Compound as PKMYT1 inhibitor and preparation method and application thereof

Abstract

The invention relates to the field of medicinal chemistry, in particular to a compound used as a PKMYT1 inhibitor or pharmaceutically acceptable salt, a preparation method of the compound, a pharmaceutical composition and application of the compound or the pharmaceutically acceptable salt to treatment of PKMYT1 related diseases.

Description

Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and in particular to a class of compounds or pharmaceutically acceptable salts used as PKMYT1 inhibitors, preparation methods and pharmaceutical compositions thereof, and use thereof in treating PKMYT1-related diseases. Background Art

[0002] Protein kinase, membrane associated tyrosine / threonine 1 (PKMYT1) belongs to the WEE family of serine / threonine kinases. PKMYT1 can specifically regulate the activity of cyclin-dependent kinase 1 (CDK1) by phosphorylating CDK1, thereby regulating the transition from G2 to M phase of the cell cycle. PKMYT1 is not essential for checkpoint-triggered cell cycle arrest after DNA damage in normal cells. Depletion of PKMYT1 with siRNA alone does not affect long-term cell growth, but PKMYT1 plays a more important role in cells with genomic instability or in the presence of replication stress or other impaired cell cycle checkpoint regulation.

[0003] CCNE1 gene amplification is a common tumor driver mutation that occurs in a variety of malignant tumors, including ovarian cancer, breast cancer, gastric cancer, and lung cancer. Cyclin E1, encoded by CCNE1, binds to and activates CDK2, promoting the transition from the G1 phase to the S phase of the cell cycle. Overexpression of Cyclin E impairs G1 / S checkpoint regulation, causing cells to enter the S phase prematurely, increasing DNA replication pressure, and leading to genomic instability. Compared with normal cells, cells with CCNE1 amplification are more dependent on the regulation of other cell cycle checkpoints and the integrity of DNA repair mechanisms.

[0004] PKMYT1 kinase inhibition and CCNE1 amplification are synthetically lethal.

[0005] WEE1, which is in the same family as PKMYT1, can also regulate the activity of CDK1 by phosphorylating it, thereby regulating the G1 / S checkpoint. PKMYT1 inhibitors and WEE1 inhibitors can target the DNA damage response (DDR) in cancer, inhibit DNA damage repair in tumor cells, and promote their apoptosis. Currently, multiple WEE1 inhibitors are being developed for the treatment of tumors. Studies have shown that compared with WEE1, PKMYT1 inhibition has less effect on normal cells, so PKMYT1 inhibitors are safer. Finding PKMYT1 inhibitors is considered a promising approach to developing new anticancer agents. Summary of the invention

[0006] In one aspect, a compound of formula (I) is provided:

[0007]

[0008] or a pharmaceutically acceptable salt thereof,

[0009] in,

[0010] Ring A is selected from benzene ring, C 5-6 Hydrocarbon rings, 5-6 membered heterocyclic rings and 5-6 membered heteroaromatic rings;

[0011] W is selected from N and CR 1 ;

[0012] R 1 Selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclyl, CN, NO2, aryl, -C 1-4 Alkylene-aryl, heteroaryl, -C 1-4 Alkylene-heteroaryl, -NR A1 R B1 、-OR A1 、-SR A1 、-C(=O)R A1 、-C(=NR E1 )R A1 、-C(=N-OR B1 )R A1 、-C(=O)OR A1 、-OC(=O)R A1 、-C(=O)NR A1 R B1 、-NR A1 C(=O)R B1 、-C(=NR E1 )NR A1 R B1 、-NR A1 C(=NR E1 )R B1 、-OC(=O)NR A1 R B1 、-NR A1 C(=O)OR B1 、-NR A1 C(=O)NR A1 R B1 、-NR A1 C(=S)NR A1 R B1 、-NRA1 C(=NR E1 )NR A1 R B1 、-S(=O) r R A1 、-S(=O)(=NR E1 )R B1 、-N=S(=O)R A1 R B1 、-S(=O)2OR A1 、-OS(=O)2R A1 、-NR A1 S(=O) r R B1 、-NR A1 S(=O)(=NR E1 )R B1 、-S(=O) r NR A1 R B1 、-S(=O)(=NR E1 )NR A1 R B1 、-NR A1 S(=O)2NR A1 R B1 and-NR A1 S(=O)(=NR E1 )NR A1 R B1 , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R X1 Substituents are substituted;

[0013] R 2 Selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclyl, CN, NO2, aryl, -C 1-4 Alkylene-aryl, heteroaryl, -C 1-4 Alkylene-heteroaryl, -NR A2 R B2 、-OR A2 、-SR A2 、-C(=O)R A2 、-C(=NR E2 )R A2 、-C(=N-OR B2 )RA2 、-C(=O)OR A2 、-OC(=O)R A2 、-C(=O)NR A2 R B2 、-NR A2 C(=O)R B2 、-C(=NR E2 )NR A2 R B2 、-NR A2 C(=NR E2 )R B2 、-OC(=O)NR A2 R B2 、-NR A2 C(=O)OR B2 、-NR A2 C(=O)NR A2 R B2 、-NR A2 C(=S)NR A2 R B2 、-NR A2 C(=NR E2 )NR A2 R B2 、-S(=O) r R A2 、-S(=O)(=NR E2 )R B2 、-N=S(=O)R A2 R B2 、-S(=O)2OR A2 、-OS(=O)2R A2 、-NR A2 S(=O) r R B2 、-NR A2 S(=O)(=NR E2 )R B2 、-S(=O) r NR A2 R B2 、-S(=O)(=NR E2 )NR A2 R B2 、-NR A2 S(=O)2NR A2 R B2 and-NR A2 S(=O)(=NR E2 )NR A2 R B2 , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from RX2 Substituents are substituted;

[0014] R 3 Selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclyl, CN, NO2, aryl, -C 1-4 Alkylene-aryl, heteroaryl, -C 1-4 Alkylene-heteroaryl, -NR A3 R B3 、-OR A3 、-SR A3 、-C(=O)R A3 、-C(=NR E3 )R A3 、-C(=N-OR B3 )R A3 、-C(=O)OR A3 、-OC(=O)R A3 、-C(=O)NR A3 R B3 、-NR A3 C(=O)R B3 、-C(=NR E3 )NR A3 R B3 、-NR A3 C(=NR E3 )R B3 、-OC(=O)NR A3 R B3 、-NR A3 C(=O)OR B3 、-NR A3 C(=O)NR A3 R B3 、-NR A3 C(=S)NR A3 R B3 、-NR A3 C(=NR E3 )NR A3 R B3 、-S(=O) r R A3 、-S(=O)(=NR E3 )R B3 、-N=S(=O)R A3 R B3 、-S(=O)2ORA3 、-OS(=O)2R A3 、-NR A3 S(=O) r R B3 、-NR A3 S(=O)(=NR E3 )R B3 、-S(=O) r NR A3 R B3 、-S(=O)(=NR E3 )NR A3 R B3 、-NR A3 S(=O)2NR A3 R B3 and-NR A3 S(=O)(=NR E3 )NR A3 R B3 , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R X3 Substituents are substituted;

[0015] Each R 4 Independently selected from halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cyclic hydrocarbon group, heterocyclic group, -C 1-4 Alkylene-heterocyclyl, CN, NO2, aryl, -C 1-4 Alkylene-aryl, heteroaryl, -C 1-4 Alkylene-heteroaryl, -NR A4 R B4 、-OR A4 、-SR A4 、-C(=O)R A4 、-C(=NR E4 )R A4 、-C(=N-OR B4 )R A4 、-C(=O)OR A4 、-OC(=O)R A4 、-C(=O)NR A4 R B4 、-NR A4 C(=O)R B4 、-C(=NR E4 )NR A4 R B4 、-NRA4 C(=NR E4 )R B4 、-OC(=O)NR A4 R B4 、-NR A4 C(=O)OR B4 、-NR A4 C(=O)NR A4 R B4 、-NR A4 C(=S)NR A4 R B4 、-NR A4 C(=NR E4 )NR A4 R B4 、-S(=O) r R A4 、-S(=O)(=NR E4 )R B4 、-N=S(=O)R A4 R B4 、-S(=O)2OR A4 、-OS(=O)2R A4 、-NR A4 S(=O) r R B4 、-NR A4 S(=O)(=NR E4 )R B4 、-S(=O) r NR A4 R B4 、-S(=O)(=NR E4 )NR A4 R B4 、-NR A4 S(=O)2NR A4 R B4 and-NR A4 S(=O)(=NR E4 )NR A4 R B4 , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R X4 Substituents are substituted;

[0016] Or any two adjacent R 4 Together with the atoms to which they are attached, they form a C 3-10 A monocyclic hydrocarbon ring or a 4-12 membered heterocyclic ring containing 1, 2 or 3 heteroatoms or a 5-10 membered heteroaromatic ring containing 1, 2 or 3 heteroatoms, wherein the heteroatoms are independently selected from oxygen, sulfur, nitrogen and phosphorus, and the ring is unsubstituted or substituted by at least one independently selected from RX4 Substituents are substituted;

[0017] R 5 Selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclyl, CN, NO2, aryl, -C 1-4 Alkylene-aryl, heteroaryl, -C 1-4 Alkylene-heteroaryl, -NR A5 R B5 、-OR A5 、-SR A5 、-C(=O)R A5 、-C(=NR E5 )R A5 、-C(=N-OR B5 )R A5 、-C(=O)OR A5 、-OC(=O)R A5 、-C(=O)NR A5 R B5 、-NR A5 C(=O)R B5 、-C(=NR E5 )NR A5 R B5 、-NR A5 C(=NR E5 )R B5 、-OC(=O)NR A5 R B5 、-NR A5 C(=O)OR B5 、-NR A5 C(=O)NR A5 R B5 、-NR A5 C(=S)NR A5 R B5 、-NR A5 C(=NR E5 )NR A5 R B5 、-S(=O) r R A5 、-S(=O)(=NR E5 )R B5 、-N=S(=O)R A5 R B5 、-S(=O)2ORA5 、-OS(=O)2R A5 、-NR A5 S(=O) r R B5 、-NR A5 S(=O)(=NR E5 )R B5 、-S(=O) r NR A5 R B5 、-S(=O)(=NR E5 )NR A5 R B5 、-NR A5 S(=O)2NR A5 R B5 and-NR A5 S(=O)(=NR E5 )NR A5 R B5 , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R X5 Substituents are substituted;

[0018] R 6 Selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclyl, CN, NO2, aryl, -C 1-4 Alkylene-aryl, heteroaryl, -C 1-4 Alkylene-heteroaryl, -NR A6 R B6 、-OR A6 、-SR A6 、-C(=O)R A6 、-C(=NR E6 )R A6 、-C(=N-OR B6 )R A6 、-C(=O)OR A6 、-OC(=O)R A6 、-C(=O)NR A6 R B6 、-NR A6 C(=O)R B6 、-C(=NR E6 )NR A6 R B6 、-NRA6 C(=NR E6 )R B6 、-OC(=O)NR A6 R B6 、-NR A6 C(=O)OR B6 、-NR A6 C(=O)NR A6 R B6 、-NR A6 C(=S)NR A6 R B6 、-NR A6 C(=NR E6 )NR A6 R B6 、-S(=O) r R A6 、-S(=O)(=NR E6 )R B6 、-N=S(=O)R A6 R B6 、-S(=O)2OR A6 、-OS(=O)2R A6 、-NR A6 S(=O) r R B6 、-NR A6 S(=O)(=NR E6 )R B6 、-S(=O) r NR A6 R B6 、-S(=O)(=NR E6 )NR A6 R B6 、-NR A6 S(=O)2NR A6 R B6 and-NR A6 S(=O)(=NR E6 )NR A6 R B6 , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R X6 Substituents are substituted;

[0019] R 7 Selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C1-4 Alkylene-heterocyclyl, CN, NO2, aryl, -C 1-4 Alkylene-aryl, heteroaryl, -C 1-4 Alkylene-heteroaryl, -NR A7 R B7 、-OR A7 、-SR A7 、-C(=O)R A7 、-C(=NR E7 )R A7 、-C(=N-OR B7 )R A7 、-C(=O)OR A7 、-OC(=O)R A7 、-C(=O)NR A7 R B7 、-NR A7 C(=O)R B7 、-C(=NR E7 )NR A7 R B7 、-NR A7 C(=NR E7 )R B7 、-OC(=O)NR A7 R B7 、-NR A7 C(=O)OR B7 、-NR A7 C(=O)NR A7 R B7 、-NR A7 C(=S)NR A7 R B7 、-NR A7 C(=NR E7 )NR A7 R B7 、-S(=O) r R A7 、-S(=O)(=NR E7 )R B7 、-N=S(=O)R A7 R B7 、-S(=O)2OR A7 、-OS(=O)2R A7 、-NR A7 S(=O) r R B7 、-NR A7 S(=O)(=NR E7 )R B7 、-S(=O) r NR A7 R B7、-S(=O)(=NR E7 )NR A7 R B7 、-NR A7 S(=O)2NR A7 R B7 and-NR A7 S(=O)(=NR E7 )NR A7 R B7 , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R X7 Substituents are substituted;

[0020] R 8 Selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclyl, CN, NO2, aryl, -C 1-4 Alkylene-aryl, heteroaryl, -C 1-4 Alkylene-heteroaryl, -NR A8 R B8 、-OR A8 、-SR A8 、-C(=O)R A8 、-C(=NR E8 )R A8 、-C(=N-OR B8 )R A8 、-C(=O)OR A8 、-OC(=O)R A8 、-C(=O)NR A8 R B8 、-NR A8 C(=O)R B8 、-C(=NR E8 )NR A8 R B8 、-NR A8 C(=NR E8 )R B8 、-OC(=O)NR A8 R B8 、-NR A8 C(=O)OR B8 、-NR A8 C(=O)NR A8 R B8 、-NR A8C(=S)NR A8 R B8 、-NR A8 C(=NR E8 )NR A8 R B8 、-S(=O) r R A8 、-S(=O)(=NR E8 )R B8 、-N=S(=O)R A8 R B8 、-S(=O)2OR A8 、-OS(=O)2R A8 、-NR A8 S(=O) r R B8 、-NR A8 S(=O)(=NR E8 )R B8 、-S(=O) r NR A8 R B8 、-S(=O)(=NR E8 )NR A8 R B8 、-NR A8 S(=O)2NR A8 R B8 and-NR A8 S(=O)(=NR E8 )NR A8 R B8 , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R X8 Substituents are substituted;

[0021] R 9 Selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclyl, CN, NO2, aryl, -C 1-4 Alkylene-aryl, heteroaryl, -C 1-4 Alkylene-heteroaryl, -NR A9 R B9 、-OR A9 、-SR A9 、-C(=O)R A9 、-C(=NR E9 )RA9 , -C(=N-OR B9 )R A9 , -C(=O)OR A9 , -OC(=O)R A9 , -C(=O)NR A9 R B9 , -NR A9 C(=O)R B9 , -C(=NR E9 )NR A9 R B9 , -NR A9 C(=NR E9 )R B9 , -OC(=O)NR A9 R B9 , -NR A9 C(=O)OR B9 , -NR A9 C(=O)NR A9 R B9 , -NR A9 C(=S)NR A9 R B9 , -NR A9 C(=NR E9 )NR A9 R B9 , -S(=O) r R A9 , -S(=O)(=NR E9 )R B9 , -N=S(=O)R A9 R B9 , -S(=O)2OR A9 , -OS(=O)2R A9 , -NR A9 S(=O) r R B9 , -NR A9 S(=O)(=NR E9 )R B9 , -S(=O) r NR A9 R B9 , -S(=O)(=NR E9 )NR A9 R B9 , -NR A9 S(=O)2NR A9 R B9 and -NR A9 S(=O)(=NR E9 )NR A9 R B9, wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R X9 Substituents are substituted;

[0022] or R 8 and R 9 Together with the atoms to which they are attached, they form a 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring containing 1, 2 or 3 heteroatoms, wherein the heteroatoms are independently selected from oxygen, sulfur and nitrogen, and the ring is unsubstituted or substituted by at least one independently selected from R X8 Substituents are substituted;

[0023] Each R A1 , R A2 , R A3 , R A4 , R A5 , R A6 , R A7 , R A8 , R A9 , R B1 , R B2 , R B3 , R B4 , R B5 , R B6 , R B7 , R B8 and R B9 independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclyl, aryl, -C 1-4 Alkylene-aryl, heteroaryl and -C 1-4 Alkylene-heteroaryl, wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R X Substituents are substituted;

[0024] or "R A1 and R B1 ” or “R A2 and R B2 ” or “R A3 and R B3 ” or “R A4 and R B4 ” or “R A5 and R B5 ” or “R A6 and R B6 ” or “RA7 and R B7 ” or “R A8 and R B8 ” or “R A9 and R B9 "together with the atoms or atoms to which they are attached, they form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, which ring is unsubstituted or substituted with 1, 2 or 3 atoms selected from R X Substituents are substituted;

[0025] Each R E1 , R E2 , R E3 , R E4 , R E5 , R E6 , R E7 , R E8 and R E9 independently selected from hydrogen, C 1-10 Alkyl, CN, NO2, -S(=O) r R a1 、-C(=O)R a1 、-C(=O)OR a1 、-C(=O)NR a1 R b1 and -S(=O) r NR a1 R b1 , wherein the alkyl group is unsubstituted or substituted with at least one independently selected from R X Substituents are substituted;

[0026] Each R X , R X1 , R X2 , R X3 , R X4 , R X5 , R X6 , R X7 , R X8 and R X9 Independently selected from halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclyl, aryl, -C 1-4 Alkylene-aryl, heteroaryl, -C 1-4 Alkylene-heteroaryl, CN, NO2, -(CR c1 R d1 )t NR a1 R b1 、-(CR c1 R d1 ) t OR b1 、-(CR c1 R d1 ) t C(=O)R a1 、-(CR c1 R d1 ) t C(=NR e1 )R a1 、-(CR c1 R d1 ) t C(=O)OR b1 、-(CR c1 R d1 ) t OC(=O)R b1 、-(CR c1 R d1 ) t C(=O)NR a1 R b1 、-(CR c1 R d1 ) t NR a1 C(=O)R b1 、-(CR c1 R d1 ) t C(=NR e1 )NR a1 R b1 、-(CR c1 R d1 ) t NR a1 C(=NR e1 )R b1 、-(CR c1 R d1 ) t OC(=O)NR a1 R b1 、-(CR c1 R d1 ) t NR a1 C(=O)OR b1 、-(CR c1 R d1 ) t NR a1 C(=O)NR a1 R b1 、-(CR c1 Rd1 ) t NR a1 C(=S)NR a1 R b1 、-(CR c1 R d1 ) t NR a1 C(=NR e1 )NR a1 R b1 、-(CR c1 R d1 ) t S(=O) r R b1 、-(CR c1 R d1 ) t S(=O)(=NR e1 )R b1 、-(CR c1 R d1 ) t N=S(=O)R a1 R b1 、-(CR c1 R d1 ) t S(=O)2OR b1 、-(CR c1 R d1 ) t OS(=O)2R b1 、-(CR c1 R d1 ) t NR a1 S(=O) r R b1 、-(CR c1 R d1 ) t NR a1 S(=O)(=NR e1 )R b1 、-(CR c1 R d1 ) t S(=O) r NR a1 R b1 、-(CR c1 R d1 ) t S(=O)(=NR e1 )NR a1 R b1 、-(CR c1 R d1 ) t NR a1S(=O)2NR a1 R b1 and-(CR c1 R d1 ) t NR a1 S(=O)(=NR e1 )NR a1 R b1 , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R Y Substituents are substituted;

[0027] Each R a1 and R b1 independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclyl, aryl, -C 1-4 Alkylene-aryl, heteroaryl and -C 1-4 Alkylene-heteroaryl, wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R Y Substituents are substituted;

[0028] or R a1 and R b1 Together with the atoms to which they are attached, they form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, which ring is unsubstituted or substituted with 1, 2 or 3 atoms selected from R Y Substituents are substituted;

[0029] Each R c1 and R d1 independently selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclyl, aryl, -C 1-4 Alkylene-aryl, heteroaryl and -C 1-4 Alkylene-heteroaryl, wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R YSubstituents are substituted;

[0030] Or each R c1 and R d1 Together with the single or multiple carbon atoms to which they are attached, they form a 3-12 membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, which ring is unsubstituted or substituted with 1, 2 or 3 heteroatoms independently selected from R Y The group substitution;

[0031] Each R e1 independently selected from hydrogen, C 1-10 Alkyl, CN, NO2, -S(=O) r R a1 、-C(=O)R a1 、-C(=O)OR a1 、-C(=O)NR a1 R b1 and -S(=O) r NR a1 R b1 , wherein the alkyl group is unsubstituted or substituted with at least one independently selected from R Y Substituents are substituted;

[0032] Each R Y Independently selected from halogen, NO2, -CN, C 1-10 Alkyl, -OH, -O(C 1-10 Alkyl), -O(C 3-10 Cycloalkyl), -O(C 1-4 Alkylene-C 3-10 Cycloalkyl), -O(heterocyclyl), -O(C 1-4 Alkylene-heterocyclyl), -SH, -S(C 1-10 Alkyl), -S(C 3-10 Cycloalkyl), -S(C 1-4 Alkylene-C 3-10 Cycloalkyl), -S(heterocyclyl), -S(C 1-4 Alkylene-heterocyclyl), -NH2, -NH(C 1-10 Alkyl), -N(C 1-10 Alkyl)2, -NH(C 3-10 Cycloalkyl), -NH(C 1-4 Alkylene-C 3-10 Cycloalkyl), -NH(heterocyclyl) and -NH(C 1-4 alkylene-heterocyclyl);

[0033] g is selected from 0, 1, 2, 3, 4, 5, 6, 7 and 8;

[0034] Each r is independently selected from 1 and 2;

[0035] Each t is independently selected from 0, 1, 2, 3 and 4.

[0036] In another aspect, a pharmaceutical composition is provided, comprising a preventively or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

[0037] In another aspect, there is provided a use of a compound of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition in the preparation of a medicament for treating a disease, disorder or condition selected from a cell proliferation disorder, in particular cancer. DETAILED DESCRIPTION

[0038] Specific embodiments are provided below to illustrate the technical contents of the present invention. Those skilled in the art can easily understand other advantages and effects of the present invention through the contents disclosed in the specification. The present invention can also be implemented or applied through other different specific embodiments. Those skilled in the art can make various modifications and changes without departing from the spirit of the present invention.

[0039] definition

[0040] Unless otherwise defined below, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art. The technology used herein refers to the technology generally understood in the art, including variants and equivalent substitutions that are obvious to those skilled in the art. Although it is believed that the following terms are easily understood by those skilled in the art, the following definitions are set forth to better illustrate the present invention. When a trade name appears herein, it refers to the corresponding commodity or its active ingredient. All patents, published patent applications and publications cited herein are incorporated herein by reference.

[0041] The term "synthetic lethality" refers to the situation where two or more individual genes simultaneously express abnormally, leading to cell death, while only one or a portion of the genes express abnormally, leading to cell death; wherein the abnormal expression includes mutation, overexpression or gene inhibition. In one embodiment, the two synthetic lethal genes are referred to as a synthetic lethal gene pair.

[0042] The term "cyclin E1" refers to the G1 / S specific cyclin E1 (gene name: CCNE1). Cells that overexpress cyclin E1 show higher cyclin E1 activity than cells that normally express cyclin E1. CCNE1-amplified cells are cells that have a higher CCNE1 gene copy number than normal cells. Cells that overexpress cyclin E1 can be CCNE1-amplified cells, for example, in one embodiment, cells that overexpress cyclin E1 have more than 2 copies of CCNE1 compared to diploid normal cells having 2 copies of CCNE1. In addition to directly detecting the copy number of the CCNE1 gene, cyclin E1 overexpression can also be determined by identifying the expression level of the gene product in the cell (e.g., mRNA transcription level or cyclin E1 protein level).

[0043] Herein, the terms "cancer overexpressing cyclin E1" and "CCNE1 amplified cancer" are used interchangeably. Examples of CCNE1 amplified cancers include, but are not limited to, uterine sarcoma, ovarian cancer, breast cancer, gastric cancer, esophageal cancer, lung cancer, liver cancer, and endometrial cancer.

[0044] The term "FBXW7" refers to F-box / WD repeat-containing protein 7 (gene name: FBXW7). An FBXW7 gene with an inactivating mutation refers to a mutant FBXW7 gene that cannot produce a normal functional FBXW7 protein or produces a reduced amount of FBXW7 protein in a cell. Examples of FBXW7 mutant cancers include, but are not limited to, blood tumors, gliomas, liver cancer (e.g., hepatocellular carcinoma), uterine cancer (e.g., endometrial cancer), colorectal cancer (e.g., colorectal adenocarcinoma), breast cancer, lung cancer (e.g., non-small cell lung cancer (NSCLC)), gastric cancer, esophageal cancer, esophageal junction adenocarcinoma, bladder cancer (e.g., urothelial bladder carcinoma), head and neck cancer (e.g., head and neck squamous cell carcinoma), cervical cancer (e.g., cervical squamous cell carcinoma), melanoma, ovarian cancer (e.g., high-grade serous ovarian cancer).

[0045] The term "p53 protein" refers to tumor protein p53 (gene name: TP53). A TP53 gene with an inactivating mutation refers to a mutant TP53 gene that cannot produce a functional p53 protein or produces a reduced amount of p53 protein in a cell.

[0046] When a certain amount, concentration or other numerical value or parameter is described in the form of a range, a preferred range or a preferred upper limit or a preferred lower limit, it should be understood as being equivalent to specifically disclosing any range formed by combining any upper limit or preferred value with any lower limit or preferred value, whether or not the range is explicitly stated. Unless otherwise stated, the numerical ranges listed herein are intended to include the endpoints of the range and all integers and fractions (decimals) within the range. For example, the expression "C1-C 10 ” or “C 1-10 " covers the range of 1-10 carbon atoms and should be understood to also cover any subranges and each point value therein, such as C 2-3 , C 2-4 , C 2-5 , C 3-4 , C 3-5 , C 3-6 , C 3-7 , C 1-2 , C 1-3 , C 1-4 , C 1-5 , C 1-6 , C 1-7 , C 1-8 , C1-9, etc., as well as C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 etc. The expression “C3-C 10 ” or “C 3-10 " should also be understood in a similar way, for example, it can cover C 3-4 , C 3-5 , C 3-6 , C 3-7 , C 3-8 , C 4-5 , C 4-6 , C4-C7, C5-C6, etc. and C3, C4, C5, C6, C7, C8, C9, C 10 For another example, the expression "3-14 yuan" should be understood to include any sub-ranges therein and each point value, such as 3-4, 3-5, 3-6, 3-7, 3-8, 4-5, 4-6, 4-7, 5-6, 3, 4, 5, 6 or 7 yuan, etc. The expressions "3-12 yuan", "4-12 yuan", "5-10 yuan", "5-6 yuan" should also be understood in a similar manner.

[0047] When any variable (such as R X ) occurs more than once in the composition or structure of a compound, its definition is independent at each occurrence. For example, the expression “each R X "Independently selected from" means that if there are multiple R X , then in each case each R XThe substituents are independent of each other. Other variables or expressions such as R 4 , R X1 , R X2 , R X3 , R X4 , R X5 , R X6 , R X7 , R X8 , R X9 , R A1 , R A2 , R A3 , R A4 , R A5 , R A6 , R A7 , R A8 , R A9 , R B1 , R B2 , R B3 , R B4 , R B5 , R B6 , R B7 , R B8 , R B9 , R E1 , R E2 , R E3 , R E4 , R E5 , R E6 , R E7 , R E8 , R E9 and R Y It should be understood in a similar way.

[0048] Unless the context clearly dictates otherwise, singular forms such as "a", "an", and "the" include plural forms. The expression "one or more" or "at least one" may mean 1, 2, 3, 4, 5, 6, 7, 8, 9 or more. In one embodiment, "at least one" means 1, 2, 3 or 4.

[0049] The terms "optional" or "optionally" mean that the subsequently described event may occur but need not occur, and that the description includes instances where said event or circumstance occurs or does not occur.

[0050] The terms "substituted" and "substituted" refer to one or more (e.g., one, two, three or four) hydrogen atoms on the designated atom being replaced by a selection from the indicated group, provided that the normal atomic valence of the designated atom in the current situation is not exceeded and the substitution forms a stable compound. Combinations of substituents and / or variables are permitted only if such combinations form stable compounds. When a substituent is described as not present, it should be understood that the substituent can be one or more hydrogen atoms, provided that the structure can achieve a stable state of the compound.

[0051] Unless otherwise indicated, as used herein, the point of attachment of a substituent may be from any convenient position of the substituent. When a bond to a substituent is shown as passing through a bond connecting two atoms in a ring, then such a substituent may be bonded to any ring-forming atom in the substitutable ring.

[0052] The expressions "comprising," "including," "containing," and "having" are open ended and do not exclude additional unrecited elements, steps, or ingredients. The expression "consisting of excludes any element, step, or ingredient not specified. The expression "consisting essentially of means that the scope is limited to the specified elements, steps, or ingredients, as well as the optional presence of elements, steps, or ingredients that do not materially affect the basic and novel characteristics of the claimed subject matter. It should be understood that the expression "comprising" includes the expressions "consisting essentially of" and "consisting of.

[0053] The term "halo" or "halogen" or "halo" is understood to mean a fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) atom, preferably a fluorine, chlorine or bromine atom.

[0054] The term "hydrocarbyl" refers to a monovalent group derived from a hydrocarbon. Examples of hydrocarbyl groups include, but are not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, and aryl.

[0055] The term "alkyl" refers to a saturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, which is connected to the rest of the molecule by a single bond. Alkyl groups include straight-chain alkyl groups and branched-chain alkyl groups. Alkyl groups can contain 1 to 10 carbon atoms, referred to as C 1-10 Alkyl groups, such as C 1-6 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl, C 1-2 Alkyl, C3 alkyl, C4 alkyl, C 3-6Alkyl. Non-limiting examples of straight-chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, etc. Non-limiting examples of branched alkyl groups include, but are not limited to, 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.

[0056] A divalent group refers to a group obtained by removing a hydrogen atom from a carbon atom with free valence electrons of a corresponding monovalent group. A divalent group has two attachment sites connected to the rest of the molecule, wherein the two attachment sites can be located on the same atom or two different atoms of the divalent group.

[0057] "Alkylene" or "alkylidene" refers to a saturated divalent hydrocarbon group. Alkylene includes straight chain or branched chain alkylene. Examples of straight chain alkylene include, but are not limited to, methylene (-CH2-), -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, etc. Examples of branched chain alkylene include, but are not limited to -CH(CH3)-, -CH(C2H5)-, -CH(CH3)-CH2-, -CH(C3H7)-, -CH(C2H5)-CH2-, -C(CH3)2-CH2-, -(CH(CH3))2-, -CH(CH3)-(CH2)2-, -CH2-CH(CH3)-CH2-, -CH(C4H9)-, -C(CH3)(C3H7)- , -C(C2H5)2-, -CH(C3H7)-CH2-, -CH(C2H5)-CH(CH3)-, -CH(C2H5)-(CH2)2-, -CH2-CH(C2H5)-CH2 -, -C(CH3)2-(CH2)2-, -CH2-C(CH3)2-CH2-, -CH(CH3)-(CH2)3-, -CH2-CH(CH3)-(CH2)2-, -CH(C5H 11)-, -C(C2H5)(C3H7)-, -C(CH3)(C4H9)-, -CH(C4H9)-CH2-, -C(C2H5)2-CH2-, -C (CH3)(C3H7)-CH2-, -CH(C2H5)-CH(C2H5)-, -CH(CH3)-CH(C3H7)-, -C(CH3)2-C( CH3)2-, -CH(C3H7)-(CH2)2-, -CH2-CH(C3H7)-CH2-, -CH(C2H5)-C(CH3)2-, -C(CH3)2-CH(CH3)-CH2-, -CH(CH3)-C(CH3)2-CH2-, -CH(C2H5)-CH(CH3)-CH2-, -CH( CH3)-CH(C2H5)-CH2-, -CH(CH3)-CH2-CH(C2H5)-, -CH(CH3)-C(CH3)2-CH2-, -(CH(CH3))3-, -C(CH3)2-(CH2)3-, -CH(C2H5)-(CH2)3-, -CH2-CH(C2H5)-(CH2)2-, -CH2-CH(CH3)-CH(CH3)-CH2-, -(CH(CH3))2-(CH2)2-, -CH(CH3)-(CH2)2-CH(CH3)-, -(CH2)2-CH(CH3)-(CH2)2-, -CH2-CH(CH3)-(CH2)3-, -CH(CH3)-(CH2)4-, etc.

[0058] 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 alkenyl group may have 2 to 8 carbon atoms, i.e., "C 2-8 Alkenyl", such as C 2-4 Alkenyl, C 3-4 Alkenyl. Non-limiting examples of alkenyl groups 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, and the like.

[0059] The term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one triple bond. The alkynyl group may have 2 to 8 carbon atoms, i.e., "C 2-8 Alkynyl", such as C 2-4 Alkynyl, C 3-4 Alkynyl. Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, and the like.

[0060] The term "alkoxy" refers to an alkyl group as defined above which is attached to an oxygen atom by a single bond. The alkoxy group is attached to the rest of the molecule via the oxygen atom. The alkoxy group may be represented by -O(alkyl). 1-8 Alkoxy" or "-O(C 1-8 "Alkyl)" refers to an alkoxy group containing 1-8 carbon atoms, wherein the alkyl portion can be a straight chain or branched structure. Alkoxy includes but is not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, n-pentoxy, etc.

[0061] The terms "hydrocarbon ring" and "cycloalkyl" each refer to a saturated or unsaturated non-aromatic ring system composed of carbon atoms and hydrogen atoms. "Hydrocarbon ring" and "cycloalkyl" preferably each contain 1 or 2 rings. The "hydrocarbon ring" and "cycloalkyl" may be a monocyclic, fused polycyclic, bridged or spirocyclic structure. "Hydrocarbon ring" and "cycloalkyl" may each have 3 to 10 carbon atoms, i.e., "C 3-10 hydrocarbon ring” (e.g., C4 hydrocarbon ring, C5 hydrocarbon ring, C6 hydrocarbon ring, C7 hydrocarbon ring) and “C 3-10 Cycloalkyl" (e.g. C 3-8 In some embodiments, the C atoms in the cycloalkyl group are optionally substituted with oxo. In some embodiments, the C atoms in the cycloalkyl group are optionally substituted with imino. In some embodiments, the imino is unsubstituted (=NH) or substituted with a group as described above. In some embodiments, the imino is substituted with -OR, wherein R is H or C 1-10 alkyl.

[0062] The terms "cyclic alkyl" and "cycloalkyl" have the same meaning herein and can be used interchangeably. Cycloalkyl refers to a saturated cyclic hydrocarbon group. A cycloalkyl group can have 3, 4, 5, 6, 7, 8, 9 or 10 ring carbon atoms (C 3-10 ). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In some embodiments, the cycloalkyl group is C 3-7 Monocyclic or bicyclic cycloalkyl, preferably C 3-6 Monocyclic cycloalkyl, in particular cyclopropyl.

[0063] The terms "heterocycle" and "heterocyclyl" each refer to a monocyclic or bicyclic ring system (3-14-membered, 7-14-membered, 3-8-membered, 3-7-membered, 4-6-membered, 5-6-membered) having, for example, 3-14 ring atoms (e.g., 7-14, 3-8, 3-7, 4-6, or 5-6 ring atoms), wherein at least one ring atom (e.g., 1, 2, or 3) is a heteroatom selected from oxygen, sulfur, nitrogen, and phosphorus, and the remaining ring atoms are C. The ring system may be saturated (also understood as the corresponding "heterocycloalkane" or "heterocycloalkyl") or unsaturated (i.e., having one or more double bonds and / or triple bonds in the ring). Optionally, "heterocycle" and "heterocyclyl" each may be benzo-fused. "Heterocycle" and "heterocyclyl" each do not have aromaticity. In some embodiments, the C, N, S, and P atoms in "heterocycle" and "heterocyclyl" are optionally substituted with oxo. In some embodiments, the C, S and P atoms in "heterocycle" and "heterocyclyl" are optionally substituted with an imino group. In some embodiments, the imino group is unsubstituted (=NH) or substituted with a group as described above. In some embodiments, the imino group is substituted with -OR, wherein R is H or C 1-10 alkyl.

[0064] The heterocyclic group can be, for example, a four-membered ring, such as azetidinyl, oxetanyl; or a five-membered ring, such as tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, oxopyrrolidinyl, 2-oxoimidazolidin-1-yl; or a six-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, 1,1-dioxo-1,2-thiazin-2-yl or trithianyl; or a seven-membered ring, such as diazepine, Base ring.

[0065] The heterocyclic group may be bicyclic, without limitation, for example, a five-membered and a five-membered ring, such as octahydrocyclopenta[c]pyrrolyl; or a five-membered and a six-membered bicyclic ring, such as octahydropyrrolo[1,2-b]pyrazinyl.

[0066] As mentioned above, the heterocycle may be unsaturated, i.e., it may contain one or more double bonds, without being limited thereto, for example, an unsaturated heterocycle containing a nitrogen atom may be a 1,6-dihydropyrimidine, a 1,2-dihydropyrimidine, a 1,4-dihydropyrimidine, a 1,6-dihydropyridine, a 1,2-dihydropyridine, a 1,4-dihydropyridine, a 2,3-dihydro-1H-pyrrole, a 3,4-dihydro-1H-pyrrole, a 2,5-dihydro-1H-pyrrolyl, a 4H-[1,3,4]thiadiazinyl, a 4,5-dihydrooxazolyl or a 4H-[1,4]thiazinyl ring, an unsaturated heterocycle containing an oxygen atom may be a 2H-pyran, a 4H-pyran, a 2,3-dihydrofuran, an unsaturated heterocycle containing a sulfur atom may be a 2H-thiopyran, a 4H-thiopyran. The heterocycle may be benzo-fused, without being limited thereto, for example, a dihydroisoquinolinyl ring.

[0067] Exemplary bicyclic heterocycles also include:

[0068]

[0069]

[0070] The term "aryl" refers to an aromatic ring group of an all-carbon monocyclic or fused polycyclic (such as a bicyclic) ring having a conjugated π electron system. For example, an aryl group may have 6-14 carbon atoms, preferably 6-10, more preferably 6 or 10. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and the like.

[0071] The terms "heteroaromatic ring" and "heteroaryl" refer to a monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 7, 8, 9 or 10 ring atoms ("5-10 heteroaryl"), in particular 5 or 6 or 9 or 10 ring atoms, and including at least one (suitably 1 to 4, more suitably 1, 2 or 3) heteroatom(s) which may be identical or different, such as oxygen, nitrogen or sulfur. Furthermore, in each case "heteroaromatic ring" and "heteroaryl" may each be benzo-fused. In particular, the heteroaryl group is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, and the like, and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, and benzo derivatives thereof, such as quinolyl, quinazolinyl, isoquinolyl, and the like; or azocinyl, indolizinyl, purinyl, and the like, and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, carbazolyl, acridinyl, and the like.

[0072] The pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof. The methods for preparing the pharmaceutically acceptable salts of the compounds of the present invention are known to those skilled in the art.

[0073] The compounds of the present invention encompass pharmaceutically acceptable salts, stereoisomers, solvates, polymorphs, tautomers, isotopic compounds, metabolites or prodrugs thereof.

[0074] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds. For example, the compounds of the present invention may exist in E or Z configurations of carbon-carbon double bonds or carbon-nitrogen double bonds, wherein "E" represents the preferred substituents on the opposite side of the carbon-carbon double bond or carbon-nitrogen double bond according to the Cahn-Ingold-Prelog priority rules, and "Z" represents the preferred substituents on the same side of the carbon-carbon double bond or carbon-nitrogen double bond. The compounds of the present invention may also exist in the form of mixtures of "E" and "Z" isomers. Isomer forms also include cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Purification and separation of such substances can be achieved by standard techniques known in the art.

[0075] The compounds of the present invention may contain a bond with hindered rotation so that two separate torsional isomers can be separated. All possible torsional isomers are included within the scope of the present invention. The separation method of torsional isomers can be a known method or a method described herein. In one embodiment, chiral chromatography is used to separate torsional isomers, for example, using supercritical CO2 and MEOH as mobile phases.

[0076] Optically pure enantiomers can be obtained by resolving racemic mixtures according to conventional methods, for example, by forming diastereomeric salts using optically active acids or bases, or by forming covalent diastereomers. A mixture of diastereoisomers can be separated into single diastereomers based on their physical and / or chemical differences by methods known in the art (e.g., by chromatography or fractional crystallization). Then, the optically active enantiomer base or acid is released from the separated diastereomeric salts. Another method for separating racemic enantiomers can use chiral chromatography (e.g., chiral HPLC columns), and the separated chiral isomers can be subjected to conventional derivatization treatment or non-derivatization before separation, depending on which method can achieve more effective separation of chiral isomers. Enzymatic methods can also be used to separate derivatized or non-derivatized chiral isomers. Similarly, optically active raw materials can be used to obtain optically pure compounds of the present invention by chiral synthesis.

[0077] The compounds of the present invention may exist in the form of solvates (preferably hydrates), wherein the compounds of the present invention contain a solvent as a structural element of the crystal lattice of the compound, in particular water, methanol or ethanol. The amount of the solvent, in particular water, may be present in a stoichiometric or non-stoichiometric ratio.

[0078] The present invention also encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be a single polymorph or a mixture of more than one polymorph in any ratio.

[0079] The compounds of the invention may exist in isotopically labeled or enriched form, containing one or more atoms having a different mass and mass number from the most common atomic mass in nature. Isotopes may be radioactive or non-radioactive isotopes. Isotopes of atoms such as hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine include, but are not limited to, 2 H. 3 H. 13 C. 14 C. 15 N. 18 O. 32 P. 35 S. 18 F. 36 Cl and 125 I.

[0080] Also included within the scope of the present invention are metabolites of the compounds of the present invention, i.e., substances formed in vivo when the compounds of the present invention are administered. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymolysis, etc. of the administered compounds.

[0081] The present invention further includes within its scope prodrugs of the compounds of the invention, which are certain derivatives of the compounds of the invention that may themselves have little or no pharmacological activity but are converted, for example by hydrolytic cleavage, into compounds of the invention having the desired activity when administered into or onto the body.

[0082] The term "polymorph" or "polymorph" refers to a single polymorph or a mixture of more than one polymorph in any proportion.

[0083] The term "crystalline form" or "crystal" refers to any solid material that exhibits a three-dimensional ordering, in contrast to amorphous solid material, which produces a characteristic X-ray powder diffraction pattern with well-defined peaks.

[0084] The term "amorphous" refers to any solid material that has no order in three dimensions.

[0085] The term "pharmaceutically acceptable" means that it is within the scope of normal medical judgment and will not cause undue toxicity, irritation, allergic response, or the like in contact with the tissues of patients.

[0086] The term "pharmaceutically acceptable carrier" refers to those substances that have no significant irritation to organisms and do not impair the biological activity and performance of the active compound. "Pharmaceutically acceptable carrier" includes, but is not limited to, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersants, disintegrants, stabilizers, solvents or emulsifiers.

[0087] The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating or preventing a target disorder, disease, or condition.

[0088] With respect to a drug, drug unit or active ingredient, the term "effective amount", "therapeutically effective amount" or "prophylactically effective amount" refers to a sufficient amount of the drug or pharmaceutical agent that can achieve the desired effect with acceptable side effects. The determination of the effective amount varies from person to person, depending on the age and general condition of the individual and on the specific active substance. The appropriate effective amount in each case can be determined by a person skilled in the art based on routine experiments.

[0089] The term "subject" includes humans or non-human animals. Exemplary human subjects include human subjects (referred to as patients) suffering from diseases (e.g., diseases described herein) or normal subjects. "Non-human animals" in the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0090] Compounds of formula (I)

[0091] In one aspect, the present invention provides a compound having the structure of formula (I):

[0092]

[0093] or a pharmaceutically acceptable salt thereof,

[0094] in,

[0095] Ring A is selected from benzene ring, C 5-6 Hydrocarbon rings, 5-6 membered heterocyclic rings and 5-6 membered heteroaromatic rings;

[0096] W is selected from N and CR 1 ;

[0097] R 1 Selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclyl, CN, NO2, aryl, -C 1-4 Alkylene-aryl, heteroaryl, -C 1-4 Alkylene-heteroaryl, -NR A1 R B1 、-OR A1 、-SR A1 、-C(=O)R A1 、-C(=NR E1 )R A1 、-C(=N-OR B1 )R A1 、-C(=O)OR A1 、-OC(=O)R A1 、-C(=O)NR A1 R B1 、-NR A1 C(=O)R B1 、-C(=NR E1 )NR A1 R B1 、-NR A1 C(=NR E1 )R B1 、-OC(=O)NR A1 R B1 、-NR A1 C(=O)OR B1 、-NR A1 C(=O)NR A1 R B1 、-NR A1 C(=S)NR A1 R B1 、-NR A1 C(=NR E1 )NR A1 R B1 、-S(=O) r R A1 、-S(=O)(=NR E1 )R B1 、-N=S(=O)R A1 R B1 、-S(=O)2OR A1 、-OS(=O)2R A1 、-NR A1 S(=O) r R B1 、-NR A1 S(=O)(=NRE1 )R B1 、-S(=O) r NR A1 R B1 、-S(=O)(=NR E1 )NR A1 R B1 、-NR A1 S(=O)2NR A1 R B1 and-NR A1 S(=O)(=NR E1 )NR A1 R B1 , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R X1 Substituents are substituted;

[0098] R 2 Selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclyl, CN, NO2, aryl, -C 1-4 Alkylene-aryl, heteroaryl, -C 1-4 Alkylene-heteroaryl, -NR A2 R B2 、-OR A2 、-SR A2 、-C(=O)R A2 、-C(=NR E2 )R A2 、-C(=N-OR B2 )R A2 、-C(=O)OR A2 、-OC(=O)R A2 、-C(=O)NR A2 R B2 、-NR A2 C(=O)R B2 、-C(=NR E2 )NR A2 R B2 、-NR A2 C(=NR E2 )R B2 、-OC(=O)NR A2 R B2 、-NR A2 C(=O)ORB2 、-NR A2 C(=O)NR A2 R B2 、-NR A2 C(=S)NR A2 R B2 、-NR A2 C(=NR E2 )NR A2 R B2 、-S(=O) r R A2 、-S(=O)(=NR E2 )R B2 、-N=S(=O)R A2 R B2 、-S(=O)2OR A2 、-OS(=O)2R A2 、-NR A2 S(=O) r R B2 、-NR A2 S(=O)(=NR E2 )R B2 、-S(=O) r NR A2 R B2 、-S(=O)(=NR E2 )NR A2 R B2 、-NR A2 S(=O)2NR A2 R B2 and-NR A2 S(=O)(=NR E2 )NR A2 R B2 , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R X2 Substituents are substituted;

[0099] R 3 Selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclyl, CN, NO2, aryl, -C 1-4 Alkylene-aryl, heteroaryl, -C 1-4 Alkylene-heteroaryl, -NR A3 R B3、-OR A3 、-SR A3 、-C(=O)R A3 、-C(=NR E3 )R A3 、-C(=N-OR B3 )R A3 、-C(=O)OR A3 、-OC(=O)R A3 、-C(=O)NR A3 R B3 、-NR A3 C(=O)R B3 、-C(=NR E3 )NR A3 R B3 、-NR A3 C(=NR E3 )R B3 、-OC(=O)NR A3 R B3 、-NR A3 C(=O)OR B3 、-NR A3 C(=O)NR A3 R B3 、-NR A3 C(=S)NR A3 R B3 、-NR A3 C(=NR E3 )NR A3 R B3 、-S(=O) r R A3 、-S(=O)(=NR E3 )R B3 、-N=S(=O)R A3 R B3 、-S(=O)2OR A3 、-OS(=O)2R A3 、-NR A3 S(=O) r R B3 、-NR A3 S(=O)(=NR E3 )R B3 、-S(=O) r NR A3 R B3 、-S(=O)(=NR E3 )NR A3 R B3 、-NR A3 S(=O)2NR A3 R B3and-NR A3 S(=O)(=NR E3 )NR A3 R B3 , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R X3 Substituents are substituted;

[0100] Each R 4 Independently selected from halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cyclic hydrocarbon group, heterocyclic group, -C 1-4 Alkylene-heterocyclyl, CN, NO2, aryl, -C 1-4 Alkylene-aryl, heteroaryl, -C 1-4 Alkylene-heteroaryl, -NR A4 R B4 、-OR A4 、-SR A4 、-C(=O)R A4 、-C(=NR E4 )R A4 、-C(=N-OR B4 )R A4 、-C(=O)OR A4 、-OC(=O)R A4 、-C(=O)NR A4 R B4 、-NR A4 C(=O)R B4 、-C(=NR E4 )NR A4 R B4 、-NR A4 C(=NR E4 )R B4 、-OC(=O)NR A4 R B4 、-NR A4 C(=O)OR B4 、-NR A4 C(=O)NR A4 R B4 、-NR A4 C(=S)NR A4 R B4 、-NR A4 C(=NR E4 )NR A4 R B4 、-S(=O)r R A4 、-S(=O)(=NR E4 )R B4 、-N=S(=O)R A4 R B4 、-S(=O)2OR A4 、-OS(=O)2R A4 、-NR A4 S(=O) r R B4 、-NR A4 S(=O)(=NR E4 )R B4 、-S(=O) r NR A4 R B4 、-S(=O)(=NR E4 )NR A4 R B4 、-NR A4 S(=O)2NR A4 R B4 and-NR A4 S(=O)(=NR E4 )NR A4 R B4 , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R X4 Substituents are substituted;

[0101] Or any two adjacent R 4 Together with the atoms to which they are attached, they form a C 3-10 A monocyclic hydrocarbon ring or a 4-12 membered heterocyclic ring containing 1, 2 or 3 heteroatoms or a 5-10 membered heteroaromatic ring containing 1, 2 or 3 heteroatoms, wherein the heteroatoms are independently selected from oxygen, sulfur, nitrogen and phosphorus, and the ring is unsubstituted or substituted by at least one independently selected from R X4 Substituents are substituted;

[0102] R 5 Selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclyl, CN, NO2, aryl, -C 1-4 Alkylene-aryl, heteroaryl, -C 1-4 Alkylene-heteroaryl, -NR A5 R B5 、-ORA5 、 -SR A5 、 -C(=O)R A5 、 -C(=NR E5 )R A5 、 -C(=N-OR B5 )R A5 、 -C(=O)OR A5 、 -OC(=O)R A5 、 -C(=O)NR A5 R B5 、 -NR A5 C(=O)R B5 、 -C(=NR E5 )NR A5 R B5 、 -NR A5 C(=NR E5 )R B5 、 -OC(=O)NR A5 R B5 、 -NR A5 C(=O)OR B5 、 -NR A5 C(=O)NR A5 R B5 、 -NR A5 C(=S)NR A5 R B5 、 -NR A5 C(=NR E5 )NR A5 R B5 、 -S(=O) r R A5 、 -S(=O)(=NR E5 )R B5 、 -N=S(=O)R A5 R B5 、 -S(=O)2OR A5 、 -OS(=O)2R A5 、 -NR A5 S(=O) r R B5 、 -NR A5 S(=O)(=NR E5 )R B5 、 -S(=O) r NR A5 R B5 、 -S(=O)(=NR E5 )NR A5 R B5 、 -NR A5 S(=O)2NR A5 R B5 and -NRA5 S(=O)(=NR E5 )NR A5 R B5 , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R X5 Substituents are substituted;

[0103] R 6 Selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclyl, CN, NO2, aryl, -C 1-4 Alkylene-aryl, heteroaryl, -C 1-4 Alkylene-heteroaryl, -NR A6 R B6 、-OR A6 、-SR A6 、-C(=O)R A6 、-C(=NR E6 )R A6 、-C(=N-OR B6 )R A6 、-C(=O)OR A6 、-OC(=O)R A6 、-C(=O)NR A6 R B6 、-NR A6 C(=O)R B6 、-C(=NR E6 )NR A6 R B6 、-NR A6 C(=NR E6 )R B6 、-OC(=O)NR A6 R B6 、-NR A6 C(=O)OR B6 、-NR A6 C(=O)NR A6 R B6 、-NR A6 C(=S)NR A6 R B6 、-NR A6 C(=NR E6 )NR A6 R B6 、-S(=O)r R A6 、-S(=O)(=NR E6 )R B6 、-N=S(=O)R A6 R B6 、-S(=O)2OR A6 、-OS(=O)2R A6 、-NR A6 S(=O) r R B6 、-NR A6 S(=O)(=NR E6 )R B6 、-S(=O) r NR A6 R B6 、-S(=O)(=NR E6 )NR A6 R B6 、-NR A6 S(=O)2NR A6 R B6 and-NR A6 S(=O)(=NR E6 )NR A6 R B6 , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R X6 Substituents are substituted;

[0104] R 7 Selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclyl, CN, NO2, aryl, -C 1-4 Alkylene-aryl, heteroaryl, -C 1-4 Alkylene-heteroaryl, -NR A7 R B7 、-OR A7 、-SR A7 、-C(=O)R A7 、-C(=NR E7 )R A7 、-C(=N-OR B7 )R A7 、-C(=O)OR A7 、-OC(=O)R A7 、-C(=O)NRA7 R B7 、-NR A7 C(=O)R B7 、-C(=NR E7 )NR A7 R B7 、-NR A7 C(=NR E7 )R B7 、-OC(=O)NR A7 R B7 、-NR A7 C(=O)OR B7 、-NR A7 C(=O)NR A7 R B7 、-NR A7 C(=S)NR A7 R B7 、-NR A7 C(=NR E7 )NR A7 R B7 、-S(=O) r R A7 、-S(=O)(=NR E7 )R B7 、-N=S(=O)R A7 R B7 、-S(=O)2OR A7 、-OS(=O)2R A7 、-NR A7 S(=O) r R B7 、-NR A7 S(=O)(=NR E7 )R B7 、-S(=O) r NR A7 R B7 、-S(=O)(=NR E7 )NR A7 R B7 、-NR A7 S(=O)2NR A7 R B7 and-NR A7 S(=O)(=NR E7 )NR A7 R B7 , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R X7 Substituents are substituted;

[0105] R 8Selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclyl, CN, NO2, aryl, -C 1-4 Alkylene-aryl, heteroaryl, -C 1-4 Alkylene-heteroaryl, -NR A8 R B8 、-OR A8 、-SR A8 、-C(=O)R A8 、-C(=NR E8 )R A8 、-C(=N-OR B8 )R A8 、-C(=O)OR A8 、-OC(=O)R A8 、-C(=O)NR A8 R B8 、-NR A8 C(=O)R B8 、-C(=NR E8 )NR A8 R B8 、-NR A8 C(=NR E8 )R B8 、-OC(=O)NR A8 R B8 、-NR A8 C(=O)OR B8 、-NR A8 C(=O)NR A8 R B8 、-NR A8 C(=S)NR A8 R B8 、-NR A8 C(=NR E8 )NR A8 R B8 、-S(=O) r R A8 、-S(=O)(=NR E8 )R B8 、-N=S(=O)R A8 R B8 、-S(=O)2OR A8 、-OS(=O)2R A8 、-NR A8 S(=O)r R B8 、-NR A8 S(=O)(=NR E8 )R B8 、-S(=O) r NR A8 R B8 、-S(=O)(=NR E8 )NR A8 R B8 、-NR A8 S(=O)2NR A8 R B8 and-NR A8 S(=O)(=NR E8 )NR A8 R B8 , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R X8 Substituents are substituted;

[0106] R 9 Selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclyl, CN, NO2, aryl, -C 1-4 Alkylene-aryl, heteroaryl, -C 1-4 Alkylene-heteroaryl, -NR A9 R B9 、-OR A9 、-SR A9 、-C(=O)R A9 、-C(=NR E9 )R A9 、-C(=N-OR B9 )R A9 、-C(=O)OR A9 、-OC(=O)R A9 、-C(=O)NR A9 R B9 、-NR A9 C(=O)R B9 、-C(=NR E9 )NR A9 R B9 、-NR A9 C(=NR E9 )R B9 、-OC(=O)NRA9 R B9 、-NR A9 C(=O)OR B9 、-NR A9 C(=O)NR A9 R B9 、-NR A9 C(=S)NR A9 R B9 、-NR A9 C(=NR E9 )NR A9 R B9 、-S(=O) r R A9 、-S(=O)(=NR E9 )R B9 、-N=S(=O)R A9 R B9 、-S(=O)2OR A9 、-OS(=O)2R A9 、-NR A9 S(=O) r R B9 、-NR A9 S(=O)(=NR E9 )R B9 、-S(=O) r NR A9 R B9 、-S(=O)(=NR E9 )NR A9 R B9 、-NR A9 S(=O)2NR A9 R B9 and-NR A9 S(=O)(=NR E9 )NR A9 R B9 , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R X9 Substituents are substituted;

[0107] or R 8 and R 9 Together with the atoms to which they are attached, they form a 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring containing 1, 2 or 3 heteroatoms, wherein the heteroatoms are independently selected from oxygen, sulfur and nitrogen, and the ring is unsubstituted or substituted by at least one independently selected from R X8 Substituents are substituted;

[0108] Each R A1 , R A2 , RA3 , R A4 , R A5 , R A6 , R A7 , R A8 , R A9 , R B1 , R B2 , R B3 , R B4 , R B5 , R B6 , R B7 , R B8 and R B9 independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclyl, aryl, -C 1-4 Alkylene-aryl, heteroaryl and -C 1-4 Alkylene-heteroaryl, wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R X Substituents are substituted;

[0109] or "R A1 and R B1 ” or “R A2 and R B2 ” or “R A3 and R B3 ” or “R A4 and R B4 ” or “R A5 and R B5 ” or “R A6 and R B6 ” or “R A7 and R B7 ” or “R A8 and R B8 ” or “R A9 and R B9 "together with the atoms or atoms to which they are attached, they form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, which ring is unsubstituted or substituted with 1, 2 or 3 atoms selected from R X Substituents are substituted;

[0110] Each R E1 , R E2 , R E3 , R E4 , RE5 , R E6 , R E7 , R E8 and R E9 independently selected from hydrogen, C 1-10 Alkyl, CN, NO2, -S(=O) r R a1 、-C(=O)R a1 、-C(=O)OR a1 、-C(=O)NR a1 R b1 and -S(=O) r NR a1 R b1 , wherein the alkyl group is unsubstituted or substituted with at least one independently selected from R X Substituents are substituted;

[0111] Each R X , R X1 , R X2 , R X3 , R X4 , R X5 , R X6 , R X7 , R X8 and R X9 Independently selected from halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclyl, aryl, -C 1-4 Alkylene-aryl, heteroaryl, -C 1-4 Alkylene-heteroaryl, CN, NO2, -(CR c1 R d1 ) t NR a1 R b1 、-(CR c1 R d1 ) t OR b1 、-(CR c1 R d1 ) t C(=O)R a1 、-(CR c1 R d1 ) t C(=NR e1 )R a1 、-(CR c1 R d1 )t C(=O)OR b1 、-(CR c1 R d1 ) t OC(=O)R b1 、-(CR c1 R d1 ) t C(=O)NR a1 R b1 、-(CR c1 R d1 ) t NR a1 C(=O)R b1 、-(CR c1 R d1 ) t C(=NR e1 )NR a1 R b1 、-(CR c1 R d1 ) t NR a1 C(=NR e1 )R b1 、-(CR c1 R d1 ) t OC(=O)NR a1 R b1 、-(CR c1 R d1 ) t NR a1 C(=O)OR b1 、-(CR c1 R d1 ) t NR a1 C(=O)NR a1 R b1 、-(CR c1 R d1 ) t NR a1 C(=S)NR a1 R b1 、-(CR c1 R d1 ) t NR a1 C(=NR e1 )NR a1 R b1 、-(CR c1 R d1 ) t S(=O) r R b1 、-(CR c1R d1 ) t S(=O)(=NR e1 )R b1 、-(CR c1 R d1 ) t N=S(=O)R a1 R b1 、-(CR c1 R d1 ) t S(=O)2OR b1 、-(CR c1 R d1 ) t OS(=O)2R b1 、-(CR c1 R d1 ) t NR a1 S(=O) r R b1 、-(CR c1 R d1 ) t NR a1 S(=O)(=NR e1 )R b1 、-(CR c1 R d1 ) t S(=O) r NR a1 R b1 、-(CR c1 R d1 ) t S(=O)(=NR e1 )NR a1 R b1 、-(CR c1 R d1 ) t NR a1 S(=O)2NR a1 R b1 and-(CR c1 R d1 ) t NR a1 S(=O)(=NR e1 )NR a1 R b1 , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R Y Substituents are substituted;

[0112] Each R a1 and R b1independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclyl, aryl, -C 1-4 Alkylene-aryl, heteroaryl and -C 1-4 Alkylene-heteroaryl, wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R Y Substituents are substituted;

[0113] or R a1 and R b1 Together with the atoms to which they are attached, they form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, which ring is unsubstituted or substituted with 1, 2 or 3 atoms selected from R Y Substituents are substituted;

[0114] Each R c1 and R d1 independently selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclyl, aryl, -C 1-4 Alkylene-aryl, heteroaryl and -C 1-4 Alkylene-heteroaryl, wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R Y Substituents are substituted;

[0115] Or each R c1 and R d1 Together with the single or multiple carbon atoms to which they are attached, they form a 3-12 membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, which ring is unsubstituted or substituted with 1, 2 or 3 heteroatoms independently selected from R Y The group substitution;

[0116] Each R e1 independently selected from hydrogen, C 1-10 Alkyl, CN, NO2, -S(=O) r R a1 、-C(=O)Ra1 、-C(=O)OR a1 、-C(=O)NR a1 R b1 and -S(=O) r NR a1 R b1 , wherein the alkyl group is unsubstituted or substituted with at least one independently selected from R Y Substituents are substituted;

[0117] Each R Y Independently selected from halogen, NO2, -CN, C 1-10 Alkyl, -OH, -O(C 1-10 Alkyl), -O(C 3-10 Cycloalkyl), -O(C 1-4 Alkylene-C 3-10 Cycloalkyl), -O(heterocyclyl), -O(C 1-4 Alkylene-heterocyclyl), -SH, -S(C 1-10 Alkyl), -S(C 3-10 Cycloalkyl), -S(C 1-4 Alkylene-C 3-10 Cycloalkyl), -S(heterocyclyl), -S(C 1-4 Alkylene-heterocyclyl), -NH2, -NH(C 1-10 Alkyl), -N(C 1-10 Alkyl)2, -NH(C 3-10 Cycloalkyl), -NH(C 1-4 Alkylene-C 3-10 Cycloalkyl), -NH(heterocyclyl) and -NH(C 1-4 alkylene-heterocyclyl);

[0118] g is selected from 0, 1, 2, 3, 4, 5, 6, 7 and 8;

[0119] Each r is independently selected from 1 and 2;

[0120] Each t is independently selected from 0, 1, 2, 3 and 4.

[0121] In one embodiment, t is 0. In one embodiment, g is selected from the group consisting of 0, 1, 2, 3, and 4. In one embodiment, g is selected from the group consisting of 0, 1, and 2.

[0122] In one embodiment, each R A1 , R A2 , R A3 , R A4 , R A5 , R A6 , R A7 , R A8 , R A9 , RB1 , R B2 , R B3 , R B4 , R B5 , R B6 , R B7 , R B8 and R B9 independently selected from hydrogen and C 1-10 Alkyl, wherein each alkyl is unsubstituted or substituted with at least one independently selected from R X substituted by a substituent.

[0123] In one embodiment, each R X , R X1 , R X2 , R X3 , R X4 , R X5 , R X6 , R X7 , R X8 and R X9 Independently selected from halogen, C 1-10 Alkyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclic group, CN, NO2, -(CR c1 R d1 ) t NR a1 R b1 、-(CR c1 R d1 ) t OR b1 、-(CR c1 R d1 ) t C(=O)R a1 、-(CR c1 R d1 ) t C(=O)OR b1 、-(CR c1 R d1 ) t OC(=O)R b1 、-(CR c1 R d1 ) t C(=O)NR a1 R b1 、-(CR c1 R d1 ) t NR a1 C(=O)R b1 、-(CRc1 R d1 ) t OC(=O)NR a1 R b1 、-(CR c1 R d1 ) t NR a1 C(=O)OR b1 、-(CR c1 R d1 ) t NR a1 C(=O)NR a1 R b1 、-(CR c1 R d1 ) t NR a1 C(=S)NR a1 R b1 、-(CR c1 R d1 ) t S(=O) r R b1 、-(CR c1 R d1 ) t S(=O)2OR b1 、-(CR c1 R d1 ) t OS(=O)2R b1 、-(CR c1 R d1 ) t NR a1 S(=O) r R b1 、-(CR c1 R d1 ) t S(=O) r NR a1 R b1 , preferably selected from halogen, C 1-10 alkyl, CN, NO2, -(CR c1 R d1 ) t NR a1 R b1 、-(CR c1 R d1 ) t OR b1 、-(CR c1 R d1 ) t C(=O)R a1 、-(CR c1 Rd1 ) t C(=O)OR b1 、-(CR c1 R d1 ) t OC(=O)R b1 、-(CR c1 R d1 ) t C(=O)NR a1 R b1 and-(CR c1 R d1 ) t NR a1 C(=O)R b1 , wherein each alkyl, alkylene, cycloalkyl and heterocyclyl is unsubstituted or substituted with at least one independently selected from R Y In one embodiment, each R X , R X1 , R X2 , R X3 , R X4 , R X5 , R X6 , R X7 , R X8 and R X9 Independently selected from halogen, C 1-10 Alkyl, CN, NO2, -(CR c1 R d1 ) t NR a1 R b1 and-(CR c1 R d1 ) t OR b1 , wherein each alkyl group is unsubstituted or substituted with at least one independently selected from R Y In one embodiment, each R a1 and R b1 independently selected from hydrogen and C 1-10 Alkyl, wherein each alkyl is unsubstituted or substituted with at least one independently selected from R Y In one embodiment, each R c1 and R d1 independently selected from hydrogen, halogen and C 1-10 Alkyl, wherein each alkyl is unsubstituted or substituted with at least one independently selected from R Y substituted by a substituent.

[0124] In one embodiment, each R Y Independently selected from halogen, NO2, -CN, C 1-10 Alkyl, -OH, -O(C1-10 Alkyl), -NH2, -NH(C 1-10 Alkyl) and -N(C 1-10 alkyl)2, preferably selected from halogen, NO2, -CN and C 1-10 alkyl.

[0125] In one embodiment, W is N. In one embodiment, W is CR 1 .

[0126] In one embodiment, R 1 Selected from hydrogen, halogen, C 1-10 Alkyl, CN, NO2, -NR A1 R B1 、-OR A1 、-SR A1 、-C(=O)R A1 、-C(=O)OR A1 、-OC(=O)R A1 、-C(=O)NR A1 R B1 、-NR A1 C(=O)R B1 、-OC(=O)NR A1 R B1 、-NR A1 C(=O)OR B1 、-NR A1 C(=O)NR A1 R B1 、-NR A1 C(=S)NR A1 R B1 、-S(=O) r R A1 、-N=S(=O)R A1 R B1 、-S(=O)2OR A1 、-OS(=O)2R A1 、-NR A1 S(=O) r R B1 、-S(=O) r NR A1 R B1 and-NR A1 S(=O)2NR A1 R B1 , wherein each alkyl group is unsubstituted or substituted with at least one independently selected from R X1 In one embodiment, R 1 Selected from hydrogen and -OR A1 , preferably selected from hydrogen and -O(C 1-10alkyl), in particular selected from hydrogen and methoxy. 1 Selected from -NR A1 R B1 、-OR A1 and -C(=O)R A1 In one embodiment, R 1 is CN or NO2. In one embodiment, R 1 is selected from halogen, such as F. In one embodiment, each R A1 and R B1 independently selected from hydrogen and C 1-10 In a particular embodiment, R 1 For hydrogen.

[0127] In one embodiment, R 2 Selected from C 1-10 Alkyl, -NR A2 R B2 、-OR A2 、-SR A2 、-OC(=O)R A2 、-NR A2 C(=O)R B2 、-NR A2 C(=NR E2 )R B2 、-OC(=O)NR A2 R B2 、-NR A2 C(=O)OR B2 、-NR A2 C(=O)NR A2 R B2 、-NR A2 C(=S)NR A2 R B2 、-NR A2 C(=NR E2 )NR A2 R B2 、-OS(=O)2R A2 、-NR A2 S(=O) r R B2 、-NR A2 S(=O)(=NR E2 )R B2 、-NR A2 S(=O)2NR A2 R B2 and-NR A2 S(=O)(=NR E2 )NR A2 R B2, wherein each alkyl group is unsubstituted or substituted with at least one independently selected from R X2 In one embodiment, R 2 Selected from C 1-10 Alkyl, -NR A2 R B2 、-OR A2 、-SR A2 、-OC(=O)R A2 、-NR A2 C(=O)R B2 、-OS(=O)2R A2 and-NR A2 S(=O) r R B2 , wherein each alkyl group is unsubstituted or substituted with at least one independently selected from R X2 In one embodiment, R 2 Selected from C 1-10 Alkyl, -NR A2 R B2 、-OR A2 and-SR A2 , preferably selected from -NR A2 R B2 AND-OR A2 , especially -NR A2 R B2 In one embodiment, each R B2 Independently selected from C 1-10 alkyl, and each R A2 In one embodiment, each R A2 and R B2 In one embodiment, each R E2 independently selected from hydrogen and C 1-10 In a particular embodiment, R 2 is -NH2.

[0128] In one embodiment, R 3 Selected from CN, -C(=O)R A3 、-C(=O)OR A3 、-C(=O)NR A3 R B3 、-S(=O) r R A3 、-S(=O)2OR A3 and -S(=O) r NR A3 R B3 , preferably selected from CN, -C(=O)R A3 、-C(=O)NR A3 R B3and -S(=O) r NR A3 R B3 , especially -C(=O)NR A3 R B3 In one embodiment, each R B3 Independently selected from C 1-10 alkyl, and each R A3 In one embodiment, each R A3 and R B3 In one embodiment, each R E3 independently selected from hydrogen and C 1-10 In a particular embodiment, R 3 It is -C(=O)NH2.

[0129] In one embodiment, each R 4 Independently selected from halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cyclic hydrocarbon group, heterocyclic group, -C 1-4 Alkylene-heterocyclyl, CN, NO2, aryl, -C 1-4 Alkylene-aryl, heteroaryl, -C 1-4 Alkylene-heteroaryl, -NR A4 R B4 、-OR A4 、-SR A4 、-C(=O)R A4 、-C(=O)OR A4 、-OC(=O)R A4 、-C(=O)NR A4 R B4 、-NR A4 C(=O)R B4 、-S(=O) r R A4 、-S(=O)2OR A4 、-OS(=O)2R A4 、-NR A4 S(=O) r R B4 and -S(=O) r NR A4 R B4 , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R X4 In a particular embodiment, each R4 Independently selected from C 1-10 Alkyl, wherein the alkyl is unsubstituted or substituted by at least one independently selected from halogen, CN, -(CR c1 R d1 ) t NR a1 R b1 、-(CR c1 R d1 ) t OR b1 and-(CR c1 R d1 ) t SR b1 In one embodiment, wherein t is 0. In one embodiment, wherein each R a1 and R b1 independently selected from hydrogen and C 1-10 In a particular embodiment, g is 2, and one R 4 Selected from C 1-10 Alkyl, another R 4 Selected from halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 3-10 Cyclic hydrocarbon group, heterocyclic group, -C 1-4 Alkylene-heterocyclyl, CN, heteroaryl, -NR A4 R B4 、-OR A4 、-SR A4 、-C(=O)R A4 、-C(=O)NR A4 R B4 and -S(=O) r R A4 wherein each alkyl, alkenyl, cycloalkyl, heterocyclyl and heteroaryl is unsubstituted or substituted by at least one independently selected from R X4 In a particular embodiment, R 4 Selected from C 1-10 In one embodiment, the halogen is selected from F, Cl and Br. In one embodiment, the C 3-10 The cycloalkyl group is C 3-10 In one embodiment, each R A4 and R B4 independently selected from hydrogen and C 1-10 In one embodiment, each R A4 and R B4 Independently selected from C 1-10 In one embodiment, each R B4 Independently selected from C 1-10 alkyl, and each RA4 In one embodiment, each R A4 and R B4 In one embodiment, each R E4 independently selected from hydrogen and C 1-10 alkyl.

[0130] In one embodiment, each R 4 independently selected from F, Cl, Br, methyl, 2-methylpropyl, cyclopropane, isopropyl, tert-butyl, diethylamino, acetyl, carbamoyl, methoxy, ethoxy, methylthio, ethylthio, methylsulfonyl, piperidinyl, morpholinyl, pyridinyl, thiazolyl, vinyl, wherein the methyl, cyclopropane, isopropyl, tert-butyl, diethylamino, acetyl, carbamoyl, methoxy, ethoxy, methylthio, ethylthio, methylsulfonyl, piperidinyl, morpholinyl, pyridinyl, thiazolyl and vinyl are unsubstituted or replaced by at least one independently selected from R X4 In one embodiment, each R 4 independently selected from Cl, methyl, 2-methylpropyl, cyclopropane, isopropyl, tert-butyl, diethylamino, acetyl, carbamoyl, methoxy, ethoxy, methylthio, ethylthio, methylsulfonyl, In one embodiment, R 4 It is methyl.

[0131] In one embodiment, any two adjacent R 4 Together with the atoms to which they are attached, they form a C 5-6 A monocyclic hydrocarbon ring or a 5-6 membered heterocyclic ring containing 1, 2 or 3 heteroatoms, wherein the heteroatoms are independently selected from oxygen, sulfur, nitrogen and phosphorus, and the ring is unsubstituted or substituted by at least one independently selected from R X4 substituted by a substituent.

[0132] In one embodiment, any two adjacent R 4 Together with the atoms to which they are attached, they form The ring is unsubstituted or substituted with at least one independently selected from R X4 substituted by a substituent; wherein Represents R 4 The site of attachment to Ring A. In one embodiment, any two adjacent R 4 Together with the atoms they are attached to, they form the following structure:

[0133] In one embodiment, R 5 Selected from C 1-10 In a particular embodiment, R 5 It is methyl.

[0134] In one embodiment, R 6 Selected from hydrogen, halogen, C 1-10 Alkyl, CN, NO2, -NR A6 R B6 AND-OR A6 , especially hydrogen and halogen, wherein each alkyl is unsubstituted or substituted by at least one independently selected from R X6 In a particular embodiment, R 6 In another particular embodiment, R 6 For F.

[0135] In one embodiment, R 7 Selected from hydrogen, halogen, C 1-10 Alkyl, CN, NO2, -NR A7 R B7 AND-OR A7 , especially hydrogen and halogen, wherein each alkyl is unsubstituted or substituted by at least one independently selected from R X7 In a particular embodiment, R 7 In another particular embodiment, R 7 For F.

[0136] In one embodiment, R 8 Selected from halogen, C 1-10 Alkyl, CN, NO2, -NR A8 R B8 AND-OR A8 , wherein each alkyl group is unsubstituted or substituted with at least one independently selected from R X8 In a particular embodiment, R 8 It is -OH.

[0137] In one embodiment, R 9 Selected from C 1-10 Alkyl, wherein each alkyl is unsubstituted or substituted with at least one independently selected from R X9 In a particular embodiment, R 9 It is methyl.

[0138] In one embodiment, R 8 and R 9 Together with the atoms to which they are attached, they form a 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring containing 1, 2 or 3 heteroatoms, and the formula (I) has the structure of the following formula (I-1):

[0139]

[0140] in,

[0141] X 1 Selected from N(R 10a )、N、O、S、C(R 10a R 10a ') and C(R 10a );

[0142] X 2 Selected from N(R 10b )、N、O、S、C(R 10b R 10b ') and C(R 10b );

[0143] X 3 Selected from N(R 10c )、N、O、S、C(R 10c R 10c ') and C(R 10c );

[0144] R 10a , R 10a '、R 10b , R 10b '、R 10c and R 10c ' are each independently selected from hydrogen and R X ;

[0145] is a single bond or a double bond;

[0146] Ring A, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , W are as defined in formula (I).

[0147] In one embodiment, X 1 Selected from N(R 10a );X 2 N; X 3 C(R 10c );X 2 With X 3 The bond between is a double bond. 10a is NH or N(CH3), especially NH. 10c Selected from hydrogen and C 1-10 Alkyl, preferably hydrogen.

[0148] In one embodiment, R 2 For-NR A2 R B2 ; R 3Selected from -C(=O)NR A3 R B3 ; R 8 Selected from -OR A8 .

[0149] In one embodiment, R 2 is -NH2; R 3 is -C(=O)NH2; R 8 is -OH, and formula (I) has the structure of formula (I-i) as follows:

[0150]

[0151] Wherein,

[0152] Ring A, R 4 , g, R 5 , R 6 , R 7 , R 9 , W are as defined in formula (I).

[0153] In one embodiment, R 2 is -NH2; R 3 is -C(=O)NH2; R 5 is methyl; R 6 is hydrogen; R 7 is hydrogen; R 8 is -OH; R 9 is methyl.

[0154] In one embodiment, ring A is selected from a benzene ring and a 5- or 6-membered heteroaromatic ring, which is substituted with g substituents independently selected from R 4 . In one embodiment, ring A is selected from thiazole, thiophene, oxazole, furan, benzene ring, which is substituted with g substituents independently selected from R 4 .

[0155] In one embodiment, ring A is selected from a 5-membered heteroaromatic ring, which is substituted with g substituents independently selected from R 4 .

[0156] In one embodiment, ring A is selected from a 5-membered heteroaromatic ring, and formula (I) has the structure of formula (II) as follows:

[0157]

[0158] Wherein,

[0159] A 1 is selected from N(R 4a ), N, O, S and C(R 4a );

[0160] A 2Selected from N(R 4b ), N, O, S and C(R 4b );

[0161] A 3 Selected from N(R 4c ), N, O, S and C(R 4c );

[0162] R 4a , R 4b and R 4c are each independently selected from hydrogen and R 4 ;

[0163] is a single bond or double bond that keeps ring A aromatic;

[0164] R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , W are as defined in formula (I).

[0165] In one embodiment, R 4b is selected from halogen, C 1-10 alkyl, C 2-10 alkenyl, C 3-10 cycloalkyl, heterocyclic group, -C 1-4 alkylene-heterocyclic group, CN, heteroaryl, -NR A4 R B4 , -OR A4 , -SR A4 , -C(=O)R A4 , -C(=O)NR A4 R B4 and -S(=O) r R A4 , wherein each alkyl, alkenyl, cycloalkyl, heterocyclic group and heteroaryl is unsubstituted or substituted by at least one substituent independently selected from R X4 . In one embodiment, R 4a and R 4c , if applicable, are each independently selected from hydrogen, halogen and C 1-10 alkyl, especially each independently selected from C 1-10 alkyl; wherein the alkyl is unsubstituted or substituted by at least one substituent independently selected from R X4 . In one embodiment, ring A is thiazole, R 4b is selected from C 1-10 alkyl; wherein the alkyl is unsubstituted or substituted by at least one independently selected from RX4 In one embodiment, ring A is thiophene, R 4b Selected from C 1-10 Alkyl; R 4a and R 4c , if applicable, each independently selected from C 1-10 Alkyl; wherein each alkyl is unsubstituted or substituted by at least one independently selected from R X4 substituted by a substituent.

[0166] In a particular embodiment, Ring A is selected from thiazole, thiophene, oxazole and furan, R 2 -NH2, R 3 is -C(=O)NH2, R 8 is -OH, and the compound of formula (Ii) or formula (II) has the structure of formula (II-i), formula (II-ii), formula (II-iii), formula (II-iv), formula (II-v), formula (II-vi), formula (II-vii) or formula (II-viii):

[0167]

[0168] in,

[0169] R 4a , R 4b , R 4c , R 5 , R 6 , R 7 , R 9 , W are as defined in formula (II).

[0170] In one embodiment, R 8 and R 9 Together with the atoms to which they are attached, they form a 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring containing 1, 2 or 3 heteroatoms, and the formula (II) has the following structure (II-1):

[0171]

[0172] in,

[0173] is a single bond or a double bond, wherein the ring A is aromatic;

[0174] X 1 , X 2 , X 3 As defined in formula (I-1);

[0175] A 1 , A 2 , A 3 , R2 , R 3 , R 5 , R 6 , R 7 , W are as defined in formula (II).

[0176] In one embodiment, ring A is selected from a benzene ring and a 6-membered heteroaromatic ring, which is independently selected from R 4 In one embodiment, ring A is a benzene ring.

[0177] In one embodiment, ring A is selected from a benzene ring and a 6-membered heteroaromatic ring, and formula (I) has the structure of formula (III):

[0178]

[0179] in,

[0180] A 4 Selected from N and C (R 4d );

[0181] A 5 Selected from N and C (R 4e );

[0182] A 6 Selected from N and C (R 4f );

[0183] A 7 Selected from N and C (R 4g );

[0184] R 4d , R 4e , R 4f and R 4g are each independently selected from hydrogen and R 4 ;

[0185] A single bond or double bond to keep ring A aromatic;

[0186] R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , W are as defined in formula (I).

[0187] In one embodiment, R 4d and R 4g For hydrogen.

[0188] In one embodiment, R 4e and R4f One of halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 3-10 Cyclic hydrocarbon group, heterocyclic group, -C 1-4 Alkylene-heterocyclyl, CN, heteroaryl, -NR A4 R B4 、-OR A4 、-SR A4 、-C(=O)R A4 、-C(=O)NR A4 R B4 and -S(=O) r R A4 , wherein each alkyl, alkenyl, cycloalkyl, heterocyclyl and heteroaryl is unsubstituted or substituted with at least one independently selected from R X4 Substituents substituted; R 4e and R 4f Another one in R 4d and R 4g , if applicable, are each independently selected from hydrogen, halogen and C 1-10 Alkyl; wherein each alkyl is unsubstituted or substituted by at least one independently selected from R X4 substituted by a substituent.

[0189] In one embodiment, R 4e and R 4f Each independently selected from C 1-10 Alkyl, wherein the alkyl group is unsubstituted or substituted with at least one independently selected from R X4 Substituents substituted; R 4d and R 4g For hydrogen.

[0190] In one embodiment, R 4d , R 4e , R 4f and R 4g For hydrogen.

[0191] In one embodiment, R 8 and R 9 Together with the atoms to which they are attached, they form a 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring containing 1, 2 or 3 heteroatoms, and the formula (III) has the following structure (III-1):

[0192]

[0193] in,

[0194] is a single bond or a double bond;

[0195] X 1, X 2 , X 3 As defined in formula (I-1);

[0196] A 1 , A 2 , A 3 , R 2 , R 3 , R 5 , R 6 , R 7 , W are as defined in formula (III).

[0197] In one embodiment, the compounds of the present invention exist as torsional isomers, which are composed of a fused ring containing ring A and R 5 , R 6 , R 7 , R 8 and R 9 The single bond rotation between the substituted phenyl groups is hindered.

[0198] In one embodiment, formula (I) has the structure of formula (Ia) or (Ib). In one embodiment, formula (I-1) has the structure of formula (Ia-1) or (Ib-1). In one embodiment, formula (II) has the structure of formula (IIa) or (IIb). In one embodiment, formula (II-1) has the structure of formula (IIa-1) or (IIb-1). In one embodiment, formula (III) has the structure of formula (IIIa) or (IIIb). In one embodiment, formula (III-1) has the structure of formula (IIIa-1) or (IIIb-1). In one embodiment, the compound of the present invention has the structure of formula (Ia), (Ia-1), (IIa), (IIa-1), (IIIa) or (IIIa-1). In one embodiment, the compound of the present invention has the structure of formula (Ib), (Ib-1), (IIb), (IIb-1), (IIIb) or (IIIb-1).

[0199]

[0200] In one embodiment, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0201]

[0202]

[0203] In one embodiment, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0204]

[0205]

[0206] In one embodiment, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0207]

[0208]

[0209]

[0210] Preparation method

[0211] In another aspect, the present invention provides a method for preparing a compound of formula (Ii) or a pharmaceutically acceptable salt thereof, comprising the following steps (1), (2) and (3):

[0212] (1) Preparation of intermediate E, which comprises the following steps (1a-1) and (1a-2), or comprises the following steps (1b-1) and (1b-2);

[0213]

[0214] in,

[0215] w 1 is selected from halogen, preferably Br or I;

[0216] Each w 2 Independently selected from halogen, preferably Br or Cl;

[0217] Ring A, R 1 , R 4 , g is as defined in formula (Ii);

[0218] Step (1a-1) includes the following steps (1a-1i), (1a-1ii) and (1a-1iii):

[0219] (1a-1i) makes w 2 Carrying out a cyanation reaction with a cyanation reagent 1 to obtain a cyano compound;

[0220] (1a-1ii) converting the cyano group of the cyano compound obtained in (1a-1i) into a carbamoyl group, said conversion being carried out by further

[0221] The original reaction or hydrolysis reaction proceeds;

[0222] (1a-1iii) reducing the nitro group to an amino group;

[0223] wherein step (1a-1iii) is performed before step (1a-1i), between step (1a-1i) and step (1a-1ii), or after step (1a-1ii), or simultaneously with step (1a-1ii);

[0224] Step (1a-2) comprises subjecting the intermediate Ea-2 to a halogenation reaction with a halogenating agent 1;

[0225] Step (1b-1) comprises subjecting the intermediate Eb-1 to a cyanation reaction with a cyanation reagent 2;

[0226] Step (1b-2) comprises subjecting the intermediate Eb-2 to a halogenation reaction with a halogenating agent 2.

[0227] In one embodiment, steps (1a-1i) are performed under heating conditions.

[0228] In one embodiment, step (1a-1ii) is carried out by a reduction reaction. In one embodiment, the reducing agent of the reduction reaction is iron powder. In one embodiment, the reduction reaction is carried out in the presence of ammonium chloride and, optionally, under heating conditions.

[0229] In one embodiment, steps (1a-1ii) are carried out by a hydrolysis reaction. In one embodiment, the hydrolysis reaction is carried out under acidic conditions, such as in concentrated sulfuric acid, and, optionally, under heating conditions.

[0230] In one embodiment, the reducing agent of the reduction reaction of step (1a-1iii) is iron powder. In one embodiment, the reduction reaction is carried out in the presence of ammonium chloride and, optionally, under heating conditions.

[0231] In one embodiment, step (1a-1iii) is performed before step (1a-1i), and step (1a-1ii) is performed by a hydrolysis reaction.

[0232] In one embodiment, step (1a-1ii) is performed by a reduction reaction, and step (1a-1iii) is performed simultaneously with step (1a-1ii).

[0233] In one embodiment, step (1b-1) is performed under heating conditions.

[0234] In one embodiment, cyanation reagent 1 and cyanation reagent 2 are independently selected from CuCN, NaCN, KCN and Zn(CN)2. Preferably, cyanation reagent 1 and cyanation reagent are CuCN.

[0235] In one embodiment, the halogenating agent 1 is NBS.

[0236] In one embodiment, the halogenating agent 2 is NIS.

[0237] (2) Preparation of intermediate T or its pharmaceutically acceptable salt:

[0238]

[0239] in,

[0240] Y is a boronic acid group or a boronic ester group, in particular a boronic acid group;

[0241] PG is a hydroxyl protecting group;

[0242] Step (2) comprises subjecting the intermediate E to a coupling reaction with the compound Q.

[0243] In one embodiment, PG is methyl.

[0244] In one embodiment, the boric acid ester is pinacol borate.

[0245] In one embodiment, the coupling reaction of step (2) is a Suzuki reaction. In one embodiment, step (2) is carried out in the presence of a palladium catalyst, and the palladium catalyst is preferably selected from Pd(dppf)Cl2, Pd(PPh3)4, SPhos-Pd-G3 and RuPhos-Pd-G3, in particular selected from Pd(dppf)Cl2 and SPhos-Pd-G3. In one embodiment, step (2) is carried out in a mixed solvent of dioxane and water, and, optionally, in the presence of a base, and, optionally, under heating conditions. In one embodiment, the base is K2CO3.

[0246] (3) The preparation of the compound of formula (Ii) or a pharmaceutically acceptable salt thereof, which comprises the following step (3a), or comprises the following step (3b-1) and step (3b-2);

[0247]

[0248] in,

[0249] Step (3a) comprises removing the protecting group PG;

[0250] Step (3b-1) comprises converting a cyano group into a carbamoyl group, wherein the conversion is carried out by a reduction reaction or a hydrolysis reaction;

[0251] Step (3b-2) involves removing the protecting group PG.

[0252] In one embodiment, PG is methyl, and the deprotecting agent in step (3a) and step (3b-2) is BBr3.

[0253] In one embodiment, step (3b-1) is carried out by a hydrolysis reaction. In one embodiment, the hydrolysis reaction of step (3b-1) is carried out in the presence of H2O2 and a reducing agent, and optionally under alkaline conditions. In a preferred embodiment, the reducing agent is DMSO. In a preferred embodiment, step (3b-1) is carried out in the presence of K2CO3.

[0254] In one embodiment, the compound of formula (Ii) has the structure of formula (II-i), and W is N, the intermediate Ea-1 has the structure of the following intermediate C, and the preparation method of the present invention further comprises the following steps:

[0255] (1') Preparation of intermediate C; comprising the following steps (1'-1) and (1'-2);

[0256]

[0257] in,

[0258] Step (1'-1) subjecting compound C-1 to a cyclization reaction with thioamide compound C-2 to prepare compound C-3;

[0259] Step (1'-2) comprises converting the amino group into a halogen, and the conversion is carried out by a diazotization reaction and a halogenation reaction carried out successively. In one embodiment, the conversion is carried out by a nitrosation reaction and a halogenation reaction carried out successively.

[0260] In one embodiment, the compound C-2 of step (1'-1) is present in excess relative to compound C-1. In one embodiment, step (1'-1) is carried out in a solvent selected from diphenyl ether, ethanol, dioxane, sulfolane, preferably in sulfolane. In one embodiment, step (1'-1) is carried out under heating conditions.

[0261] In one embodiment, w 2 is Br, and the halogenating agent 3 is CuBr2. In one embodiment, the diazotizing agent (nitrosating agent) of step (1'-2) is tert-butyl nitrite.

[0262] PROTAC compounds and antibody-drug conjugates (ADCs)

[0263] In another aspect, the present invention provides a PROTAC compound comprising a compound of the present invention, an E3 ubiquitin ligase binding ligand, and a linker connecting the compound of the present invention and the E3 ubiquitin ligase binding ligand. The compound of the present invention can be used as a ligand to bind to PKMYT1. In one embodiment, the PROTAC compound can be used to promote the degradation of PKMYT1 by UPS.

[0264] In yet another aspect, the present invention provides an antibody-drug conjugate comprising a compound of the present invention, an antibody capable of binding to a target, and a linker connecting the compound of the present invention and the antibody.

[0265] Pharmaceutical compositions and pharmaceutical preparations

[0266] Another object of the present invention is to provide a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer, isotope compound, metabolite or prodrug thereof, and at least one pharmaceutically acceptable carrier.

[0267] The pharmaceutical composition of the present invention can be administered in any manner as long as it achieves the effect of preventing, alleviating, preventing or treating human or animal symptoms. For example, various suitable dosage forms can be prepared according to the route of administration. For example, it can be administered orally or parenterally to a patient in the form of a conventional preparation. The conventional preparations are such as capsules, microcapsules, tablets, granules, powders, lozenges, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions and emulsions.

[0268] The dosage of the compound administered to a subject can be adjusted to a considerable extent. The dosage can vary depending on the specific route of administration and the needs of the subject, and can be subject to the judgment of a healthcare professional.

[0269] Treatments and uses

[0270] According to certain embodiments of the present invention, the present invention or its pharmaceutically acceptable salts, stereoisomers, solvates, polymorphs, tautomers, isotopic compounds, metabolites or prodrugs or pharmaceutical compositions of the present invention can be used to prevent or treat PKMYT1-mediated diseases, or diseases responsive to the inhibition of PKMYT1, including but not limited to abnormal cell proliferation diseases, such as cancer.

[0271] Therefore, in another aspect, the present invention also provides the use of the compound of the present invention or its pharmaceutically acceptable salt or the pharmaceutical composition of the present invention in the preparation of a medicament for treating a disease, disorder or condition, wherein the disease, disorder or condition is selected from a cell proliferation abnormality disease, and the compound or its pharmaceutically acceptable salt or pharmaceutical composition is optionally used in combination with a second therapeutic agent.

[0272] In another aspect, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present invention, optionally in combination with a second therapeutic agent, for use in treating a cell proliferation disorder.

[0273] In a further aspect, the present invention provides a method for treating a cell proliferation disorder, the method comprising administering to an individual in need thereof an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention, wherein the compound or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition is optionally used in combination with a second therapeutic agent.

[0274] In one embodiment, the disease, disorder or condition is selected from a cancerous proliferative disease (eg, cancer).

[0275] In one embodiment, the disease, disorder or condition is cancer, for example selected from: (a) a solid tumor or a blood-borne tumor selected from the following cancers: bladder cancer, endometrial cancer, squamous cell lung cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, small cell lung cancer, esophageal cancer, gallbladder cancer, brain cancer, head and neck cancer, ovarian cancer, pancreatic cancer, gastric cancer, cervical cancer, thyroid cancer, prostate cancer and skin cancer; (b) a hematopoietic tumor of the lymphoid lineage selected from the following: leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, (c) hematopoietic neoplasms of the myeloid lineage selected from the group consisting of acute and chronic myeloid leukemias, myelodysplastic syndromes and promyelocytic leukemias; (d) tumors of mesenchymal origin selected from the group consisting of fibrosarcomas and rhabdomyosarcomas; (e) tumors of the central and peripheral nervous systems selected from the group consisting of astrocytomas, neuroblastomas, gliomas and schwannomas; and (f) melanomas, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, follicular thyroid carcinoma and Kaposi's sarcoma.

[0276] In one embodiment, the disease, disorder or condition is selected from CCNE1 amplified cancer. In one embodiment, the disease, disorder or condition is selected from uterine sarcoma, ovarian cancer, breast cancer, gastric cancer, esophageal cancer, lung cancer, liver cancer and endometrial cancer.

[0277] In one embodiment, the disease, disorder or condition is selected from FBXW7 mutant cancer, such as a cancer with an inactivating mutation in the FBXW7 gene. In one embodiment, the disease, disorder or condition is selected from a blood tumor, a glioma, a liver cancer (e.g., hepatocellular carcinoma), a uterine cancer (e.g., endometrial carcinoma), a colorectal cancer (e.g., colorectal adenocarcinoma), a breast cancer, a lung cancer (e.g., non-small cell lung cancer (NSCLC)), a gastric cancer, an esophageal cancer, an esophageal junction adenocarcinoma, a bladder cancer (e.g., urothelial bladder carcinoma), a head and neck cancer (e.g., head and neck squamous cell carcinoma), a cervical cancer (e.g., cervical squamous cell carcinoma), a melanoma, an ovarian cancer (e.g., high-grade serous ovarian cancer).

[0278] In one embodiment, the disease, disorder or condition is selected from a TP53 mutant cancer, such as a cancer in which the TP53 gene has an inactivating mutation.

[0279] In a particular embodiment, the disease, disorder or condition is breast cancer or ovarian cancer.

[0280] Combination therapy

[0281] The compound of the present invention or its pharmaceutically acceptable salt or the pharmaceutical composition of the present invention can be used alone or in combination with other therapeutic agents.

[0282] For example, the use of an adjuvant can enhance the therapeutic effect of the compounds of the present invention (for example, the therapeutic benefit of using an adjuvant alone is minimal, but when used in combination with another drug, the therapeutic benefit of the individual can be enhanced), or, for example, the compound of the present invention combined with another therapeutic agent that also has therapeutic effects can enhance the therapeutic benefit of the individual. For example, when treating cancer, when using the compound of the present invention, the combined use of another drug for treating cancer may enhance the clinical benefit. Therapies that can be combined include but are not limited to physical therapy, psychotherapy, radiotherapy, chemotherapeutic agents, small molecule targeted therapeutic agents (such as kinase inhibitors, immune agonists), immunotherapy (anti-PD-1, anti-PDL-1, CAR-T cells), etc. Regardless of the disease, disorder or condition, the two therapies should have an additive effect or a synergistic effect to benefit the treatment of the individual.

[0283] In one embodiment, the other therapeutic agent is selected from inhibitors of WEE family members, such as WEE1 inhibitors. In one embodiment, the other therapeutic agent is selected from cancer therapeutic agents targeting DNA, such as therapeutic agents that directly destroy DNA structure or DNA topoisomerase inhibitors. Examples of therapeutic agents that directly destroy DNA structure include, but are not limited to, DNA double strand breakers, DNA alkylating agents, and DNA intercalators.

[0284] In one embodiment, the additional therapeutic agent is selected from a WEE1 inhibitor, a FEN1 (flap-specific endonuclease 1) inhibitor, a TOP1 (DNA topoisomerase I) inhibitor, a RRM1 (ribonucleotide reductase catalytic subunit M1) inhibitor, a RRM2 (ribonucleotide reductase regulatory subunit M2) inhibitor, an AURKB (aurora kinase B) inhibitor, a TOP2A (DNA topoisomerase IIα) inhibitor, an ATR (ataxia telangiectasia mutated and RAD-3-related protein kinase) inhibitor, a TTK (TTK protein kinase) inhibitor, a SOD1 (superoxide dismutase 1) inhibitor, a SOD2 (superoxide dismutase 2) inhibitor, a BUB1 (BUB1 mitotic checkpoint serine / threonine kinase B) inhibitor, a CDC7 (cell division cycle protein 7) inhibitor, a SAE1 (SU MO1 activating enzyme subunit 1) inhibitors, PLK1 (polo-like kinase 1) inhibitors, UBA2 (ubiquitin-like modifier activating enzyme 2) inhibitors, DUT (deoxyuridine triphosphatase) inhibitors, HDAC3 (histone deacetylase 3) inhibitors, CHEK1 (checkpoint kinase 1) inhibitors, AURKA (aurora kinase A) inhibitors, menin inhibitors, DOT1L (DOT1-like histone lysine methyltransferase) inhibitors, CREBBP (CREB-binding protein) inhibitors, EZH2 (polycomb repressive complex 2 subunit enhancer of zeste gene human homolog 2) inhibitors, PLK4 (polo-like kinase 4) inhibitors, HASPIN (histone H3-associated protein kinase) inhibitors, METTL3 (methyltransferase 3) inhibitors, nucleoside analogs, platinum-based DNA damaging agents.

[0285] Beneficial Effects

[0286] The novel small molecule PKMYT1 inhibitor provided by the present invention shows outstanding PKMYT1 inhibitory activity and cell proliferation inhibitory activity.

[0287] Therefore, the compounds of the present invention can prevent or treat diseases mediated by PKMYT1, or diseases responsive to the inhibition of PKMYT1, including but not limited to abnormal cell proliferation diseases such as cancer, and have good prospects for development as drugs.

[0288] The compounds of the present invention achieve at least one of the following technical effects:

[0289] (1) It has high inhibitory activity against target cells.

[0290] (2) Excellent physicochemical properties (e.g. solubility, physical and / or chemical stability).

[0291] (3) Excellent pharmacokinetic properties (e.g., good stability in plasma, appropriate half-life and duration of action).

[0292] (4) Excellent safety (lower toxicity and / or fewer side effects to non-target normal cells or tissues, wider therapeutic window), etc.

[0293] Example

[0294] In order to more clearly illustrate the purpose and technical scheme of the present invention, the present invention is further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The specific experimental methods not mentioned in the following examples are all carried out according to conventional experimental methods.

[0295] Instruments, Materials and Reagents

[0296] Unless otherwise specified, the instruments and reagents used in the examples are commercially available and can be used directly without further purification.

[0297] LCMS: SHIMADZ LCMS2020, Column: Waters SunFire TM C18 5μm 50*4.6mm; mobile phase A: H2O (containing 0.1% formic acid); mobile phase B: CH3CN (containing 0.1% formic acid).

[0298] NMR: Bruker Avance III 400M.

[0299] Synthesis scheme

[0300] The compound of formula (I) or its pharmaceutically acceptable salt can be synthesized by different methods, some exemplary methods are provided below and in the Examples. Other synthetic methods can be easily proposed by those skilled in the art based on the information disclosed in the present invention.

[0301] In the reactions described below, it may be necessary to protect the active groups to prevent them from participating in other undesirable reactions: such groups as hydroxyl, amino, imino, sulfhydryl or carboxyl groups, which are contained in the final product. Commonly used protecting groups can be found in TW Greene and PGM Wuts in "Protective Groups in Organic Chemistry" John Wiley and Sons, 1991.

[0302] The synthetic schemes of all compounds of the present invention are illustrated by the following schemes and examples. The raw materials used are commercially available or can be prepared according to existing process methods or the methods exemplified herein.

[0303] As shown in Synthesis Scheme 1, the compound of formula (I) can be prepared from compound M1 and compound M2 by various methods. 1 is a leaving group, for example, selected from halogen, OTf, especially halogen; Y in M2 is a boronic acid group or a boronic ester group, especially a boronic acid group. 2 '、R 3 '、R 5 '、R 6 '、R 7 '、R 8 '、R 9 ' are R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 Alternatively, group conversion (including but not limited to deprotection) can be performed by conventional reactions to obtain R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 In one embodiment, the coupling reaction is a Suzuki reaction.

[0304]

[0305] Synthesis Scheme 1

[0306] Compound M1 and Compound M2 used as starting materials are known, or can be prepared by known methods, or by the method provided by the present invention.

[0307] In some cases, the order in which the above reaction schemes are carried out can be changed to promote the reaction or to avoid unwanted reaction products. The following examples are provided so that the present invention can be more fully understood. These examples are illustrative only and should not be construed as limiting the present invention in any way.

[0308] Example 16-amino-5-(3-hydroxy-2,6-dimethylphenyl)-2,3-dimethylthieno[3,2-b]pyridine- 7-Carboxamide (Compound 001)

[0309]

[0310] 1.1 Synthesis of intermediate 1-2:

[0311]

[0312] 3-Amino-4-methylthiophene-2-carboxylic acid methyl ester (5g) was dissolved in acetonitrile (50mL), trifluoroacetic anhydride (6mL) and pyridine (2.8mL) were added at 0°C, and stirred at 25°C for 2 hours. The reaction solution was poured into ice water (100mL) to quench, extracted with ethyl acetate (60mLx3), the organic phase was washed with saturated brine (50mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100:1 to 10:1) to obtain intermediate 1-2 (7.5g). LCMS: MS m / z (ESI): 268.0 [M+H] + .

[0313] 1.2 Synthesis of intermediate 1-3:

[0314]

[0315] Intermediate 1-2 (5.5 g) was dissolved in acetic acid (50 mL), and liquid bromine (1.6 mL) was added, and the mixture was reacted at 35 ° C for 3 hours. Saturated sodium thiosulfate aqueous solution (100 mL) was added to the reaction solution to quench, and the mixture was stirred for 10 minutes. Solids precipitated, and the solids were filtered and the filter cake was washed with water (100 mL). The filter cake was dried in vacuo to obtain intermediate 1-3 (6.6 g). LCMS: MS m / z (ESI): 346.0 [M+H] + .

[0316] 1.3 Synthesis of intermediate 1-4:

[0317]

[0318] Intermediate 1-3 (36.5 g) was dissolved in methanol (300 mL), and 2 mol / L potassium carbonate aqueous solution (260 mL) was added, and the mixture was reacted at 80°C for 3 hours. The reaction solution was cooled and concentrated under reduced pressure, dissolved in water (100 mL), and extracted with ethyl acetate (200 mL x 3). The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain intermediate 1-4 (24.5 g). LCMS: MS m / z (ESI): 250.0 [M+H] + .

[0319] 1.4 Synthesis of intermediate 1-5:

[0320]

[0321] Intermediate 1-4 (5.0 g) was dissolved in dioxane (50 mL) and water (5 mL), and trimethylcyclotriboroxane (11.1 mL), potassium carbonate (5.5 g), and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (1.4 g) were added in sequence, and the mixture was reacted at 120° C. for 16 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure. The residue was chromatographed on a silica gel column (petroleum ether: ethyl acetate = 100:1 to 15:1) to obtain intermediate 1-5 (2.3 g).

[0322] LCMS:MS m / z(ESI):186.1[M+H] + .

[0323] 1.5 Synthesis of intermediate 1-6:

[0324]

[0325] Intermediate 1-5 (3 g) was dissolved in ethanol (30 mL), and 45% potassium hydroxide aqueous solution (15 mL) was added, and stirred at 100°C for 1 hour. The reaction solution was cooled to room temperature, and hydrochloric acid (6 N) was slowly added in an ice-water bath to adjust the pH to 2, and stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure, and solids precipitated after adding isopropanol (100 mL). The insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain intermediate 1-6 (3.1 g, crude product).

[0326] LCMS:MS m / z(ESI):128.1[M+H] + .

[0327] 1.6 Synthesis of intermediate 1-7:

[0328]

[0329] 2,2-dimethyl-1,3-dioxane-4,6-dione (2.03 g) was dissolved in trimethyl orthoformate (15.3 mL) and stirred at 90°C for 2 hours under nitrogen protection. The reaction solution was cooled to room temperature, and intermediate 1-6 (1.8 g) was added and stirred at 90°C for 6 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the residue was chromatographed on a silica gel column (petroleum ether: ethyl acetate = 60:1 to 10:1) to obtain intermediate 1-7 (1.8 g).

[0330] 1.7 Synthesis of intermediate 1-8:

[0331]

[0332] Intermediate 1-7 (1.1 g) was dissolved in diphenyl ether (10 mL) and stirred at 260°C for 40 minutes. Petroleum ether (50 mL) was added to the reaction solution until a large amount of solid precipitated, filtered, and the filter cake was dried under vacuum to obtain Intermediate 1-8 (0.57 g). LCMS: MS m / z (ESI): 180.1 [M+H] + .

[0333] 1.8 Synthesis of intermediate 1-9:

[0334]

[0335] Intermediate 1-8 (3.2 g) was dissolved in propionic acid (40 mL), fuming nitric acid (1.5 mL) was added at 110 ° C, and the temperature was raised to 150 ° C and stirred for 60 minutes. After cooling to room temperature, ether (100 mL) was added until a large amount of solid precipitated, and filtered. The filter cake was first washed with water (80 mL) and then with a mixed solution of methanol and ether (60 mL, 1:1). The obtained solid was vacuum dried to obtain intermediate 1-9 (2.8 g).

[0336] LCMS:MS m / z(ESI):225.1[M+H] + .

[0337] 1.9 Synthesis of intermediate 1-10:

[0338]

[0339] Intermediate 1-9 (2.67 g) was dissolved in acetonitrile (40 mL), phosphorus oxybromide (10.23 g) was added, and the temperature was raised to 90°C and stirred for 2 hours. The reaction solution was cooled to room temperature, the pH was adjusted to 7 with saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate (60 mL x 3), the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 1-10 (3.1 g). LCMS: MS m / z (ESI): 287.0 [M+H] + .

[0340] 1.10 Synthesis of intermediate 1-11:

[0341]

[0342] Dissolve the intermediate 1-10 (2.4 g) in a mixed solution of ethanol (30 mL) and water (3 mL), add iron powder (2.3 g) and ammonium chloride (2.2 g), heat to 85 ° C and stir for 3 hours. Filter the reaction solution, dilute the filtrate with saturated brine (50 mL), and extract with ethyl acetate (50 mL x 3). The organic phase is dried over anhydrous sodium sulfate and filtered, and the filtrate is concentrated under reduced pressure to obtain the intermediate 1-11 (2.1 g, crude product). LCMS: MS m / z (ESI): 257.0 [M+H] + .

[0343] 1.11 Synthesis of intermediate 1-12:

[0344]

[0345] The intermediate 1-11 (1g) was dissolved in pyrrolidone (10mL), and cuprous cyanide (698mg) was added. The reaction was carried out under the protection of nitrogen at 180°C for 80 minutes by microwave. The reaction solution was filtered, and solids were precipitated after the filtrate was added with water (100mL). The precipitated solids were filtered, the filter cake was dissolved with hydrochloric acid (2N, 50mL), and then extracted with dichloromethane (50mLx3). The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain the intermediate 1-12 (305mg). LCMS: MS m / z (ESI): 204.1 [M+H] + .

[0346] 1.12 Synthesis of intermediate 1-13:

[0347]

[0348] The intermediate 1-12 (300 mg) was dissolved in acetic acid (5 mL), and tribromopyridinium salt (496 mg) and sodium acetate (241 mg) were added, and the mixture was reacted at 25°C for 4 hours. The reaction solution was added with saturated sodium bicarbonate aqueous solution to adjust the pH to 7, extracted with dichloromethane (30 mL x 3), and the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated and purified by thin layer preparation (petroleum ether: ethyl acetate = 3:1) to obtain the intermediate 1-13 (100 mg). LCMS: MSm / z (ESI): 282.0 [M+H] + .

[0349] 1.13 Synthesis of intermediate 1-14:

[0350]

[0351] Intermediate 1-13 (50 mg) was dissolved in sulfuric acid (1 mL) and reacted at 55 ° C for 1 hour. The reaction solution was adjusted to pH 7 with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane (30 mL x 3), the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was added to a mixed solution of petroleum ether and ethyl acetate (2 mL, petroleum ether: ethyl acetate = 10: 1) for slurrying. The obtained solid was filtered and the filter cake was dried in vacuo to obtain intermediate 1-14 (40 mg). LCMS: MS m / z (ESI): 300.0 [M + H] + .

[0352] 1.14 Synthesis of intermediate 1-15:

[0353]

[0354] Intermediate 1-14 (40 mg) was dissolved in dioxane (2 mL) and water (0.2 mL), and (3-methoxy-2,6-dimethylphenyl)boronic acid (117 mg), potassium carbonate (53.9 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (9.5 mg) were added, and microwave reaction was carried out at 140°C for 1 hour under nitrogen protection. After cooling, the reaction solution was concentrated under reduced pressure, and the residue was purified by thin layer preparative chromatography (petroleum ether: ethyl acetate = 2:1) to obtain intermediate 1-15 (10 mg). LCMS: MS m / z (ESI): 356.2 [M+H] + .

[0355] 1.15 Synthesis of Compound 001:

[0356]

[0357] The intermediate 1-15 (8 mg) was dissolved in dichloromethane (1 mL), cooled to 0°C, and boron tribromide (1 mL) was added dropwise to the reaction system. The reaction was stirred at 25°C for 60 minutes. Saturated sodium bicarbonate solution was added to the reaction solution to quench, and the pH of the reaction solution was adjusted to 7. The reaction solution was concentrated under reduced pressure, the residue was dissolved in methanol (5 mL), filtered, and the filter cake was washed with methanol (5 mL x 3). After the filtrate was concentrated, it was purified by high performance liquid preparative chromatography (chromatographic column: Sunfire Prep C18 OBD 19*250mm, 10um; mobile phase A: H2O (0.1% formic acid), mobile phase B: CH3CN, A: B = 90%-5% gradient change) to obtain the target compound 6-amino-5-(3-hydroxy-2,6-dimethylphenyl)-2,3-dimethylthieno[3,2-b]pyridine-7-carboxamide (Compound 001) (1.25 mg).

[0358] 1H NMR (400MHz, DMSO) δ9.22(s,1H),7.90(s,2H),6.97(d,J=8.2Hz,1H),6.81(d,J =8.2Hz,1H),4.83(s,2H),2.43(s,3H),2.18(s,3H),1.83(s,3H),1.76(s,3H).

[0359] LCMS:MS m / z(ESI):342.2[M+H] + .

[0360] Example 26-amino-5-(3-hydroxy-2,6-dimethylphenyl)-2-methylthiazolo[5,4-b]pyridine-7-carboxylate Amide (Compound 002)

[0361]

[0362] 2.1 Synthesis of intermediate 2-2:

[0363]

[0364] Dissolve 2-chloropyridin-4-amine (5 g) in concentrated sulfuric acid (100 mL) at 0°C, and add potassium nitrate (15.8 g) in batches at 0°C. Stir the reaction at 0°C for 30 min, warm to room temperature and stir for another 30 min, heat to 60°C and stir the reaction for 4 hours. Cool to 0°C, slowly add the reaction solution into ice water (300 mL), and a large amount of solid precipitates. Filter and dry the filter cake to obtain intermediate 2-2 (3 g). LCMS: MS m / z (ESI): 217.0 [MH] - .

[0365] 2.2 Synthesis of intermediate 2-3:

[0366]

[0367] Dissolve intermediate 2-2 (3 g) in sulfolane (30 mL), add ethylthioamide (4.14 g), heat the reaction solution to 100 ° C, and stir for 16 hours. Cool to room temperature, add ice water (60 mL) to the reaction solution to quench, and solid precipitates. Filter and wash the filter cake with a mixed solvent of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 10:1). After the obtained filter cake is dried in vacuo, intermediate 2-3 (2.5 g) is obtained.

[0368] 2.3 Synthesis of intermediate 2-4:

[0369]

[0370] Dissolve tert-butyl nitrite (2.85 g) in acetonitrile (30 mL), add cuprous bromide (6.17 g), and add an acetonitrile solution of intermediate 2-3 (2.9 g dissolved in 30 mL acetonitrile) at 0°C. Stir the reaction at 0°C for 15 minutes, then warm the reaction solution to room temperature and react for 16 hours. Add water (40 mL) to the reaction solution for dilution, extract with ethyl acetate (40 mL x 3), wash the organic phase with saturated brine (30 mL), dry over anhydrous sodium sulfate, and filter. The filtrate is concentrated under reduced pressure, and the residue is separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether: 0% to 2.5%) to obtain intermediate 2-4 (1.1 g). LCMS: MS m / z (ESI): 273.9 [M+H] + .

[0371] 2.4 Synthesis of intermediate 2-5:

[0372]

[0373] Intermediate 2-4 (1.5 g) was dissolved in N-methylpyrrolidone (15 mL), and cuprous cyanide (985 mg) was added. Under argon protection, the reaction was carried out at 180 ° C in a microwave for 1 hour. Methanol (50 mL) was added to the reaction solution, filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, diluted with water (20 mL), extracted with ethyl acetate (30 mL x 3), and the organic phase was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether: 0% to 12.5%) to obtain intermediate 2-5 (165 mg). LCMS: MS m / z (ESI): 221.0 [M+H] + .

[0374] 2.5 Synthesis of intermediate 2-6:

[0375]

[0376] Intermediate 2-5 (165 mg) was dissolved in a mixed solution of ethanol (5 mL) and water (0.5 mL), iron powder (168 mg) and ammonium chloride (160 mg) were added in sequence, and the temperature was raised to 90°C for reaction for 3 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain intermediate 2-6 (100 mg). LCMS: MS m / z (ESI): 209.1 [M+H] + .

[0377] 2.6 Synthesis of intermediate 2-7:

[0378]

[0379] Dissolve intermediate 2-6 (100 mg) in acetonitrile (1 mL), add N-bromosuccinimide (128 mg), and react at 25 ° C for 2 hours. Add water (5 mL) to the reaction solution for dilution, extract with ethyl acetate (5 mL x 3), wash the organic phase with saturated brine (10 mL), dry over anhydrous sodium sulfate and filter. The filtrate is concentrated under reduced pressure, and the residue is separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain intermediate 2-7 (50 mg). LCMS: MS m / z (ESI): 286.9 [M+H] + .

[0380] 2.7 Synthesis of intermediate 2-8:

[0381]

[0382] Dissolve intermediate 2-7 (50 mg) in 1,4-dioxane (1 mL), and add (3-methoxy-2,6-dimethylphenyl)boric acid (158 mg), potassium phosphate (111 mg), 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl (72 mg), water (0.1 mL), SPhos Pd G3 (14 mg) in sequence. Replace with argon three times, heat the reaction solution to 90 ° C for 3 hours. The reaction solution is cooled to room temperature, water (5 mL) is added, and extracted with ethyl acetate (5 mL x 3). The organic phase is washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain a crude product, which was then separated and purified by high performance liquid preparative chromatography (chromatographic column: Sunfire Prep C18 OBD 19*250mm, 10um; mobile phase A: H2O (0.1% formic acid), mobile phase B: CH3CN, A:B = 70%-5% gradient change) to obtain intermediate 2-8 (15 mg). LCMS: MS m / z (ESI): 343.1 [M+H] + .

[0383] 2.8 Synthesis of Compound 002:

[0384]

[0385] Intermediate 2-8 (15 mg) was dissolved in dichloromethane (0.5 mL), and boron tribromide (0.1 mL) was added to react at room temperature for 1 hour. Methanol (1 mL) was added to the reaction solution to quench, and the reaction solution was concentrated under reduced pressure. The residue was purified by high performance liquid preparative chromatography (chromatographic column: Sunfire Prep C18 OBD 19*250mm, 10um; mobile phase A: H2O (0.1% formic acid), mobile phase B: CH3CN, A:B = 90%-5% gradient change) to obtain the target product 6-amino-5-(3-hydroxy-2,6-dimethylphenyl)-2-methylthiazolo[5,4-b]pyridine-7-carboxamide (Compound 002) (1.02 mg).

[0386] 1 H NMR (400MHz, DMSO) δ9.53 (s, 1H), 9.29 (s, 1H), 8.02 (s, 1H), 6.98 (d, J = 8.1Hz, 1 H),6.82(d,J=8.1Hz,1H),6.55(s,2H),2.86(s,3H),1.82(s,3H),1.75(s,3H).

[0387] LCMS:MS m / z(ESI):329.1[M+H] + .

[0388] Example 35-Amino-6-(3-hydroxy-2,6-dimethylphenyl)-2-methylbenzo[d]thiazole-4-carboxamide (Compound 003)

[0389]

[0390] 3.1 Synthesis of intermediate 3-2:

[0391]

[0392] 5-Amino-2-methylbenzo[d]thiazole (5.0 g) was dissolved in pyridine (50.0 mL) at room temperature, acetic anhydride (4.66 g) was added, and the reaction was stirred at 25°C for 16 hours. Water (500.0 mL) was added to the reaction solution to quench the reaction, and the mixture was stirred at room temperature for 30 minutes. A large amount of yellow solid precipitated, which was filtered and the filter cake was washed with water three times and dried in vacuo to obtain intermediate 3-2 (6.0 g). LCMS: MS m / z (ESI): 207.1 [M+H] + .

[0393] 3.2 Synthesis of intermediate 3-3:

[0394]

[0395] At room temperature, the intermediate 3-2 (6.0 g) was dissolved in acetic acid (60.0 mL), and liquid bromine (1.47 mL) was added. The reaction solution was reacted at 25°C for 2 hours. Water (60.0 mL) was added to the reaction solution for dilution, and extracted with ethyl acetate (100 mL x 3). The organic phases were combined and washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-25%) to obtain intermediate 3-3 (7.3 g). LCMS: MS m / z (ESI): 285.0 [M+H] + .

[0396] 3.3 Synthesis of intermediate 3-4:

[0397]

[0398] Dissolve the intermediate 3-3 (7.3 g) in ethanol (70.0 mL), add concentrated hydrochloric acid (45.0 mL), and react the reaction solution at 80°C for 2 hours. Pour the reaction solution into water (700.0 mL), adjust the pH to 7-8 with saturated potassium carbonate aqueous solution, and a large amount of solid precipitates. Filter and vacuum dry the filter cake to obtain the intermediate 3-4 (5.5 g). LCMS: MS m / z (ESI): 242.9 [M+H] + .

[0399] 3.4 Synthesis of intermediate 3-5:

[0400]

[0401] At room temperature, the intermediate 3-4 (1.5 g) was dissolved in N-methylpyrrolidone (10.0 mL), and cuprous cyanide (722 mg) was added. The reaction system was replaced with argon three times and reacted at 180 ° C for 2 hours under microwave conditions. Water (10 mL) was added to the reaction solution, extracted with ethyl acetate (20 mL x 3), and the organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (ethyl acetate / petroleum ether = 0-20%) to obtain intermediate 3-5 (2.5 g). LCMS: MS m / z (ESI): 190.1 [M+H] + .

[0402] 3.5 Synthesis of intermediate 3-6:

[0403]

[0404] At room temperature, the intermediate 3-5 (300 mg) was dissolved in N, N-dimethylformamide (6.0 mL), and N-iodosuccinimide (393 mg) was added. The reaction solution was reacted at 60 ° C for 12 hours. Water (6 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL x 3), and the organic phase was washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (ethyl acetate / petroleum ether = 0-20%) to obtain intermediate 3-6 (200 mg). LCMS: MS m / z (ESI): 315.9 [M+H] + .

[0405] 3.6 Synthesis of intermediate 3-7:

[0406]

[0407] At room temperature, the intermediate 3-6 (150 mg) was dissolved in dioxane (2.0 mL), and (3-methoxy-2,6-dimethylphenyl)boric acid (432 mg), potassium phosphate (305 mg), 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl (197 mg), water (0.2 mL) and SPhos-Pd-G3 (39 mg) were added in sequence. The reaction system was replaced with argon three times, and the reaction solution was reacted at 90 ° C for 3 hours under argon protection. Cool to room temperature, add water (2 mL) to the reaction solution, extract with ethyl acetate (5 mL x 2), wash the organic phase with saturated brine (5 mL x 2), dry over anhydrous sodium sulfate and filter. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (ethyl acetate / petroleum ether = 0-25%) to obtain intermediate 3-7 (110 mg). LCMS: MS m / z (ESI): 324.1 [M+H] + .

[0408] 3.7 Synthesis of intermediate 3-8:

[0409]

[0410] At room temperature, the intermediate 3-7 (100 mg) was dissolved in dimethyl sulfoxide (1.0 mL), and hydrogen peroxide (30%, 70 mg) and potassium carbonate (86 mg) were added, and the mixture was reacted at 25°C for 1 hour. Water (2 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (5 mL x 3). The organic phase was washed with saturated brine (5 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the intermediate 3-8 (50 mg). LCMS: MS m / z (ESI): 342.1 [M+H] + .

[0411] 3.8 Synthesis of Compound 003:

[0412]

[0413] Intermediate 3-8 (50 mg) was dissolved in dichloromethane (2.0 mL) at room temperature, and boron tribromide (1 M, 0.45 mL) was added, and the reaction solution was reacted at room temperature for 1 hour. Methanol (2.0 mL) was added to the reaction solution to quench, and the reaction solution was concentrated under reduced pressure and purified by high performance liquid preparative chromatography (mobile phase A: H2O (0.1% formic acid), mobile phase B: CH3CN, A:B = 97%-5% gradient) to obtain the target product 5-amino-6-(3-hydroxy-2,6-dimethylphenyl)-2-methylbenzo[d]thiazole-4-carboxamide (Compound 003) (1.25 mg).

[0414] 1 H NMR (400MHz, MeOD) δ7.47(s,1H),7.00(d,J=8.0Hz,1H),6.77(d,J=8.0Hz,1H),2.85(s,3H),1.92(s,3H),1.88(s,3H).

[0415] LCMS:MS m / z(ESI):328.2[M+H] + .

[0416] Example 4 (R)-6-amino-5-(3-hydroxy-2,6-dimethylphenyl)-2,3-dimethylthieno[3,2-b]pyrrolidone Phenylidene-7-carboxamide (Compound 001-P1) and (S)-6-amino-5-(3-hydroxy-2,6-dimethylphenyl)-2,3-dimethylthiazole Hepta[3,2-b]pyridine-7-carboxamide (Compound 001-P2)

[0417]

[0418] Compound 001 was separated by SFC chiral preparative separation (chiral column: OJ, 250*25mm10μm; mobile phase A: Supercritical CO2, mobile phase B: IPA (+0.1% 7.0mol / l Ammonia in MEOH), A:B=80:20), to obtain two isomers: (R)-6-amino-5-(3-hydroxy-2,6-dimethylphenyl)-2,3-dimethylthieno[3,2-b]pyridine-7-carboxamide (compound 001-P1) and (S)-6-amino-5-(3-hydroxy-2,6-dimethylphenyl)-2,3-dimethylthieno[3,2-b]pyridine-7-carboxamide (compound 001-P2).

[0419] Compound 001-P1 (Rt=8.0 min):

[0420] 1H NMR (400MHz, DMSO) δ9.23(s,1H),7.91(s,2H),6.97(d,J=8.2Hz,1H),6.81(d,J=8.2Hz,1H),4. 83(s,2H),2.43(s,3H),2.18(s,3H),1.83(s,3H),1.76(s,3H).LCMS:MSm / z(ESI):342.1[M+H] + .

[0421] Compound 001-P2 (Rt=11.5 min):

[0422] 1 H NMR (400MHz, DMSO) δ9.23(s,1H),7.91(s,2H),6.97(d,J=8.2Hz,1H),6.81(d,J=8.2Hz,1H),4. 83(s,2H),2.43(s,3H),2.18(s,3H),1.83(s,3H),1.75(s,3H).LCMS:MSm / z(ESI):342.1[M+H] + .

[0423] Example 56-amino-2-ethyl-5-(3-hydroxy-2,6-dimethylphenyl)-3-methylthieno[3,2-b]pyrrolidone Pyridine-7-carboxamide (Compound 043)

[0424]

[0425] 5.1 Synthesis of intermediate 43-2:

[0426]

[0427] 3-Mercapto-2-pentanone (25.00 g) was dissolved in toluene (300.0 mL), cooled to 0°C, sodium methoxide (1.14 g) was added, and then methyl 3-methoxyacrylate (24.60 g) was slowly added, and the mixture was stirred at 0°C for 16 hours. The reaction solution was directly used in the next step.

[0428] 5.2 Synthesis of intermediate 43-3:

[0429]

[0430] At 0°C, concentrated hydrochloric acid (12M, 35.25mL) was added dropwise to the reaction solution obtained in the previous step, slowly warmed to room temperature, and stirred overnight. Water (1.0L) was added to dilute, extracted with ethyl acetate (3×1.0L), the organic phase was washed with saturated sodium chloride solution (3×500.0mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100:1 to 40:1) to obtain intermediate 43-3 (29.9g). LCMS: MS m / z (ESI): 185.2 [M+H] + .

[0431] 5.3 Synthesis of intermediate 43-4:

[0432]

[0433] At room temperature, the intermediate 43-3 (54.0 g) was dissolved in a mixed solution of methanol (500.0 mL) and water (100.0 mL), and sodium hydroxide (40.0 g) was slowly added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to remove methanol, and the remaining aqueous solution was adjusted to pH 4 with 1N dilute hydrochloric acid. Solids precipitated and were filtered. The filter cake was vacuum dried to obtain the intermediate 43-4 (40 g). LCMS: MSm / z(ESI):170.9[M+H] + .

[0434] 5.4 Synthesis of intermediate 43-5:

[0435]

[0436] Intermediate 43-4 (43 g) was dissolved in tert-butyl alcohol (500.0 mL) at room temperature, DIEA (48.9 g) and diphenylphosphoryl azide (69.5 g) were added at room temperature, and the mixture was stirred at 85°C for 12 hours under nitrogen protection. The mixture was cooled to room temperature, diluted with water (500.0 mL), extracted with ethyl acetate (500.0 mL×3), and the combined organic phases were washed with saturated aqueous sodium chloride solution (3×500.0 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (EA / PE: 0-30%) to obtain intermediate 43-5 (40 g). LCMS: MS m / z (ESI): 242.2 [M+H] + .

[0437] 5.5 Synthesis of intermediate 43-6:

[0438]

[0439] At room temperature, the intermediate 43-5 (10.0 g) was dissolved in a methanol solution of hydrochloric acid (4 M, 50 mL) and stirred at 50°C for 2 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure to obtain a crude intermediate 43-6 (7.1 g). LCMS: MS m / z (ESI): 142.0 [M+H] + The crude product was used directly in the next step.

[0440] 5.6 Synthesis of Compound 043:

[0441] The remaining steps refer to Example 1, replacing intermediate 1-6 with intermediate 43-6 of this example, and finally obtaining the target compound: 6-amino-2-ethyl-5-(3-hydroxy-2,6-dimethylphenyl)-3-methylthieno[3,2-b]pyridine-7-carboxamide (Compound 043).

[0442] 1 H NMR(400MHz,MeOD)δ7.03(d,J=8.2Hz,1H),6.82(d,J=8.2Hz,1H),2.96–2.88( m,2H),2.29(s,3H),1.93(s,3H),1.89(s,3H),1.33(t,J=7.7Hz,3H).LCMS:MS m / z(ESI):356.0[M+H] + .

[0443] Compounds 004-042 and 044 listed in Table 1 were prepared in substantially the same manner as in Examples 1-5, and the starting materials used were commercially available or prepared according to literature methods. Table 1 shows the names and structures of compounds 004-042 and 044.

[0444] Table 1

[0445]

[0446]

[0447]

[0448]

[0449]

[0450]

[0451] Effect Example 1 PKMYT1 enzyme activity inhibition experiment

[0452] The inhibition of the compound on PKMYT1 kinase was detected by ADP-Glo ​​assay. First, prepare the reaction buffer (Assay buffer): 50mM HEPES, 10mM MgCl, 1mM EGTA, 0.01% Brij-35, 2mM DTT, and then dilute the MYT1 enzyme (Carna, 05-176, final concentration of 20nM) and the reaction substrate (ATP with a final concentration of 40μM and inactivated CDK1 with a final concentration of 40nM, Signalchem ​​C22-14G) with the reaction buffer. Dilute the test compound 3 times into 10 concentrations, with a starting concentration of 3μM. Transfer 50nL of the diluted compound to a 384-well plate, transfer 5μL of the MYT1 enzyme solution to a 384-well plate, and incubate at 25°C for 10 minutes. Transfer 5μL of the reaction substrate solution to a 384-well plate and incubate at 25°C for 180 minutes. Then transfer 5 μL of ADP-Glo ​​Reagent (Promega, V9101) to a 384-well plate, incubate for 40 minutes at 25°C, and finally transfer 10 μL of ADP-Glo ​​Detection reagent to a 384-well plate and incubate for 40 minutes at 25°C. Use a microplate reader (BMG) to measure the luminescence intensity of the sample. XLfit 5.5.0 software was used to establish a nonlinear regression equation for concentration-response curve fitting and IC 50 The experimental results are shown in Table 2.

[0453] Table 2 Results of PKMYT1 enzymatic activity test of compounds

[0454] Compound <![CDATA[PKMYT1 enzyme inhibition activity IC 50 (nM)]]> 001 1.31 002 4.01 003 23.9 001-P1 430 001-P2 0.90 043 4.02

[0455] Effect Example 2 WEE1 Enzyme Activity Inhibition Experiment

[0456] The inhibition of the compound on WEE1 kinase was detected by ADP-Glo ​​assay. First, prepare the reaction buffer (Assaybuffer): 50mM HEPES, 10mM MgCl, 1mM EGTA, 0.01% Brij-35, 2mM DTT, and then dilute the WEE1 enzyme (Carna, 05-177, final concentration of 10nM) and reaction substrate (ATP with a final concentration of 20μM and Poly (Lys-Tyr, 4:1) with a final concentration of 400ng / μL, BPS Bioscience, 79910) respectively with the reaction buffer. Dilute the test compound 3 times into 10 concentrations, with a starting concentration of 3μM. Transfer 25nL of the diluted compound to a 384-well plate, transfer 2.5μL of the WEE1 enzyme solution to a 384-well plate, and incubate at 25°C for 10 minutes. Transfer 2.5μL of the reaction substrate solution to a 384-well plate and incubate at 25°C for 180 minutes. Then transfer 4 μL ADP-Glo ​​Reagent (Promega, V9101) to a 384-well plate, incubate for 40 minutes at 25°C, and finally transfer 8 μL ADP-Glo ​​Detection reagent to a 384-well plate and incubate for 40 minutes at 25°C. Use a microplate reader (BMG) to measure the luminescence intensity of the sample. XLfit 5.5.0 software was used to establish a nonlinear regression equation for concentration-response curve fitting and IC 50 The experimental results are shown in Table 3.

[0457] Table 3 Enzymatic activity test results of compound WEE1

[0458] Compound <![CDATA[IC of enzymatic inhibitory activity of WEE1 50 (nM)]]> 001 >3000 002 >3000 003 >3000 001-P2 >3000 043 >3000

[0459] Effect Example 3 Tumor Cell Proliferation Inhibition Test

[0460] Prepare a suspension of HCC1569 cells (ATCC, CRL-2330) at 10,000 cells / mL and transfer 195 μL to a 96-well flat-bottom cell culture plate (Corning, #3603) for overnight culture at 37°C and 5% CO2. Dilute the stock solution of the compound to be tested to an intermediate concentration using DMSO and dilute it to 10 concentration points at a ratio of 1:3. Transfer 5 μL of the diluted compound solution to the wells of the cells that have been incubated overnight, with the initial maximum concentration being 10 μM. Incubate at 37°C and 5% CO2 for 7 days. On the eighth day, remove the cell culture plate from the incubator, allow it to return to room temperature, add 100 μL of Celltiter-Glo reagent (Promega, G7573), shake for 2 minutes to completely mix, and then incubate at room temperature in the dark for 30 minutes. Quantify using a BMG microplate reader (BMG, PHERAstar FSX). XLfit 5.5.0 software was used to establish a nonlinear regression equation for concentration-response curve fitting and IC50 determination. The test results are shown in Table 4.

[0461] Table 4 Test results of the inhibitory activity of compounds on HCC1569 cell proliferation

[0462] Compound HCC1569 IC50(nM) 001 439.72 001-P1 >10000 001-P2 135.32 002 841.05 043 511.9

Claims

1. Compounds of formula (I): or a pharmaceutically acceptable salt thereof, in, Ring A is selected from benzene ring, C 5-6 Hydrocarbon rings, 5-6 membered heterocyclic rings and 5-6 membered heteroaromatic rings; W is selected from N and CR 1 ; R 1 Selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclyl, CN, NO2, aryl, -C 1-4 Alkylene-aryl, heteroaryl, -C 1-4 Alkylene-heteroaryl, -NR A1 R B1 、-OR A1 、-SR A1 、-C(=O)R A1 、-C(=NR E1 )R A1 、-C(=N-OR B1 )R A1 、-C(=O)OR A1 、-OC(=O)R A1 、-C(=O)NR A1 R B1 、-NR A1 C(=O)R B1 、-C(=NR E1 )NR A1 R B1 、-NR A1 C(=NR E1 )R B1 、-OC(=O)NR A1 R B1 、-NR A1 C(=O)OR B1 、-NR A1 C(=O)NR A1 R B1 、-NR A1 C(=S)NR A1 R B1 、-NR A1 C(=NR E1 )NR A1 R B1 、-S(=O) r R A1 、-S(=O)(=NR E1 )R B1 、-N=S(=O)R A1 R B1 、-S(=O)2OR A1 、-OS(=O)2R A1 、-NR A1 S(=O) r R B1 、-NR A1 S(=O)(=NR E1 )R B1 、-S(=O) r NR A1 R B1 、-S(=O)(=NR E1 )NR A1 R B1 、-NR A1 S(=O)2NR A1 R B1 and-NR A1 S(=O)(=NR E1 )NR A1 R B1 , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R X1 Substituents are substituted; R 2 Selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclyl, CN, NO2, aryl, -C 1-4 Alkylene-aryl, heteroaryl, -C 1-4 Alkylene-heteroaryl, -NR A2 R B2 、-OR A2 、-SR A2 、-C(=O)R A2 、-C(=NR E2 )R A2 、-C(=N-OR B2 )R A2 、-C(=O)OR A2 、-OC(=O)R A2 、-C(=O)NR A2 R B2 、-NR A2 C(=O)R B2 、-C(=NR E2 )NR A2 R B2 、-NR A2 C(=NR E2 )R B2 、-OC(=O)NR A2 R B2 、-NR A2 C(=O)OR B2 、-NR A2 C(=O)NR A2 R B2 、-NR A2 C(=S)NR A2 R B2 、-NR A2 C(=NR E2 )NR A2 R B2 、-S(=O) r R A2 、-S(=O)(=NR E2 )R B2 、-N=S(=O)R A2 R B2 、-S(=O)2OR A2 、-OS(=O)2R A2 、-NR A2 S(=O) r R B2 、-NR A2 S(=O)(=NR E2 )R B2 、-S(=O) r NR A2 R B2 、-S(=O)(=NR E2 )NR A2 R B2 、-NR A2 S(=O)2NR A2 R B2 and-NR A2 S(=O)(=NR E2 )NR A2 R B2 , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R X2 Substituents are substituted; R 3 Selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclyl, CN, NO2, aryl, -C 1-4 Alkylene-aryl, heteroaryl, -C 1-4 Alkylene-heteroaryl, -NR A3 R B3 、-OR A3 、-SR A3 、-C(=O)R A3 、-C(=NR E3 )R A3 、-C(=N-OR B3 )R A3 、-C(=O)OR A3 、-OC(=O)R A3 、-C(=O)NR A3 R B3 、-NR A3 C(=O)R B3 、-C(=NR E3 )NR A3 R B3 、-NR A3 C(=NR E3 )R B3 、-OC(=O)NR A3 R B3 、-NR A3 C(=O)OR B3 、-NR A3 C(=O)NR A3 R B3 、-NR A3 C(=S)NR A3 R B3 、-NR A3 C(=NR E3 )NR A3 R B3 、-S(=O) r R A3 、-S(=O)(=NR E3 )R B3 、-N=S(=O)R A3 R B3 、-S(=O)2OR A3 、-OS(=O)2R A3 、-NR A3 S(=O) r R B3 、-NR A3 S(=O)(=NR E3 )R B3 、-S(=O) r NR A3 R B3 、-S(=O)(=NR E3 )NR A3 R B3 、-NR A3 S(=O)2NR A3 R B3 and-NR A3 S(=O)(=NR E3 )NR A3 R B3 , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R X3 Substituents are substituted; Each R 4 Independently selected from halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cyclic hydrocarbon group, heterocyclic group, -C 1-4 Alkylene-heterocyclyl, CN, NO2, aryl, -C 1-4 Alkylene-aryl, heteroaryl, -C 1-4 Alkylene-heteroaryl, -NR A4 R B4 、-OR A4 、-SR A4 、-C(=O)R A4 、-C(=NR E4 )R A4 、-C(=N-OR B4 )R A4 、-C(=O)OR A4 、-OC(=O)R A4 、-C(=O)NR A4 R B4 、-NR A4 C(=O)R B4 、-C(=NR E4 )NR A4 R B4 、-NR A4 C(=NR E4 )R B4 、-OC(=O)NR A4 R B4 、-NR A4 C(=O)OR B4 、-NR A4 C(=O)NR A4 R B4 、-NR A4 C(=S)NR A4 R B4 、-NR A4 C(=NR E4 )NR A4 R B4 、-S(=O) r R A4 、-S(=O)(=NR E4 )R B4 、-N=S(=O)R A4 R B4 、-S(=O)2OR A4 、-OS(=O)2R A4 、-NR A4 S(=O) r R B4 、-NR A4 S(=O)(=NR E4 )R B4 、-S(=O) r NR A4 R B4 、-S(=O)(=NR E4 )NR A4 R B4 、-NR A4 S(=O)2NR A4 R B4 and-NR A4 S(=O)(=NR E4 )NR A4 R B4 , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R X4 Substituents are substituted; Or any two adjacent R 4 Together with the atoms to which they are attached, they form a C 3-10 A monocyclic hydrocarbon ring or a 4-12 membered heterocyclic ring containing 1, 2 or 3 heteroatoms or a 5-10 membered heteroaromatic ring containing 1, 2 or 3 heteroatoms, wherein the heteroatoms are independently selected from oxygen, sulfur, nitrogen and phosphorus, and the ring is unsubstituted or substituted by at least one independently selected from R X4 Substituents are substituted; R 5 Selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclyl, CN, NO2, aryl, -C 1-4 Alkylene-aryl, heteroaryl, -C 1-4 Alkylene-heteroaryl, -NR A5 R B5 、-OR A5 、-SR A5 、-C(=O)R A5 、-C(=NR E5 )R A5 、-C(=N-OR B5 )R A5 、-C(=O)OR A5 、-OC(=O)R A5 、-C(=O)NR A5 R B5 、-NR A5 C(=O)R B5 、-C(=NR E5 )NR A5 R B5 、-NR A5 C(=NR E5 )R B5 、-OC(=O)NR A5 R B5 、-NR A5 C(=O)OR B5 、-NR A5 C(=O)NR A5 R B5 、-NR A5 C(=S)NR A5 R B5 、-NR A5 C(=NR E5 )NR A5 R B5 、-S(=O) r R A5 、-S(=O)(=NR E5 )R B5 、-N=S(=O)R A5 R B5 、-S(=O)2OR A5 、-OS(=O)2R A5 、-NR A5 S(=O) r R B5 、-NR A5 S(=O)(=NR E5 )R B5 、-S(=O) r NR A5 R B5 、-S(=O)(=NR E5 )NR A5 R B5 、-NR A5 S(=O)2NR A5 R B5 and-NR A5 S(=O)(=NR E5 )NR A5 R B5 , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R X5 Substituents are substituted; R 6 Selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclyl, CN, NO2, aryl, -C 1-4 Alkylene-aryl, heteroaryl, -C 1-4 Alkylene-heteroaryl, -NR A6 R B6 、-OR A6 、-SR A6 、-C(=O)R A6 、-C(=NR E6 )R A6 、-C(=N-OR B6 )R A6 、-C(=O)OR A6 、-OC(=O)R A6 、-C(=O)NR A6 R B6 、-NR A6 C(=O)R B6 、-C(=NR E6 )NR A6 R B6 、-NR A6 C(=NR E6 )R B6 、-OC(=O)NR A6 R B6 、-NR A6 C(=O)OR B6 、-NR A6 C(=O)NR A6 R B6 、-NR A6 C(=S)NR A6 R B6 、-NR A6 C(=NR E6 )NR A6 R B6 、-S(=O) r R A6 、-S(=O)(=NR E6 )R B6 、-N=S(=O)R A6 R B6 、-S(=O)2OR A6 、-OS(=O)2R A6 、-NR A6 S(=O) r R B6 、-NR A6 S(=O)(=NR E6 )R B6 、-S(=O) r NR A6 R B6 、-S(=O)(=NR E6 )NR A6 R B6 、-NR A6 S(=O)2NR A6 R B6 and-NR A6 S(=O)(=NR E6 )NR A6 R B6 , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R X6 Substituents are substituted; R 7 Selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclyl, CN, NO2, aryl, -C 1-4 Alkylene-aryl, heteroaryl, -C 1-4 Alkylene-heteroaryl, -NR A7 R B7 、-OR A7 、-SR A7 、-C(=O)R A7 、-C(=NR E7 )R A7 、-C(=N-OR B7 )R A7 、-C(=O)OR A7 、-OC(=O)R A7 、-C(=O)NR A7 R B7 、-NR A7 C(=O)R B7 、-C(=NR E7 )NR A7 R B7 、-NR A7 C(=NR E7 )R B7 、-OC(=O)NR A7 R B7 、-NR A7 C(=O)OR B7 、-NR A7 C(=O)NR A7 R B7 、-NR A7 C(=S)NR A7 R B7 、-NR A7 C(=NR E7 )NR A7 R B7 、-S(=O) r R A7 、-S(=O)(=NR E7 )R B7 、-N=S(=O)R A7 R B7 、-S(=O)2OR A7 、-OS(=O)2R A7 、-NR A7 S(=O) r R B7 、-NR A7 S(=O)(=NR E7 )R B7 、-S(=O) r NR A7 R B7 、-S(=O)(=NR E7 )NR A7 R B7 、-NR A7 S(=O)2NR A7 R B7 and-NR A7 S(=O)(=NR E7 )NR A7 R B7 , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R X7 Substituents are substituted; R 8 Selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclyl, CN, NO2, aryl, -C 1-4 Alkylene-aryl, heteroaryl, -C 1-4 Alkylene-heteroaryl, -NR A8 R B8 、-OR A8 、-SR A8 、-C(=O)R A8 、-C(=NR E8 )R A8 、-C(=N-OR B8 )R A8 、-C(=O)OR A8 、-OC(=O)R A8 、-C(=O)NR A8 R B8 、-NR A8 C(=O)R B8 、-C(=NR E8 )NR A8 R B8 、-NR A8 C(=NR E8 )R B8 、-OC(=O)NR A8 R B8 、-NR A8 C(=O)OR B8 、-NR A8 C(=O)NR A8 R B8 、-NR A8 C(=S)NR A8 R B8 、-NR A8 C(=NR E8 )NR A8 R B8 、-S(=O) r R A8 、-S(=O)(=NR E8 )R B8 、-N=S(=O)R A8 R B8 、-S(=O)2OR A8 、-OS(=O)2R A8 、-NR A8 S(=O) r R B8 、-NR A8 S(=O)(=NR E8 )R B8 、-S(=O) r NR A8 R B8 、-S(=O)(=NR E8 )NR A8 R B8 、-NR A8 S(=O)2NR A8 R B8 and-NR A8 S(=O)(=NR E8 )NR A8 R B8 , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R X8 Substituents are substituted; R 9 Selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclyl, CN, NO2, aryl, -C 1-4 Alkylene-aryl, heteroaryl, -C 1-4 Alkylene-heteroaryl, -NR A9 R B9 、-OR A9 、-SR A9 、-C(=O)R A9 、-C(=NR E9 )R A9 、-C(=N-OR B9 )R A9 、-C(=O)OR A9 、-OC(=O)R A9 、-C(=O)NR A9 R B9 、-NR A9 C(=O)R B9 、-C(=NR E9 )NR A9 R B9 、-NR A9 C(=NR E9 )R B9 、-OC(=O)NR A9 R B9 、-NR A9 C(=O)OR B9 、-NR A9 C(=O)NR A9 R B9 、-NR A9 C(=S)NR A9 R B9 、-NR A9 C(=NR E9 )NR A9 R B9 、-S(=O) r R A9 、-S(=O)(=NR E9 )R B9 、-N=S(=O)R A9 R B9 、-S(=O)2OR A9 、-OS(=O)2R A9 、-NR A9 S(=O) r R B9 、-NR A9 S(=O)(=NR E9 )R B9 、-S(=O) r NR A9 R B9 、-S(=O)(=NR E9 )NR A9 R B9 、-NR A9 S(=O)2NR A9 R B9 and-NR A9 S(=O)(=NR E9 )NR A9 R B9 , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R X9 Substituents are substituted; or R 8 and R 9 Together with the atoms to which they are attached, they form a 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring containing 1, 2 or 3 heteroatoms, wherein the heteroatoms are independently selected from oxygen, sulfur and nitrogen, and the ring is unsubstituted or substituted by at least one independently selected from R X8 Substituents are substituted; Each R A1 , R A2 , R A3 , R A4 , R A5 , R A6 , R A7 , R A8 , R A9 , R B1 , R B2 , R B3 , R B4 , R B5 , R B6 , R B7 , R B8 and R B9 independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclyl, aryl, -C 1-4 Alkylene-aryl, heteroaryl and -C 1-4 Alkylene-heteroaryl, wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R X Substituents are substituted; or "R A1 and R B1 ” or "R A2 and R B2 ” or "R A3 and R B3 ” or "R A4 and R B4 ” or "R A5 and R B5 ” or "R A6 and R B6 ” or "R A7 and R B7 ” or "R A8 and R B8 ” or "R A9 and R B9 "together with the atoms or atoms to which they are attached, they form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, which ring is unsubstituted or substituted with 1, 2 or 3 atoms selected from R X Substituents are substituted; Each R E1 , R E2 , R E3 , R E4 , R E5 , R E6 , R E7 , R E8 and R E9 independently selected from hydrogen, C 1-10 Alkyl, CN, NO2, -S(=O) r R a1 、-C(=O)R a1 、-C(=O)OR a1 、-C(=O)NR a1 R b1 and -S(=O) r NR a1 R b1 , wherein the alkyl group is unsubstituted or substituted with at least one independently selected from R X Substituents are substituted; Each R X , R X1 , R X2 , R X3 , R X4 , R X5 , R X6 , R X7 , R X8 and R X9 Independently selected from halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclyl, aryl, -C 1-4 Alkylene-aryl, heteroaryl, -C 1-4 Alkylene-heteroaryl, CN, NO2, -(CR c1 R d1 ) t NR a1 R b1 、-(CR c1 R d1 ) t OR b1 、-(CR c1 R d1 ) t C(=O)R a1 、-(CR c1 R d1 ) t C(=NR e1 )R a1 、-(CR c1 R d1 ) t C(=O)OR b1 、-(CR c1 R d1 ) t OC(=O)R b1 、-(CR c1 R d1 ) t C(=O)NR a1 R b1 、-(CR c1 R d1 ) t NR a1 C(=O)R b1 、-(CR c1 R d1 ) t C(=NR e1 )NR a1 R b1 、-(CR c1 R d1 ) t NR a1 C(=NR e1 )R b1 、-(CR c1 R d1 ) t OC(=O)NR a1 R b1 、-(CR c1 R d1 ) t NR a1 C(=O)OR b1 、-(CR c1 R d1 ) t NR a1 C(=O)NR a1 R b1 、-(CR c1 R d1 ) t NR a1 C(=S)NR a1 R b1 、-(CR c1 R d1 ) t NR a1 C(=NR e1 )NR a1 R b1 、-(CR c1 R d1 ) t S(=O) r R b1 、-(CR c1 R d1 ) t S(=O)(=NR e1 )R b1 、-(CR c1 R d1 ) t N=S(=O)R a1 R b1 、-(CR c1 R d1 ) t S(=O)2OR b1 、-(CR c1 R d1 ) t OS(=O)2R b1 、-(CR c1 R d1 ) t NR a1 S(=O) r R b1 、-(CR c1 R d1 ) t NR a1 S(=O)(=NR e1 )R b1 、-(CR c1 R d1 ) t S(=O) r NR a1 R b1 、-(CR c1 R d1 ) t S(=O)(=NR e1 )NR a1 R b1 、-(CR c1 R d1 ) t NR a1 S(=O)2NR a1 R b1 and-(CR c1 R d1 ) t NR a1 S(=O)(=NR e1 )NR a1 R b1 , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R Y Substituents are substituted; Each R a1 and R b1 independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclyl, aryl, -C 1-4 Alkylene-aryl, heteroaryl and -C 1-4 Alkylene-heteroaryl, wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R Y Substituents are substituted; or R a1 and R b1 Together with the atoms or atoms to which they are attached, they form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, which ring is unsubstituted or substituted with 1, 2 or 3 atoms selected from R Y Substituents are substituted; Each R c1 and R d1 independently selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclyl, aryl, -C 1-4 Alkylene-aryl, heteroaryl and -C 1-4 Alkylene-heteroaryl, wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R Y Substituents are substituted; Or each R c1 and R d1 Together with the single or multiple carbon atoms to which they are attached, they form a 3-12 membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, which ring is unsubstituted or substituted with 1, 2 or 3 heteroatoms independently selected from R Y The group substitution; Each R e1 independently selected from hydrogen, C 1-10 Alkyl, CN, NO2, -S(=O) r R a1 、-C(=O)R a1 、-C(=O)OR a1 、-C(=O)NR a1 R b1 and -S(=O) r NR a1 R b1 , wherein the alkyl group is unsubstituted or substituted with at least one independently selected from R Y Substituents are substituted; Each R Y Independently selected from halogen, NO2, -CN, C 1-10 Alkyl, -OH, -O(C 1-10 Alkyl), -O(C 3-10 Cycloalkyl), -O(C 1-4 Alkylene-C 3-10 Cycloalkyl), -O(heterocyclyl), -O(C 1-4 Alkylene-heterocyclyl), -SH, -S(C 1-10 Alkyl), -S(C 3-10 Cycloalkyl), -S(C 1-4 Alkylene-C 3-10 Cycloalkyl), -S(heterocyclyl), -S(C 1-4 Alkylene-heterocyclyl), -NH2, -NH(C 1-10 Alkyl), -N(C 1-10 Alkyl)2, -NH(C 3-10 Cycloalkyl), -NH(C 1-4 Alkylene-C 3-10 Cycloalkyl), -NH(heterocyclyl) and -NH(C 1-4 alkylene-heterocyclyl); g is selected from 0, 1, 2, 3, 4, 5, 6, 7 and 8; Each r is independently selected from 1 and 2; Each t is independently selected from 0, 1, 2, 3 and 4.

2. The compound of claim 1, wherein R 1 Selected from hydrogen and -OR A1 ; Preferably, R 1 Selected from hydrogen and -O(C 1-10 Alkyl), in particular selected from hydrogen and methoxy.

3. The compound of claim 1 or 2, wherein R 2 Selected from C 1-10 Alkyl, -NR A2 R B2 、-OR A2 、-SR A2 、-OC(=O)R A2 、-NR A2 C(=O)R B2 、- OS(=O)2R A2 and-NR A2 S(=O) r R B2 , wherein each alkyl group is unsubstituted or substituted with at least one independently selected from R X2 Substituents are substituted; Preferably, R 2 Selected from -NR A2 R B2 , especially -NH2.

4. The compound of any one of claims 1 to 3, wherein R 3 Selected from CN, -C(=O)R A3 、-C(=O)OR A3 、-C(=O)NR A3 R B3 、-S(=O) r R A3 、-S(=O)2OR A3 and -S(=O) r NR A3 R B3 ; Preferably, R 3 Selected from CN, -C(=O)R A3 、-C(=O)NR A3 R B3 and -S(=O) r NR A3 R B3 , especially -C(=O)NH2.

5. The compound of any one of claims 1 to 4, wherein Each R 4 Independently selected from halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cyclic hydrocarbon group, heterocyclic group, -C 1-4 Alkylene-heterocyclyl, CN, NO2, aryl, -C 1-4 Alkylene-aryl, heteroaryl, -C 1-4 Alkylene-heteroaryl, -NR A4 R B4 、-OR A4 、-SR A4 、-C(=O)R A4 、-C(=O)OR A4 、-OC(=O)R A4 、-C(=O)NR A4 R B4 、-NR A4 C(=O)R B4 、-S(=O) r R A4 、-S(=O)2OR A4 、-OS(=O)2R A4 、-NR A4 S(=O) r R B4 and -S(=O) r NR A4 R B4 , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R X4 or any two adjacent R 4 Together with the atoms to which they are attached, they form a C 5-6 A monocyclic hydrocarbon ring or a 5-6 membered heterocyclic ring containing 1, 2 or 3 heteroatoms, wherein the heteroatoms are independently selected from oxygen, sulfur, nitrogen and phosphorus, and the ring is unsubstituted or substituted by at least one independently selected from R X4 Substituents are substituted; Preferably, each R 4 independently selected from F, Cl, Br, methyl, 2-methylpropyl, cyclopropane, isopropyl, tert-butyl, diethylamino, acetyl, carbamoyl, methoxy, ethoxy, methylthio, ethylthio, methylsulfonyl, piperidinyl, morpholinyl, pyridinyl, thiazolyl, vinyl, wherein the methyl, cyclopropane, isopropyl, tert-butyl, diethylamino, acetyl, carbamoyl, methylthio, methylsulfonyl, piperidinyl, morpholinyl, pyridinyl, thiazolyl and vinyl are unsubstituted or replaced by at least one independently selected from R X4 or any two adjacent R 4 Together with the atoms to which they are attached, they form The ring is unsubstituted or substituted with at least one independently selected from R X4 Substituents are substituted; More preferably, each R 4 independently selected from Cl, methyl, 2-methylpropyl, cyclopropane, isopropyl, tert-butyl, diethylamino, acetyl, carbamoyl, methoxy, ethoxy, methylthio, ethylthio, methylsulfonyl, Especially methyl; or any two adjacent R 4 Together with the atoms to which they are attached, they form 6. The compound of any one of claims 1 to 5, wherein R 5 Selected from C 1-10 Alkyl, wherein each alkyl is unsubstituted or substituted with at least one independently selected from R X5 Substituents are substituted; Preferably, R 5 It is methyl.

7. The compound of any one of claims 1 to 6, wherein R 6 Selected from hydrogen, halogen, C 1-10 Alkyl, CN, NO2, -NR A6 R B6 AND-OR A6 , especially hydrogen and halogen, wherein each alkyl is unsubstituted or substituted by at least one independently selected from R X6 Substituents are substituted; Preferably, R 6 For hydrogen.

8. The compound of any one of claims 1 to 7, wherein R 7 Selected from hydrogen, halogen, C 1-10 Alkyl, CN, NO2, -NR A7 R B7 AND-OR A7 , especially hydrogen and halogen, wherein each alkyl is unsubstituted or substituted by at least one independently selected from R X7 Substituents are substituted; Preferably, R 7 For hydrogen.

9. The compound of any one of claims 1 to 8, wherein R 8 Selected from halogen, C 1-10 Alkyl, CN, NO2, -NR A8 R B8 AND-OR A8 , especially -OH.

10. The compound of any one of claims 1 to 9, wherein R 9 Selected from C 1-10 Alkyl, wherein each alkyl is unsubstituted or substituted with at least one independently selected from R X9 Substituents are substituted; Preferably, R 9 It is methyl.

11. The compound of claim 1, wherein Formula (I) has the structure of Formula (Ia) or Formula (Ib):

12. A compound selected from:

13. A pharmaceutical composition comprising a preventively or therapeutically effective amount of a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

14. Use of a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 13, in the preparation of a medicament for treating a disease, disorder or condition selected from a cell proliferation disorder.

15. Use of a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 13 in the preparation of a medicament for treating a disease, disorder or condition, wherein The disease, disorder or condition is cancer; Preferably, the cancer is selected from: (a) a solid tumor or a blood-derived tumor selected from the following cancers: bladder cancer, uterine cancer, endometrial cancer, uterine sarcoma, squamous cell lung cancer, breast cancer, colorectal cancer, kidney cancer, liver cancer, lung cancer, small cell lung cancer, esophageal cancer, esophageal cancer, esophageal junction adenocarcinoma, gallbladder cancer, brain cancer, head and neck cancer, ovarian cancer, pancreatic cancer, gastric cancer, cervical cancer, thyroid cancer, prostate cancer and skin cancer; (b) a hematopoietic tumor of the lymphoid system selected from the following: leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma , Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma and Burkett's lymphoma; (c) hematopoietic neoplasms of the myeloid lineage selected from the group consisting of acute and chronic myeloid leukemias, myelodysplastic syndromes and promyelocytic leukemias; (d) tumors of mesenchymal origin selected from the group consisting of fibrosarcoma and rhabdomyosarcoma; (e) tumors of the central and peripheral nervous system selected from the group consisting of astrocytoma, neuroblastoma, glioma and schwannoma; and (f) melanoma, seminoma, teratoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, follicular thyroid carcinoma and Kaposi's sarcoma.

Images