Cyclically substituted amide compounds, compositions thereof, and uses thereof

Abstract

Provided are novel cyclic-substituted amide compounds or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing the same, and use as KIF18A inhibitors in the prevention or treatment of related diseases.

Description

Ring-substituted amide compounds, compositions and uses thereof

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

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

[0003] Chinese invention patent application No. CN202410107219.5 filed with the State Intellectual Property Office of China on January 25, 2024,

[0004] Chinese invention patent application No. CN202410288450.9 filed with the State Intellectual Property Office of China on March 13, 2024, and

[0005] Chinese invention patent application No. CN202410793797.9 submitted to the State Intellectual Property Office of China on June 19, 2024. Technical Field

[0006] The present disclosure relates to a ring-substituted 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

[0007] 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.

[0008] 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.

[0009] 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. Summary of the Invention

[0010] The present disclosure provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof:

[0011] In formula (II):

[0012] 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);

[0013] X1, X2, X3, X4 and X5 are each independently CR aor nitrogen; where R a are each independently selected from absent, H or halogen;

[0014] R 1 is absent, H, C1-C6 alkyl, cyano, C1-C6 alkoxy, (CH2) r -C(O)R d , halogen, OH, (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)2;

[0015] R 2 is H, OH, C1-C6 alkyl, cyano, C1-C6 alkoxy, C(O)R d , halogen, C1-C6 haloalkyl or C1-C6 haloalkoxy;

[0016] 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

[0017] R 3 is selected from C1-C6 alkyl or C2-C6 alkenyl, wherein the C1-C6 alkyl is optionally substituted by one or more halogen or OH.

[0018] In some embodiments, R 3 is selected from C1-C6 alkyl groups optionally substituted by one or more halogen or OH.

[0019] In some embodiments, in Formula (II):

[0020] 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);

[0021] 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;

[0022] R 1 is absent, H, C1-C6 alkyl, cyano, C1-C6 alkoxy, (CH2) r -C(O)R d , halogen, OH, (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)2;

[0023] R 2 is H, C1-C6 alkyl, cyano, C1-C6 alkoxy, C(O)R d , halogen, C1-C6 haloalkyl or C1-C6 haloalkoxy;

[0024] 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

[0025] R 3 is selected from C1-C6 alkyl groups optionally substituted by one or more halogen or OH.

[0026] In some embodiments, in the formula (II):

[0027] 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);

[0028] 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;

[0029] R 1 is absent, H, C1-C6 alkyl, cyano, C1-C6 alkoxy, (CH2) r -C(O)R d , halogen, OH, (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)2;

[0030] R 2 is H, OH, C1-C6 alkyl, cyano, C1-C6 alkoxy, C(O)R d, halogen, C1-C6 haloalkyl or C1-C6 haloalkoxy;

[0031] 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

[0032] R 3 is selected from C1-C6 alkyl groups optionally substituted by one or more halogen or OH.

[0033] In some embodiments, in the formula (II):

[0034] 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);

[0035] 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;

[0036] R 1 is absent, H, C1-C6 alkyl, cyano, C1-C6 alkoxy, OH, 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)2;

[0037] R 2 is H, OH, C1-C6 alkyl, cyano, C1-C6 alkoxy, C(O)R d , halogen, C1-C6 haloalkyl or C1-C6 haloalkoxy;

[0038] 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 R 3 is selected from C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted by one or more halogen or OH.

[0039] In some embodiments, in the formula (II):

[0040] 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);

[0041] X1, X4 and X5 are each independently CR a or nitrogen; where R a are each independently selected from absent, H or halogen;

[0042] One of X2 and X3 is C and the other is N;

[0043] R 1 is absent, H, C1-C6 alkyl, cyano, C1-C6 alkoxy, (CH2) r -C(O)R d , halogen, OH, (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-C10 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)2;

[0044] R 2 is H, OH, C1-C6 alkyl, cyano, C1-C6 alkoxy, C(O)R d , halogen, C1-C6 haloalkyl or C1-C6 haloalkoxy;

[0045] 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

[0046] R 3 is selected from C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted by one or more halogen or OH.

[0047] In some embodiments, X1 is C, one of X2 and X3 is C, and the other is N.

[0048] In some embodiments, 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 The aryl or 5-10 membered heteroaryl is optionally substituted by 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)2.

[0049] 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:

[0050] In formula (III'):

[0051] 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);

[0052] X1, X2, and X3 are each independently C or N;

[0053] R 1 is absent, H, C1-C6 alkyl, cyano, C1-C6 alkoxy, (CH2) r -C(O)R d , halogen, OH, (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)2;

[0054] R 2 is H, OH, C1-C6 alkyl, cyano, C1-C6 alkoxy, C(O)R d , halogen, C1-C6 haloalkyl or C1-C6 haloalkoxy;

[0055] Rd is selected from OH, C1-C6 alkyl, O(C1-C4 alkyl), NH2, NH(C1-C4 alkyl) or N(C1-C4 alkyl)2; and

[0056] R 3 is selected from C1-C6 alkyl or C2-C6 alkenyl, wherein the C1-C6 alkyl is optionally substituted by one or more halogen or OH.

[0057] In some embodiments, R 3 is selected from C1-C6 alkyl groups optionally substituted by one or more halogen or OH.

[0058] In some embodiments, in Formula (III'):

[0059] 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);

[0060] X1, X2, and X3 are each independently C or N;

[0061] R 1 is absent, H, C1-C6 alkyl, cyano, C1-C6 alkoxy, (CH2) r -C(O)R d , halogen, OH, (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 10Aryl 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)2;

[0062] R 2 is H, C1-C6 alkyl, cyano, C1-C6 alkoxy, C(O)R d , halogen, C1-C6 haloalkyl or C1-C6 haloalkoxy;

[0063] 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

[0064] R 3 is selected from C1-C6 alkyl groups optionally substituted by one or more halogen or OH.

[0065] In some embodiments, in the formula (III'):

[0066] In formula (III'):

[0067] 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);

[0068] X1, X2, and X3 are each independently C or N;

[0069] R 1 is absent, H, C1-C6 alkyl, cyano, C1-C6 alkoxy, (CH2) r -C(O)R d , halogen, OH, (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)2;

[0070] R 2 is H, OH, C1-C6 alkyl, cyano, C1-C6 alkoxy, C(O)R d , halogen, C1-C6 haloalkyl or C1-C6 haloalkoxy;

[0071] 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

[0072] R 3 is selected from C1-C6 alkyl groups optionally substituted by one or more halogen or OH.

[0073] In some embodiments, in the formula (III'):

[0074] 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);

[0075] X1, X2, and X3 are each independently C or N;

[0076] R 1 is absent, H, C1-C6 alkyl, cyano, C1-C6 alkoxy, OH, halogen, (CH2) r -C3-C 10 Cycloalkyl, (CH2) r -C5-C 10 Cycloalkenyl, (CH2) r -4-10 membered heterocyclic group, (CH2) r -C6-C10 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)2;

[0077] R 2 is H, OH, C1-C6 alkyl, cyano, C1-C6 alkoxy, C(O)R d , halogen, C1-C6 haloalkyl or C1-C6 haloalkoxy;

[0078] 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

[0079] R 3 is selected from C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted by one or more halogen or OH.

[0080] In some embodiments, in the formula (III'):

[0081] 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);

[0082] X1 is independently C or N; one of X2 and X3 is C, and the other is N;

[0083] R 1 is absent, H, C1-C6 alkyl, cyano, C1-C6 alkoxy, (CH2) r -C(O)R d , halogen, OH, (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)2;

[0084] R 2 is H, OH, C1-C6 alkyl, cyano, C1-C6 alkoxy, C(O)R d , halogen, C1-C6 haloalkyl or C1-C6 haloalkoxy;

[0085] 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

[0086] R 3 is selected from C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted by one or more halogen or OH.

[0087] In some embodiments, in the formula (II), formula (III') and the following sub-formula (III), X1 is C or N, X2 is N, and X3 is C.

[0088] In some embodiments, in the formula (II), formula (III') and the following sub-formula (III), X1 is C, X2 is N, X3 is C; A is a monocyclic or bicyclic ring selected from a 4-10 membered carbocyclic ring or a 4-10 membered heterocyclic ring, and the 4-10 membered carbocyclic ring or the 4-10 membered heterocyclic ring is replaced 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).

[0089] In some embodiments, the compounds represented by formula (II), formula (III') and the following sub-formulas of formula (III) do not include the following compounds:

[0090] In some embodiments, the compounds represented by formula (II), formula (III') and the following sub-formulas of formula (III) do not include the following compounds:

[0091] In some embodiments, the compounds represented by formula (II), formula (III') and the following sub-formulas of formula (III) do not include the following compounds:

[0092] In some embodiments, the compounds represented by formula (II), formula (III') and the following sub-formulas of formula (III) do not include the following compounds:

[0093] In some embodiments, in the compounds represented by formula (II), formula (III') and the following sub-formula (III), the structural unit Not the following structures:

[0094] In some embodiments, in the compounds represented by formula (II), formula (III') and the following sub-formulas of formula (III):

[0095] When A is a 5-membered heterocyclic monocyclic ring containing only one N atom as a heteroatom, the 5-membered heterocyclic monocyclic ring containing only one N atom as a heteroatom is replaced by one or more R b Replacement, R b As defined in formula (II) but R b Not methoxy and -CF3;

[0096] When A is a monocyclic 6-membered heterocyclic ring containing only one nitrogen atom as a heteroatom and X1 is C, the compound satisfies at least one of the following conditions (1) and (2): (1) R 1 and R 2 are not hydrogen and when R 1 When it is hydrogen, R 2 is not F, and when R 2 When it is hydrogen, R 1Not F and cyano; (2) Ring A is replaced by one or more R b Replace, and R b Not for F;

[0097] When A is a monocyclic 6-membered heterocyclic ring containing only one nitrogen atom as a heteroatom and X1 is N, the compound satisfies at least one of the following conditions (1) and (2): (1) R 2 Not hydrogen; (2) Ring A is replaced by one or more R b replace;

[0098] When A is a monocyclic 6-membered heterocyclic ring containing one N and one O or two N as heteroatoms, the compound satisfies at least one of the following conditions (1) and (2): (1) R 1 and R 2 are not hydrogen at the same time; (2) Ring A is surrounded by one or more R b Replace, and R b Not methyl;

[0099] When A is a 6-membered carbocyclic or heterocyclic bicyclic ring containing only one nitrogen atom as a heteroatom, and the 6-membered carbocyclic or heterocyclic bicyclic ring is a condensed ring of a 3-membered ring and a 5-membered ring, the compound satisfies at least one of the following conditions (1) and (2): (1) R 1 and R 2 are not hydrogen at the same time, and when R 2 When it is hydrogen, R 1 (2) the six-membered carbocyclic or heterocyclic bicyclic ring is replaced by one or more R b Substituted; and when the 6-membered heterocyclic bicyclic ring is as R b When two F or two methyl groups are substituted, the bicyclic ring of the 6-membered heterocyclic ring is additionally further substituted with one or more R b Substitution and / or R 1 is not hydrogen and cyano; when the 6-membered carbocyclic bicyclic ring is used as R b When two F are substituted, the six-membered carbocyclic bicyclic ring is additionally further substituted with one or more R b Substitution and / or R 1 is not absent, cyano and methoxy; the other one or more R b As defined in formula II;

[0100] When A is a 7-membered ring, the 7-membered ring is selected from a 7-membered carbocyclic or 7-membered heterocyclic monocycle, a 7-membered carbocyclic bicyclic ring, or a 7-membered heterocyclic fused bicyclic ring; and the 7-membered heterocyclic fused bicyclic ring is a bicyclic ring composed of a 4-membered ring and a 5-membered ring;

[0101] When A is a 7-membered heterocyclic monocyclic ring containing one N and one O as heteroatoms, the compound satisfies at least one of the following conditions (1) and (2): (1) Ring A is surrounded by one or more Rb Substitution; (2) R 1 and R 2 Not simultaneously hydrogen;

[0102] When A is an 8-membered ring, the 8-membered ring is selected from an 8-membered carbocyclic or 8-membered heterocyclic monocyclic ring, an 8-membered carbocyclic bicyclic ring, or an 8-membered heterocyclic fused-ring bicyclic ring;

[0103] When A is a monocyclic 8-membered heterocyclic ring containing one N as a heteroatom, the compound satisfies at least one of the following conditions (1) and (2): (1) Ring A is surrounded by one or more R b Substitution; (2) R 1 and R 2 Not hydrogen at the same time.

[0104] In some embodiments, R in the formula (II) or formula (III') 1 and R 2 When one of is H, the other is not H, methyl, CN or halogen.

[0105] In some embodiments, A in the formula (II) or (III') 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 replaced by one or more R b Replace, each R b independently selected from OH, 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).

[0106] In some embodiments, A in the formula (II) or (III') 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 replaced by one or more R b Replace, each R b independently 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).

[0107] In some embodiments, the structural unit in formula (II) or formula (III') Selected from

[0108] In some embodiments, the structural unit in formula (II) or formula (III') Selected from

[0109] In some embodiments, the structural unit in formula (II) or formula (III') Selected from

[0110] In some embodiments, X1, X2, X3, X4 and X5 in the formula (II) are each independently CR a or N; where R a Each is independently selected from absent, H or F.

[0111] In some embodiments, X1, X2, X3, X4 and X5 in formula (II) are each independently C or N.

[0112] In some embodiments, X5 in formula (II) is N.

[0113] In some embodiments, at least one of X1, X2, X3, X4 and X5 in formula (II) is N.

[0114] In some embodiments, one, two or three of X1, X2, X3, X4 and X5 in formula (II) are N.

[0115] In some embodiments, two of X1, X2, X3, X4 and X5 in formula (II) are N.

[0116] In some embodiments, three of X1, X2, X3, X4 and X5 in formula (II) are N.

[0117] In some embodiments, X2 and X5 in formula (II) are both N; in some embodiments, X3 and X5 in formula (II) are both N; in some embodiments, X4 and X5 in formula (II) are both N.

[0118] In some embodiments, X4 in formula (II) is C, X5 is N, one of X2 and X3 is C, and the other is N.

[0119] In some embodiments, X1 in formula (II) is C or N; one of X2 and X3 is C, and the other is N.

[0120] In some embodiments, X4 in the formula (II) is C, and X5 is C or N.

[0121] In some embodiments, X1, X3, and X4 in formula (II) are C, and X2 and X5 are both N.

[0122] In some embodiments, X1, X2, and X4 in formula (II) are C, and X3 and X5 are both N.

[0123] In some embodiments, X3 and X4 in formula (II) are C, and X1, X2 and X5 are N.

[0124] In some embodiments, X1, X2, X4 and X5 in formula (II) are C, and X3 is N.

[0125] In some embodiments, the compound of formula (II) or (III') or a pharmaceutically acceptable salt thereof is selected from the compound of formula (III) or a pharmaceutically acceptable salt thereof:

[0126] In formula (III):

[0127] 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);

[0128] X1, X2, and X3 are each independently C or N;

[0129] R 1 is absent, H, C1-C6 alkyl, cyano, C1-C6 alkoxy, (CH2) r -C(O)R d , halogen, OH, (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 10Aryl 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)2;

[0130] R 2 is H, OH, C1-C6 alkyl, cyano, C1-C6 alkoxy, C(O)R d , halogen, C1-C6 haloalkyl or C1-C6 haloalkoxy;

[0131] 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

[0132] R 3 is selected from C1-C6 alkyl or C2-C6 alkenyl, wherein the C1-C6 alkyl is optionally substituted by one or more halogen or OH.

[0133] In some embodiments, R 3 is selected from C1-C6 alkyl groups optionally substituted by one or more halogen or OH.

[0134] In some embodiments, in Formula (III):

[0135] 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);

[0136] X1, X2, and X3 are each independently C or N;

[0137] R 1 is absent, H, C1-C6 alkyl, cyano, C1-C6 alkoxy, (CH2) r -C(O)R d , halogen, OH, (CH2) r -C3-C 10 Cycloalkyl, (CH2) r -C5-C10 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)2;

[0138] R 2 is H, C1-C6 alkyl, cyano, C1-C6 alkoxy, C(O)R d , halogen, C1-C6 haloalkyl or C1-C6 haloalkoxy;

[0139] 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

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

[0141] In some embodiments, in Formula (III):

[0142] 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);

[0143] X1, X2, and X3 are each independently C or N;

[0144] R 1is absent, H, C1-C6 alkyl, cyano, C1-C6 alkoxy, (CH2) r -C(O)R d , halogen, OH, (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)2;

[0145] R 2 is H, OH, C1-C6 alkyl, cyano, C1-C6 alkoxy, C(O)R d , halogen, C1-C6 haloalkyl or C1-C6 haloalkoxy;

[0146] 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

[0147] R 3 is selected from C1-C6 alkyl groups optionally substituted by one or more halogen or OH.

[0148] In some embodiments, R in the formula (II), formula (III') or formula (III) 2 is H, C1-C6 alkyl, cyano, C1-C6 alkoxy, C(O)R d , halogen, C1-C6 haloalkyl or C1-C6 haloalkoxy.

[0149] In some embodiments, R in the formula (II), formula (III') or formula (III) 1is 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 The aryl or 5-10 membered heteroaryl is optionally substituted by 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)2.

[0150] In some embodiments, R in the formula (II), formula (III') or formula (III) 1 is absent, H, OH, C1-C6 alkyl, halogen, cyano, C1-C6 alkoxy, 5-10 membered heteroaryl, or C(O)R d , the C1-C6 alkyl group is optionally substituted by one or more halogens, and the 5-10 membered heteroaryl group is optionally substituted by one or more C1-C6 alkyl groups.

[0151] In some embodiments, R in the formula (II), formula (III') or formula (III) 1 is absent, H, OH, C1-C6 alkyl, halogen, cyano, C1-C6 alkoxy, or 5-10 membered heteroaryl, the C1-C6 alkyl being optionally substituted with one or more halogen, the 5-10 membered heteroaryl being optionally substituted with one or more C1-C6 alkyl.

[0152] In some embodiments, R in the formula (II), formula (III') or formula (III) 1 is absent, H, OH, C1-C6 alkyl, halogen, cyano, C1-C6 alkoxy or C(O)R d , the C1-C6 alkyl group is optionally substituted by one or more halogens.

[0153] In some embodiments, R in the formula (II), formula (III') or formula (III) 1 is absent, H, OH, C1-C6 alkyl, halogen, cyano, or C1-C6 alkoxy, wherein the C1-C6 alkyl is optionally substituted with one or more halogens.

[0154] In some embodiments, R in the formula (II), formula (III') or formula (III) 1 is absent, H, OH, methoxy, halogen, CN, CF3 or

[0155] In some embodiments, R in the formula (II), formula (III') or formula (III) 1 is absent, H, OH, methoxy, halogen, CN or CF3.

[0156] In some embodiments, R in the formula (II), formula (III') or formula (III) 1 is H, OH, methoxy, halogen or CF3.

[0157] In some embodiments, R in the formula (II), formula (III') or formula (III) 1 For OH.

[0158] In some embodiments, R in the formula (II), formula (III') or formula (III) 2 is H, OH, C1-C6 alkyl, cyano, C1-C6 alkoxy or C(O)R d .

[0159] In some embodiments, R in the formula (II), formula (III') or formula (III) 2 is H, C1-C6 alkyl, cyano, C1-C6 alkoxy or C(O)R d .

[0160] In some embodiments, R in the formula (II), formula (III') or formula (III) 2 is H, OH, C1-C6 alkyl, cyano or C1-C6 alkoxy.

[0161] In some embodiments, R in the formula (II), formula (III') or formula (III) 2 It is H, OH, or C1-C6 alkyl.

[0162] In some embodiments, R in the formula (II), formula (III') or formula (III) 2 It is H, OH, or C1-C4 alkyl.

[0163] In some embodiments, R in the formula (II), formula (III') or formula (III) 2 For H.

[0164] In some embodiments, R in the formula (II), formula (III') or formula (III) 2 For OH.

[0165] In some embodiments, R in the formula (II), formula (III') or formula (III) 3 is selected from C1-C4 alkyl or C2-C3 alkenyl, wherein the C1-C4 alkyl is optionally substituted by one or more halogen or OH.

[0166] In some embodiments, R in the formula (II), formula (III') or formula (III) 3 is selected from C1-C4 alkyl groups optionally substituted by one or more halogen or OH.

[0167] In some embodiments, R in the formula (II), formula (III') or formula (III) 3 is selected from C1-C4 alkyl or C2-C3 alkenyl, wherein the C1-C4 alkyl is optionally substituted with one or more OH groups.

[0168] In some embodiments, R in the formula (II), formula (III') or formula (III) 3 is selected from C1-C4 alkyl groups optionally substituted by one or more OH groups.

[0169] In some embodiments, R in the formula (II), formula (III') or formula (III) 3 Selected from methyl, ethyl, vinyl or

[0170] In some embodiments, R in the formula (II), formula (III') or formula (III) 3 Selected from methyl, ethyl or

[0171] In some embodiments, R in the formula (II), formula (III') or formula (III) 3 Selected from methyl or

[0172] In some embodiments, R in the formula (II), formula (III') or formula (III) 3 Selected from

[0173] In some embodiments, X1 in Formula (II), Formula (III') or Formula (III) is C, and X2 and X3 are each independently C or N.

[0174] In some embodiments, X1 in Formula (II), Formula (III') or Formula (III) is C, one of X2 and X3 is C, and the other is N.

[0175] In some embodiments, A in the formula (II), formula (III') or formula (III) is selected from a monocyclic or bicyclic ring of 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 replaced by one or more R b Replace, each R b Independently selected from OH, F or C1-C4 alkyl.

[0176] In some embodiments, A in the formula (II), formula (III') or formula (III) is selected from a monocyclic or bicyclic ring of 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 replaced by one or more R b Replace, each R b Independently selected from F or C1-C4 alkyl.

[0177] In some embodiments, each R b Independently selected from OH, F, methyl or ethyl.

[0178] In some embodiments, each R b Independently selected from F, methyl or ethyl.

[0179] In some embodiments, the structural unit in formula (II) or formula (III') Selected from optionally one or more R b Substituted with the following groups:

[0180] In some embodiments, the structural unit in formula (II) or a structural unit of formula (III') or formula (III) Selected from optionally one or more R b Substituted with the following groups:

[0181] In some embodiments, the structural unit in formula (II) or a structural unit of formula (III') or formula (III) Selected from

[0182] In some embodiments, the structural unit in formula (II) or a structural unit of formula (III') or formula (III) Selected from

[0183] In some embodiments, the structural unit in formula (II) or a structural unit of formula (III') or formula (III) Selected from

[0184] In some embodiments, the compound represented by formula (II), formula (III') or formula (III) of the present disclosure or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof:

[0185] The present disclosure also provides a pharmaceutical composition comprising a compound represented by formula (II), formula (III') or formula (III) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0186] Furthermore, the present disclosure relates to the use of a compound represented by Formula (II), Formula (III') or Formula (III) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for preventing or treating KIF18A-related diseases.

[0187] Furthermore, the present disclosure relates to the use of a compound represented by formula (II), formula (III') or formula (III) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for preventing or treating tumors.

[0188] Furthermore, the present disclosure relates to the use of a compound represented by Formula (II), Formula (III') or Formula (III) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in preventing or treating KIF18A-related diseases.

[0189] Furthermore, the present disclosure relates to the use of a compound represented by Formula (II), Formula (III') or Formula (III) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in preventing or treating tumors.

[0190] Furthermore, the present disclosure relates to a compound of formula (II), formula (III') or formula (III) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preventing or treating a KIF18A-related disease.

[0191] Furthermore, the present disclosure relates to a compound of formula (II), formula (III') or formula (III) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preventing or treating tumors.

[0192] The present disclosure also relates to a method for treating a KIF18A-related disease, comprising administering to a patient a therapeutically effective amount of a compound of Formula (II), Formula (III') or Formula (III) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (II), Formula (III') or Formula (III) or a pharmaceutically acceptable salt thereof.

[0193] 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 (II), formula (III') or formula (III) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (II), formula (III') or formula (III) or a pharmaceutically acceptable salt thereof, as described in the present disclosure.

[0194] In some embodiments, the KIF18A-related disease is selected from tumors.

[0195] In some embodiments, the tumor is selected from melanoma, breast cancer, ovarian cancer, endometrial cancer, cervical cancer, brain cancer, head and neck cancer, thyroid cancer, lung cancer, bronchial cancer, esophageal cancer, gastric cancer, liver cancer, kidney cancer, pancreatic cancer, gallbladder cancer, colon cancer, bladder cancer, prostate cancer, testicular cancer, skin cancer, bone cancer and blood tumor; the lung cancer includes but is not limited to small cell lung cancer and non-small cell lung cancer; the blood tumor includes but is not limited to leukemia, lymphoma, myeloma; the brain cancer includes but is not limited to glioma, neuroblastoma, astrocytoma, meningioma.

[0196] Definitions and Explanations of Terms

[0197] 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 definitions as examples, 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 as undefined or unclear unless specifically defined, but should be understood according to its ordinary 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.

[0198] In this article Indicates the attachment site.

[0199] The term "tautomer" refers to functional group isomers resulting from the rapid shift of an atom in a molecule between two positions. The 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 usually result in 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.

[0200] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and diastereomers.

[0201] The compounds of the present invention 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 invention 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 the compounds of the present invention and mixtures thereof. Additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms or asymmetric phosphorus atoms may be present in substituents such as alkyl groups, and all of which are within the definition of the compounds of the present invention 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.

[0202] 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.

[0203] 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.

[0204] 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.

[0205] When the number of a linking group is 0, such as -(CH2)0-, it means that the linking group is a bond.

[0206] 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.

[0207] 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 ”.

[0208] 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 attached to any position on the ring.

[0209] 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.

[0210] The term "alkyl" refers to a group of the formula C n H 2n+1 The term "C1-C 10 The 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".

[0211] The term "alkenyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one double bond. The term "C2-C6 alkenyl" is understood to mean a straight or branched unsaturated hydrocarbon group, comprising one or more double bonds and having 2, 3, 4, 5 or 6 carbon atoms, and it is understood that when the alkenyl comprises more than one double bond, the double bonds may be separated or conjugated from each other. The 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.

[0212] 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 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.

[0213] The term "C3-C 10 The term "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, fused, bridged or spirocyclic ring, and having 3 to 10 ring carbon atoms.

[0214] 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. Although some bicyclic heterocyclyl groups in the present disclosure partially contain a benzene ring or a heteroaromatic ring, the heterocyclyl group as a whole is still non-aromatic.

[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 "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 generally 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 "5-6 membered heteroaryl" refers to an aromatic ring system having 5 or 6 ring atoms and containing 1-3, for example, 1-2 heteroatoms independently selected from N, O and S, including but not limited to thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl.

[0217] The term "halo" or "halogen" refers to fluorine, chlorine, bromine or iodine.

[0218] The term "hydroxy" refers to an -OH group.

[0219] The term "cyano" refers to a -CN group.

[0220] The term "mercapto" refers to a -SH group.

[0221] The term "amino" refers to a -NH2 group.

[0222] The term "nitro" refers to a -NO2 group.

[0223] The term "therapeutically effective amount" means an amount of a compound of the present 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 present 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 own knowledge and this disclosure.

[0224] 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.

[0225] 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.

[0226] 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.

[0227] 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.

[0228] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure or their salts and a pharmaceutically acceptable excipient. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present disclosure to an organism.

[0229] 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.

[0230] 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".

[0231] 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 the 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.

[0232] 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 18F 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.

[0233] 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.

[0234] Typical routes of administration of the disclosed compounds, 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.

[0235] 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.

[0236] 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.

[0237] 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.

[0238] The pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.

[0239] In all administration methods of the compounds of formula (II), formula (III') or formula (III) 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.

[0240] The compounds disclosed herein 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 the same 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 disclosed herein.

[0241] The chemical reactions of the embodiments of the present disclosure are carried out in a suitable solvent that is 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 synthetic steps or reaction schemes based on existing embodiments.

[0242] This disclosure uses the following abbreviations: DETAILED DESCRIPTION

[0243] 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 specific 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.

[0244] Unless otherwise specified, the ratios expressed for mixed solvents are volume ratios.

[0245] Unless otherwise specified, % refers to weight %.

[0246] Compounds are manually or Software naming, commercially available compounds use supplier catalog names.

[0247] 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.

[0248] The eluent or mobile phase may be a mixed eluent or mobile phase consisting of two or more solvents, the ratio of which is the volume ratio of each solvent.

[0249] Example 1 Synthesis of Compound 6-1

[0250] Step 1: Synthesis of compound 1b

[0251] Compound 1a (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 react fully at room temperature. Saturated aqueous ammonium chloride (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, and filtered. The filtrate was concentrated and slurried with petroleum ether to afford compound 1b (3.20 g).

[0252] Step 2: Synthesis of compound 1d

[0253] 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 1d (1.0 g).

[0254] MS m / z(ESI):448.2[M+H] + .

[0255] Step 3: Synthesis of compound 1e

[0256] Compound 1d (500 mg, 1.12 mmol), compound 1b (400 mg, 1.68 mmol), potassium phosphate (635 mg, 3 mmol), and (1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (160 mg, 1.12 mmol) were added to DMF (5 mL), followed by cuprous iodide (381 mg, 2 mmol). 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 afford compound 1e (680 mg).

[0257] MS m / z(ESI):559.3[M+H] + .

[0258] Step 4: Synthesis of compound 1f

[0259] Compound 1e (0.60 g, 1.07 mmol) was added to methanol (6 mL) and ethyl acetate (4 mL), and palladium on carbon (0.20 g, 10% loading) was added, and the mixture was allowed to react under a hydrogen atmosphere at 25°C. The reaction mixture was filtered, the filtrate was spin-dried, and the mixture was slurried with petroleum ether (5 mL) to obtain compound 1f (314 mg).

[0260] MS m / z(ESI):469.3[M+H] + .

[0261] Step 5: Synthesis of compound 1i

[0262] Compound 1g (617 mg, 2.81 mmol), compound 1h hydrochloride (250 mg, 1.87 mmol), and cesium carbonate (1.83 g, 5.61 mmol) were added to acetonitrile (4 mL), and the mixture was fully reacted at 80°C. Water (20 mL) was added to the system, and extraction was performed with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was then spin-dried to give crude product 1i (550 mg).

[0263] MS m / z(ESI):296.9 / 298.9[M+H] + .

[0264] Step 6: Synthesis of compound 1j

[0265] Compound 1i (550 mg, 1.85 mmol) and ammonium chloride (953 mg, 18.51 mmol) were added to water (5 mL) and ethanol (25 mL), followed by iron powder (1.03 g, 18.51 mmol). The mixture was allowed to react at 80°C. The reaction mixture was filtered, the filter cake was washed with ethyl acetate, and the filtrate was concentrated and purified by column chromatography (petroleum ether:ethyl acetate = 100:0-80:20) to obtain compound 1j (460 mg).

[0266] MS m / z(ESI):267.0 / 269.0[M+H] + .

[0267] Step 7: Synthesis of compound 1k

[0268] A solution of compound 1j (450 mg, 1.68 mmol) in water (2 mL) and acetonitrile (10 mL) was heated to 80°C. Iodine (2.13 g, 8.40 mmol) was added to the mixture and the reaction was maintained at 80°C for complete reaction. The reaction solution was poured into saturated aqueous sodium bicarbonate (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated sodium thiosulfate solution (50 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by column chromatography (petroleum ether:ethyl acetate = 75:25) to obtain compound 1k (340 mg).

[0269] MS m / z(ESI):263.0 / 265.0[M+H] + .

[0270] Step 8: Synthesis of compound 1m

[0271] Under nitrogen, Pd2dba3 (139 mg, 152 μmol), cesium carbonate (619 mg, 1.90 mmol), and Xantphos (88 mg, 152 μmol) were added to a solution of compound 1l (356 mg, 3.04 mmol) and compound 1k (200 mg, 761 μmol) in dioxane (4 mL). The mixture was reacted at 100°C. The reaction solution was filtered, the filtrate was dried, and purified by column chromatography to afford compound 1m (210 mg).

[0272] MS m / z(ESI):300.1[M+H] + .

[0273] Step 9: Synthesis of compound 1n

[0274] Trifluoroacetic acid (1 mL) was added dropwise to a solution of compound 1m (200 mg, 668 μmol) in dichloromethane (5 mL), and the mixture was fully reacted at room temperature. The reaction solution was concentrated, and the residue was dissolved in water and extracted with ethyl acetate (20 mL x 3). The organic phase was discarded, and the pH of the aqueous phase was adjusted to 10. The aqueous phase was extracted three times with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give compound 1n (85 mg).

[0275] MS m / z(ESI):200.1[M+H] + .

[0276] Step 10: Synthesis of compound 6-1

[0277] Compound 1f (47 mg, 100 μmol), nitrogen-methylimidazole (NMI, 44 mg, 533 μmol), and N,N,N,N-tetramethylchloroformamidine hexafluorophosphate (TCFH, 45 mg, 160 μmol) were added to acetonitrile (2 mL) and stirred at room temperature for 15 minutes. A solution of compound 1n (20 mg, 100 μmol) in acetonitrile (0.5 mL) was added dropwise to the reaction mixture, and the mixture was heated to 60°C for reaction. After cooling to room temperature, pyridine hydrofluoride (29 mg, 300 μmol) was added, and the reaction mixture was allowed to react at room temperature. The product was directly purified by flash reverse-phase column chromatography (acetonitrile:water = 10:90 to 90:10) to afford compound 6-1 (33 mg).

[0278] 1 H-NMR (400MHz, DMSO-d6) δ12.37(s,1H),10.06(s,1H),8.34(dd,J=7.0,2.0Hz,1H),8.02(d,J=8.6H z,1H),7.25(d,J=2.1Hz,1H),7.22–7.13(m,2H),7.07(dd,J=8.6,2.1Hz,1H),4.91(s,1H),4.17(dd, J=10.6,6.2Hz,1H),4.06(d,J=10.7Hz,1H),3.80–3.69(m,4H),3.34(t,J=6.5Hz,2H),3.08–2.91(m, 4H),2.65–2.57(m,1H),2.47–2.39(m,1H),2.11–1.98(m,2H),1.94–1.49(m,4H),0.34–0.21(m,4H).

[0279] MS m / z(ESI):536.2[M+H] + .

[0280] Example 2 Synthesis of Compound 6-2

[0281] Step 1: Synthesis of compound 2c

[0282] Compound 2c (352 mg) was synthesized and purified using the same method as in Step 5 of Example 1 using compound 2a (0.3 g, 1.2 mmol) and 2b hydrochloride (560 mg, 3.6 mmol) as starting materials.

[0283] Step 2: Synthesis of compound 2d

[0284] Compound 2d (205 mg) was synthesized and purified using compound 2c (311 mg, 0.89 mmol) as starting material in the same manner as in step 6 of Example 1.

[0285] Step 3: Synthesis of compound 2e

[0286] Compound 2e (151 mg) was synthesized and purified using compound 2d (202 mg, 0.63 mmol) as starting material in the same manner as in step 7 of Example 1.

[0287] Step 4: Synthesis of compound 2f

[0288] Compound 2f (30 mg) was synthesized and purified using compound 2e (80 mg, 0.25 mmol) as starting material in the same manner as in step 8 of Example 1.

[0289] Step 5: Synthesis of compound 2g

[0290] Compound 2g (17 mg) was synthesized and purified using compound 2f (30 mg, 0.085 mmol) as starting material in the same manner as in step 9 of Example 1.

[0291] MS m / z(ESI):252.1[M+H] + .

[0292] Step 6: Synthesis of compound 6-2

[0293] By the same method as step 10 of Example 1, using compound 2g (10 mg, 0.04 mmol) and compound 1f (17 mg, 0.04 mmol) as raw materials, compound 6-2 (3.1 mg) was synthesized and purified.

[0294] 1H-NMR (400MHz, DMSO-d6) δ12.23(s,1H),10.08(s,1H),8.22(d,J=8.6Hz,1H),7.99(d,J=8.6 Hz,1H),7.23(s,1H),7.06(d,J=8.6Hz,1H),6.76(d,J=8.8Hz,1H),4.95(s,1H),4.67(dd,J=1 2.1,6.5Hz,1H),4.49(d,J=12.1Hz,1H),3.89(s,3H),3.76(t,J=6.5Hz,2H),3.73–3.68(m,1 H),3.54–3.46(m,1H),3.35–3.34(m,2H),3.03–2.88(m,4H),1.88–1.62(m,4H),0.30(s,4H).

[0295] MS m / z(ESI):588.2[M+H] + .

[0296] Example 3 Synthesis of Compound 6-3

[0297] Step 1: Synthesis of compound 3a

[0298] Compound 3a (760 mg) was synthesized and purified using the same method as in Step 5 of Example 1 using compound 1g (1.56 g, 7.07 mmol) and 2b hydrochloride (1.0 g, 6.43 mmol) as starting materials.

[0299] Step 2: Synthesis of compound 3b

[0300] Compound 3b (430 mg) was synthesized and purified using compound 3a (710 mg, 2.22 mmol) as starting material in the same manner as in step 6 of Example 1.

[0301] Step 3: Synthesis of compound 3c

[0302] Compound 3c (140 mg) was synthesized and purified using compound 3b (290 mg, 1.0 mmol) as starting material in the same manner as in step 7 of Example 1.

[0303] Step 4: Synthesis of compound 3d

[0304] Under nitrogen, lithium bistrimethylsilylamide (1 M, 2.10 mmol, 2.10 mL) was slowly added dropwise to a solution of compound 3c (120 mg, 421 μmol) in tetrahydrofuran (4 mL) at -70°C. The mixture was stirred at -78°C for 10 minutes. A solution of iodomethane (179 mg, 1.26 mmol) in tetrahydrofuran (1 mL) was added dropwise to the reaction solution, and the mixture continued to react at -78°C. The mixture was quenched by the addition of saturated ammonium chloride solution (10 mL), extracted with ethyl acetate (50 mL x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and purified by column chromatography to yield compound 3d (50 mg).

[0305] Step 5: Synthesis of compound 3e

[0306] Compound 3e (39 mg) was synthesized and purified using compound 3d (40 mg, 0.13 mmol) as starting material in the same manner as in step 8 of Example 1.

[0307] Step 6: Synthesis of compound 3f

[0308] Compound 3f (23 mg) was synthesized and purified using compound 3e (36 mg, 0.11 mmol) as starting material in the same manner as in step 9 of Example 1.

[0309] MS m / z(ESI):236.1[M+H] + .

[0310] Step 7: Synthesis of compound 6-3

[0311] By the same method as step 10 of Example 1, using compound 3f (21 mg, 0.1 mmol) and compound 1f (47 mg, 0.1 mmol) as raw materials, compound 6-3 (15 mg) was synthesized and purified.

[0312] 1H-NMR(400MHz,DMSO-d6)δ12.38(s,1H),8.39(dd,J=7.0,2.1Hz,1H),8.05–8.00(m,1 H),7.26(s,1H),7.23–7.15(m,2H),7.07(d,J=8.7Hz,1H),4.92(s,1H),4.55(dd,J=1 1.8,6.4Hz,1H),4.39(d,J=11.8Hz,1H),3.76(t,J=6.5Hz,2H),3.38–3.33(m,2H),3. 24(dd,J=12.7,6.2Hz,1H),3.07–2.92(m,4H),1.96–1.62(m,7H),0.37–0.25(m,4H).

[0313] MS m / z(ESI):572.2[M+H] + .

[0314] Synthesis of Compounds 6-4 and 6-5 in Example 4 and Example 5

[0315] Step 1: Synthesis of compound 4b

[0316] Compound 4b (342 mg) was synthesized and purified using the same method as in Step 5 of Example 1 using compound 1g (0.23 g, 1.05 mmol) and 4a hydrochloride (170 mg, 1.25 mmol) as starting materials.

[0317] Step 2: Synthesis of compound 4c

[0318] Compound 4c (249 mg) was synthesized and purified using compound 4b (300 mg, 1.0 mmol) as starting material in the same manner as in step 6 of Example 1.

[0319] Step 3: Synthesis of mixture 4d / 4e

[0320] By the same method as in Step 7 of Example 1, using compound 4c (245 mg, 0.91 mmol) as starting material, mixture 4d / 4e (191 mg) was synthesized and purified.

[0321] Step 4: Synthesis of mixture 4f / 4g

[0322] By the same method as in Step 8 of Example 1, using mixture 4d / 4e (160 mg, 0.6 mmol) as starting material, mixture 4f / 4g (269 mg) was synthesized and purified.

[0323] Step 5: Synthesis of mixture 4h / 4i

[0324] By the same method as in Step 9 of Example 1, using mixture 4f / 4g (250 mg, 0.83 mmol) as starting material, mixture 4h / 4i (67 mg) was synthesized and purified.

[0325] MS m / z(ESI):202.1[M+H] + .

[0326] Step 6: Synthesis of compound 6-4 / 6-5

[0327] By the same method as in step 10 of Example 1, mixture 4h / 4i (50 mg, 0.25 mmol) and compound 1f (141 mg, 0.3 mmol) were used as starting materials to synthesize and purify mixture 6-4 / 6-5, which was then purified by preparative purification (acetonitrile:water, 20-85%, 0.1% ammonia water) to obtain:

[0328] Compound 6-4 (4.3 mg)

[0329] 1 H-NMR (400MHz, DMSO-d6) δ12.25(s,1H),8.35(dd,J=7.3,1.7Hz,1H),8.01(d,J=8.6Hz,1H),7.24( d,J=2.2Hz,1H),7.19–7.10(m,2H),7.05(dd,J=8.6,2.1Hz,1H),4.23–4.16(m,1H),4.11–4.03(m, 1H),3.76(t,J=6.5Hz,2H),3.36–3.33(m,2H),3.24–3.18(m,1H),3.07–2.93(m,4H),2.89–2.80(m ,1H),2.36–2.31(m,1H),2.08–2.00(m,1H),1.93–1.59(m,5H),1.01(t,J=7.4Hz,3H),0.30(s,4H).

[0330] MS m / z(ESI):538.2[M+H] + .

[0331] Compound 6-5(2.8mg)

[0332] 1H-NMR (400MHz, DMSO-d6) δ12.32(s,1H),8.29(dd,J=6.9,2.1Hz,1H),8.00(d,J=8.5Hz,1H),7. 24(d,J=2.2Hz,1H),7.17–7.09(m,2H),7.06(dd,J=8.6,2.1Hz,1H),4.33(dd,J=10.3,7.8Hz,1 H),3.81–3.72(m,3H),3.35(t,J=6.5Hz,2H),3.16–3.09(m,1H),3.08–3.02(m,1H),3.02–2.93 (m,4H),2.69–2.62(m,1H),1.77(s,4H),1.69–1.62(m,2H),0.97(t,J=7.4Hz,3H),0.29(s,4H).

[0333] MS m / z(ESI):538.2[M+H] + .

[0334] Example 6 Synthesis of Compound 6-6

[0335] Step 1: Synthesis of compound 6c

[0336] Under nitrogen, sodium tert-butoxide (950 mg, 9.90 mmol) was added to a solution of compound 6a (1.00 g, 3.30 mmol), compound 6b (1.11 g, 9.90 mmol), and XPhos-Pd-G3 (276 mg, 330 μmol) in dioxane (5 mL), and the mixture was fully reacted at 80°C. After cooling, saturated ammonium chloride solution (10 mL) was added, and the mixture was extracted with ethyl acetate (60 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried and purified by flash column chromatography (petroleum ether:ethyl acetate = 100:0-90:10) to obtain compound 6c (320 mg).

[0337] Step 2: Synthesis of compound 6d

[0338] Hydroxylamine hydrochloride (187 mg, 2.69 mmol) was added to a solution of compound 6c (300 mg, 897 μmol) and sodium acetate (368 mg, 4.49 mmol) in methanol (5 mL). The mixture was stirred at room temperature for sufficient reaction. The reaction solution was poured into water (25 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and spin-dried to obtain crude compound 6d (310 mg).

[0339] Step 3: Synthesis of compound 6e

[0340] Methanesulfonyl chloride (305 mg, 2.66 mmol) was slowly added dropwise to a solution of compound 6d (310 mg, 887 μmol) and 2,4,6-trimethylpyridine (538 mg, 4.44 mmol) in dichloromethane (5 mL). The mixture was stirred at room temperature for sufficient reaction. The reaction solution was poured into water (50 mL) and extracted with dichloromethane (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and dried by spin drying. Compound 6e (180 mg, 61% yield) was isolated by column chromatography (petroleum ether:ethyl acetate = 100:0-95:5).

[0341] Step 4: Synthesis of compound 6f

[0342] Compound 6f (60 mg) was synthesized and purified using compound 6e (100 mg, 0.3 mmol) as starting material in the same manner as in step 9 of Example 1.

[0343] MS m / z(ESI):232.1[M+H] + .

[0344] Step 5: Synthesis of compound 6g

[0345] Compound 6g (26 mg) was synthesized and purified using the same method as in step 10 of Example 1 using compound 6f (46 mg, 0.2 mmol) and compound 1f (94 mg, 0.2 mmol) as starting materials.

[0346] Step 6: Synthesis of compound 6-6

[0347] Boron tribromide (1.30 g, 5.19 mmol) was added dropwise to a solution of compound 6g (21 mg, 37 μmol) in dichloromethane (2.5 mL), and the mixture was allowed to react fully at 50°C. After cooling, water (25 mL) was added to quench the mixture, and the mixture was extracted with dichloromethane (25 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried and purified using preparative purification (acetonitrile:water, 20-85%, 0.1% ammonia water) to obtain compound 6-6 (11 mg).

[0348] 1H-NMR (400MHz, DMSO-d6) δ12.65(s,1H),10.18(s,1H),10.06(s,1H),8.01(d,J=8. 6Hz,1H),7.59(d,J=8.1Hz,1H),7.27(d,J=2.1Hz,1H),7.08(dd,J=8.6,2.0Hz,1H), 6.39(d,J=8.2Hz,1H),4.95(s,1H),3.76(t,J=6.5Hz,2H),3.39–3.36(m,2H),3.13– 3.05(m,2H),3.03–2.91(m,6H),1.91–1.84(m,2H),1.84–1.53(m,8H),0.31(s,4H).

[0349] MS m / z(ESI):554.2[M+H] + .

[0350] Example 7 Synthesis of Compound 6-7

[0351] Step 1: Synthesis of compound 7b

[0352] Compound 7b (440 mg) was synthesized and purified using the same method as in Step 1 of Example 6 using compounds 7a (1.00 g, 3.25 mmol) and 6b (1.09 g, 9.75 mmol) as starting materials.

[0353] Step 2: Synthesis of compound 7c

[0354] Compound 7c (375 mg) was synthesized and purified using compound 7b (400 mg, 1.18 mmol) as starting material in the same manner as in step 2 of Example 6.

[0355] Step 3: Synthesis of compound 7d

[0356] Compound 7d (145 mg) was synthesized and purified using compound 7c (333 mg, 0.94 mmol) as starting material in the same manner as in step 3 of Example 6.

[0357] Step 4: Synthesis of compound 7e

[0358] Compound 7e (71 mg) was synthesized and purified using the same method as in Step 9 of Example 1 using compound 7d (135 mg, 0.4 mmol) as starting material.

[0359] MS m / z(ESI):236.1[M+H] + .

[0360] Step 5: Synthesis of compound 6-7

[0361] Compound 6-7 (31 mg) was synthesized and purified using the same method as in step 10 of Example 1, using compound 7e (47 mg, 0.2 mmol) and compound 1f (94 mg, 0.2 mmol) as starting materials.

[0362] 1 H-NMR (400MHz, DMSO-d6) δ12.97(s,1H),10.27(s,1H),8.03(d,J=8.6Hz,1H),7.79(d,J=8.3Hz,1H),7.33–7.27(m,2H),7.11(dd,J=8.6,2.1Hz,1H), 4.95(s,1H),3.76(t,J=6.4Hz,2H),3.37(t,J=6.5Hz,2H),3.23–3.15(m,2 H),3.07–2.94(m,6H),1.94–1.84(m,2H),1.84–1.52(m,8H),0.32(s,4H).

[0363] MS m / z(ESI):572.2[M+H] + .

[0364] Example 8 Synthesis of Compound 6-8

[0365] Step 1: Synthesis of compound 8b

[0366] Compound 8b (650 mg) was synthesized and purified using the same method as in Step 8 of Example 1 using compound 8a (2.0 g, 5.7 mmol) and 1i (0.7 g, 6.0 mmol) as starting materials.

[0367] Step 2: Synthesis of compound 8c

[0368] Compound 8c (77 mg) was synthesized and purified using the same method as in Step 1 of Example 6 using compounds 8b (0.64 g, 1.87 mmol) and 6b (0.37 g, 3.3 mmol) as starting materials.

[0369] Step 3: Synthesis of compound 8d

[0370] Compound 8d (67 mg) was synthesized and purified using compound 8c (75 mg, 0.2 mmol) as starting material in the same manner as in step 2 of Example 6.

[0371] Step 4: Synthesis of compound 8e

[0372] Compound 8e (49 mg) was synthesized and purified using compound 8d (62 mg, 0.16 mmol) as starting material in the same manner as in step 3 of Example 6.

[0373] Step 5: Synthesis of compound 8f

[0374] Compound 8f (29 mg) was synthesized and purified using compound 8e (41 mg, 0.11 mmol) as starting material in the same manner as in step 9 of Example 1.

[0375] MS m / z(ESI):270.1[M+H] + .

[0376] Step 6: Synthesis of Compound 6-8

[0377] Compound 6-8 (8.2 mg) was synthesized and purified using the same method as in step 10 of Example 1 using compound 8f (27 mg, 0.1 mmol) and compound 1f (47 mg, 0.1 mmol) as starting materials.

[0378] 1 H-NMR (400MHz, DMSO-d6) δ13.17(s,1H),8.03(d,J=8.7Hz,1H),7.91(d,J=8.2Hz,1H),7.72(d,J=8.3Hz,1H),7.28(d,J=2.1Hz,1H),7.09(dd,J=8. 6,2.1Hz,1H),3.76(t,J=6.4Hz,2H),3.39–3.36(m,2H),3.10–2.97(m,6H ),2.89–2.82(m,2H),1.93–1.85(m,2H),1.84–1.53(m,8H),0.32(s,4H).

[0379] MS m / z(ESI):606.2[M+H] + .

[0380] Synthesis of Compounds 6-9 and 6-10 in Examples 9 and 10

[0381] Step 1: Synthesis of mixture 9b / 9c

[0382] By the same method as in Step 1 of Example 6, using compounds 6a (1.8 g, 6.5 mmol) and 9a (1.0 g, 6.75 mmol) as starting materials, mixture 9b / 9c (1.9 g) was synthesized and purified.

[0383] Step 2: Synthesis of mixture 9d / 9e

[0384] By the same method as in Step 2 of Example 6, using mixture 9b / 9c (1.6 g, 4.7 mmol) as starting material, mixture 9d / 9e (1.6 g) was synthesized and purified.

[0385] Step 3: Synthesis of mixture 9f / 9g

[0386] By the same method as in step 3 of Example 6, mixture 9d / 9e (1.6 g, 4.5 mmol) was used as starting material to synthesize and purify mixture 9f / 9g (445 mg).

[0387] Step 4: Synthesis of mixture 9h / 9i

[0388] By the same method as in Step 9 of Example 1, using mixture 9f / 9g (380 mg, 1.13 mmol) as starting material, mixture 9h / 9i (117 mg) was synthesized and purified.

[0389] MS m / z(ESI):238.1[M+H] + .

[0390] Step 6: Synthesis of Compound 6-9 and Compound 6-10

[0391] By the same method as in step 10 of Example 1, mixture 9h / 9i (95 mg, 0.4 mmol) and compound 1f (230 mg, 0.5 mmol) were used as starting materials to synthesize and purify mixture 6-9 / 6-10, which was then preparatively purified (acetonitrile:water, 20-85%, 0.1% ammonia water) to obtain:

[0392] Compound 6-9 (15 mg)

[0393] 1 H NMR (400MHz, DMSO-d6) δ13.02 (s, 1H), 10.21 (s, 1H), 8.06 (d, J = 8.6Hz, 1H), 7.88 (dd,J=7.6,1.2Hz,1H),7.40–7.30(m,2H),7.25(dd,J=8.9,7.5Hz,1H),7.12(dd, J=8.6,2.1Hz,1H),4.94(s,1H),3.77(t,J=6.5Hz,2H),3.37(t,J=6.5Hz,2H),3. 10–2.96(m,6H),2.92–2.81(m,2H),2.30–2.12(m,4H),1.76(s,4H),0.33(s,4H).

[0394] MS m / z(ESI):574.1[M+H] + .

[0395] Compound 6-10 (8.0 mg)

[0396] 1 H NMR (400MHz, DMSO-d6) δ12.99(s,1H),10.23(s,1H),8.05(d,J=8.6Hz,1H),7.88(dd,J=7.6,1.2H z,1H),7.44(dd,J=8.9,1.2Hz,1H),7.31(d,J=2.2Hz,1H),7.26(dd,J=8.8,7.5Hz,1H),7.11(dd, J=8.6,2.1Hz,1H),4.93(s,1H),3.77(t,J=6.4Hz,2H),3.46(t,J=13.6Hz,2H),3.37(t,J=6.5Hz, 2H),3.13–3.04(m,2H),3.01(t,J=5.4Hz,4H),2.44–2.34(m,2H),1.94–1.60(m,6H),0.32(s,4H).

[0397] MS m / z(ESI):574.2[M+H] + .

[0398] Example 11 Synthesis of Compound 6-11

[0399] Step 1: Synthesis of compound 11b

[0400] To a solution of compound 11a (1.0 g, 4.42 mmol) in dichloromethane (10 mL) at 0°C was slowly added DAST (diethylaminosulfur trifluoride) (1.78 g, 11.1 mmol). The mixture was slowly allowed to warm to room temperature and stirred for sufficient reaction. Methanol (5 mL) was added to the reaction solution to quench the reaction. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 4:1) to afford compound 11b (0.90 g).

[0401] Step 2: Synthesis of compound 11c

[0402] To a solution of compound 11b (8.1 g, 32.7 mmol) in tetrahydrofuran (50 mL) at 0°C, sodium borohydride (3.7 g, 98 mmol) and boron trifluoride etherate (13.9 g, 98 mmol) were added. The mixture was allowed to react fully after returning to room temperature. The reaction solution was added to ice water (200 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 4:1) to afford compound 11c (5.60 g).

[0403] Step 3: Synthesis of compound 11d

[0404] To a solution of compound 11c (4.0 g, 18.7 mmol) in tetrahydrofuran (50 mL) at 0°C, sodium hydride (972 mg, 24.3 mmol, 60% dispersion in mineral oil) was added portionwise. The mixture was stirred at 0°C, followed by the addition of benzenesulfonyl chloride (3.30 g, 18.7 mmol). After returning to room temperature, stirring was continued for thorough reaction. The reaction solution was slowly poured into ice water (200 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to afford compound 11d (5.60 g).

[0405] Step 4: Synthesis of compound 11f

[0406] Under nitrogen, compound 11d (1.00 g, 2.82 mmol) and tetramethylethylenediamine (656 mg, 5.65 mmol) were added to tetrahydrofuran (15 mL). Lithium diisopropylamide (2 M, 1.69 mL) was added dropwise to the mixture at 0°C. The mixture was stirred at 0°C, and compound 11e (1.10 g, 3.39 mmol) was added to the system, and the reaction was continued at this temperature. The reaction solution was poured into saturated ammonium chloride solution (60 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and separated and purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain compound 11f (960 mg).

[0407] Step 5: Synthesis of compound 11g

[0408] Compound 11f (540 mg, 981 μmol) and sodium tert-butoxide (189 mg, 1.96 mmol) were added to dioxane (5 mL), and the mixture was reacted at 80°C for 4 h. The reaction solution was poured into water and extracted with ethyl acetate (100 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and isolated and purified by column chromatography (petroleum ether:ethyl acetate = 6:1) to obtain compound 11g (190 mg).

[0409] Step 6: Synthesis of compound 11h

[0410] By the same method as in Step 8 of Example 1, using compounds 11g (170 mg, 602 μmol) and 11 (282 mg, 2.41 mmol) as starting materials, a mixture 11h (50 mg) was synthesized and purified.

[0411] Step 7: Synthesis of compound 11i

[0412] By the same method as in Step 9 of Example 1, compound 11h (45 mg, 141 μmol) was used as starting material to synthesize and purify compound 11i (15 mg).

[0413] Step 8: Synthesis of Compound 6-11

[0414] By the same method as in step 10 of Example 1, using compounds 11i (10 mg, 46 μmol) and 1f (20 mg, 43 μmol) as starting materials, compound 6-11 (1.5 mg) was synthesized and purified.

[0415] 1 H NMR (400MHz, DMSO-d6) δ11.17(s,1H),9.92(s,1H),7.86(d,J=8.5Hz,1H),7.80(d,J=7.7Hz,1H) ,7.28(dd,J=8.5,2.3Hz,1H),7.17(d,J=2.1Hz,1H),7.10(t,J=8.1Hz,1H),7.03(dd,J=8.5,2.0 Hz,1H),4.96(s,1H),4.29–4.17(m,2H),3.77(t,J=6.5Hz,2H),3.40–3.35(m,2H),3.08–2.93(m ,4H),2.93–2.81(m,2H),1.86–1.76(m,2H),1.73–1.62(m,4H),1.49–1.38(m,4H),0.28(s,4H).

[0416] MS m / z(ESI):555.2[M+H] + .

[0417] Example 12 Synthesis of Compound 6-12

[0418] Compound 6-12 (3.6 mg) was synthesized and purified using compounds 12a and 6b as starting materials in the same manner as in Example 6.

[0419] MS m / z(ESI):554.2[M+H] + .

[0420] Example 14 Synthesis of Compound 6-14

[0421] Step 1: Synthesis of compound 14a

[0422] Compound 14a (127 mg) was synthesized and purified using the same method as in Step 1 of Example 6 using compounds 6a (300 mg, 1.10 mmol) and 14b (375 mg, 2.20 mmol) as starting materials.

[0423] Step 2: Synthesis of compound 14b

[0424] Compound 14b (133 mg) was synthesized and purified using compound 14a (127 mg, 352 μmol) as starting material in the same manner as in step 2 of Example 6.

[0425] Step 3: Synthesis of compound 14c

[0426] Compound 14c (45.4 mg) was synthesized and purified using compound 14b (133 mg, 352 μmol) as starting material in the same manner as in step 3 of Example 6.

[0427] Step 4: Synthesis of compound 14d

[0428] Compound 14d (14.6 mg) was synthesized and purified using compound 14c (45.5 mg, 126 μmol) as starting material in the same manner as in Step 9 of Example 1.

[0429] Step 5: Synthesis of compound 14e

[0430] By the same method as in Step 10 of Example 1, using compounds 14d (14.6 mg, 68 μmol) and 1f (32.1 mg, 68.0 μmol) as starting materials, compound 14e (22 mg) was synthesized and purified.

[0431] Step 6: Synthesis of compound 6-14

[0432] Compound 14e (22 mg, 40 μmol) was added to methanol (3 mL), and sodium borohydride (5.5 mg, 144 μmol) was added at 0°C. The mixture was allowed to react fully at 0°C. Hydrochloric acid (2 mL, 1N) was added to the system, and extraction was performed with ethyl acetate (1 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and dried to afford compound 6-14 (6.1 mg).

[0433] MS m / z(ESI):554.3[M+H] + .

[0434] Example 15 Synthesis of Compound 6-15

[0435] Step 1: Synthesis of compound 15a

[0436] Compound 15a (1.5 g) was synthesized and purified using the same method as in Step 1 of Example 6 using compounds 6a (2.7 g, 10 mmol) and 6b (1.35 g, 12 mmol) as starting materials.

[0437] Step 2: Synthesis of compound 15b

[0438] Compound 15b (1.5 g) was synthesized and purified using compound 15a (1.5 g, 5 mmol) as starting material in the same manner as in step 2 of Example 6.

[0439] Step 3: Synthesis of compound 15c

[0440] Compound 15c (0.6 g) was synthesized and purified using compound 15b (1.5 g, 4.7 mmol) as starting material in the same manner as in step 3 of Example 6.

[0441] Step 4: Synthesis of compound 15d

[0442] Compound 15c (100 mg, 332 μmol) was added to dichloromethane (4 mL) and n-hexane (1 mL). A dichloromethane solution of NBS (35.4 mg, 199 μmol) (5 mL) was added dropwise at -60°C, and the mixture was allowed to react fully at this temperature. Saturated aqueous sodium thiosulfate solution (10 mL) was added to the system, and the mixture was extracted with dichloromethane (5 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was spin-dried. Compound 15d (44 mg) was then purified by flash column chromatography (petroleum ether:ethyl acetate = 4:1) to afford compound 15d.

[0443] Step 5: Synthesis of compound 15e

[0444] Compound 15d (44 mg, 116 μmol), zinc cyanide (8.2 mg, 70 mmol), and bis(diphenylphosphino)ferrocene (6.42 mg, 11.6 μmol) were added to DMF (0.5 mL) and water (0.02 mL), followed by Pd2(dba)3 (5.30 mg, 5.8 μmol) and allowed to react at 120°C. After cooling, dilute ammonia solution (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 15e (27.2 mg) was obtained by purification via flash column chromatography (petroleum ether:ethyl acetate = 2:1).

[0445] Step 6: Synthesis of compound 15f

[0446] Compound 15f (11.8 mg) was synthesized and purified using compound 15e (27.2 mg, 83.4 μmol) as starting material in the same manner as in Step 9 of Example 1.

[0447] Step 7: Synthesis of compound 6-15

[0448] By the same method as in step 10 of Example 1, using compounds 15f (9.8 mg, 43 μmol) and 1f (20 mg, 43 μmol) as starting materials, compound 6-15 (6.9 mg) was synthesized and purified.

[0449] MS m / z(ESI):563.2[M+H] + .

[0450] Example 16 Synthesis of Compound 6-16

[0451] Step 1: Synthesis of compound 16a

[0452] Compound 6b (571 mg, 5.1 mmol) and DIPEA (713 mg, 5.5 mmol) were added to diethyl ether (10 mL). 9-Iodoborobicyclo[3.3.1]nonane (1 M in hexane, 5.50 mL, 5.50 mmol) was added dropwise at 0°C. The mixture was allowed to react at room temperature. A solution of trimethylsilyl cyanide (1.63 g, 5.99 mmol) in diethyl ether (10 mL) was then added. The mixture was allowed to react fully at room temperature. The reaction solution was filtered through silica gel and dried to give compound 16a (697 mg, crude product).

[0453] Step 2: Synthesis of compound 16b

[0454] Compound 16a (697 mg, 5.09 mmol) was added to hydrazine hydrate (5 mL) and anhydrous ethanol (15 mL) and reacted at 80° C. The reaction solution was concentrated and purified by flash column chromatography (acetonitrile:water = 0-50%) to give compound 16b (300 mg).

[0455] Step 3: Synthesis of compound 16d

[0456] Compounds 16b (50 mg, 331 μmol) and 16c (95 mg, 662 μmol) were added to anhydrous ethanol (1 mL), followed by the addition of hydrochloric acid (0.2 mL, 2N), and the mixture was allowed to react at 60°C. The reaction mixture was dried and purified by reverse-phase column chromatography (acetonitrile:water = 0-50%) to afford compound 16d (30.1 mg).

[0457] Step 4: Synthesis of compound 6-16

[0458] By the same method as in step 10 of Example 1, using compounds 16d (8.6 mg, 43 μmol) and 1f (20 mg, 43 μmol) as starting materials, compound 6-16 (6.3 mg) was synthesized and purified.

[0459] 1 H-NMR (400MHz, DMSO-d6) δ13.64(s,1H),8.36(d,J=2.7Hz,1H),8.34(s,1H),7.94(d,J=8.8Hz,1H),7.82(d,J=5.0Hz,1H),7.08(d,J=2.1Hz,1H),6.89 (d,8.7Hz,1H),3.74(t,J=6.6Hz,2H),3.12(t,J=6.6Hz,2H),3.09–2.94(m, 6H),2.90–2.82(m,2H),1.94–1.84(m,2H),1.84–1.63(m,6H),0.36(s,4H).

[0460] MS m / z(ESI):539.2[M+H] + .

[0461] Example 17 Synthesis of Compound 6-17

[0462] Step 1: Synthesis of compound 17b

[0463] By the same method as in step 3 of Example 16, using compounds 16b (50.0 mg, 331 μmol) and 17a (54.9 mg, 662 μmol) as starting materials, compound 17b (25.7 mg) was synthesized and purified.

[0464] Step 2: Synthesis of compound 6-17

[0465] By the same method as in step 10 of Example 1, using compounds 17b (9.2 mg, 43 μmol) and 1f (20 mg, 43 μmol) as starting materials, compound 6-17 (8.2 mg) was synthesized and purified.

[0466] 1 H-NMR (400MHz, DMSO-d6) δ13.39(s,1H),8.09(d,J=8.6Hz,1H),7.71(s,1H),7.35(s,1H),7.16(d,J=8.6Hz,1H),3.78(t,J= 6.4Hz,2H),3.02(t,J=5.5Hz,2H),3.02–2.94(m,6H),2.89–2.79(m,2H),1.92–1.82(m,2H),1.80–1.60(m,6H),0.36(s,4H).

[0467] MS m / z(ESI):553.3[M+H] + .

[0468] Example 18 Synthesis of Compound 6-18

[0469] Compound 6-18 (2.1 mg) was synthesized and purified using compound 9f as the starting material in the same manner as in Example 15.

[0470] 1 H NMR (400MHz, DMSO-d6) δ13.45(s,1H),8.07(d,J=8.7Hz,1H),8.00(d,J=8.2Hz,1H),7.97(d,J=8.2Hz,1H),7.34(d,J=2.1Hz,1H),7.14(dd,J=8.7, 2.1Hz,1H),3.76(t,J=6.4Hz,2H),3.38(t,J=6.4Hz,2H),3.16–3.06(m,4 H),3.06–2.96(m,4H),2.32–2.18(m,4H),1.85–1.64(m,4H),0.35(s,4H).

[0471] MS m / z(ESI):599.2[M+H] + .

[0472] Example 19 Synthesis of Compound 6-19

[0473] Compound 6-19 (3.5 mg) was synthesized and purified using compound 9a (5.00 g, 33.7 mmol) as starting material using the same method as Example 16.

[0474] 1 H NMR (400MHz, DMSO-d6) δ13.58 (s, 1H), 10.36 (s, 1H), 8.44 (d, J = 5.0Hz, 1H), 8.09 (d,J=8.8Hz,1H),7.86(d,J=5.0Hz,1H),7.35(s,1H),7.15(d,J=8.5Hz,1H),4.9 1(s,1H),3.77(t,J=6.4Hz,2H),3.38–3.36(m,2H),3.10–3.04(m,2H),3.04–2.9 4(m,4H),2.94–2.86(m,2H),2.29–2.13(m,4H),1.93–1.68(m,4H),0.36(s,4H).

[0475] MS m / z(ESI):575.2[M+H] + .

[0476] Example 20 Synthesis of Compound 6-20

[0477] Step 1: Synthesis of compound 20a

[0478] Compound 20a (0.80 g) was synthesized and purified using the same method as in Step 10 of Example 1 using compound 9h (400 mg, 1.69 mmol) and compound 1c (590 mg, 1.65 mmol) as starting materials.

[0479] Step 2: Synthesis of compound 6-20

[0480] Under nitrogen, compound 20a (100 mg, 173 μmol), methanesulfonamide 19b (21 mg, 225 μmol), (1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (25 mg, 173 μmol), cuprous iodide (17 mg, 87 μmol), and potassium phosphate (184 mg, 867 μmol) were added to DMF (2 mL). The mixture was allowed to react fully at 100°C. After cooling, it was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to dryness. It was then purified by reverse-phase column chromatography (acetonitrile:water = 30-95%) to afford compound 6-20 (60.1 mg).

[0481] 1H NMR (400MHz, DMSO-d6) δ13.02 (s, 1H), 10.28 (s, 1H), 8.07 (d, J = 8.6Hz, 1H), 7.8 9(dd,J=7.5,1.2Hz,1H),7.37(dd,J=8.9,1.2Hz,1H),7.30(d,J=2.2Hz,1H),7. 25(dd,J=8.9,7.5Hz,1H),7.12(dd,J=8.6,2.1Hz,1H),3.13(s,3H),3.09–2.98 (m,6H),2.90–2.83(m,2H),2.31–2.11(m,4H),1.91–1.62(m,4H),0.33(s,4H).

[0482] MS m / z(ESI):544.2[M+H] + .

[0483] Example 21 Synthesis of Compound 6-21

[0484] Compound 6-21 (51 mg) was synthesized and purified using the same method as in step 2 of Example 20 using compound 20a (100 mg, 173 μmol) and ethanesulfonamide 21a (25 mg, 225 μmol) as starting materials.

[0485] 1 H NMR (400MHz, DMSO-d6) δ13.01(s,1H),10.27(s,1H),8.04(d,J=8.6Hz,1H),7.88(dd,J =7.5,1.2Hz,1H),7.37(dd,J=8.7,1.2Hz,1H),7.31(d,J=2.2Hz,1H),7.25(dd,J=8.8,7 .5Hz,1H),7.11(dd,J=8.6,2.1Hz,1H),3.22(q,J=7.3Hz,2H),3.12–2.96(m,6H),2.90– 2.82(m,2H),2.30–2.11(m,4H),1.85–1.64(m,4H),1.21(t,J=7.3Hz,3H),0.33(s,4H).

[0486] MS m / z(ESI):558.2[M+H] + .

[0487] Example 22 Synthesis of Compound 6-22

[0488] Compound 6-22 (8.5 mg) was synthesized and purified using the same method as Example 17 using compound 19b (100 mg, 535 μmol) and 17a (83 mg, 1.0 mmol) as starting materials.

[0489] MS m / z(ESI):589.2[M+H] + .

[0490] Example 23 Synthesis of Compound 6-23

[0491] Compound 6-9 (28 mg, 50 μmol) and triethylamine (15 mg, 150 μmol) were dissolved in dichloromethane (1 mL), and methanesulfonic anhydride (17 mg, 100 μmol) was added dropwise. The mixture was fully reacted at room temperature, and the volatiles were removed under reduced pressure. The residue was purified by reverse column chromatography (acetonitrile: water = 45-99%) to give compound 6-23 (9 mg).

[0492] MS m / z(ESI):556.2[M+H] + .

[0493] Biological activity evaluation

[0494] Test Example 1: KIF18A enzyme activity assay

[0495] Based on ADP-Glo TM Kinase Assay: Detect the amount of ADP generated in the reaction to reflect KIF18A enzyme activity.

[0496] 1. Experimental instruments and materials

[0497] 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).

[0498] 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.

[0499] Other reagents and consumables required for the experiment are as follows

[0500] 2. Experimental steps

[0501] 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 the gradient dilution sample concentration 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 taken as [RLU]background), and 1 column of wells with enzyme but no compound (chemiluminescence value is taken as [RLU]enzyme). The chemiluminescence value of the drug-added group is [RLU]cpd. 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%, and the inhibitory activity IC of the compound on enzyme activity is 2. 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.

[0502] Table 1: KIF18A inhibitory activity of the disclosed compounds In the above table, “++++” indicates the IC value of the enzyme inhibitory activity of the tested compound. 50The range is <200nM; “+++” indicates the IC value of the enzyme inhibitory activity of the tested compound. 50 The range is 200~500nM.

[0503] Test Example 2: Proliferation inhibition test of the disclosed compounds on OVCAR-3 cells

[0504] 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), Cell-Titer Glo reagent (Promega#G7568) was purchased from Promega (USA); Echo was purchased from PerkinElmer.

[0505] 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.

[0506] 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. Starting at 30 μM, the sample was serially diluted three-fold for a total of 11 concentration points. The volume of compound or DMSO added was 100 nL.

[0507] OVCAR3 cells were digested and resuspended in RPMI 1640 complete medium. The cells were plated in 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).

[0508] 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.

[0509] Data Analysis:

[0510] 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 .

[0511] Inhibition percentage: %Inhibition=(1-(Signal-Bottom) / (Top-Bottom))×100%.

[0512] Signal: Cell-Titer Glo reading of the wells with added compounds;

[0513] Bottom: Cell-Titer Glo reading of negative control well;

[0514] Top: Cell-Titer Glo readings of positive control wells.

[0515] Experimental results:

[0516] The inhibitory activity of the disclosed compounds on OVCAR3 proliferation is shown in Table 2.

[0517] Table 2: Inhibitory activity of the disclosed compounds on OVCAR3 proliferation In the above table, “++++” indicates the IC value of the tested compound for the inhibition of OVCAR3 proliferation. 50 The range is <200nM.

[0518] Test Example 3: Inhibition test of the disclosed compounds on CYP enzymes

[0519] The metabolic reactions of representative substrates of the five major human CYP isoforms (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 / 5) were evaluated using 150 pooled human liver microsomes (Corning, Cat. No. 452117). The effects of varying 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).

[0520] 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.

[0521] Peak areas were calculated from the chromatograms.

[0522] The residual activity ratio (%) was calculated using the following formula:

[0523] Peak area ratio = metabolite peak area / internal standard peak area

[0524] Residual activity ratio (%) = peak area ratio of the test compound group / peak area ratio of the blank group

[0525] CYP half-maximal inhibitory concentration (IC 50 ) was calculated using Excel XLfit 5.3.1.3.

[0526] The test results show that the disclosed compounds have no significant inhibitory effect on multiple CYP subtypes, and are expected to have good drug safety and low drug-drug interactions.

[0527] Test Example 4: Caco-2 permeability test

[0528] 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 ).

[0529] 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 200 PRO microplate reader was purchased from Tecan, and MTS2 / 4 orbital shaker was purchased from IKA Labortechnik.

[0530] First step: cell culture and plating

[0531] 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 / cm 2 Begin medium changes 24 hours after inoculation and continue culturing for 14-18 days, changing the medium every other day. To change the medium, 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.

[0532] Step 2: Evaluation of cell monolayer integrity

[0533] 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.

[0534] Step 3 Solution preparation

[0535] 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).

[0536] 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.

[0537] Step 4: Drug penetration test

[0538] 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.

[0539] 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.

[0540] 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.

[0541] Combine the upper and lower transport devices and incubate at 37°C for 2 hours.

[0542] 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.

[0543] 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 the 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.

[0544] Step 5: Data Analysis

[0545] All calculations were performed using Microsoft Excel. Peak areas were determined using extracted ion chromatograms.

[0546] Apparent permeability coefficient (P app , unit: cm / s×10 -6 ) is calculated using the following formula:

[0547] 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.

[0548] The efflux ratio is calculated using the following formula:

[0549] In the formula: P app(B-A) is the apparent permeability from the base end to the top end;

[0550] P app(A-B) is the apparent permeability from the top to the base.

[0551] The recovery rate (%) was calculated using the following formula:

[0552] In the formula: V A is the volume of the solution at the receiving end (unit: mL); V D is the volume of the solution at the administration end (unit: mL).

[0553] The leakage rate (Percentage leakage (%) or LY (%)) is calculated using the following formula:

[0554] 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 dosing hole

[0555] The fluorescence density of (0.1mL) is expressed as LY (%). LY < 1.5% indicates that the monolayer 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.

[0556] The test results show that the disclosed compound exhibits relatively excellent in vitro membrane permeability and is expected to have good oral absorption capacity.

[0557] Test Example 5: Pharmacokinetics of the compounds disclosed in this invention in rats

[0558] SD rats were used as test animals, and the drug concentrations in the plasma of the disclosed compounds at different time points after intravenous and oral administration were determined by LC / MS / MS. The pharmacokinetic behavior of the disclosed compounds in rats was studied and their pharmacokinetic characteristics were evaluated.

[0559] Each group consisted of 3 healthy 6-8 week old male SD rats.

[0560] 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;

[0561] 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.

[0562] After overnight fasting, SD rats were intravenously injected (dose: 1 mg / kg) or orally administered (dose: 5 mg / kg).

[0563] Rats were intravenously administered with the compound of the present application. 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.

[0564] Alternatively, rats were orally administered with the compound of the present application, 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 the plasma was separated by centrifugation at 3500 rpm for 10 minutes at 4°C and stored at -75°C.

[0565] 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.

[0566] The test results show that the compounds disclosed herein exhibit excellent pharmacokinetic properties, including lower apparent clearance, longer half-life and higher plasma exposure.

Claims

1. A compound of formula (II) or a pharmaceutically acceptable salt thereof: In formula (II): A is a monocyclic or bicyclic ring selected from 4- to 10-membered carbocyclic or 4- to 10-membered heterocyclic rings, said 4- to 10-membered carbocyclic or 4- to 10-membered heterocyclic rings being optionally substituted by one or more R b substituents, each R b independently being selected from halogen, OH, C1-C6 alkyl, O(C1-C4 alkyl), NH2, NH(C1-C4 alkyl) or N(C1-C4 alkyl)2, said C1-C6 alkyl being optionally substituted by one or more groups independently selected from halogen, cyano, OH, NH2 or O(C1-C4 alkyl); X1, X2, X3, X4 and X5 are each independently CR a or nitrogen; wherein R a is independently selected from absent, H or halogen; R 1 is absent, H, C1-C6 alkyl, cyano, C1-C6 alkoxy, (CH2) r -C(O)R d , halogen, OH, (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, where r is 0, 1, 2 or 3, said 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 by one or more groups independently selected from halogen, CN, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic group, O(C1-C4 alkyl), NH(C1-C4 alkyl) or N(C1-C4 alkyl)2; R 2 is H, OH, C1-C6 alkyl, cyano, C1-C6 alkoxy, C(O)R d , halogen, C1-C6 haloalkyl or C1-C6 haloalkoxy; R d selected from OH, C1-C6 alkyl, O(C1-C4 alkyl), NH2, NH(C1-C4 alkyl) or N(C1-C4 alkyl)2; and R 3 selected from C1-C6 alkyl or C2-C6 alkenyl, said C1-C6 alkyl optionally being substituted by one or more halogens or OH.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: R 1 is absent, H, C1-C6 alkyl, cyano, C1-C6 alkoxy, OH, halogen, (CH2) r -C3-C 10 cycloalkyl, (CH2) r -C5-C 10 cycloalkenyl, (CH2) r -4- to 10-membered heterocyclic group, (CH2) r -C6-C 10 aryl or (CH2) r -5- to 10-membered heteroaryl, where r is 0, 1, 2 or 3, and the C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 cycloalkyl, C5-C 10 cycloalkenyl, 4- to 10-membered heterocyclic group, C6-C 10 aryl or 5- to 10-membered heteroaryl is optionally substituted by one or more groups independently selected from halogen, CN, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 4- to 7-membered heterocyclic group, O(C1-C4 alkyl), NH(C1-C4 alkyl) or N(C1-C4 alkyl)2; and R 3 selected from C1-C6 alkyl, where the C1-C6 alkyl is optionally substituted by one or more halogens or OH; The compound represented by the formula (II) does not include the following compounds:

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein, both X2 and X5 are N.

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein, The compound represented by formula (II) or a pharmaceutically acceptable salt thereof is selected from the compound represented by formula (III’) or a pharmaceutically acceptable salt thereof:

5. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein X1 is C or N, X2 is N, and X3 is C.

6. The compound according to any one of claims 1-5 or a pharmaceutically acceptable salt thereof, wherein, The compound does not include the following compounds:

7. The compound according to any one of claims 1-6 or a pharmaceutically acceptable salt thereof, wherein, The R 1 is absent, H, OH, C1-C6 alkyl, halogen, cyano, C1-C6 alkoxy, 5-10 membered heteroaryl or C(O)R d , the C1-C6 alkyl is optionally substituted by one or more halogens, the 5-10 membered heteroaryl is optionally substituted by one or more C1-C6 alkyls; or The R 1 is absent, H, OH, C1-C6 alkyl, halogen, cyano, C1-C6 alkoxy or 5-10 membered heteroaryl, the C1-C6 alkyl is optionally substituted with one or more halogens, and the 5-10 membered heteroaryl is optionally substituted with one or more C1-C6 alkyls; or The R 1 is absent, H, OH, C1-C6 alkyl, halogen, cyano, or C1-C6 alkoxy, wherein the C1-C6 alkyl is optionally substituted by one or more halogens; or R 1 is absent, H, OH, methoxy, halogen, CN, CF3 or Or Said R 1 is absent, H, OH, methoxy, halogen, CN or CF3.

8. The compound according to any one of claims 1-7 or a pharmaceutically acceptable salt thereof, wherein, The R 2 is H, OH, C1-C6 alkyl, cyano, C1-C6 alkoxy or C(O)R d ; or The R 2 is H, OH, C1-C6 alkyl, cyano or C1-C6 alkoxy; or The R 2 is H, OH, C1-C4 alkyl group.

9. The compound according to any one of claims 1-8 or a pharmaceutically acceptable salt thereof, wherein, The R 3 is selected from C1-C4 alkyl or C2-C3 alkenyl, and the C1-C4 alkyl is optionally substituted by one or more halogens or OH; or Said R 3 Selected from C1-C4 alkyl optionally substituted by one or more OH; or The said R 3 is selected from methyl, ethyl, vinyl or Or The said R 3 is selected from methyl, ethyl or 10. The compound according to any one of claims 1-9 or a pharmaceutically acceptable salt thereof, wherein, A is a monocyclic or bicyclic ring selected from 4- to 10-membered carbocycles or 4- to 10-membered heterocycles, and the 4- to 10-membered carbocycle or 4- to 10-membered heterocycle is optionally substituted with one or more R b substituents, and each R b is independently selected from OH, F or C1-C4 alkyl, and the C1-C4 alkyl is optionally substituted with one or more groups independently selected from F or O(C1-C4 alkyl).

11. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from one of the following structures:

12. A pharmaceutical composition comprising the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

13. Use of the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 12, in the preparation of a medicament for preventing or treating KIF18A-related diseases.

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