synthesis of compound 112b

[1603] Compound 112b (678 mg) was synthesized and purified using the same method as in Step 1 of Example 50 using Compound 112a (600 mg, 2.76 mmol) and Compound 50b (651 mg, 3.0 mmol) as starting materials.

[1604] Step 2: Synthesis of compound 112c

[1605] Compound 112c (623 mg) was synthesized and purified using the same method as in Step 1 of Example 30 using compound 112b (660 mg, 1.59 mmol) and compound 79c (198 mg, 2.0 mmol) as starting materials.

[1606] Step 3: Synthesis of compound 112d

[1607] Compound 112d (482 mg) was synthesized and purified using compound 112c (600 mg, 1.22 mmol) as starting material in the same manner as in step 3 of Example 4.

[1608] Step 4: Synthesis of compound 112e

[1609] Compound 112e (212 mg) was synthesized and purified using compound 112d (460 mg, 1.0 mmol) as starting material in the same manner as in step 3 of Example 30.

[1610] Step 5: Synthesis of compound 112f

[1611] Compound 112f (34 mg) was synthesized and purified using compound 112e (100 mg, 0.22 mmol) as starting material in the same manner as in Step 5 of Example 50.

[1612] MS m / z(ESI):260.2[M+H] + .

[1613] Step 6: Synthesis of compound 112

[1614] Compound 112 (5.4 mg) was synthesized and purified using the same method as in Step 5 of Example 23 using compound 4g (48 mg, 0.10 mmol) and 112f (26 mg, 0.1 mmol) as starting materials.

[1615] MS m / z(ESI):596.3[M+H] + .

[1616] 1 H NMR (400MHz, DMSO-d6) δ12.66(s,1H),8.37(d,J=8.6Hz,1H),8.05(d,J=8.6Hz ,1H),7.70(d,J=8.6Hz,1H),7.28(d,J=2.1Hz,1H),7.10(dd,J=8.5,2.1Hz,1H) ,4.51(d,J=6.9Hz,2H),3.89(s,3H),3.76(t,J=6.5Hz,2H),3.36(t,J=6.6Hz, 2H), 3.15 (d, J = 8.0Hz, 2H), 3.07–2.95 (m, 4H), 1.90–1.69 (m, 8H), 0.31 (s, 4H).

[1617] Example 113 Synthesis of Compound 113

[1618] Step 1: Synthesis of compound 113a

[1619] Compound 113a (90 mg) was synthesized and purified using compound 112e (100 mg, 0.22 mmol) as starting material in the same manner as in Step 2 of Example 45.

[1620] Step 2: Synthesis of compound 113b

[1621] Compound 113b (58 mg) was synthesized and purified using the same method as in Step 2 of Example 1 using compound 113a (90 mg, 0.2 mmol) and ethylamine hydrochloride (33 mg, 0.4 mmol) as starting materials.

[1622] Step 3: Synthesis of compound 113c

[1623] Compound 113c (14 mg) was synthesized and purified using compound 113b (50 mg, 0.1 mmol) as starting material in the same manner as in Step 5 of Example 50.

[1624] MS m / z(ESI):273.2[M+H] + .

[1625] Step 4: Synthesis of compound 113

[1626] Compound 113 (4.3 mg) was synthesized and purified using the same method as in Step 5 of Example 23 using compound 4g (48 mg, 0.10 mmol) and 113c (13 mg, 0.05 mmol) as starting materials.

[1627] MS m / z(ESI):609.3[M+H] + .

[1628] 1H NMR (400MHz, DMSO-d6) δ12.50(s,1H),10.14(br,1H),8.54(d,J=5.6Hz,1H),8.29(d,J=8.2Hz, 1H),8.04(d,J=8.6Hz,1H),7.27(d,J=2.1Hz,1H),7.19(d,J=8.2Hz,1H),7.09(dd,J=8.6,2.1H z,1H),3.92(t,J=5.7Hz,2H),4.34(d,J=8.0Hz,2H),3.76(q,J=6.1Hz,2H),3.36(t,J=6.7Hz,2 H),3.12(d,J=8.0Hz,2H),2.99(br,4H),1.95–1.68(m,8H),1.15(t,J=7.2Hz,3H),0.30(s,4H).

[1629] Example 114 Synthesis of Compound 114

[1630] Step 1: Synthesis of compound 114a

[1631] Compound 114a (71 mg) was synthesized and purified using the same method as in Step 4 of Example 22 using compound 28b (100 mg, 0.41 mmol) and 86a (hydrochloride salt, 61 mg, 0.41 mmol) as starting materials.

[1632] Step 2: Synthesis of compound 114b

[1633] Compound 114b (47 mg) was synthesized and purified using compound 114a (70 mg, 0.25 mmol) as starting material in the same manner as in step 3 of Example 4.

[1634] MS m / z(ESI):253.3[M+H] + .

[1635] Step 3: Synthesis of compound 114

[1636] Compound 114 (18.0 mg) was synthesized and purified using the same method as in Step 5 of Example 23 using compound 114b (25 mg, 0.1 mmol) and compound 4g (48 mg, 0.1 mmol) as starting materials.

[1637] MS m / z(ESI):589.5[M+H] + .

[1638] Example 115 Synthesis of Compound 115

[1639] Step 1: Synthesis of compound 115b

[1640] Compound 115b (17.0 g) was synthesized and purified using compound 115a (15 g, 76.5 mmol) as starting material in the same manner as in Step 1 of Example 26.

[1641] Step 2: Synthesis of compound 115d

[1642] Compound 115d (5.5 g) was synthesized and purified using the same method as in Step 2 of Example 26 using compounds 115b (5.1 g, 15.2 mmol) and 115c (5.4 g, 16.7 mmol) as starting materials.

[1643] Step 3: Synthesis of compound 115e

[1644] Compound 115e (2.0 g) was synthesized and purified using compound 115d (5.3 mg, 10.0 mmol) as starting material in the same manner as in step 3 of Example 26.

[1645] Step 4: Synthesis of compound 115f

[1646] Compound 115f (1.05 g) was synthesized and purified using the same method as in Step 4 of Example 30 using compound 115e (1.0 g, 3.8 mmol) and benzophenone imine (820 mg, 4.5 mmol) as starting materials.

[1647] Step 5: Synthesis of compound 115g

[1648] Compound 115g (168 mg) was synthesized and purified using compound 115f (1.0 g, 2.7 mmol) as starting material in the same manner as in step 5 of Example 30.

[1649] MS m / z(ESI):201.1[M+H] + .

[1650] Step 6: Synthesis of compound 115

[1651] Compound 115 (12.1 mg) was synthesized and purified using the same method as in Step 5 of Example 23 using Compound 115g (96 mg, 0.2 mmol) and Compound 4g (40 mg, 0.2 mmol) as starting materials.

[1652] MS m / z(ESI):537.2[M+H] + .

[1653] 1 H NMR (400MHz, DMSO-d6) δ11.16(s,1H),10.06(s,1H),7.90(d,J=8.5Hz,1H),7.84(d ,J=7.7Hz,1H),7.25–7.17(m,2H),7.10–7.01(m,2H),6.45(s,1H),4.96(s,1H),4.3 6–4.17(m,2H),3.78(t,J=6.6Hz,2H),3.39–3.37(m,2H),3.09–2.98(m,4H),2.95– 2.86(m,2H),1.87–1.76(m,2H),1.74–1.59(m,4H),1.56–1.42(m,4H),0.29(s,4H).

[1654] Biological activity evaluation

[1655] Test Example 1: KIF18A enzyme activity assay

[1656] Based on ADP-Glo TM Kinase Assay: Detect the amount of ADP generated in the reaction to reflect KIF18A enzyme activity.

[1657] 1. Experimental instruments and materials

[1658] The human KIF18A (1-376aa) protease used in the experiment was expressed by Panchao Biotechnology and stored at -80°C (freeze-thaw no more than 5 times).

[1659] Detection kit (ADP-Glo TM The Kinase Assay was purchased from Promega under the catalog number V9101 and stored at -30°C. The kit detects enzyme activity by measuring the ADP generated during the enzyme reaction. KIF18A enzyme reacts with ATP to generate ADP, and the remaining ATP in the reaction is consumed by the ADP-Glo ​​reagent. The ADP generated during the KIF18A enzyme reaction is reduced to ATP by the detection reagent. ATP is then converted to ATP in the Ultra-Glo TM Under the action of luciferase, it reacts with luciferin to emit light, and the luminescence signal is positively correlated with the KIF18A enzyme activity.

[1660] The information of other reagents and consumables required for the experiment is as follows

[1661] 2. Experimental steps

[1662] The compound was diluted 3-fold with a starting concentration of 10 μM, and 10 concentration points were added. The compound and pure DMSO (control) were added to each well of a 384-well plate using an Echo instrument. The total volume of the compound and DMSO was 100 nL. The instrument obtained gradient dilution sample concentrations through different ratios. KIF18A enzyme reaction buffer was prepared: 15 nM Tris, 10 mM MgCl2, 0.01% Pluronic F-68, 1 μM Taxol, and 50 μg / mL Microtubule. KIF18A was mixed with the enzyme reaction buffer and added to a 384-well plate. After incubation at room temperature for 15 minutes, ATP (Km 70 μM) was added to the mixture. After incubation at room temperature for 15 minutes, 10 μL ADP-Glo ​​was added. TM Reagent was mixed with 10 μL of reaction mixture and incubated at room temperature for 40 minutes. Finally, 20 μL of ADP-Glo ​​was added. TM Detection Reagent, incubate at room temperature for 30 minutes. Use Envision plate reader (PerkinElmer, emission wavelength 400-700nm) to measure the chemiluminescence signal in each well. In the experiment, set up 1 column of wells without compound and enzyme (chemiluminescence value is used as [RLU] background ([RLU]background)), 1 column of wells with enzyme but no compound (chemiluminescence value is used as [RLU] enzyme ([RLU]enzyme)), the chemiluminescence value of the drug-added group is [RLU]cpd, and the inhibition rate of the compound on proliferation is calculated according to the following formula: Inhibition rate (%) = ([RLU]enzyme-[RLU]cpd) / ([RLU]enzyme–[RLU]background)×100%, the inhibitory activity of the compound on enzyme activity IC 50 The values ​​were calculated using a four-parameter logistic model. In the following formula, x represents the logarithm of the compound concentration; F(x) represents the effect size (the inhibition rate of enzyme activity under the conditions of this concentration): F(x) = (A + ((BA) / (1 + ((C / x)^D)))). A, B, C, and D are the four parameters. IC was calculated using Xlfit. 50 The values ​​were further calculated as the compound concentration required for 50% inhibition of enzyme activity in the best fitting curve. The KIF18A inhibitory activities of the disclosed compounds are shown in Table 1.

[1663] Table 1: KIF18A inhibitory activity of the disclosed compounds

[1664] In the above table, “++++” indicates the inhibitory activity of the tested compound on the enzyme IC 50The range is <200nM; "+++" indicates the IC value of the enzyme inhibitory activity of the tested compound. 50 The range is <500nM.

[1665] Test Example 2: Proliferation inhibition test of the disclosed compounds on OVCAR-3 cells

[1666] Cells and materials: Human ovarian cancer cell line OVCAR3 was purchased from ATCC (catalog number HTB-161 TM ), RPMI 1640 medium (Gibco#A1049101), penicillin-streptomycin (Gibco#15140122) and 0.25% Trypsin-EDTA (Gibco#25200056) were purchased from Gibco (USA), bovine insulin (Yisheng#40107ES60) was purchased from Yisheng, 384-well plates (Corning#CLS3765) were purchased from Corning (USA), and Cell-Titer Glo reagent (Promega#G7568) was purchased from Promega (USA).

[1667] Cell culture: OVCAR3 cells were cultured in RPMI 1640 complete medium (RPMI 1640 medium containing 20% ​​fetal bovine serum, 10 μg / mL bovine insulin, and 1% penicillin-streptomycin) at 37°C in a 5% CO2 incubator. Cells in the logarithmic growth phase were used for experiments.

[1668] Cell proliferation activity assay: Cell-Titer Glo reagent was used to detect the inhibitory effect of compounds on the proliferation of OVCAR3 cells. Compounds prepared in DMSO and pure DMSO (control) were added to a 384-well plate using an Echo instrument. Compounds were diluted three-fold starting at 30 μM for a total of 11 concentration points. The volume of compound or DMSO added was 100 nL.

[1669] OVCAR3 cells were digested and resuspended in RPMI 1640 complete medium. The cells were plated into a 384-well plate (1000 cells / 50 μL / well), mixed with the compound, and cultured in a 37°C, 5% CO2 incubator for 3 days. 25 μL of Cell-Titer Glo reagent was added to each well, mixed by vortexing, and incubated for 10 minutes. Cell-Titer Glo readings were measured using a Multimode Plate Reader (PerkinElmer, Model: SIC-PV-018).

[1670] A negative control group (Bottom) was set up. The negative control group consisted of the culture medium wells added with 0.2% DMSO, which was defined as 100% proliferation inhibition. The positive control group (Top) consisted of the OVCAR3 cell wells added with 0.2% DMSO.

[1671] Data Analysis:

[1672] The percentage of proliferation inhibition (% Inhibition) was calculated using the four-parameter formula: Y = Bottom + (Top-Bottom) / (1 + (IC 50 / X)^HillSlope) fitting curve to obtain the compound proliferation inhibition IC 50 .

[1673] Inhibition percentage: %Inhibition=(1-(Signal-Bottom) / (Top-Bottom))×100%.

[1674] Signal: Cell-Titer Glo reading of the wells with added compounds;

[1675] Bottom: Cell-Titer Glo reading of negative control well;

[1676] Top: Cell-Titer Glo readings of positive control wells.

[1677] Experimental results:

[1678] The inhibitory activity of the disclosed compounds on OVCAR3 proliferation is shown in Table 2.

[1679] Table 2: Inhibitory activity of the disclosed compounds on OVCAR3 proliferation

[1680] Test Example 3: CYP enzyme inhibition test of the compounds of the present invention

[1681] Pooled human liver microsomes from 150 donors (Corning, Cat. No. 452117) were used to evaluate the metabolic reactions of representative substrates of the five major human CYP isoforms (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 / 5). The effects of various concentrations of the test compounds on the metabolic reactions of phenacetin (CYP1A2), diclofenac sodium (CYP2C9), S-mephenytoin (CYP2C19), bufuralol hydrochloride (CYP2D6), and midazolam (CYP3A4 / 5) were determined by liquid chromatography-tandem mass spectrometry (LC / MS / MS).

[1682] A 200 μL reaction mixture (100 mmol / L phosphate buffer, pH 7.4, containing 0.3% DMSO, 0.6% acetonitrile, and 0.1% methanol by volume) containing 30 μM phenacetin, 10 μM diclofenac sodium, 35 μM S-mephenytoin, 5 μM bufuralol hydrochloride, 3 μM midazolam, 1 mM reduced nicotinamide adenine dinucleotide phosphate (NADPH), test compounds (at concentrations of 0.1, 0.3, 1, 3, 10, and 30 μmol / L), positive compounds, or a blank control, was incubated with mixed human liver microsomes (0.2 mg / mL) at 37°C for 5 minutes. Then, 200 μL of an acetonitrile solution containing 3% formic acid and 40 nM internal standard verapamil was added, and the mixture was centrifuged at 4000 rpm for 50 minutes. The mixture was cooled on ice for 20 minutes and then centrifuged at 4000 rpm for 20 minutes to precipitate the protein. Take 200 μL of the supernatant for LC-MS / MS analysis.

[1683] Peak areas were calculated from the chromatograms.

[1684] The residual activity ratio (%) was calculated using the following formula:

[1685] Peak area ratio = metabolite peak area / internal standard peak area

[1686] Residual activity ratio (%) = peak area ratio of the test compound group / peak area ratio of the blank group

[1687] CYP half-maximal inhibitory concentration (IC 50 ) was calculated using Excel XLfit 5.3.1.3.

[1688] Test Example 4: Caco-2 permeability test

[1689] The apparent permeability coefficient (P) of the drug was determined by liquid chromatography-tandem mass spectrometry (LC-MS / MS) using a Caco-2 cell model. app ).

[1690] In this test example, Caco-2 cells were purchased from the American Type Culture Collection (ATCC), 4-hydroxyethylpiperazineethanesulfonic acid (HEPES) was purchased from Beijing Solebold Technology Co., Ltd., Hank's balanced salt solution (HBSS) and non-essential amino acids (NEAA) were purchased from Thermo Fisher Scientific, penicillin, streptomycin, and trypsin / EDTA were purchased from Solebold, fetal bovine serum (FBS) and DMEM medium were purchased from Corning, HTS-96-well Transwell plates and other sterile consumables were purchased from Corning, and the Millicell resistance measurement system was purchased from Millipore. K2 was purchased from Nexcelom Bioscience, Infinite 200PRO microplate reader was purchased from Tecan, and MTS2 / 4 orbital shaker was purchased from IKA Labortechnik.

[1691] First step: cell culture and plating

[1692] Caco-2 was cultured in a cell culture flask. The incubator was set at 37°C, 5% CO2, and relative humidity was maintained at 95%. When the cell confluence reached 70-90%, it could be used to inoculate Transwell. Before cell inoculation, 50 μL of cell culture medium was added to each well of the upper chamber of the Transwell, and 25 mL of cell culture medium was added to the lower culture plate. The culture plate was placed in a 37°C, 5% CO2 incubator and incubated for 1 hour before it could be used to inoculate cells. After cell digestion, the cell suspension was aspirated and transferred to a round-bottom centrifuge tube and centrifuged at 120 g for 5 minutes. The cells were resuspended in culture medium to a final concentration of 6.86×10 5 Cell suspension was added to the chamber of a 96-well Transwell culture plate at 50 μL per well, with a final seeding density of 2.4×10 5 cells / cm2. Medium changes should begin 24 hours after seeding and continue every other day for 14-18 days. The medium change procedure is as follows: separate the Transwell chamber from the receiver plate, discard the medium in the receiver plate first, then discard the medium in the Transwell chamber. Finally, add 75 μL of fresh medium to each chamber and 25 mL of fresh medium to the receiver plate.

[1693] Step 2: Evaluation of cell monolayer integrity

[1694] After about 14 days of culture, Caco-2 cells reach confluence and complete differentiation. At this point, they can be used for permeation tests. The resistance of the monolayer membrane is measured using a resistance meter (Millipore, USA), and the resistance of each well is recorded. After the measurement is completed, the Transwell culture plate is returned to the incubator. Calculation of resistance value: measured resistance value (ohms) × membrane area (cm 2 )=TEER value (ohm·cm 2 ), if the TEER value is <230ohms·cm 2 , then the hole cannot be used for penetration test.

[1695] Step 3 Solution preparation

[1696] Weigh 2.38 g HEPES and 0.35 g sodium bicarbonate respectively, add 900 mL pure water to dissolve them, then add 100 mL 10× HBSS and stir evenly, adjust the pH to 7.4, and finally filter to obtain 1 L transport buffer (HBSS, 10 mM HEPES, pH 7.4).

[1697] A 1 mM DMSO stock solution of the test compound to be tested was diluted with transport buffer to yield a 5 μM test solution. A control compound, digoxin or minoxidil, was diluted to 2 mM with DMSO and then diluted to 10 μM with the aforementioned transport buffer to yield a control compound test solution. Separately, DMSO was also diluted with the aforementioned transport buffer to yield a 0.5% DMSO-containing receiving solution.

[1698] Step 4: Drug penetration test

[1699] Remove the Transwell plate from the incubator, rinse the cell monolayer twice with transport buffer (10 mM HEPES, pH 7.4), and incubate at 37°C for 30 minutes.

[1700] To measure the rate of compound transport from the apical to basolateral side, add 125 μL of test solution to each well of the upper (apical) chamber. Immediately transfer 50 μL of the solution from the apical side to 200 μL of acetonitrile containing the internal standard (0.1 μM tolbutamide) as the initial apical-to-basolateral sample. Add 235 μL of receiver solution to each well of the lower (basolateral) chamber.

[1701] To measure the rate of compound transport from the basolateral to the apical side, add 285 μL of the receiver solution to each well of the upper (apical) chamber. Immediately transfer 50 μL of the solution from the apical side to 200 μL of acetonitrile containing the internal standard (0.1 μM tolbutamide) as the initial basolateral-to-apical sample. Add 75 μL of the test solution to each well of the lower (basolateral) chamber.

[1702] Combine the upper and lower transport devices and incubate at 37°C for 2 hours.

[1703] After incubation, 50 μL of sample was collected from each well of the upper and lower chambers of the Transwell culture plate and added to a new sample tube. 200 μL of acetonitrile containing the internal standard (0.1 μM tolbutamide) was added to each sample tube. After vortexing for 10 minutes, the tube was centrifuged at 3220 g for 40 minutes. 150 μL of the supernatant was aspirated and diluted with 150 μL of water for LC-MS / MS analysis. All samples were prepared in triplicate.

[1704] After 2 hours of incubation, the integrity of the cell monolayer was assessed by leakage of Lucifer Yellow. The Lucifer Yellow stock solution was diluted to a final concentration of 100 μM using transport buffer (10 mM HEPES, pH 7.4). 100 μL of Lucifer Yellow solution was added to each well of the upper Transwell insert, and 300 μL of transport buffer (10 mM HEPES, pH 7.4) was added to each well of the lower receiver plate. After incubation at 37°C for 30 minutes, 80 μL of solution was aspirated from each well into a new 96-well plate. Fluorescence was measured using a microplate reader with an excitation wavelength of 485 nm and an emission wavelength of 530 nm.

[1705] Step 5: Data Analysis

[1706] All calculations were performed using Microsoft Excel. Peak areas were determined using extracted ion chromatograms.

[1707] Apparent permeability coefficient (P app , unit: cm / s×10 -6 ) is calculated using the following formula:

[1708] In the formula: V A is the volume of the receiving end solution (Ap→Bl is 0.3 mL, Bl→Ap is 0.1 mL), and Area (membrane area) is the Transwell-96 well plate membrane area (0.143 cm 2 ); time (time) is the incubation time (unit: s); [drug] receiver ([drug] 接收端 ) is the drug concentration at the receiving end; [drug] initial, donor ([drug] 初始，供体 ) is the initial drug concentration at the drug delivery end.

[1709] The efflux ratio is calculated using the following formula:

[1710] In the formula: P app(B-A) is the apparent permeability from the base end to the top end;

[1711] P app(A-B) is the apparent permeability from the top to the base.

[1712] The recovery rate (%) was calculated using the following formula:

[1713] In the formula: V A is the volume of the solution at the receiving end (unit: mL); V Dis the volume of the solution at the administration end (unit: mL).

[1714] The leakage rate (Percentage leakage (%) or LY (%)) is calculated using the following formula:

[1715] In the formula: I receiver (I 接收端 ) refers to the fluorescence density of the receiving well (0.3 mL), I donor (I 供体 ) refers to the drug addition hole (0.1mL)

[1716] The fluorescence density is expressed as LY (%). LY < 1.5% indicates that the cell membrane is intact. For individual cases where LY > 1.5%, if P app The value is close to other parallels, and based on scientific judgment, the final data can be adopted.

[1717] Test Example 5: In vitro metabolic stability test of rat hepatocytes

[1718] The compound concentrations in the reaction system were determined by LC / MS / MS to calculate the intrinsic clearance of the test compounds and to evaluate their in vitro metabolic stability in rat hepatocytes.

[1719] 198 μL of 0.5×10 6 The reaction was initiated by adding a mixture of rat hepatocytes at 50 cells / mL and 2.0 μL of 100 μM test compound or positive control to the incubation plate. Incubation was performed at 37°C and 900 rpm. At 0, 15, 30, 60, 90, and 120 minutes, 25 μL of the incubation system was transferred to a stop plate (150 μL of acetonitrile containing 100 nM alprazolam, 200 nM caffeine, and 100 nM tosylbutamide per well). The plate was then vortexed for 5 minutes. The stop plate was centrifuged at 3220 g for 45 minutes. 100 μL of the supernatant of each compound was transferred to a 96-well sample plate, and 100 μL of purified water was added to dilute the sample.

[1720] The resulting samples were quantified by ion chromatogram. The residual rate was calculated based on the peak area of ​​the test compound or positive control. The slope k was determined by linear regression of the natural logarithm of the residual rate against the incubation time using Microsoft Excel.

[1721] Intrinsic clearance (in vitro CL int , μL / min / 10 6 cells) was calculated from the slope value k according to the following equation:

[1722] in vitro CL int =-kV / N

[1723] V = incubation volume (0.25 mL);

[1724] N = number of cells per well (0.125 × 10 6 cell)

[1725] Test Example 6: In vitro metabolic stability test of human hepatocytes

[1726] The compound concentrations in the reaction system were determined by LC / MS / MS to calculate the intrinsic clearance of the test compounds and to evaluate their in vitro metabolic stability in human hepatocytes.

[1727] 198 μL of 0.5×10 6 The reaction was initiated by adding a mixture of 100 μM human hepatocytes (cells / mL) and 2.0 μL of a 100 μM test compound or positive control to an incubation plate. The reaction was incubated at 37°C and 900 rpm. At 0, 15, 30, 60, 90, and 120 minutes, 25 μL of the incubation system was transferred to a stop plate (150 μL of acetonitrile containing 100 nM alprazolam, 200 nM caffeine, and 100 nM tosylbutamide per well). The plate was then vortexed for 5 minutes. The stop plate was centrifuged at 3220 g for 45 minutes. 100 μL of the supernatant of each compound was transferred to a 96-well sample plate, and 100 μL of purified water was added to dilute the sample.

[1728] The resulting samples were quantified by ion chromatogram. The residual rate was calculated based on the peak area of ​​the test compound or positive control. The slope k was determined by linear regression of the natural logarithm of the residual rate against the incubation time using Microsoft Excel.

[1729] Intrinsic clearance (in vitro CL int , μL / min / 10 6 cells) was calculated from the slope value according to the following equation:

[1730] in vitro CL int =-kV / N

[1731] V = incubation volume (0.25 mL);

[1732] N = number of cells per well (0.125 × 10 6 cell)

[1733] Test Example 7: Compound Solid Solubility (PBS pH 7.4) Test

[1734] The solubility of the test compound solid in PBS pH 7.4 was determined by LC / MS / MS.

[1735] Accurately weigh approximately 1 mg of powdered compound of each type into a glass vial and add DMSO to a volume of 1 mL per mg of compound. Add a stir bar to each vial and shake the solubility vial at 25°C and 1100 rpm for 2 hours to completely dissolve the powder and prepare a 1 mg / mL test sample solution. Mix 5 μL of the 1 mg / mL solution with 5 μL of PBS pH 7.4 and add it to 490 μL of a 1:1 mixture of water and acetonitrile containing an internal standard to prepare a 10 μg / mL standard concentration solution for the test sample. Furthermore, dilute 10 μL of the 10 μg / mL solution with 90 μL of a 1:1 mixture of water and acetonitrile containing an internal standard to prepare a 1 μg / mL standard concentration solution for the test sample. The dilution factor of the standard solution can be adjusted based on the LC / MS response.

[1736] Accurately weigh approximately 1 mg of each compound powder into a glass vial and add PBS, pH 7.4, at a volume of 1 mL per mg of compound. Add a stir bar to each vial and shake the solubility vials at 25°C and 1100 rpm for 24 hours. After shaking, remove the stir bar, transfer the sample to a filter plate, and filter using a vacuum manifold. The filtrate is diluted with a 1:1 mixture of water and acetonitrile containing the internal standard. The dilution factor can be adjusted based on the solubility value and the LC / MS response.

[1737] The obtained samples were analyzed by LC / MS / MS. The sample solubility was calculated based on the peak area of ​​the test compound solution and the standard concentration solution. The calculation formula is as follows:

[1738] [Sample] is the solubility of the sample to be tested;

[1739] Area ratio sample (Area Ratio 样品 ) is the ratio of the sample peak area to the internal standard peak area in the sample to be tested;

[1740] INJ VOL STD is the injection volume of the standard concentration solution;

[1741] DF sample (DF 样品 ) is the dilution factor of the sample solution to be tested;

[1742] [STD] is the concentration of the standard concentration solution;

[1743] INJ VOL sample (INJ VOL 样品 ) is the injection volume of the sample solution to be tested;

[1744] Area ratio STD is the ratio of the sample peak area to the internal standard peak area in the standard concentration solution.

[1745] Test Example 8: Compound Solubility (PBS pH 7.4) Test

[1746] The solubility of the test compounds in PBS pH 7.4 was determined by LC / MS / MS.

[1747] Mix 6 μL of a 10 mM DMSO solution of the test compound with 194 μL of DMSO to create a 300 μM solution. Mix 5 μL of this solution with 5 μL of PBS pH 7.4 and add 490 μL of water and acetonitrile (1:1) containing the internal standard to create a 3 μM standard solution. The dilution factor of the standard solution can be adjusted based on the LC / MS response.

[1748] Take 15 μL of a 10 mM solution of the test compound in DMSO and add it to 485 μL of PBS, pH 7.4. Add a stir bar and shake the solubility vial at 25°C and 1100 rpm for 2 hours. After shaking, remove the stir bar, transfer the sample to a filter plate, and filter using a vacuum manifold. Mix 5 μL of the filtrate with 5 μL of PBS, pH 7.4, and add 490 μL of a 1:1 mixture of water and acetonitrile containing an internal standard to prepare the test solution. The dilution factor can be adjusted based on the solubility value and the strength of the LC / MS response.

[1749] The obtained samples were analyzed by LC / MS / MS. The sample solubility was calculated based on the peak area of ​​the test compound solution and the standard concentration solution. The calculation formula is as follows:

[1750] [Sample] is the solubility of the sample to be tested;

[1751] Area ratio sample is the ratio of the sample peak area to the internal standard peak area in the sample to be tested;

[1752] INJ VOL STD is the injection volume of the standard concentration solution;

[1753] DF sample is the dilution ratio of the sample solution to be tested;

[1754] [STD] is the concentration of the standard concentration solution;

[1755] INJ VOL sample is the injection volume of the sample solution to be tested;

[1756] Area ratio STD is the ratio of the sample peak area to the internal standard peak area in the standard concentration solution.

[1757] Test Example 9: Pharmacokinetics of the Compounds of the Invention in Rats

[1758] SD rats were used as test animals, and the drug concentrations in the plasma of the compound of the present invention at different time points after intravenous injection and oral gavage were determined by LC / MS / MS to study the pharmacokinetic behavior of the compound of the present invention in rats and evaluate its pharmacokinetic characteristics.

[1759] Each group consisted of 3 healthy 6-8 week old male SD rats.

[1760] Intravenous administration: Weigh a certain amount of drug and add 10% by volume of N,N-dimethylacetamide, 33% by volume of triethylene glycol, and 57% by volume of normal saline to prepare a 1 mg / mL colorless, clear liquid;

[1761] Oral administration: Weigh a certain amount of drug and add 0.5% by mass of hydropropyl methylcellulose, 0.1% by volume of Tween 80 and 99.6% by volume of normal saline to prepare a 1 mg / mL white suspension.

[1762] SD rats were fasted overnight and then given intravenously or orally.

[1763] Rats were intravenously administered with the compound of the present invention. 0.2 mL of blood was collected from the jugular vein at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration. The blood was placed in a tube containing EDTA-K2 and centrifuged at 4000 rpm for 5 minutes at 4°C to separate the plasma, which was then stored at -75°C.

[1764] Alternatively, rats were orally administered with the compound of the present invention, and 0.2 mL of blood was collected from the jugular vein at 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration. The blood was placed in a tube containing EDTA-K2 and centrifuged at 3500 rpm for 10 minutes at 4°C to separate the plasma, which was then stored at -75°C.

[1765] Determination of the test compound content in rat plasma after oral administration of different drug concentrations: 30 μL of rat plasma at each time point after administration was added with 200 μL of acetonitrile solution of internal standard dexamethasone (50 ng / mL), vortexed for 30 seconds, and centrifuged at 4700 rpm for 15 minutes at 4°C. The supernatant of the plasma sample was diluted three times with water, and 2.0 μL was taken for LC-MS / MS analysis.

[1766] Test Example 10: In vitro assessment of PXR activation potential in DPX2 cells

[1767] Prepare DMSO solutions of the test compounds and the control compound, rifampicin, and dilute them to the respective test concentrations using Puracyp dosing medium (Puracyp, Cat. No. D-500-100) at 37°C. Final test compound concentrations are 30 μM, 10 μM, and 1 μM, respectively, and the final rifampicin concentration is 20 μM. The final DMSO concentration in the test solution is 0.1%. Separately, prepare a 0.1% DMSO solution using Puracyp dosing medium as a control.

[1768] DPX2 cells were suspended in Puracyp Culture medium (Puracyp, Product No. C-500-100) at a cell density of 4.5*10 5 cell / mL. 100 μL was placed into each well of a 96-well culture plate and incubated at 37°C for 24 hours. The medium in the appropriate wells of the 96-well culture plate was replaced with 100 μL of the test compound solution and the control compound solution, repeating three times per well. After replacement, the culture medium was incubated at 37°C for 24 hours. The culture medium was replaced again with freshly prepared test compound solution and rifampicin solution per well, repeating three times per well, and the culture medium was incubated at 37°C for another 24 hours.

[1769] The culture medium in the 96-well culture plate was aspirated and washed twice with PBS. 50 μL CellTiter-Fluor was added to each well. TM Dilute the reagents in the Cell Viability Assay Kit (Promega, Cat. No. G6082) as required and incubate at 37°C for 0.5 hours. Cool the 96-well plate to room temperature and measure the fluorescence value of each well at 505 nm using a microplate reader in fluorescence mode with an excitation wavelength of 400 nm. Add 50 μL of the reagents prepared in the One-Glo Luciferase Assay System (Promega, Cat. No. E6120) as required to each well and incubate at room temperature for 5 minutes. Read the luminescence value of each well using a luminometer.

[1770] Normalized luciferase activity is determined by RLU / RFU, where RLU refers to the relative luminescence units of each test compound at each dose, and RFU refers to the relative fluorescence units of each test compound at each dose. RLU and RFU of each sample are the average of duplicate wells.

[1771] The percentage of positive control is calculated as follows: %Positive control = (fold activation test compound - 1) / (fold activation positive control compound - 1) * 100%

[1772] Fold of activation is the activation fold of PXR by the sample to be tested;

[1773] RLU sample is the relative luminescence intensity of the sample to be tested;

[1774] RFU sample is the relative fluorescence intensity of the sample to be tested;

[1775] RLU vehicle is the relative luminescence intensity of the blank control;

[1776] RFU vehicle is the relative fluorescence intensity of the blank control;

[1777] %Positive control is the activation rate of the test compound relative to the positive compound (rifampicin) on PXR.

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof: in, Ring A is selected from 5-membered heteroaryl, pyridinone, azapyridinone, 10-16 membered tricyclic heterocyclyl, 12-20 membered tetracyclic heterocyclyl or 11-14 membered tricyclic heteroaryl; The 5-membered heteroaryl group is optionally substituted by one or more R 1a Replace, each R 1a independently selected from halogen, CN, OH, NH2, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C5-C 10 Cycloalkenyl, 4-10 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl, the OH, NH2, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C5-C 10 Cycloalkenyl, 4-10 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally substituted with one or more R 1b Replace, when two R 1a When located at the ortho position of a 5-membered heteroaryl group, the two R 1a They can also form, together with the atoms to which they are attached, a C5-C7 monocycloalkenyl, a 4-7 membered monoheterocyclic group, a phenyl group or a 5-6 membered monoheteroaryl group, wherein the C5-C7 monocycloalkenyl, the 4-7 membered monoheterocyclic group, the phenyl group or the 5-6 membered monoheteroaryl group is optionally substituted by one or more R 1b replace; The pyridone group, azapyridone group, 10-16 membered tricyclic heterocyclic group, 12-20 membered tetracyclic heterocyclic group or 11-14 membered tricyclic heteroaryl group are optionally substituted by one or more R 2b replace; The ring M is selected from C4-C7 monocycloalkenyl, 4-7 membered monoheterocyclic group, phenyl or 5-6 membered monoheteroaryl, and the structural unit By one or more R 3a Substituted, the R 3a Selected from C3-C 10 Cycloalkyl, C5-C 10 Cycloalkenyl, 4-10 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl; optionally, the 3a Replaced Can be further divided into one or more R 3b replace; The X 1 、X 2 、X 3 、X 4 、X 5 、X 6 1, 2 or 3 of them are selected from N, and the rest are selected from CR 4 , or, the X 3 、X 4 、X 5 、X 6 One of them does not exist, and the other three are the same as X 1 、X 2 Together constitute a 5-membered heteroaryl, the 5-membered heteroaryl is optionally substituted by one or more R 4b replace; Every R 4 Each independently selected from absent, H or R 4b ; The ring Q is selected from C5-C7 monocycloalkenyl, 4-7 membered monoheterocyclic group, phenyl or 5-6 membered monoheteroaryl, and the C5-C7 monocycloalkenyl, 4-7 membered monoheterocyclic group, phenyl or 5-6 membered monoheteroaryl is optionally substituted by one or more R 4b replace; R 1 is selected from H or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more halogens; R 2 Selected from described Optionally one or more R x Replace, each R x are independently selected from halogen, CN, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl or 4-7 membered heterocyclic group, wherein the OH, NH2, C1-C6 alkyl C3-C6 cycloalkyl or 4-7 membered heterocyclic group is optionally substituted by one or more R xb Replace, when The same carbon atom on the x When substituted, the two R x It can also form C3-C 10 Cycloalkyl, C3-C 10 Cycloalkenyl or 4-10 membered heterocyclic group, the C3-C 10 Cycloalkyl, C3-C 10 Cycloalkenyl or 4-10 membered heterocyclic group is optionally substituted by one or more R xb replace; R 3 Selected from L 1 -L 2 -R y , L 1 Selected from-NR 5 -, -O-, -S-, -S(=O)-, -SO2-, -C(=O)-, -NR 5 SO2-、-NR 5 C(=O)-、-NR 5 -S(=O)(=NR 5 )-、-S(=O)(=NR 5 )-、-S=N-、 Every R 5 Independently selected from H or C1-C4 alkyl, each R 5a 、R 5b Each is independently selected from C1-C4 alkyl, C3-C6 cycloalkyl or 4-7 membered heterocyclic group, or the R 5a 、R 5b and the atoms to which they are connected together form a 4-7 membered heterocyclic group, L 2 Selected from chemical bonds or C1-C4 alkylene, R y is selected from H, C3-C6 cycloalkyl or 4-7 membered heterocyclyl, each of which C1-C4 alkyl, C1-C4 alkylene, C3-C6 cycloalkyl or 4-7 membered heterocyclyl is optionally substituted with one or more halogen, CN, OH, NH2, O(C1-C4 alkyl), NH(C1-C4 alkyl) or N(C1-C4 alkyl)2; X, Y, and Z are each independently selected from N or CR 6 , R 6 is selected from H, halogen, CN, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, O(C1-C4 alkyl), NH(C1-C4 alkyl) or N(C1-C4 alkyl)2, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, O(C1-C4 alkyl), NH(C1-C4 alkyl) or N(C1-C4 alkyl)2 is optionally substituted with one or more halogen or CN; Every R 1b 、R 2b 、R 3b 、R 4b 、R xb independently selected from halogen, CN, OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C5-C 10 Cycloalkenyl, C(O)R d , C3-C6 cycloalkyl, 4-14 membered heterocyclyl, O(C1-C4 alkyl), NH(C1-C4 alkyl) or N(C1-C4 alkyl) 2, the C1-C6 alkyl, C2-C6 alkenyl, C5-C 10 Cycloalkenyl, C3-C6 cycloalkyl, 4-14 membered heterocyclyl, O(C1-C4 alkyl), NH(C1-C4 alkyl) or N(C1-C4 alkyl) 2 are optionally substituted by one or more R c replace; Every R c Independently selected from halogen, CN, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, O(C1-C4 alkyl), NH(C1-C4 alkyl) or N(C1-C4 alkyl)2; R d Selected from OH, C1-C6 alkyl, O(C1-C4 alkyl), NH2, NH(C1-C4 alkyl) or N(C1-C4 alkyl)2.

2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The azapyridone group, 10-16 membered tricyclic heterocyclic group, 12-20 membered tetracyclic heterocyclic group or 11-14 membered tricyclic heteroaryl group in the ring A is selected from the group optionally replaced by one or more R 2b Substituted with the following groups:

3. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that: The structural unit in the ring A The ring M in is selected from C4-C7 monocycloalkenyl, 5-6 membered monoheteroaryl or 4-7 membered monoheterocyclic group, and the structural unit By one or more R 3a substituted; optionally, by one or more R 3a Substituted structural units Can be further divided into one or more R 3b Replace; or The structural unit Selected from one or more R 3a Substituted with the following groups: Optionally, one or more R 3a The above-mentioned substituted groups may be further substituted by one or more R 3b replace.

4. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, characterized in that: The structural unit in the ring A Selected from Ring atom Y 1 、Y 2 、Y 3 、Y 4 、Y 5 1, 2 or 3 of them are N, and the rest are C, R A6 、R A8 Any one of R A7 and the atoms to which they are attached together form a C5-C7 monocycloalkenyl, a 4-7 membered monoheterocyclic group, a phenyl group or a 5-6 membered monoheteroaryl group, wherein the C5-C7 monocycloalkenyl, the 4-7 membered monoheterocyclic group, the phenyl group or the 5-6 membered monoheteroaryl group is optionally substituted by one or more R 4b Substitution; R not involved in ring formation A6 、R A8 、R A9 、R A10 Each independently selected from absent, H or R 4b ;or The structural unit Selected from Ring atom Y 1 、Y 2 、Y 3 、Y 4 、Y 5 One or two of them are N, and the rest are selected from C, R A6 、R A8 Any one of R A7 and the atoms to which they are attached together form a C5 monocycloalkenyl or a 5-6 membered monoheteroaryl, wherein the C5 monocycloalkenyl or the 5-6 membered monoheteroaryl is optionally substituted by one or more R 4b Substitution; R not involved in ring formation A6 、R A8 、R A9 、R A10 Each independently selected from absent, H or R 4b ;or The structural unit Selected from optionally one or more R 4b Substituted with the following groups:

5. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, characterized in that: The R 3a is selected from C3-C6 cycloalkyl or 4-7 membered heterocyclyl, for example cyclobutyl, piperidinyl, morpholinyl or azabicyclo[3.1.0]hexyl; or The R 3a is selected from C3-C6 cycloalkyl or 4-7 membered heterocyclyl, such as cyclobutyl, piperidinyl or morpholinyl; and / or The R 3b is selected from halogen or C1-C6 alkyl, such as F, Cl and methyl; Optionally, the R 3b is selected from halogen, such as F.

6. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, characterized in that: Every R 1b 、R 2b 、R 3b 、R 4b 、R xb independently selected from halogen, CN, OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, 4-14 membered heterocyclyl, O(C1-C4 alkyl), NH(C1-C4 alkyl) or N(C1-C4 alkyl)2, wherein the C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, 4-14 membered heterocyclyl, O(C1-C4 alkyl), NH(C1-C4 alkyl) or N(C1-C4 alkyl)2 is optionally replaced by one or more R c Replace; or The R 2b and / or R 4b Each independently selected from halogen, CN, C1-C6 alkyl, C3-C6 cycloalkyl, 4-10 membered heterocyclyl, C2-C4 alkenyl, C5-C 10 Cycloalkenyl, C(O)R d , or O(C1-C4 alkyl), the C1-C6 alkyl, C3-C6 cycloalkyl, 4-10 membered heterocyclyl, C2-C4 alkenyl, C5-C 10 Cycloalkenyl or O(C1-C4 alkyl) optionally substituted by one or more R c Substituted, the R c are independently selected from halogen, CN, OH, NH2, C1-C4 alkyl or O(C1-C4 alkyl); said R d independently selected from O(C1-C4 alkyl), NH2, NH(C1-C4 alkyl) or N(C1-C4 alkyl)2; or The R 2b and / or R 4b Each independently selected from halogen, CN, C1-C6 alkyl, C3-C6 cycloalkyl, 4-10 membered heterocyclyl, C2-C4 alkenyl, C5-C 10 Cycloalkenyl, C(O)R d , or O(C1-C4 alkyl), the C1-C6 alkyl, C3-C6 cycloalkyl, 4-10 membered heterocyclyl, C2-C4 alkenyl, C5-C 10 Cycloalkenyl or O(C1-C4 alkyl) optionally substituted by one or more R c Substituted, the R c are independently selected from halogen or O(C1-C4 alkyl); said R d independently selected from O(C1-C4 alkyl), NH2, NH(C1-C4 alkyl) or N(C1-C4 alkyl)2; or The R 2b and / or R 4b Each is independently selected from halogen, CN, C1-C6 alkyl, C3-C6 cycloalkyl, 4-10 membered heterocyclyl, C2-C4 alkenyl or O(C1-C4 alkyl), wherein the C1-C6 alkyl, C3-C6 cycloalkyl, 4-10 membered heterocyclyl, C2-C4 alkenyl or O(C1-C4 alkyl) is optionally replaced by one or more R c Substituted, the R c independently selected from halogen, CN, OH, NH2 or C1-C4 alkyl; or The R 2b independently selected from halogen, CN, C1-C6 alkyl, C3-C6 cycloalkyl, 4-10 membered heterocyclyl, C5-C 10 Cycloalkenyl, C(O)R d or O(C1-C4 alkyl), the C1-C6 alkyl, C3-C6 cycloalkyl, 4-10 membered heterocyclic group, C5-C 10 Cycloalkenyl or O(C1-C4 alkyl) optionally substituted by one or more R c substituted, and the R c is selected from halogen or O(C1-C4 alkyl); or said R 2b independently selected from halogen, CN, C1-C6 alkyl, C3-C6 cycloalkyl, 4-10 membered heterocyclyl, C5-C 10 Cycloalkenyl, C(O)R d , or O(C1-C4 alkyl), the C1-C6 alkyl, 4-10 membered heterocyclic group and C5-C 10 The cycloalkenyl group is optionally substituted with one or more R c substituted, and the R c is selected from halogen; or said R 2b is selected from cyano, halogen, C1-C4 alkyl, O(C1-C4 alkyl) or piperidinyl, wherein the C1-C4 alkyl, O(C1-C4 alkyl) or piperidinyl is optionally substituted with one or more F, and / or the R 4b is selected from C1-C4 alkyl, O(C1-C4 alkyl), 4-10 membered heterocyclyl or C2-C4 alkenyl, wherein the C1-C4 alkyl, O(C1-C4 alkyl), 4-10 membered heterocyclyl or C2-C4 alkenyl is optionally substituted with one or more F; or The R 2b Selected from CN, F, methyl, trifluoromethyl, methoxy, methoxymethyl, cyclopropyl, methoxycarbonyl or ethylaminocarbonyl, or said R 2b Selected from CN, F, methyl, trifluoromethyl, methoxy, cyclopropyl, methoxycarbonyl or ethylaminocarbonyl, or said R 2b Selected from CN, F, methyl, methoxy or and / or the R 4b Selected from methyl, isopropyl, CF3CH2CH2, CF3CH2CH2O, Or vinyl.

7. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, characterized in that: The ring A is selected from 8. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, characterized in that: The R 1 Selected from H or C1-C4 alkyl.

9. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, characterized in that: The R 2 Selected from described The same carbon atom on the x Substitute, the two R x Together with the carbon atom, it forms a C3-C6 cycloalkyl, C3-C6 cycloalkenyl or 4-7 membered heterocyclic group, wherein the C3-C6 cycloalkyl, C3-C6 cycloalkenyl or 4-7 membered heterocyclic group is optionally substituted by one or more R xb Replace; or The R 2 Selected from described The carbon atom in the x Substitute, the two R x Together with the carbon atom, it forms a C3-C6 cycloalkyl, C3-C6 cycloalkenyl or 4-7 membered heterocyclic group, wherein the C3-C6 cycloalkyl, C3-C6 cycloalkenyl or 4-7 membered heterocyclic group is optionally substituted by one or more R xb Replace; or The R 2 Selected from described The carbon atom in the x Substitute, the two R x Together with the carbon atom, it forms a C3-C6 cycloalkyl group, wherein the C3-C6 cycloalkyl group is optionally substituted by one or more R xb Replace; or The R 2 Selected from 10. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, characterized in that: R 3 Selected from L 1 -L 2 -R y , L 1 Selected from -NH-, -O-, -S-, -S(=O)-, -SO2-, -C(=O)-, -NHSO2-, -NH(C=O)- or The R 5a 、R 5b Each independently selected from C1-C4 alkyl, or said R 5a 、R 5b and the atoms to which they are connected together form a 4-7 membered heterocyclic group, L 2 Selected from chemical bonds or C1-C4 alkylene, R y is selected from H, C3-C6 cycloalkyl or 4-7 membered heterocyclyl, each of which C1-C4 alkyl, C1-C4 alkylene, C3-C6 cycloalkyl or 4-7 membered heterocyclyl is optionally substituted with one or more halogen, CN, OH or NH2; or R 3 Selected from L 1 -L 2 -R y , L 1 is selected from -NH-, -O-, -S-, -S(=O)-, -SO2-, -(C=O)-, -NHSO2- or -NH(C=O)-, L 2 Selected from C1-C4 alkylene, R y is selected from H, said C1-C4 alkylene being optionally substituted with one or more halogen, CN, OH or NH2; or R 3 Selected from L 1 -L 2 -R y , L 1 Selected from -NHSO2-, L 2 Selected from C1-C4 alkylene, R y is selected from H, wherein the C1-C4 alkylene group is optionally substituted with one or more halogen or OH; or R 3 Selected from L 1 -L 2 -R y , L 1 Selected from -NHSO2-, L 2 Selected from C1-C4 alkylene, R y is selected from H, wherein the C1-C4 alkylene group is optionally substituted with one or more OH groups; R 3 Selected from or R 3 Selected from 11. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, characterized in that: X, Y, and Z are all selected from CH.

12. A compound or a pharmaceutically acceptable salt thereof, characterized in that: The compound is selected from one of the following structures:

13. A pharmaceutical composition comprising the compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

14. Use of the compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 13, in the preparation of a medicament for preventing or treating a KIF18A-related disease.

15. The use according to claim 14, wherein the KIF18A-related disease is selected from tumors; or The KIF18A-related disease is ovarian cancer.

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