Compound as pkmyt1 inhibitor

Abstract

The present invention relates to the field of pharmaceutical chemistry, and in particular to a compound serving as a PKMYT1 inhibitor or a pharmaceutically acceptable salt thereof, a preparation method therefor, a pharmaceutical composition, and a use of the compound, the pharmaceutically acceptable salt thereof and the pharmaceutical composition in the treatment of PKMYT1-related diseases.

Description

Compounds as pkmyt1 inhibitors TECHNICAL FIELD

[0001] The present application relates to the field of medicinal chemistry, in particular to a class of compounds or pharmaceutically acceptable salts as PKMYT1 inhibitors, their preparation methods, pharmaceutical compositions and their use in the treatment of PKMYT1 related diseases. BACKGROUND

[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, and further regulate the transition from G2 phase to M phase of the cell cycle. PKMYT1 is not essential for the cell cycle arrest triggered by the DNA damage checkpoint in normal cells. Depleting PKMYT1 with siRNA does not affect the long-term growth of cells alone, but PKMYT1 plays a more important role in cells with genomic instability or under replication stress or other impaired cell cycle checkpoint regulation.

[0003] CCNE1 gene amplification is a common tumor driver mutation, which occurs in many malignant tumors such as ovarian cancer, breast cancer, gastric cancer, lung cancer, etc. Cyclin E1 (Cyclin E1) encoded by CCNE1 binds and activates CDK2, promoting the transition from G1 phase to S phase of the cell cycle. Overexpression of Cyclin E damages the G1 / S checkpoint regulation, making cells enter the S phase earlier, increasing the DNA replication stress, and leading to genomic instability. Compared with normal cells, CCNE1 amplified cells are more dependent on the regulation of other cell cycle checkpoints and the integrity of DNA repair mechanisms.

[0004] PKMYT1 kinase inhibition is synthetically lethal with CCNE1 amplification.

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

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

[0007] or a pharmaceutically acceptable salt thereof,

[0008] wherein,

[0009] E 1 and E 2 are each independently selected from O and S;

[0010] Ring A is a 5-membered heteroaromatic ring;

[0011] R 1 is selected from hydrogen, C 1-10 alkyl, C 3-10 alkenyl, C 1-4 alkynyl, C 3-10 cycloalkyl, heterocyclyl, -C 1-4 alkylene-heterocyclyl, CN, NO2, -C(=O)R A1 , -C(=O)OR A1 , -C(=O)NR A1 R B1 , -S(=O) r R A1 , -S(=O)(=NR E1 )R B1 , -S(=O) r NR A1 R B1 , and -S(=O)(=NR E1 )NR A1 R B1 , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is unsubstituted or substituted with at least one substituent independently selected from R X1

[0012] R 2 is 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, heterocyclyl, -C 1-4 alkylene-heterocyclyl, CN, NO2, -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 B2wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl and heterocyclyl is unsubstituted or substituted with at least one substituent independently selected from R X2 ;

[0013] W is absent, or is CR 3 R 3 ;

[0014] R 3 and R 3 are independently selected from the group consisting of 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, heterocyclyl, -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 Each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is unsubstituted or is selected independently from R. X3 Substituents of the substituents;

[0015] R 4 Selected from hydrogen, halogens, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, -C 1-4 Alkylene-C 3- 10 Cycloalkyl, heterocyclic, -C 1-4 alkylene-heterocyclic, 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)RA4 -C(=O)NR A4 R B4 -NR A4 C(=O)R B4 -C(=NR E4 )R 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 -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 substituent selected independently from R X4 ;

[0016] 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, heterocyclyl, -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 , -NRA5 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 Each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is unsubstituted or is selected independently from R. X5 Substituents of the substituents;

[0017] R 6 Selected from hydrogen, halogens, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, -C 1-4 Alkylene-C 3- 10 Cycloalkyl, heterocyclic, -C 1-4 alkylene-heterocyclic, 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 Each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is unsubstituted or is selected independently from R. X6 Substituents of the substituents;

[0018] R 7 Selected from hydrogen, halogens, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, -C 1-4 Alkylene-C 3- 10 Cycloalkyl, heterocyclic, -C 1-4alkylene-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)(=NRE7 )NR A7 R B7 -NR A7 S(=O)2NR A7 R B7 and -NR A7 S(=O)(=NR E7 )NR A7 R B7 Each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is unsubstituted or is selected independently from R. X7 Substituents of the substituents;

[0019] R 8 Selected from hydrogen, halogens, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, -C 1-4 Alkylene-C 3- 10 Cycloalkyl, heterocyclic, -C 1-4 alkylene-heterocyclic, 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 by at least one substituent independently selected from the group consisting of R X8 ;

[0020] R 9 is selected from the group consisting of 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, heterocyclyl, -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(=NRE9 )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 B9wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X9 ;

[0021] or R 8 and R 9 together with the atoms to which they are attached form a C 5-6 hydrocarbon ring or a 5-6 membered heterocyclic or heteroaromatic ring containing 1, 2 or 3 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen, which ring is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X8 ;

[0022] R 10 is selected from the group consisting of 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, heterocyclyl, -C 1-4 alkylene-heterocyclyl, CN, NO2, aryl, -C 1-4 alkylene-aryl, heteroaryl, -C 1-4 alkylene-heteroaryl, -NR A10 R B10 , -OR A10 , -SR A10 , -C(=O)R A10 , -C(=NR E10 )R A10 , -C(=N-OR B10 )R A10 , -C(=O)OR A10 , -OC(=O)R A10 , -C(=O)NR A10 R B10 , -NR A10 C(=O)R B10 , -C(=NR E10 )NR A10 R B10 , -NR A10 C(=NR E10 )R B10 , -OC(=O)NR A10 R B10 , -NR A10 C(=O)OR B10 , -NR A10 C(=O)NR A10 R B10 , -NRA10 C(=S)NR A10 R B10 -NR A10 C(=NR E10 )NR A10 R B10 -S (=O) r R A10 -S(=O)(=NR) E10 )R B10 -N = S(=O)R A10 R B10 -S(=O)2OR A10 -OS(=O)2R A10 -NR A10 S(=O) r R B10 -NR A10 S(=O)(=NR E10 )R B10 -S (=O) r NR A10 R B10 -S(=O)(=NR) E10 )NR A10 R B10 -NR A10 S(=O)2NR A10 R B10 and -NR A10 S(=O)(=NR E10 )NR A10 R B10 Each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is unsubstituted or is selected independently from R. X10 Substituents of the substituents;

[0023] R 11 Selected from hydrogen, halogens, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, -C 1-4 Alkylene-C 3- 10 Cycloalkyl, heterocyclic, -C 1-4 alkylene-heterocyclic, CN, NO2, aryl, -C 1-4 alkylene-aryl, heteroaryl, -C 1-4 alkylene-heteroaryl, -NR A11 R B11 -OR A11 -SR A11 -C(=O)R A11, -C(=NR E11 )R A11 , -C(=N-OR B11 )R A11 , -C(=O)OR A11 , -OC(=O)R A11 , -C(=O)NR A11 R B11 , -NR A11 C(=O)R B11 , -C(=NR E11 )NR A11 R B11 , -NR A11 C(=NR E11 )R B11 , -OC(=O)NR A11 R B11 , -NR A11 C(=O)OR B11 , -NR A11 C(=O)NR A11 R B11 , -NR A11 C(=S)NR A11 R B11 , -NR A11 C(=NR E11 )NR A11 R B11 , -S(=O) r R A11 , -S(=O)(=NR E11 )R B11 , -N=S(=O)R A11 R B11 , -S(=O)2OR A11 , -OS(=O)2R A11 , -NR A11 S(=O) r R B11 , -NR A11 S(=O)(=NR E11 )R B11 , -S(=O) r NR A11 R B11 , -S(=O)(=NR E11 )NR A11 R B11 , -NR A11 S(=O)2NR A11 R B11 and -NR A11 S(=O)(=NR E11 )NR A11 RB11 wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X11 ; and wherein each R

[0024] or R 10 and R 11 together with the atoms to which they are attached form a C 3-10 monocyclic hydrocarbon ring or a 4-12 membered heterocyclic ring containing 1, 2 or 3 heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen and phosphorus or a 6-10 membered aromatic ring or a 5-10 membered heteroaromatic ring containing 1, 2 or 3 heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen and phosphorus, which ring is substituted with h substituents independently selected from the group consisting of R 12 ; and wherein each R

[0025] R 12 is selected from the group consisting of 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, heterocyclyl, -C 1-4 alkylene-heterocyclyl, CN, NO2, aryl, -C 1-4 alkylene-aryl, heteroaryl, -C 1- 4alkylene-heteroaryl, -NR A12 R B12 , -OR A12 , -SR A12 , -C(=O)R A12 , -C(=NR E12 )R A12 , -C(=N-OR B12 )R A12 , -C(=O)OR A12 , -OC(=O)R A12 , -C(=O)NR A12 R B12 , -NR A12 C(=O)R B12 , -C(=NR E12 )NR A12 R B12 , -NR A12 C(=NR E12 )R B12 , -OC(=O)NR A12 R B12 , -NR A12 C(=O)OR B12 , -NR A12 C(=O)NR A12 RB12 -NR A12 C(=S)NR A12 R B12 -NR A12 C(=NR E12 )NR A12 R B12 -S(=O) r R A12 -S(=O)(=NR E12 )R B12 -N=S(=O)R A12 R B12 -S(=O)2OR A12 -OS(=O)2R A12 -NR A12 S(=O) r R B12 -NR A12 S(=O)(=NR E12 )R B12 -S(=O) r NR A12 R B12 -S(=O)(=NR E12 )NR A12 R B12 -NR A12 S(=O)2NR A12 R B12 and -NR A12 S(=O)(=NR E12 )NR A12 R B12 wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from R X12 ;

[0026] is a single or double bond;

[0027] each R A1 , R A2 , R A3 , R A4 , R A5 , R A6 , R A7 , R A8 , R A9 , R A10 , R A11 , R A12 , R B1 , R B2 , R B3 , R B4 , RB5 R B6 R B7 R B8 R B9 R B10 R B11 R B12 are independently selected from the group consisting of 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, heterocyclyl, -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 substituent independently selected from the group consisting of R X ;

[0028] 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 " or "R A10 and R B10 " or "R A11 and R B11 " or "R A12 and R B12 " together with the single or multiple atom to which they are attached form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen and phosphorus, which ring is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of R X ;

[0029] each R E1 , R E2 , R E3 , R E4 , R E5 , R E6 , RE7 R E8 R E9 R E10 R E11 R E12 are independently selected from the group consisting of 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 alkyl is unsubstituted or substituted by at least one substituent independently selected from the group consisting of R X ;

[0030] each R X , R X1 , R X2 , R X3 , R X4 , R X5 , R X6 , R X7 , R X8 , R X9 , R X10 , R X11 and R X12 are independently selected from the group consisting of 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, heterocyclyl, -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(=NRe1 )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 Each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is unsubstituted or is selected independently from R. Y Substituents of the substituents;

[0031] each R a1 and R b1 is independently selected from the group consisting of 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, heterocyclyl, -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 substituent independently selected from the group consisting of R Y ;

[0032] or R a1 and R b1 together with the single or multiple atoms to which they are attached form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen and phosphorus, which ring is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from the group consisting of R Y ;

[0033] each R c1 and R d1 is independently selected from the group consisting of 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, heterocyclyl, -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 substituent independently selected from the group consisting of R Y ;

[0034] or each R c1 and R d1 together with the single or multiple carbon atoms to which they are attached form a 3-12 membered ring containing 0, 1 or 2 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen, which ring is unsubstituted or substituted with 1, 2 or 3 groups independently selected from R Y ;

[0035] each R e1 is independently selected from the group consisting of hydrogen, C 1-10alkyl, 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 alkyl is unsubstituted or substituted with at least one substituent independently selected from R Y ;

[0036] each R Y is independently selected from the group consisting of 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);

[0037] g is selected from 0, 1 and 2;

[0038] h is selected from 0, 1, 2, 3, 4, 5, 6, 7 and 8;

[0039] each r is independently selected from 1 and 2;

[0040] each t is independently selected from 0, 1, 2, 3 and 4.

[0041] In another aspect, there is provided a pharmaceutical composition comprising a compound of the application, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

[0042] In another aspect, there is provided use of a compound of the application, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment of a disease, disorder or condition selected from a disease of abnormal cell proliferation, in particular cancer. BRIEF DESCRIPTION OF DRAWINGS

[0043] Figure 1 shows the effect of compound 051-P1 on tumor volume in a mouse HCC1569 model.

[0044] Figure 2 shows the effect of compound 051-P1 on body weight in a mouse HCC1569 model.

[0045] Figure 3 shows the effect of compound 005-P1 on tumor volume in a mouse HCC1569 model.

[0046] Figure 4 shows the effect of compound 005-P1 on body weight in a mouse HCC1569 model. DETAILED DESCRIPTION

[0047] The specific embodiments provided below are illustrative of the technical content of the present application. Other advantages and effects of the present application can be easily understood by those skilled in the art from the content disclosed in the specification. The present application can also be implemented or applied by other different specific embodiments. Various modifications and changes can be made by those skilled in the art without departing from the spirit of the present application.

[0048] DEFINITIONS

[0049] Unless otherwise defined herein, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Technical terms used herein refer to the art as commonly understood by one of ordinary skill in the art, including variations and equivalents that are apparent to one of ordinary skill in the art. Although the following terms are believed to be well understood by one of ordinary skill in the art, the following definitions are set forth to better illustrate the present application. When a name of an article is mentioned herein, it refers to the corresponding article or its active ingredient. All patents, published patent applications, and publications recited herein are incorporated by reference.

[0050] The term "synthetic lethality" refers to the phenomenon that when two or more individual genes have abnormal expression simultaneously, it leads to cell death, while when only one or a part of the genes have abnormal expression, it does not lead to cell death; wherein the abnormal expression includes mutation, overexpression or gene inhibition. In an embodiment, the two genes of synthetic lethality are referred to as a synthetic lethal gene pair.

[0051] The term "cyclin E1" refers to G1 / S-specific cyclin E1 (gene name: CCNE1). A cell overexpressing cyclin E1 exhibits higher cyclin E1 activity than a cell normally expressing cyclin E1. A CCNE1-amplified cell is a cell having a higher copy number of CCNE1 gene than a normal cell. A cell overexpressing cyclin E1 can be a CCNE1-amplified cell, for example, in one embodiment, a cell overexpressing cyclin E1 has more than 2 copies of CCNE1 as compared to a diploid normal cell having 2 copies of CCNE1. Cyclin E1 overexpression can also be determined by identifying the expression level of the gene product (e.g., mRNA transcription level or cyclin E1 protein level) in a cell, in addition to directly detecting the copy number of CCNE1 gene.

[0052] In this context, the terms "a cancer overexpressing cyclin E1" and "a CCNE1-amplified cancer" can be used interchangeably. Examples of CCNE1-amplified cancer include, but are not limited to, uterine sarcoma, ovarian cancer, breast cancer, gastric cancer, esophageal cancer, lung cancer, liver cancer, and endometrial cancer.

[0053] The term "FBXW7" refers to F-box / WD repeat-containing protein 7 (gene name: FBXW7). A FBXW7 gene with inactivating mutation refers to a mutant FBXW7 gene that is unable to produce normal functional FBXW7 protein or produces a reduced amount of FBXW7 protein in a cell. Examples of FBXW7 mutant cancer include, but are not limited to, hematological tumors, glioma, 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, esophagogastric junction adenocarcinoma, bladder cancer (e.g., bladder urothelial 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 carcinoma).

[0054] The term "p53 protein" refers to tumor protein p53 (gene name: TP53). A TP53 gene with inactivating mutation refers to a mutant TP53 gene that is unable to produce functional p53 protein or produces a reduced amount of p53 protein in a cell.

[0055] When a range, preferably range or preferred upper or lower limit, is recited in the form of a 10 ” or “C 1-10 ” encompasses a range of 1-10 carbon atoms, and is to be understood to also encompass any sub-range within that range, as well as each individual number in that range, e.g., 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 manner, e.g., can encompass 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., as well as C3, C4, C5, C6, C7, C8, C9, C 10 , etc. For example, the expression “3-14 membered” should be understood to encompass any sub-range within that range, as well as each individual number in that range, e.g., 3-4, 3-5, 3-6, 3-7, 3-8, 4-5, 4-6, 4-7, 5-6, 3, 4, 5, 6, or 7 membered, etc. The expressions “3-12 membered,” “3-7 membered,” “4-8 membered” should also be understood in a similar manner. The expression “p is an integer selected from 0 to 13” means that p is any integer from 0-13, e.g., p can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13. Other similar expressions, e.g., p1and p2, should also be understood in a similar manner.

[0056] When any variable (e.g., R X) are independent in each instance of which they occur in the composition or structure of the compound. For example, the expression "each R X is independently selected" means that if there are multiple R X , each R X is independently selected in each instance. The options for each substituent are independent of each other. Other variables or expressions such as R 3 are to be interpreted in a similar manner.

[0057] The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. The expressions "one or more" or "at least one" can mean 1, 2, 3, 4, 5, 6, 7, 8, 9, or more. In an embodiment, "at least one" means 1, 2, 3, or 4.

[0058] The terms "optionally" or "optional" mean that the subsequently described event or circumstance can occur but does not necessarily occur and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0059] The terms "substituted" and "substitution" mean the replacement of one or more (e.g., one, two, three, or four) hydrogens on the designated atom with a selection from the indicated group, provided that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. When a substitution is described, it is understood that the substitution can be one or more hydrogen atoms, provided that the structure enables the compound to be in a stable state.

[0060] Unless indicated, as used herein, the point of attachment of a substituent can be from any suitable position of the substituent. When the bond to a substituent is shown as a line drawn through a ring atom that connects two atoms in the ring, then such substituent can be bonded to either ring atom in the ring that can be substituted.

[0061] 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" limits the scope of a composition or process to the specified materials or steps plus an optional ingredient, step, or procedure that does not materially affect the basic and novel characteristics of the claimed subject matter. It is understood that the expression "comprising" includes the expressions "consisting of" and "consisting essentially of."

[0062] The term "halo" or "halogen" or "halo" is understood to mean a fluorine (F), chlorine (CI), bromine (Br), or iodine (I) atom, preferably a fluorine, chlorine, or bromine atom.

[0063] The term "hydrocarbyl" refers to a monovalent radical derived from a hydrocarbon. Examples of hydrocarbyl groups include, but are not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, and aryl.

[0064] The term "alkyl" refers to a saturated aliphatic hydrocarbon radical derived by the removal of one hydrogen atom from a straight chain or branched chain alkane. Alkyl groups can contain 1-10 carbon atoms, referred to as C 1-10 alkyl, for example, C 1-6 alkyl, C 1-4 alkyl, C 1-3 alkyl, C 1-2 alkyl, C3alkyl, C4alkyl, C 3-6 alkyl. Non-limiting examples of straight chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, and the like. Non-limiting examples of branched alkyl groups include, but are not limited to, isopropyl, isobutyl, sec-butyl, t-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, and the like.

[0065] A divalent radical refers to a radical obtained by removing one hydrogen atom from a carbon atom having a free valence electron of a corresponding monovalent radical. A divalent radical has two attachment sites to the rest of the molecule, where the two attachment sites can be on the same atom or on two different atoms of the divalent radical.

[0066] "Alkylene" or "alkylidene" refers to a saturated divalent hydrocarbon radical. Alkylene groups include straight chain or branched chain alkylene groups. Examples of straight chain alkylene groups include, but are not limited to, methylene (-CH2-), -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, and the like. Examples of branched chain alkylene groups 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)-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-, and the like.

[0067] The term "alkenyl" refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms, with at least one double bond. Alkenyl groups can have 2-8 carbon atoms, i.e., "C6H ... 2-8 "Alkenyl", for example, C 2-4 alkenyl, C 3-4 Alkenyl. Non-limiting examples of alkenyl include, but are not limited to, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, etc.

[0068] The term "alkynyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms, with at least one triple bond. Alkynyl groups can have 2-8 carbon atoms, i.e., "C6H ... 2-8 "Alkyne group", such as C 2-4 alkynyl group, C 3-4 Alkynyl. Non-limiting examples of alkynyl include, but are not limited to, ethynyl, prop-1-alkynyl, prop-2-alkynyl, but-1-alkynyl, but-2-alkynyl, but-3-alkynyl, etc.

[0069] The term "alkoxy group" refers to an alkyl group as defined above, which is bonded to an oxygen atom by a single bond. The alkoxy group is connected to the rest of the molecule via an oxygen atom. An alkoxy group can be represented as -O (alkyl). "C 1-8 "alkoxy" or "-O(C)" 1-8 "Alkyl" refers to an alkoxy group containing 1-8 carbon atoms, where the alkyl moiety can be straight-chain or branched. Alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, n-pentoxy, etc.

[0070] The terms "hydrocarbon ring" and "cyclic hydrocarbon group" each refer to a saturated or unsaturated non-aromatic ring system composed of carbon and hydrogen atoms. Preferably, each of the "hydrocarbon ring" and "cyclic hydrocarbon group" comprises one or two rings. The "hydrocarbon ring" and "cyclic hydrocarbon group" can be monocyclic, fused polycyclic, bridged, or spirocyclic structures. Each of the "hydrocarbon ring" and "cyclic hydrocarbon group" can have 3-10 carbon atoms, i.e., "C..." 3-10 Hydrocarbon rings (e.g., C4, C5, C6, C7) and "C 3-10 Cyclic hydrocarbon groups (e.g., C) 3-8Cycloalkyl, C5cycloalkyl, C6cycloalkyl, C7cycloalkyl). Non-limiting examples of hydrocarbon rings include, but are not limited to, cyclopentane, cyclohexane, cycloheptane, cyclopentene, cyclohexene, and the like. Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, bicyclo[2.2.1]heptane, and spiro[3.3]heptane, cyclopentenyl, cyclohexenyl, and the like. In some embodiments, a C atom in a cycloalkyl group is optionally substituted with oxo. In some embodiments, a C atom in a cycloalkyl group is optionally substituted with imino. In some embodiments, the imino is unsubstituted (=NH), or is substituted with a group as described in context. In some embodiments, the imino is substituted with -OR, wherein R is H or C 1-10 Alkyl.

[0071] The terms "cyclic alkyl" and "cycloalkyl" have the same meaning herein and are used interchangeably. Cycloalkyl refers to saturated cycloalkyl groups. Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9, or 10 ring-forming carbon atoms (C 3-10 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. In some embodiments, a cycloalkyl group is C 3-7 Monocyclic or bicyclic cycloalkyl, preferably C 3-6 Monocyclic cycloalkyl, in particular cyclopropyl.

[0072] 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., having 7-14, 3-8, 3-7, 4-6, or 5-6), 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 can be saturated (as can also be understood as a corresponding "heterocycloalkane" or "heterocycloalkyl") or unsaturated (i.e., having one or more double and / or triple bonds within the ring). Optionally, "heterocycle" and "heterocyclyl" each can be benzo-fused. "Heterocycle" and "heterocyclyl" each are not aromatic. In some embodiments, a C, N, S, and P atom in "heterocycle" and "heterocyclyl" is optionally substituted with oxo. In some embodiments, a C, S, and P atom in "heterocycle" and "heterocyclyl" is optionally substituted with imino. In some embodiments, the imino is unsubstituted (=NH), or is substituted with a group as described in context. In some embodiments, the imino is substituted with -OR, wherein R is H or C 1-10 Alkyl.

[0073] Heterocyclyl can be, for example, a four-membered ring, such as an azetidinyl, oxetanyl; or a five-membered ring, such as a tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, oxopyrrolidinyl, 2-oxoimidazolidin-1-yl; or a six-membered ring, such as a tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, 1,1-dioxo-1,2-thiazinan-2-yl or trithianyl; or a seven-membered ring, such as a diazepinyl, oxazepinyl, thiazepinyl or diazepinyl. Base ring.

[0074] Heterocyclyl can be bicyclic, without being limited thereto, for example a five-membered and five-membered ring, such as an octahydrocyclopenta[c]pyrrolyl; or a five-membered and six-membered bicyclic ring, such as an octahydropyrrolo[1,2-b]pyrazinyl.

[0075] As mentioned above, the heterocycle can be unsaturated, i.e. it can contain one or more double bonds, without being limited thereto, for example an unsaturated heterocycle containing a nitrogen atom can be a 1,6-dihydropyrimidine, 1,2-dihydropyrimidine, 1,4-dihydropyrimidine, 1,6-dihydropyridine, 1,2-dihydropyridine, 1,4-dihydropyridine, 2,3-dihydro-1H-pyrrole, 3,4-dihydro-1H-pyrrole, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl or a 4H-[1,4]thiazinyl ring, an unsaturated heterocycle containing an oxygen atom can be a 2H-pyran, 4H-pyran, 2,3-dihydrofuran, an unsaturated heterocycle containing a sulfur atom can be a 2H-thiopyran, 4H-thiopyran. The heterocycle can be benzo-fused, without being limited thereto, for example a dihydroisoquinolinyl ring.

[0076] Exemplary bicyclic heterocycles also include:

[0077] The terms "aromatic ring" and "aryl" each refer to a fully carbon monocyclic or fused polycyclic (such as bicyclic) aromatic ring system having a conjugated pi electron system, which can have from 6 to 14 carbon atoms, suitably from 6 to 10, more suitably 6 or 10. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthryl, and the like.

[0078] The terms "heteroaromatic ring" and "heteroaryl" each refer to a monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 7, 8, 9 or 10 ring atoms ("5-10 membered heteroaryl"), in particular 5 or 6 or 9 or 10 ring atoms, and of which ring atoms at least one (suitably 1-4, more suitably 1, 2 or 3) can be the same or different heteroatoms, such as oxygen, nitrogen or sulfur. Furthermore, in each case "heteroaromatic ring" and "heteroaryl" each can be benzo-fused. In particular, heteroaryl is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl and the like, and their benzo derivatives, such as benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like, and their benzo derivatives, such as quinolinyl, quinazolinyl, isoquinolinyl and the like; or azocinyl, indolizinyl, purinyl and the like, and their benzo derivatives; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, carbazolyl, acridinyl and the like.

[0079] Pharmaceutically acceptable salts of the compounds of the present application include acid addition salts and base addition salts. Methods for preparing pharmaceutically acceptable salts of the compounds of the present application are known to those skilled in the art.

[0080] The compounds of the present application encompass pharmaceutically acceptable salts, stereoisomers, solvates, polymorphs, tautomers, isotopically enriched compounds, metabolites or prodrugs thereof.

[0081] The compounds of the present application can exist in particular geometric or stereoisomeric forms. The present application contemplates all such compounds. For example, the carbon-carbon double bonds or carbon-nitrogen double bonds of the compounds of the present application can exist in E or Z form, where "E" represents the more substituted side of the carbon-carbon double bond or carbon-nitrogen double bond being in the exo position according to the Cahn-Ingold-Prelog priority rules, and "Z" represents the more substituted side of the carbon-carbon double bond or carbon-nitrogen double bond being in the endo position. The compounds of the present application can also exist as mixtures of the "E" and "Z" isomers. Isomeric forms also include cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, as well as racemic mixtures and other mixtures well-known in the art, for example, mixtures of enantiomers or diastereomers. All such isomeric forms are within the scope of the present application. Purification and separation of such isomeric forms can be achieved by standard techniques known in the art.

[0082] The compounds of the present application can contain bonds with restricted rotation, such that two separate atropisomers can be isolated. All possible atropisomers are included within the scope of the present application. Methods for the separation of atropisomers can be known methods or employ methods described herein. In one embodiment, the atropisomers are resolved using chiral chromatography, for example using supercritical CO2 and MeOH as the mobile phase.

[0083] Optically pure enantiomers can be obtained from racemic mixtures according to conventional procedures, for example by the formation of diastereomeric salts using an optically active acid or base, or by the formation of covalent diastereomers. Mixtures of diastereomers can be separated by known methods, for example by chromatography or fractional crystallization based on the physical and / or chemical differences between them. The optically active base or acid added to form the salts of the enantiomeric bases or acids having optical activity can then be liberated 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 or can not be derivatized prior to separation, depending on which method allows for more efficient separation of the chiral isomers. Enzymatic methods can also be used to separate derivatized or non-derivatized chiral isomers. Likewise, optically pure compounds of the present application can be obtained by chiral synthesis using starting materials having optical activity.

[0084] The compounds of the present application can exist in solvated (preferably hydrated) forms, wherein the compounds of the present application contain solvent, particularly, for example, water, methanol or ethanol, as a structural element of the crystal lattice of the compound. The amount of solvent, particularly water, can be present in stoichiometric or non-stoichiometric amounts.

[0085] The present application also encompasses all possible crystalline forms or polymorphs of the compounds of the present application, which can be a single polymorph or a mixture of more than one polymorph in any ratio.

[0086] The compounds of the present application can exist in isotopically-labeled or enriched forms, containing one or more atoms which differ from the most abundant or naturally occurring isotopic form. The isotopes can be radioactive or non-radioactive isotopes. Isotopes of atoms such as hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, 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.

[0087] Also included within the scope of the application are metabolites of the compounds of the present application, i.e., substances produced within the body that arise from the administration of a compound of the present application. Such products can result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic cleavage, and the like.

[0088] The present application further includes within its scope prodrugs of the compounds of the application, which are certain derivatives of the compounds of the application that have less or no pharmacological activity as such but, when administered into or onto the body, are converted into the compounds of the application having the desired activity, for example, by hydrolytic cleavage.

[0089] The term "polymorph" or "polymorphs" refers to a single polymorph or a mixture of more than one polymorph in any ratio.

[0090] The term "crystal form" or "crystal" refers to any solid material that exhibits a three-dimensional order, as opposed to amorphous solid material, which produces a characteristic X-ray powder diffraction pattern with well-defined peaks.

[0091] The term "amorphous" refers to any solid material that has no order in three dimensions.

[0092] The term "pharmaceutically acceptable" means, within the scope of normal medical judgment, that contact with the tissues of the patient will not cause undue toxicity, irritation, allergic response, and the like.

[0093] The term "pharmaceutically acceptable carrier" means a material that is not biologically or otherwise undesirable, i.e., the material can be administered to an organism without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. The carrier would naturally be

[0094] The term "active ingredient", "therapeutic agent", "active substance" or "active agent" refers to a chemical entity that is effective in treating or preventing a disorder, disease, or condition of interest.

[0095] The term "effective amount", "therapeutically effective amount" or "prophylactically effective amount" in relation to a drug, pharmaceutical unit or active ingredient means a sufficient amount of the drug or agent to produce a desired effect, which is acceptable in view of side effects. The determination of an effective amount is dependent on the age and general condition of the individual, as well as on the particular active substance, and an effective amount in a given case can be determined by a person skilled in the art according to routine tests.

[0096] The term "individual" includes a human or non-human animal. Exemplary human individuals include a human individual (referred to as a patient) suffering from a disease (e.g., a disease described herein) or a normal individual. "Non-human animals" in the present application include all vertebrates, e.g., non-mammals (e.g., birds, amphibians, reptiles), and mammals, e.g., non-human primates, domestic animals, and / or laboratory models (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0097] The compound of formula (I)

[0098] In one aspect, the present application provides a compound having the structure of formula (I):

[0099] or a pharmaceutically acceptable salt thereof,

[0100] wherein,

[0101] E 1 and E 2 are each independently selected from O and S;

[0102] Ring A is a 5-membered heteroaromatic ring;

[0103] R 1 is selected from hydrogen, C 1-10 alkyl, C 3-10 alkenyl, C 1-4 alkynyl, C 3-10 cycloalkyl, heterocyclyl, -C 1-4 alkylene-heterocyclyl, CN, NO2, -C(=O)R A1 , -C(=O)OR A1 , -C(=O)NR A1 R B1 , -S(=O) r R A1 , -S(=O)(=NR E1 )R B1 , -S(=O) r NR A1 R B1 , and -S(=O)(=NR E1 )NR A1 R B1 , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is unsubstituted or substituted with at least one substituent independently selected from R X1 ;

[0104] R 2 is selected from hydrogen, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, -C 1-4 alkylene-C3- 10 cycloalkyl, heterocyclyl, -C 1-4 alkylene-heterocyclyl, CN, NO2, -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)(=NRE2 )NR A2 R B2 -NR A2 S(=O)2NR A2 R B2 and -NR A2 S(=O)(=NR E2 )NR A2 R B2 Each alkyl, alkylene, alkenyl, ynyl, cycloalkyl, and heterocyclic group is unsubstituted or is selected independently from R X2 Substituents of the substituents;

[0105] W does not exist, or it is CR. 3 R 3 ';

[0106] R 3 and R 3 'Independently selected from halogens, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 Cyclic hydrocarbon group, -C 1-4 Alkylene-C 3-10 Cyclic hydrocarbon groups, heterocyclic groups, -C 1-4 alkylene-heterocyclic, 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 -NRA3 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 Each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is unsubstituted or is selected independently from R. X3 Substituents of the substituents;

[0107] R 4 Selected from hydrogen, halogens, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, -C 1-4 Alkylene-C 3- 10 Cycloalkyl, heterocyclic, -C 1-4 alkylene-heterocyclic, CN, NO2, aryl, -C 1-4 alkylene-aryl, heteroaryl, -C 1-4 alkylene-heteroaryl, -NR A4 R B4 -ORA4 , -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 -NRA4 S(=O)(=NR E4 )NR A4 R B4 Each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is unsubstituted or is selected independently from R. X4 Substituents of the substituents;

[0108] R 5 Selected from hydrogen, halogens, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, -C 1-4 Alkylene-C 3- 10 Cycloalkyl, heterocyclic, -C 1-4 alkylene-heterocyclic, 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 by at least one substituent independently selected from the group consisting of R X5 ;

[0109] R 6 is selected from the group consisting of 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, heterocyclyl, -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)RA6 -C(=O)NR A6 R B6 -NR A6 C(=O)R B6 -C(=NR E6 )R 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 -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 by at least one substituent independently selected from the group consisting of R X6 ;

[0110] 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, heterocyclyl, -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 , -NRA7 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 substituent independently selected from the group consisting of R X7 ;

[0111] R 8 is selected from the group consisting of 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, heterocyclyl, -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 Each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is unsubstituted or is selected independently from R. X8 Substituents of the substituents;

[0112] R 9 Selected from hydrogen, halogens, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, -C 1-4 Alkylene-C 3- 10 Cycloalkyl, heterocyclic, -C 1-4alkylene-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)(=NRE9 )NR A9 R B9 -NR A9 S(=O)2NR A9 R B9 and -NR A9 S(=O)(=NR E9 )NR A9 R B9 Each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is unsubstituted or is selected independently from R. X9 Substituents of the substituents;

[0113] Or R 8 and R 9 Together with the atoms bonded to them, they form a C 5-6 A hydrocarbon ring or a 5-6 membered heterocycle or a 5-6 membered heteroaromatic ring containing 1, 2 or 3 heteroatoms, wherein each heteroatom is independently selected from oxygen, sulfur and nitrogen, and the ring is unsubstituted or has at least one heteroatom independently selected from R. X8 Substituents of the substituents;

[0114] R 10 Selected from hydrogen, halogens, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, -C 1-4 Alkylene-C 3- 10 Cycloalkyl, heterocyclic, -C 1-4 alkylene-heterocyclic, CN, NO2, aryl, -C 1-4 alkylene-aryl, heteroaryl, -C 1-4 alkylene-heteroaryl, -NR A10 R B10 -OR A10 -SR A10 -C(=O)R A10 -C(=NR) E10 )R A10 -C(=N-OR) B10 )R A10 -C(=O)OR A10 -OC(=O)R A10 -C(=O)NR A10 R B10 -NR A10 C(=O)R B10 -C(=NR) E10 )NR A10 R B10 -NR A10 C(=NRE10 )R B10 -OC(=O)NR A10 R B10 -NR A10 C(=O)OR B10 -NR A10 C(=O)NR A10 R B10 -NR A10 C(=S)NR A10 R B10 -NR A10 C(=NR E10 )NR A10 R B10 -S (=O) r R A10 -S(=O)(=NR) E10 )R B10 -N = S(=O)R A10 R B10 -S(=O)2OR A10 -OS(=O)2R A10 -NR A10 S(=O) r R B10 -NR A10 S(=O)(=NR E10 )R B10 -S (=O) r NR A10 R B10 -S(=O)(=NR) E10 )NR A10 R B10 -NR A10 S(=O)2NR A10 R B10 and -NR A10 S(=O)(=NR E10 )NR A10 R B10 Each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is unsubstituted or is selected independently from R. X10 Substituents of the substituents;

[0115] R 11 Selected from hydrogen, halogens, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, -C 1-4 Alkylene-C 3- 10 Cycloalkyl, heterocyclic, -C1-4 alkylene-heterocyclic, CN, NO2, aryl, -C 1-4 alkylene-aryl, heteroaryl, -C 1-4 alkylene-heteroaryl, -NR A11 R B11 -OR A11 -SR A11 -C(=O)R A11 -C(=NR) E11 )R A11 -C(=N-OR) B11 )R A11 -C(=O)OR A11 -OC(=O)R A11 -C(=O)NR A11 R B11 -NR A11 C(=O)R B11 -C(=NR) E11 )NR A11 R B11 -NR A11 C(=NR E11 )R B11 -OC(=O)NR A11 R B11 -NR A11 C(=O)OR B11 -NR A11 C(=O)NR A11 R B11 -NR A11 C(=S)NR A11 R B11 -NR A11 C(=NR E11 )NR A11 R B11 -S (=O) r R A11 -S(=O)(=NR) E11 )R B11 -N = S(=O)R A11 R B11 -S(=O)2OR A11 -OS(=O)2R A11 -NR A11 S(=O) r R B11 -NR A11 S(=O)(=NR E11 )R B11 -S (=O) r NR A11 R B11-S(=O)(=NR E11 )NR A11 R B11 , -NR A11 S(=O)2NR A11 R B11 , and -NR A11 S(=O)(=NR E11 )NR A11 R B11 wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X11 ;

[0116] or R 10 and R 11 together with the atoms to which they are attached form a C 3-10 monocyclic hydrocarbon ring or a 4-12 membered heterocyclic ring containing 1, 2 or 3 heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen and phosphorus or a 6-10 membered aromatic ring or a 5-10 membered heteroaromatic ring containing 1, 2 or 3 heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen and phosphorus, which ring is substituted with h substituents independently selected from the group consisting of R 12 ;

[0117] R 12 is selected from the group consisting of 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, heterocyclyl, -C 1-4 alkylene-heterocyclyl, CN, NO2, aryl, -C 1-4 alkylene-aryl, heteroaryl, -C 1- 4alkylene-heteroaryl, -NR A12 R B12 , -OR A12 , -SR A12 , -C(=O)R A12 , -C(=NR E12 )R A12 , -C(=N-OR B12 )R A12 , -C(=O)OR A12 , -OC(=O)R A12 , -C(=O)NR A12 R B12 , -NR A12 C(=O)R B12 , -C(=NR E12 )NR A12 R B12 , -NRA12 C(=NR E12 )R B12 -OC(=O)NR A12 R B12 -NR A12 C(=O)OR B12 -NR A12 C(=O)NR A12 R B12 -NR A12 C(=S)NR A12 R B12 -NR A12 C(=NR E12 )NR A12 R B12 -S (=O) r R A12 -S(=O)(=NR) E12 )R B12 -N = S(=O)R A12 R B12 -S(=O)2OR A12 -OS(=O)2R A12 -NR A12 S(=O) r R B12 -NR A12 S(=O)(=NR E12 )R B12 -S (=O) r NR A12 R B12 -S(=O)(=NR) E12 )NR A12 R B12 -NR A12 S(=O)2NR A12 R B12 and -NR A12 S(=O)(=NR E12 )NR A12 R B12 Each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is unsubstituted or is selected independently from R. X12 Substituents of the substituents;

[0118] It can be a single bond or a double bond;

[0119] Each R A1 R A2 R A3 R A4 R A5 R A6R A7 R A8 R A9 R A10 R A11 R A12 R B1 R B2 R B3 R B4 R B5 R B6 R B7 R B8 R B9 R B10 R B11 and R B12 are independently selected from the group consisting of 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, heterocyclyl, -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 substituent independently selected from the group consisting of R X ;

[0120] 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 " or "R A10 and R B10 " or "R A11 and R B11 " or "R A12 and R B12together with the single or multiple atoms to which they are attached, 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 substituents selected from R X ;

[0121] each R E1 , R E2 , R E3 , R E4 , R E5 , R E6 , R E7 , R E8 , R E9 , R E10 , R E11 and R E12 are 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 alkyl is unsubstituted or substituted with at least one substituent independently selected from R X ;

[0122] each R X , R X1 , R X2 , R X3 , R X4 , R X5 , R X6 , R X7 , R X8 , R X9 , R X10 , R X11 and R X12 are 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, heterocyclyl, -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 substituent independently selected from the group consisting of R Y ;

[0123] each R a1 and R b1 is independently selected from the group consisting of 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, heterocyclyl, -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 substituent independently selected from the group consisting of R Y ;

[0124] or R a1 and R b1 together with the single or multiple atoms to which they are attached form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen and phosphorus, which ring is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of R Y ;

[0125] each R c1 and R d1 is independently selected from the group consisting of 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, heterocyclyl, -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 substituent independently selected from the group consisting of R Ysubstituents selected from the group consisting of R

[0126] or each R c1 and R d1 together with the single or multiple carbon atom to which they are attached form a 3-12 membered ring containing 0, 1, or 2 heteroatoms independently selected from the group consisting of oxygen, sulfur, and nitrogen, which ring is unsubstituted or substituted with 1, 2, or 3 groups independently selected from R Y

[0127] each R e1 is independently selected from the group consisting of 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 alkyl is unsubstituted or substituted with at least one substituent selected from the group consisting of R Y

[0128] each R Y is independently selected from the group consisting of 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);

[0129] g is selected from 0, 1, and 2;

[0130] h is selected from 0, 1, 2, 3, 4, 5, 6, 7, and 8;

[0131] ​​each r is independently selected from 1 and 2;

[0132] each t is independently selected from 0, 1, 2, 3, and 4.

[0133] In one embodiment, E 1 is O. In one embodiment, E 2 is O. In one embodiment, t is 0. In one embodiment, g is selected from 1 and 2. In one embodiment, h is selected from 0, 1, 2, 3, and 4. In one embodiment, h is selected from 0, 1, and 2.

[0134] In one embodiment, each R A1 , R A2 , R A3 , R A4 , R A5 , R A6 , R A7 , R A8 , R A9 , R A10 , R A11 , R A12 , R B1 , R B2 , R B3 , R B4 , R B5 , R B6 , R B7 , R B8 , R B9 , R B10 , R B11 , and R B12 are independently selected from hydrogen and C 1-10 alkyl, wherein each alkyl is unsubstituted or substituted with at least one substituent independently selected from R X In one embodiment, each R X , R X1 , R X2 , R X3 , R X4 , R X5 , R X6 , R X7 , R X8 , R X9 , R X10 , R X11 , and R X12 are independently selected from halogen, C 1-10 alkyl, C 3-10 cycloalkyl, -C 1-4 alkylene-C 3-10 cycloalkyl, heterocyclyl, -C 1- 4 alkylene-heterocyclyl, CN, NO2, -(CR c1 Rd1 ) 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 , -(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 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 halogens, 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 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 and -(CR c1 R d1 ) t NR a1 C(=O)R b1 Each alkyl, alkylene, cycloalkyl, and heterocyclic group is unsubstituted or is independently selected from R Y Substituents are substituted. In one embodiment, each R... E1 R E2 R E3 R E4 R E5 R E6 R E7 R E8 R E9 R E10 R E11 and R E12 Independently selected from hydrogen and C1-10 Alkyl group, wherein the alkyl group is unsubstituted or is selected independently from R. X Substituents are substituted. In one embodiment, each R... X R X1 R X2 R X3 R X4 R X5 R X6 R X7 R X8 R X9 R X10 R X11 and R X12 Independently selected from halogens, C 1-10 Alkyl group, CN, and NO2, wherein each alkyl group is unsubstituted or is selected independently from R. Y Substituents are substituted. In one embodiment, each R... a1 and R b1 Independently selected from hydrogen and C 1-10 Alkyl groups, wherein each alkyl group is unsubstituted or is independently selected from R. Y Substituents are substituted. In one embodiment, each R... c1 and R d1 Independently selected from hydrogen, halogens and C 1-10 Alkyl groups, wherein each alkyl group is unsubstituted or is independently selected from R. Y Substituents are substituted. In one embodiment, each R... Y Independently selected from halogens, NO2, -CN, C 1- 10 Alkyl, -OH, -O(C) 1-10 Alkyl groups, -NH2, -NH(C) 1-10 alkyl) and -N(C) 1-10 Alkyl group 2, preferably selected from halogens, NO2, -CN and C 1-10 alkyl.

[0135] In one implementation scheme, R 1 Selected from hydrogen, C 1-10 Alkyl and C 3-10 Cycloalkyl groups, preferably selected from hydrogen and C24. 1-10 Alkyl groups, wherein the alkyl and cycloalkyl groups are unsubstituted or are selected independently from R. X1 Substituents are substituted. In one embodiment, R 1 It is hydrogen.

[0136] In one implementation scheme, R 2 The component is selected from hydrogen, halogens, CN, and NO2. In one embodiment, R... 2 It is hydrogen. In one embodiment, R2 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 , -NR E2 C(=NR B2 )R A2 , -OC(=O)NR B2 R A2 , -NR B2 C(=O)OR A2 , -NR A2 C(=O)NR B2 R A2 , -NR A2 C(=S)NR B2 R A2 , -NR E2 C(=NR A2 )NR B2 R A2 , -OS(=O)2R A2 , -NR r S(=O) B2 R A2 , -NR E2 S(=O)(=NR B2 )R A2 , -NR A2 S(=O)2NR B2 R A2 , and -NR E2 S(=O)(=NR A2 )NR B2 R X2 wherein alkyl is unsubstituted or substituted with at least one substituent selected independently from 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 B2wherein alkyl is unsubstituted or substituted with at least one substituent independently selected from R X2 In one embodiment, R 2 is selected from C 1-10 alkyl, -NR A2 R B2 , -OR A2 and -SR A2 , preferably from -NR A2 R B2 and -OR A2 , in particular -NR A2 R B2 . In one embodiment, each R B2 is independently selected from C 1-10 alkyl, and each R A2 is hydrogen. In one embodiment, each R A2 and R B2 is hydrogen. In one embodiment, each R E2 is independently selected from hydrogen and C 1-10 alkyl. In a particular embodiment, R 2 is -NH2. In one embodiment, R 2 is selected from -NR A2 R B2 and hydrogen, preferably from -NH2and hydrogen.

[0137] In one embodiment, W is absent. In one embodiment, W is CR 3 R 3 '. In one embodiment, R 3 and R 3 ' are independently selected from hydrogen, C 1-10 alkyl and C 3-10 cycloalkyl, preferably from hydrogen and C 1-10 alkyl, wherein alkyl and cycloalkyl are unsubstituted or substituted with at least one substituent independently selected from R X3 . In one embodiment, R 3 and R 3 ' are hydrogen. In one embodiment, W is CH2.

[0138] In one embodiment, each R 4 is 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, heterocyclyl, -C 1-4 alkylene-heterocyclyl, CN, NO2, aryl, -C 1-4 alkylene-aryl, heteroaryl, -C1-4 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 , -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 , -S(=O) r R A4 , -N=S(=O)R A4 R B4 , -S(=O)2OR A4 , -OS(=O)2R A4 , -NR A4 S(=O) r R B4 , -S(=O) r NR A4 R B4 and -NR A4 S(=O)2NR A4 R B4 , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X4 In one embodiment, each R 4 is independently selected from the group consisting of halogen, C 1-10 1-6alkyl, C 2-10 1-6alkenyl, C 2-10 1-6alkynyl, C 3-10 3-6cycloalkyl, -C 1-4 1-6alkylene-C 3-10 3-6cycloalkyl, heterocyclyl, -C 1-4 1-6alkylene-heterocyclyl, CN, NO2, aryl, -C 1-4 1-6alkylene-aryl, heteroaryl, -C 1- 4alkylene-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 substituent independently selected from the group consisting of R X4 In one embodiment, each R 4 is independently selected from the group consisting of halogen, C 1-10 alkyl, C 3-10 cycloalkyl, CN, -NR A4 R B4 , -OR A4 , -SR A4 and -C(=O)R A4 , in particular from the group consisting of halogen, CN and C 1-10 alkyl, wherein each alkyl, alkylene and cycloalkyl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X4 In one embodiment, each R B4 is independently selected from the group consisting of C 1-10 alkyl, and each R A4 is hydrogen. In one embodiment, each R A4 and R B4 is hydrogen. In one embodiment, each R 4 is independently selected from the group consisting of F, Cl, Br, CN, OH, C 1-10 alkyl and -O(C 1-10 alkyl), in particular from the group consisting of F, Cl, Br, CN and C 1-10 alkyl, wherein each alkyl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X4 In one embodiment, each R 4 is independently selected from the group consisting of F, Cl, methyl and ethyl. In a particular embodiment, each R 4 is methyl.

[0139] In one embodiment, R 5 is selected from the group consisting of 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, heterocyclyl, -C 1-4 alkylene-heterocyclyl, CN, NO2, -NR A5 R B5 , -OR A5 , -SR A5 , -C(=O)R A5 , -C(=O)OR A5 , -OC(=O)R A5 , -C(=O)NR A5 R B5 , -NR A5 C(=O)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 , -S(=O) r R A5 , -S(=O)2OR A5 , -OS(=O)2R A5 , -NR A5 S(=O) r R B5 , -S(=O) r NR A5 R B5 and -NR A5 S(=O)2NR A5 R B5 , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl and heterocyclyl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X5 In one embodiment, R 5 is selected from the group consisting of halogen, C 1-10 alkyl, C 2-10 alkenyl, C 3-10 alkynyl, C 1-4 cycloalkyl, -C 3-10 alkylene-C 1-4 cycloalkyl, heterocyclyl, -C A5 alkylene-heterocyclyl, CN, NO2, -NRR B5 , -OR A5 , -SR A5 , -C(=O)R A5 , -C(=O)OR A5 , -OC(=O)R A5 , -C(=O)NR A5 R B5 , -NR A5 C(=O)R B5 , -S(=O) r R A5 , -S(=O)2OR A5 , -OS(=O)2R A5 , -NR A5 S(=O) r R B5 and -S(=O) r NR A5 R B5 , preferably selected from halogen, C 1-10 1-6alkyl, C 3-10 3-6cycloalkyl, -C 1-4 1-6alkylene-C 3-10 3-6cycloalkyl, CN, NO2, -NR A5 R B5 and -OR A5 , in particular selected from halogen, C 1-10 1-6alkyl, C 3-10 3-6cycloalkyl, -C 1-4 1-6alkylene-C 3-10 3-6cycloalkyl, CN and NO2, wherein each alkyl, alkylene, cycloalkyl and heterocyclyl is unsubstituted or substituted with at least one substituent independently selected from R X5 . In one embodiment R 5 is selected from halogen and C 1-10 1-6alkyl, wherein alkyl is unsubstituted or substituted with at least one substituent independently selected from R X5 . In one embodiment R 5 is selected from Cl and methyl. In one embodiment R 5 is Cl. In one embodiment R 5 is selected from C 1-10 1-6alkyl, wherein alkyl is unsubstituted or substituted with at least one substituent independently selected from R X5 . In one preferred embodiment R 5 is methyl or ethyl, wherein methyl and ethyl are unsubstituted or substituted with at least one substituent independently selected from R X5 . In one particular embodiment R 5 is methyl.

[0140] In one embodiment, R 6 is selected from the group consisting of hydrogen, halogen, C 1-10 alkyl, CN, NO2, -NR A6 R B6 , -OR A6 , -SR A6 , -C(=O)R A6 , -C(=O)OR A6 , -OC(=O)R A6 , -C(=O)NR A6 R B6 , -NR A6 C(=O)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 , -S(=O) r R A6 , -S(=O)2OR A6 , -OS(=O)2R A6 , -NR A6 S(=O) r R B6 , -S(=O) r NR A6 R B6 and -NR A6 S(=O)2NR A6 R B6 , wherein alkyl is unsubstituted or substituted by at least one substituent independently selected from the group consisting of R X6 . In one embodiment, R 6 is selected from the group consisting of hydrogen, halogen, C 1-10 alkyl, CN, NO2, -NR A6 R B6 and -OR A6 , in particular from the group consisting of hydrogen, halogen, C 1-10 alkyl, CN and NO2, wherein alkyl is unsubstituted or substituted by at least one substituent independently selected from the group consisting of R X6 . In one embodiment, R 6 is selected from halogen, in particular F. In a particular embodiment, R 6 is hydrogen.

[0141] In one embodiment, R 7 is selected from the group consisting of hydrogen, halogen, C1-10 alkyl, CN, NO2, -NR A7 R B7 , -OR A7 , -SR A7 , -C(=O)R A7 , -C(=O)OR A7 , -OC(=O)R A7 , -C(=O)NR A7 R B7 , -NR A7 C(=O)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 , -S(=O) r R A7 , -S(=O)2OR A7 , -OS(=O)2R A7 , -NR A7 S(=O) r R B7 , -S(=O) r NR A7 R B7 and -NR A7 S(=O)2NR A7 R B7 wherein alkyl is unsubstituted or substituted by at least one substituent independently selected from the group consisting of R X7 . In one embodiment, R 7 is selected from the group consisting of hydrogen, halogen, C 1-10 1-6alkyl, CN, NO2, -NR A7 R B7 and -OR A7 wherein alkyl is unsubstituted or substituted by at least one substituent independently selected from the group consisting of R X7 . In a particular embodiment, R 7 is hydrogen. In another particular embodiment, R 7 is selected from halogen, in particular F.

[0142] In one embodiment, R 8 is selected from the group consisting of halogen, C 1-10 1-6alkyl, CN, NO2, -NR A8 R B8 , -OR A8, -SR A8 , -C(=O)R A8 , -C(=O)OR A8 , -OC(=O)R A8 , -C(=O)NR A8 R B8 , -NR A8 C(=O)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 , -S(=O) r R A8 , -S(=O)2OR A8 , -OS(=O)2R A8 , -NR A8 S(=O) r R B8 , -S(=O) r NR A8 R B8 and -NR A8 S(=O)2NR A8 R B8 wherein alkyl is unsubstituted or substituted by at least one substituent selected independently from R X8 In one embodiment, R 8 is selected from halogen, C 1- 10 alkyl, CN, NO2, -NR A8 R B8 and -OR A8 wherein alkyl is unsubstituted or substituted by at least one substituent selected independently from R X8 In one embodiment, R 8 is selected from -NR A8 R B8 and -OR A8 , preferably -OR A8 In a particular embodiment, R 8 is -OH.

[0143] In one embodiment, R 9 is selected from hydrogen, halogen, C 1-10 alkyl, CN, NO2, -NR A9 R B9 , -OR A9-SR A9 -C(=O)R A9 -C(=O)OR A9 -OC(=O)R A9 -C(=O)NR A9 R B9 -NR A9 C(=O)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 -S(=O) r R A9 -S(=O)2OR A9 -OS(=O)2R A9 -NR A9 S(=O) r R B9 -S(=O) r NR A9 R B9 and -NR A9 S(=O)2NR A9 R B9 wherein alkyl is unsubstituted or substituted with at least one substituent independently selected from R X9 In one embodiment, R 9 is selected from hydrogen, halogen, C 1-10 alkyl, CN, NO2, -NR A9 R B9 , -OR A9 , -SR A9 , -C(=O)R A9 , -C(=O)OR A9 , -OC(=O)R A9 , -C(=O)NR A9 R B9 , -NR A9 C(=O)R B9 , -S(=O) r R A9 , -S(=O)2OR A9 , -OS(=O)2R A9 , -NR A9 S(=O) r R B9 and -S(=O)r NR A9 R B9 , preferably selected from halogen, C 1-10 alkyl, CN, NO2, -NR A9 R B9 and -OR A9 , in particular from C 1-10 alkyl, wherein alkyl is unsubstituted or substituted with at least one substituent independently selected from R X9 . In one embodiment R 9 is hydrogen. In one embodiment R 9 is selected from halogen and C 1-10 alkyl, wherein alkyl is unsubstituted or substituted with at least one substituent independently selected from R X9 . In one embodiment R 9 is selected from Cl and methyl. In one embodiment R 9 is Cl. In one embodiment R 9 is selected from C 1-10 alkyl. In one particular embodiment R 9 is methyl.

[0144] In one embodiment the structure in formula (I) is selected from In one particular embodiment the structure in formula (I) is selected from In particular

[0145] In one embodiment R 8 and R 9 together with the atoms to which they are attached form a C 5-6 hydrocarbon ring or a 5-6 membered heterocyclic or heteroaromatic ring containing 1, 2 or 3 heteroatoms, each heteroatom being independently selected from oxygen, sulfur and nitrogen, which ring is unsubstituted or substituted with at least one substituent independently selected from R X8 . In one embodiment R 8 and R 9 together with the atoms to which they are attached form a C5 hydrocarbon ring or a 5-membered heterocyclic or heteroaromatic ring containing 1, 2 or 3 heteroatoms, each heteroatom being independently selected from oxygen, sulfur and nitrogen, in particular nitrogen, which ring is unsubstituted or substituted with at least one substituent independently selected from R X8 . In one embodiment R 8 and R 9together with the atom to which they are attached form a pyrazole ring; the ring is unsubstituted or substituted by at least one substituent independently selected from R X8

[0146] In one embodiment, the structure in formula (I) is

[0147] In one embodiment, the structure in formula (I) is selected from In one embodiment, the structure in formula (I) is selected from

[0148] In one embodiment, R 10 is 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, heterocyclyl, -C 1-4 alkylene-heterocyclyl, CN, NO2, 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 by at least one substituent independently selected from R X10 In one embodiment, R 10 is C 1-10 alkyl, wherein alkyl is unsubstituted or substituted by at least one substituent independently selected from R X10 In one embodiment, R 10 is selected from aryl, -C 1-4 alkylene-aryl, heteroaryl and -C 1-4 alkylene-heteroaryl, wherein each alkylene, aryl and heteroaryl is unsubstituted or substituted by at least one substituent independently selected from R X10 In one embodiment, the heteroaryl is a nitrogen-containing heteroaryl, preferably a 5-6 membered nitrogen-containing heteroaryl. In one embodiment, R 10 is selected from methyl, phenyl, pyrazolyl, pyridyl and pyrimidyl, wherein methyl, phenyl, pyrazolyl, pyridyl and pyrimidyl are unsubstituted or substituted by at least one substituent independently selected from R X10 In one embodiment, R 10 is selected from methyl, phenyl, pyrrolyl and pyridyl, wherein methyl, phenyl, pyrrolyl and pyridyl are unsubstituted or substituted by at least one substituent independently selected from R X10 ​​​​substituted by at least one substituent independently selected from the group consisting of R X10 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)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 alkyl is unsubstituted or substituted by at least one substituent independently selected from the group consisting of R Y In one embodiment, each R X10 is independently selected from the group consisting of methyl and dimethylaminomethyl.

[0149] In one embodiment, R 10 is selected from the group consisting of methyl, phenyl, The structure is unsubstituted or substituted by at least one substituent independently selected from the group consisting of R X10 In one embodiment, R 10 is selected from the group consisting of methyl, phenyl,

[0150] In one embodiment, R 11 is selected from the group consisting of hydrogen, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, -C 1-4 alkylene-C 3-10 cycloalkyl, heterocyclyl, -C 1-4 alkylene-heterocyclyl, CN, NO2, -NR A11 R B11 , -OR A11 , -SR A11 , -C(=O)R A11-C(=O)OR A11 -OC(=O)R A11 -C(=O)NR A11 R B11 -NR A11 C(=O)R B11 -S(=O) r R A11 -S(=O)2OR A11 -OS(=O)2R A11 -NR A11 S(=O) r R B11 and -S(=O) r NR A11 R B11 , preferably selected from hydrogen, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, -C 1-4 alkylene-C 3-10 cycloalkyl, CN, NO2, -NR A11 R B11 and -OR A11 , in particular selected from hydrogen, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, -C 1-4 alkylene-C 3-10 cycloalkyl, CN and NO2, wherein each alkyl, alkylene, cycloalkyl and heterocyclyl is unsubstituted or substituted with at least one substituent independently selected from R X11 . In one embodiment, R 11 is hydrogen.

[0151] In one embodiment, R 10 and R 11 together with the atoms to which they are attached form a 6-10 membered aromatic ring or a 5-10 membered heteroaromatic ring containing 1, 2 or 3 heteroatoms, in particular a phenyl ring or a 5-6 membered heteroaromatic ring, wherein each heteroatom is independently selected from oxygen, sulfur, nitrogen and phosphorus, which ring is substituted with h substituents independently selected from R 12 . In one embodiment, R 10 and R 11 together with the atoms to which they are attached form a phenyl ring, a pyridine, a pyrazole, an imidazole or a benzimidazole, wherein the phenyl ring, the pyridine, the pyrazole and the benzimidazole are substituted with h substituents independently selected from R 12 .

[0152] In one embodiment, R 10 and R 11 together with the atoms to which they are attached form the following structure: which is substituted with h substituents independently selected from R 12 In one embodiment, R 10 and R 11 together with the atoms to which they are attached form the following structure: In one embodiment, R 10 and R 11 together with the atoms to which they are attached form the following structure: In particular which is substituted with h substituents independently selected from R 12 In one embodiment, R 10 and R 11 together with the atoms to which they are attached form the following structure: In particular

[0153] In one embodiment, formula (I) has the structure of formula (I-1):

[0154] wherein,

[0155] B is a C 3-10 monocyclic hydrocarbon ring or a 4-12 membered heterocyclic ring containing 1, 2, or 3 heteroatoms or a 6-10 membered aromatic ring or a 5-10 membered heteroaromatic ring containing 1, 2, or 3 heteroatoms, wherein each heteroatom is independently selected from oxygen, sulfur, nitrogen, and phosphorus;

[0156] Ring A, R 1 , R 2 , W, R 4 , g, R 5 , R 6 , R 7 , R 8 , R 9 , R 12 , h, E 1 and E 2 are as defined in formula (I).

[0157] In one embodiment, B is a benzene ring, pyridine, pyrazole, imidazole, or benzimidazole.

[0158] In one embodiment, the structure in formula (I-1) is selected from: In particular In one embodiment, the structure in formula (I-1) is selected from: In particular is selected from

[0159] In one implementation scheme, R 12 Selected from halogens, C 1-10 Alkyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclic groups, CN, NO2, -NR A12 R B12 -OR A12 -SR A12 -C(=O)R A12 -C(=O)OR A12 -OC(=O)R A12 -C(=O)NR A12 R B12 -NR A12 C(=O)R B12 -S (=O) r R A12 -S(=O)2OR A12 -OS(=O)2R A12 -NR A12 S(=O) r R B12 and -S (=O) r NR A12 R B12 Preferably selected from halogens, C 1- 10 Alkyl, C 3-10 cycloalkyl, -C 1-4 Alkylene-C 3-10 cycloalkyl, CN, NO2, -NR A12 R B12 and -OR A12 Especially those selected from halogens, C 1-10 Alkyl, NO2, -CN and -OR A12 Each alkyl, alkylene, cycloalkyl, and heterocyclic group is unsubstituted or is selected independently from R X12 Substituents are substituted. In one embodiment, R 12 Selected from halogens, NO2, -CN, C 1-10 Alkyl, -OH and -O(C 1-10 Alkyl groups), wherein each alkyl group is unsubstituted or is independently selected from R. X12 Substituents are substituted. In one embodiment, R 12 Selected from F, methyl, and methoxy. In a particular embodiment, R 12 It is a methyl group.

[0160] In one embodiment, R 1 is hydrogen; R 2 is -NH2; E 1 and E 2 are O.

[0161] In one embodiment, ring A is selected from a nitrogen-containing 5-membered heteroaromatic ring. In one embodiment, ring A is selected from pyrrole and pyrazole. In a particular embodiment, ring A is pyrazole.

[0162] In a particular embodiment, formula (I) has the structure of formula (I-i) or formula (I-ii) as follows:

[0163] In one embodiment, formula (I) has the structure of formula (II) as follows:

[0164] wherein,

[0165] A 1 is selected from C, N and C(R 4a );

[0166] A 2 is selected from N and C(R 4b );

[0167] A 3 is selected from N, C(R 4c ) and N(R 4c );

[0168] B 1 is selected from N(R 12a ), N, O, S and C(R 12a );

[0169] B 2 is selected from N(R 12b ), N, O, S and C(R 12b );

[0170] B 3 is selected from N(R 12c ), N, O, S and C(R 12c );

[0171] B 4 is absent, or is selected from N(R 12d ), N, O, S and C(R 12d );

[0172] R 4a , R 4b and R 4c are each independently selected from hydrogen and R 4 ;

[0173] R12a , R 12b , R 12c and R 12d are each independently selected from hydrogen and R 12 ;

[0174] is a single or double bond;

[0175] the ring containing A 1 , A 2 and A 3 is a heteroaromatic ring; the ring containing B 1 , B 2 , B 3 and B 4 is an aromatic or heteroaromatic ring;

[0176] R 1 , R 2 , W, R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 12 , E 1 and E 2 are as defined in formula (I).

[0177] In one embodiment, B 4 is absent. In one embodiment, A 1 is C, A 2 is N, A 3 is N(R 4c ). In one embodiment, A 1 is C, A 2 is N, A 3 is N(R 4c ); R 4c is methyl. In one embodiment, A 1 is C, A 2 is C(R 4b ), A 3 is N(R 4c ). In one embodiment, A 1 is C, A 2 is C(R 4b ), A 3 is N(R 4c ); R 4b is selected from hydrogen, halogen and methyl, preferably from hydrogen and halogen, in particular hydrogen; R 4c is methyl. In one embodiment, the halogen is Cl. In one embodiment, B 1 is N(R 12a ), B2 is N, B 3 is C(R 12c ), B 4 is absent. In one embodiment, B 1 is N(R 12a ), B 2 is N, B 3 is C(R 12c ), B 4 is absent; R 12a is methyl; R 12c is hydrogen or methyl. In one embodiment, R 12c is hydrogen. In one embodiment, R 12c is methyl. In one embodiment, B 1 is C(R 12a ), B 2 is N(R 12b ), B 3 is N, B 4 is absent. In one embodiment, B 1 is C(R 12a ), B 2 is N(R 12b ), B 3 is N, B 4 is absent; R 12a is hydrogen; R 12b is methyl. In one embodiment, B 1 is N(R 12a ), B 2 is C(R 12b ), B 3 is N, B 4 is absent. In one embodiment, B 4 is C(R 12d ). In one embodiment, R 12d is selected from H and methyl. In one embodiment, B 1 is C(R 12a ), B 2 is C(R 12b ), B 3 is C(R 12c ), B 4 is C(R 12d ). In one embodiment, B 1 is C(R 12a ), B 2 is C(R 12b ), B 3 is N, B 4 is C(R 12d ). In one embodiment, R 12a , R 12b and R12d each independently selected from H and methyl, in particular H. In one embodiment, B 1 is C(R 12a ), B 2 is N, B 3 is C(R 12c ), B 4 is C(R 12d ). In one embodiment, R 12a , R 12c and R 12d each independently selected from H and methyl, in particular H.

[0178] In one embodiment, the compounds of the present application exist as atropisomers, which are formed by a single bond rotation between the fused ring comprising ring A and the phenyl group substituted with R 5 , R 6 , R 7 , R 8 and R 9 being hindered.

[0179] In one embodiment, Formula (I) has the structure of Formula (la) or Formula (lb) as follows. In one embodiment, Formula (I-1) has the structure of Formula (la-1) or Formula (lb-1) as follows. In one embodiment, Formula (I-i) has the structure of Formula (la-i) or Formula (lb-i) as follows. In one embodiment, Formula (I-ii) has the structure of Formula (la-ii) or Formula (lb-ii) as follows. In one embodiment, Formula (II) has the structure of Formula (IIa) or Formula (IIb) as follows.

[0180] In one embodiment, the present application provides a compound, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0181] In one embodiment, the present application provides a compound, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0182] In one embodiment, the present application provides a compound, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0183] PROTAC compounds and antibody-drug conjugates (ADCs)

[0184] In yet another aspect, the present application provides a PROTAC compound comprising a compound of the present application, an E3 ubiquitin ligase binding ligand, and a linker linking the compound of the present application and the E3 ubiquitin ligase binding ligand. The compound of the present application can serve as a ligand to bind to PKMYT1. In an embodiment, the PROTAC compound can be used to facilitate the degradation of PKMYT1 via the UPS.

[0185] In yet another aspect, the present application provides an antibody-drug conjugate comprising a compound of the present application, an antibody capable of binding to a target, and a linker linking the compound of the present application and the antibody.

[0186] Pharmaceutical compositions and pharmaceutical formulations

[0187] It is another object of the present application to provide a pharmaceutical composition comprising a compound of the present application or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer, isotopically enriched compound, metabolite, or prodrug thereof, and at least one pharmaceutically acceptable carrier.

[0188] The pharmaceutical composition of the present application can be administered in any manner that achieves the intended prophylactic, palliative, preventative, or therapeutic effect on the symptoms of a human or animal. For example, various suitable dosage forms can be prepared depending on the route of administration. For example, the compound of the present application can be administered orally or parenterally to a patient in the form of a conventional formulation. The conventional formulation is, for example, a capsule, a microcapsule, a tablet, a granule, a powder, a lozenge, a pill, a suppository, an injection, a suspension, a syrup, a patch, a cream, a lotion, an ointment, a gel, a spray, a solution, and an emulsion.

[0189] 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 judged by a health care professional.

[0190] Therapeutic methods and uses

[0191] According to certain embodiments of the present application, a compound of the present application or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer, isotopically enriched compound, metabolite, or prodrug thereof, or a pharmaceutical composition of the present application can be used to prevent or treat a PKMYT1-mediated disease, or a disease responsive to the inhibition of PKMYT1, including but not limited to a disease of abnormal cell proliferation, such as cancer.

[0192] Accordingly, in yet another aspect, the present application also provides the use of a compound of the present application or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present application in the manufacture of a medicament for the treatment of a disease, disorder, or condition selected from a disease of abnormal cell proliferation, the compound or pharmaceutically acceptable salt or pharmaceutical composition thereof being optionally used in combination with a second therapeutic agent.

[0193] In another aspect, the present application provides a compound of the present application or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present application, optionally in combination with a second therapeutic agent, for use in the treatment of a disease of abnormal cell proliferation.

[0194] In a further aspect, the present application provides a method of treating a disease of abnormal cell proliferation, the method comprising administering to an individual in need thereof an effective amount of a compound of the present application or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present application, optionally in combination with a second therapeutic agent.

[0195] In an embodiment, the disease, disorder or condition is selected from a cancerous proliferative disease (e.g. a cancer).

[0196] In an embodiment, the disease, disorder or condition is a cancer, for example selected from: (a) a solid tumor or a tumor of hematological origin selected from the group consisting of bladder cancer, endometrial cancer, lung squamous cell carcinoma, 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, stomach cancer, cervical cancer, thyroid cancer, prostate cancer, and skin cancer; (b) a hematopoietic tumor of lymphoid lineage selected from the group consisting of leukemia, acute lymphoblastic leukemia, acute lymphoblastic T-cell leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, hairy cell lymphoma, and Burkitt’s lymphoma; (c) a hematopoietic tumor of myeloid lineage selected from the group consisting of acute and chronic myelogenous leukemia, myelodysplastic syndrome, and promyelocytic leukemia; (d) a tumor of mesenchymal origin selected from the group consisting of fibrosarcoma and rhabdomyosarcoma; (e) a tumor of the central and peripheral nervous system selected from the group consisting of astrocytoma, neuroblastoma, glioma, and schwannoma; or (f) melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderma pigmentosum, keratoactanthoma, thyroid follicular cancer, or Kaposi’s sarcoma.

[0197] In an embodiment, the disease, disorder or condition is selected from a CCNE1-amplified cancer. In an 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.

[0198] In an embodiment, the disease, disorder, or condition is selected from a FBXW7 mutant cancer, e.g., a cancer in which an inactivating mutation in the FBXW7 gene occurs. In an embodiment, the disease, disorder, or condition is selected from a hematological tumor, a glioma, a liver cancer (e.g., a hepatocellular carcinoma), a uterine cancer (e.g., an endometrial carcinoma), a colorectal cancer (e.g., a colorectal adenocarcinoma), a breast cancer, a lung cancer (e.g., a non-small cell lung cancer (NSCLC)), a gastric cancer, an esophageal cancer, an esophagogastric junction adenocarcinoma, a bladder cancer (e.g., a bladder urothelial carcinoma), a head and neck cancer (e.g., a head and neck squamous cell carcinoma), a cervical cancer (e.g., a cervical squamous cell carcinoma), a melanoma, an ovarian cancer (e.g., a high-grade serous ovarian cancer).

[0199] In an embodiment, the disease, disorder, or condition is selected from a TP53 mutant cancer, e.g., a cancer in which an inactivating mutation in the TP53 gene occurs.

[0200] In a particular embodiment, the disease, disorder, or condition is a breast cancer, an ovarian cancer.

[0201] Combination therapy

[0202] The compounds of the present application, or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions of the present application, can be used alone or in combination with other therapeutic agents.

[0203] For example, the use of an adjuvant can enhance the therapeutic effect of the compounds of the present application (e.g., the therapeutic benefit of the adjuvant alone is minimal, but when used in combination with another agent, the therapeutic benefit to the individual is enhanced), or, for example, the use of a compound of the present application in combination with another therapeutic agent that also has therapeutic benefit can enhance the therapeutic benefit to the individual. For example, in the treatment of cancer, the use of a compound of the present application in combination with another agent that treats cancer can result in enhanced clinical benefit. Therapies that can be combined include, but are not limited to, physical therapy, psychological therapy, radiation therapy, chemotherapeutic agents, small molecule targeted therapeutic agents (e.g., kinase inhibitors, immune agonists), immunotherapies (anti-PD-1, anti-PDL-1, CAR-T cells, etc.), and the like. Regardless of the disease, disorder, or condition, the therapeutic benefit to the individual from the two therapies should have an additive or synergistic effect.

[0204] In an embodiment, the other therapeutic agent is selected from an inhibitor of a WEE family member, e.g., a WEE1 inhibitor. In an embodiment, the other therapeutic agent is selected from a cancer therapeutic agent that targets DNA, e.g., can be a therapeutic agent that directly damages DNA structure or a DNA topoisomerase inhibitor. Examples of therapeutic agents that directly damage DNA structure include, but are not limited to, a DNA double strand breaker, a DNA alkylating agent, a DNA intercalator.

[0205] In an embodiment, the other therapeutic agent is selected from a WEE1 inhibitor, a FEN1 (flap structure-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, a AURKB (aurora kinase B) inhibitor, a TOP2A (DNA topoisomerase II alpha) inhibitor, a 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 (SUMO1 activating enzyme subunit 1) inhibitor, a PLK1 (polo-like kinase 1) inhibitor, a UBA2 (ubiquitin-like modifier activating enzyme 2) inhibitor, a DUT (deoxyuridine triphosphatase) inhibitor, a HDAC3 (histone deacetylase 3) inhibitor, a CHEK1 (checkpoint kinase 1) inhibitor, a AURKA (aurora kinase A) inhibitor, a menin inhibitor, a DOT1L (DOT1-like histone lysine methyltransferase) inhibitor, a CREBBP (CREB binding protein) inhibitor, a EZH2 (enhancer of zeste homolog 2 polycomb repressive complex 2 subunit) inhibitor, a PLK4 (polo-like kinase 4) inhibitor, a HASPIN (histone H3 associated protein kinase) inhibitor, a METTL3 (methyltransferase 3) inhibitor, a nucleoside analogue, a platinum-based DNA damaging agent. Beneficial effects

[0206] The novel small molecule PKMYT1 inhibitors provided by the present application show outstanding PKMYT1 inhibitory activity and cell proliferation inhibitory activity, and show excellent pharmacokinetic properties.

[0207] Therefore, the compounds of the present application can 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, and have good prospects for development as drugs.

[0208] The compounds of the present application are advantageous in at least one of the following:

[0209] (1) High inhibitory activity on target cells.

[0210] (2) Excellent physicochemical properties (e.g., solubility, physical and / or chemical stability).

[0211] (3) excellent pharmacokinetic properties (e.g. good stability in plasma, suitable half-life and duration of action).

[0212] (4) excellent safety (lower toxicity and / or fewer side effects to non-target normal cells or tissues, wider therapeutic window), etc.

[0213] The inventors have also surprisingly found that at least some of the compounds of the present application can be obtained as a rotamer by chromatographic means. Some of the rotamers obtained are shown to have different activities. By obtaining rotamers, the activity of the compounds of the present application is further improved and the above-mentioned excellent properties can be achieved.

[0214] In order to more clearly illustrate the purpose and technical solutions of the present application, the present application is further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present application and not used to limit the scope of the present application. The specific experimental methods not mentioned in the following examples are all carried out according to the conventional experimental methods.

[0215] Unless otherwise specified, the instruments and reagents used in the examples are commercially available. The reagents can be used directly without further purification.

[0216] LCMS: SHIMADZ LCMS2020, column: Waters SunFire C18 5μm 50*4.6mm; mobile phase A: H2O(containing 0.1% formic acid); mobile phase B: CH3CN(containing 0.1% formic acid). TM C18 5μm 50*4.6mm; mobile phase A: H2O(containing 0.1% formic acid); mobile phase B: CH3CN(containing 0.1% formic acid).

[0217] NMR: Bruker Avance III 400M.

[0218] The compounds of formula (I) or pharmaceutically acceptable salts thereof can be synthesized by different methods, some exemplary methods are provided below and in the examples. Other synthetic methods can be readily proposed by a person skilled in the art based on the information disclosed in the present application.

[0219] In the reactions described below, it can be necessary to protect reactive groups to prevent them from undergoing undesired reactions: these groups are for example hydroxyl, amino, imino, thiol or carboxyl groups in the final product. Commonly used protecting groups can be referred to T.W. Greene and P.G.M. Wuts in "Protective Groups in Organic Chemistry" John Wiley and Sons, 1991.

[0220] The synthetic scheme of all compounds of the present application is illustrated by the following scheme and examples. The starting materials used are either commercially available or can be prepared according to known procedures or the procedures exemplified herein.

[0221] As shown in synthetic scheme 1, the compound of formula (I) can be prepared via various methods from an amide or thioamide compound M1 known in the literature or well known to those skilled in the art and an active methylene reagent M2. In M1, w 1 is a leaving group, for example selected from halogen, OTf, in particular halogen; w 2 is a leaving group, or is a group which can be converted into a leaving group by a suitable method, for example w 2 may be a hydroxyl group protected by a hydroxyl protecting group which can be deprotected to a hydroxyl group and then converted into a leaving group OTf. R in M2 is alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted or unsubstituted.

[0222] In synthetic scheme 1, for example, M1 and M2 are subjected to a substitution reaction or a coupling reaction to give an intermediate M3; M3 is subjected to a condensation reaction to give an intermediate M4; M4 is subjected to a suitable reaction (for example, by w 2 coupling with a suitable reagent) to give an intermediate M5; M5 is subjected to a suitable reaction (for example, acid amine condensation or carbamate exchange) to give a compound of formula (I).

[0223] Synthetic scheme 1

[0224] In one embodiment, the coupling reaction is a Ullmann reaction or a Buchwald reaction. In one embodiment, the active methylene reagent M2 is methyl cyanoacetate, wherein X and Y in M2 are CN and COOMe, respectively. In one embodiment, the condensation reaction to prepare M4 is carried out in the presence of a copper reagent (for example, CuI) and in the presence of a base (for example, potassium carbonate). In one embodiment, the condensation reaction is carried out under heating. In one embodiment, the following processes are completed in one synthetic step: the reaction of M1 and M2 to give M3, and the conversion of M3 to M4.

[0225] The amide or thioamide compound M1 as a starting material can be prepared using known methods, for example, by acid amine condensation of a carboxyl compound and an amino compound corresponding thereto to give the target amide, and for example, by thio reaction of an amide compound corresponding thereto to give the target thioamide.

[0226] In certain cases, the order of performing the above reaction schemes can be changed to facilitate the reaction or to avoid unwanted reaction products. The following examples are provided so that the application might be more fully understood. These examples are illustrative only and should not be construed as limiting the application in any way.

[0227] Example 1 5-amino-4-(3-hydroxy-2,6-dimethylphenyl)-2-methyl-2,7-dihydro-3H-1,2,4,7- tetrazabenzocd,h]azulene-3,6(4H)-dione (Compound 001)

[0228] 1.1 Synthesis of Intermediate 1-2:

[0229] Methylhydrazine sulfate (10.0 g) was dissolved in methanol (100 mL) and water (50 mL) at room temperature, and triethylamine (22 mL) was added. After stirring at room temperature for 30 min, dimethyl but-2-ynedioate (10.0 g) was added, and the reaction was stirred at 70 °C for 12 h. The reaction was cooled to room temperature, and a solid was precipitated. The solid was filtered and dried to give Intermediate 1-2 (5 g). LCMS: MS m / z (ESI): 157.0 [M+H] + .

[0230] 1.2 Synthesis of Intermediate 1-3:

[0231] Intermediate 1-2 (9.5 g) was dissolved in acetonitrile (50.0 mL) at room temperature, and N-bromosuccinimide (11.5 g) was added at 0 °C. The reaction was stirred at 60 °C for 2 h under nitrogen. The reaction was cooled to room temperature, and saturated sodium thiosulfate solution (300.0 mL) was added to quench the reaction. The mixture was extracted with dichloromethane (3 x 200.0 mL), and the combined organic phase was washed with saturated sodium chloride solution (3 x 20.0 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was slurried with petroleum ether (100.0 mL). The solid was filtered and dried to give Intermediate 1-3 (12.1 g). LCMS: MS m / z (ESI): 234.9 [M+H] + .

[0232] 1.3 Synthesis of Intermediate 1-4:

[0233] Intermediate 1-3 (10 g) and 3-methoxy-2,6-dimethylaniline (6.45 g) were dissolved in dioxane (160 mL) at room temperature, and trimethylaluminum (1.6 M, 80.1 mL) was added dropwise to the reaction solution. The reaction was carried out at 100 °C overnight under nitrogen protection. After cooling to room temperature, methanol (30 mL) was added dropwise to quench the reaction, and the reaction solution was directly concentrated under reduced pressure. Water (40.0 mL) was added to the residue to dilute, and the mixture was extracted with ethyl acetate (3 x 20.0 mL). The combined organic phase was washed with saturated sodium chloride solution (3 x 20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was washed with petroleum ether (100.0 mL) and filtered. The obtained solid was dried to give intermediate 1-4 (5.1 g). LCMS: MS m / z (ESI): 354.0 [M+H] + .

[0234] 1.4 Synthesis of intermediate 1-5:

[0235] Intermediate 1-4 (1.6 g) was dissolved in N,N-dimethylformamide (20 mL) at room temperature, and benzyl bromide (930 mg) and potassium carbonate (810 mg) were added. The reaction was stirred at 25 °C for 3 hours. Water (50.0 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 x 50.0 mL). The combined organic phase was washed with saturated sodium chloride solution (3 x 50.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA / PE: 0-30%) to give intermediate 1-5 (800 mg). LCMS: MS m / z (ESI): 444.0 [M+H] + .

[0236] 1.5 Synthesis of intermediate 1-6:

[0237] Intermediate 1-5 (3.5 g) was dissolved in dimethyl sulfoxide (30.0 mL) at room temperature, and methyl cyanoacetate (940 mg), cuprous iodide (2.14 g), and potassium carbonate (2.33 g) were added. The reaction was stirred at 85 °C for 4 hours under nitrogen protection. After cooling to room temperature, water (50.0 mL) was added to the reaction solution to dilute, and the mixture was extracted with ethyl acetate (3 x 50.0 mL). The combined organic phase was washed with saturated sodium chloride solution (3 x 50.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA / PE: 0-50%) to give intermediate 1-6 (2.5 g). LCMS: MS m / z (ESI): 463.1 [M+H] + .

[0238] 1.6 Synthesis of intermediate 1-7:

[0239] Intermediate 1-6 (2.3 g) was dissolved in tetrahydrofuran (10 mL) at room temperature, and palladium hydroxide on carbon (460 mg) was added to the reaction solution. The reaction was carried out in a high-pressure kettle (3.5 MPa) at 50 °C under hydrogen for 12 hours. After cooling to room temperature, the reaction solution was filtered with diatomite, and the filtrate was concentrated under reduced pressure to obtain intermediate 1-7 (1.7 g). LCMS: MS m / z (ESI): 373.0 [M+H] + .

[0240] 1.7 Synthesis of intermediate 1-8:

[0241] Intermediate 1-7 (500 mg) was dissolved in chloroform (10 mL) at room temperature, and N-phenyl bis(trifluoromethanesulfonyl)imide (576 mg), triethylamine (204 mg), and 4-dimethylaminopyridine were added. The reaction was carried out at 75 °C for 3 hours. After cooling to room temperature, water (20.0 mL) was added to the reaction solution to dilute, and extraction was performed with ethyl acetate (3 x 20.0 mL). The combined organic phase was washed with saturated sodium chloride solution (3 x 20.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA / PE: 0-50%) to obtain intermediate 1-8 (430 mg). LCMS: MS m / z (ESI): 505.0 [M+H] + .

[0242] 1.8 Synthesis of intermediate 1-9:

[0243] Intermediate 1-8 (200 mg) was dissolved in toluene (12.5 mL), water (1.25 mL), and ethanol (1.25 mL) at room temperature, and (2-aminophenyl)boronic acid (163 mg), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (29 mg), and cesium carbonate (388 mg) were added. The reaction was carried out in a microwave at 150 °C for 1 hour under argon. After cooling to room temperature, water (20.0 mL) was added to dilute, and extraction was performed with ethyl acetate (3 x 30.0 mL). The combined organic phase was washed with saturated sodium chloride solution (3 x 30.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA / PE: 0-50%) to obtain intermediate 1-9 (200 mg). LCMS: MS m / z (ESI): 448.1 [M+H] + .

[0244] 1.9 Synthesis of intermediate 1-10:

[0245] Intermediate 1-9 (200 mg) was dissolved in dioxane (1 mL) at room temperature, trimethylaluminum (1.6 M, 0.84 mL) was added, and the reaction was stirred at 100 °C for 12 h under nitrogen. The reaction was cooled to room temperature, poured into methanol (40.0 mL), and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (30.0 mL), washed with saturated brine (2 x 30.0 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was slurried with petroleum ether and ethyl acetate (3:1), filtered, and dried to give intermediate 1-10 (180 mg). LCMS: MS m / z (ESI): 416.1 [M+H] + .

[0246] 1.10 Synthesis of compound 001:

[0247] Intermediate 1-10 (180 mg) was dissolved in dichloromethane (5 mL) at room temperature, and boron tribromide (3 mL, 1 M) was added dropwise. The reaction was stirred at 25 °C for 2 h. The reaction was quenched with methanol, and the pH of the reaction was adjusted to 7 with saturated sodium bicarbonate solution. The reaction was extracted with dichloromethane (3 x 5 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (column: Sunfire Prep C18 OBD 19*250mm 10um; mobile phase A: H2O (containing 0.1% FA) mobile phase B: CH3CN; A / B = 90%~5% gradient change) to give the target product 5-amino-4-(3-hydroxy-2,6-dimethylphenyl)-2-methyl-2,7-dihydro-3H-1,2,4,7-tetrazabenzocd,h]azulene-3,6(4H)-dione (compound 001) (46.65 mg). LCMS: MS m / z (ESI): 402.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 9.61 (s, 1H), 9.00 (s, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.16 - 7.04 (m, 3H), 6.97 - 6.84 (m, 2H), 4.11 (s, 3H), 1.88 (s, 3H), 1.80 (s, 3H).

[0248] 1.11 Resolution of compound 001:

[0249] Compound 001 was resolved by chiral column Mobile phase A: Supercritical CO2, mobile phase B: isopropanol, containing 0.1% 7.0 mol / L Ammonia in MEOH; A:B = 55:45), two isomers were obtained.

[0250] Compound 001-P1: (Rt = 7.5 min)

[0251] 1 H NMR (400 MHz, DMSO) δ 9.57 (s, 1H), 9.01 (s, 1H), 7.88 (d, J = 7.8 Hz, 1H), 7.15 - 7.05 (m, 3H), 6.96 - 6.86 (m, 2H), 4.11 (s, 3H), 1.87 (s, 3H), 1.80 (s, 3H). LCMS: MS m / z (ESI): 402.1 [M+H] +

[0252] Compound 001-P2: (Rt = 8.8 min)

[0253] 1 H NMR (400 MHz, DMSO) δ 9.57 (s, 1H), 9.01 (s, 1H), 7.88 (d, J = 7.8 Hz, 1H), 7.15 - 7.05 (m, 3H), 6.96 - 6.86 (m, 2H), 4.11 (s, 3H), 1.87 (s, 3H), 1.80 (s, 3H). LCMS: MS m / z (ESI): 402.1 [M+H] +

[0254] Example 2 5-Amino-8,10-difluoro-4-(3-hydroxy-2,6-dimethylphenyl)-2-methyl-2,7- dihydro-3H-1,2,4,7-tetrazadibenzo[cd,h]azulene-3,6(4H)-dione (Compound 002)

[0255] Referring to the synthetic method of Example 1, (2-aminophenyl)boronic acid pinacol ester in Step 1.8 was replaced with (2-amino-3,5-difluorophenyl)boronic acid pinacol ester to obtain Compound 002.

[0256] 1H NMR (400 MHz, DMSO) δ 9.59 (s, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 6.3 Hz, 1H), 7.22 - 7.09 (m, 1H), 7.09 (d, J = 8.3 Hz, 1H), 7.02 - 6.93 (m, 1H), 6.90 (d, J = 8.3 Hz, 1H), 4.13 (s, 3H), 1.88 (s, 3H), 1.80 (s, 3H). LCMS: MS m / z (ESI): 420.0 [M+H] + .

[0257] Example 3 5-amino-8-fluoro-4-(3-hydroxy-2,6-dimethylphenyl)-2-methyl-2,7-dihydro- 3H-1,2,4,7-tetrazabor[cd,h]azoline-3,6(4H)-dione (Compound 003)

[0258] Following the synthetic procedure of Reference Example 1, (2-aminophenyl)boronic acid in Step 1.8 was replaced with 2-amino-3-fluorophenylboronic acid pinacol ester to afford Compound 003.

[0259] 1 H NMR (400 MHz, DMSO) δ 9.59 (s, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 6.3 Hz, 1H), 7.22 - 7.09 (m, 1H), 7.09 (d, J = 8.3 Hz, 1H), 7.02 - 6.93 (m, 1H), 6.90 (d, J = 8.3 Hz, 1H), 4.13 (s, 3H), 1.88 (s, 3H), 1.80 (s, 3H). LCMS: MS m / z (ESI): 420.0 [M+H] + .

[0260] Example 4 5-amino-10-fluoro-4-(3-hydroxy-2,6-dimethylphenyl)-2-methyl-2,7-dihydro- 3H-1,2,4,7-tetrazabor[cd,h]azoline-3,6(4H)-dione (Compound 004)

[0261] Following the synthetic procedure of Reference Example 1, (2-aminophenyl)boronic acid in Step 1.8 was replaced with 2-amino-5-fluorophenylboronic acid pinacol ester to afford Compound 004.

[0262] 1H NMR (400 MHz, DMSO) δ 9.60 (s, 1H), 9.08 (s, 1H), 7.53 (dd, J = 10.1, 3.1 Hz, 1H), 7.16 - 7.05 (m, 2H), 7.02 - 6.94 (m, 1H), 6.90 (d, J = 8.2 Hz, 1H), 4.11 (s, 3H), 1.87 (s, 3H), 1.79 (s, 3H). LCMS: MS m / z (ESI): 420.0 [M+H] + .

[0263] Example 5 5-amino-4-(3-hydroxy-2,6-dimethylphenyl)-2,8-dimethyl-2,4,7,8- tetrahydro-l,2,4,7,8,9-hexazabenzo[cd]cyclopenta[h]azulene-3,6-dione (Compound 005)

[0264] 5.1 Synthesis of Intermediate 5-2:

[0265] Intermediate 5-2: 4-(4,4-dimethyl-2-oxo-l,3-oxazolidin-5-yl)-l-methyl-lH- pyrazole-5-carboxylic acid tert-butyl ester + .

[0266] 5.2 Synthesis of Intermediate 5-3:

[0267] Intermediate 5-2 (1.4 g) was dissolved in anhydrous tetrahydrofuran (10 mL) under nitrogen, cooled to -78 °C, and n-butyllithium (2.5 mol / L in hexane, 1.8 mL) was added. The mixture was stirred at -78 °C for 30 min, and then a solution of trimethyl borate (773 mg) in tetrahydrofuran (5 mL) was added. The mixture was stirred and allowed to warm to room temperature slowly, and the reaction was allowed to proceed for 1 h. 2M aqueous hydrochloric acid was added and stirred for 30 min. Water (20 mL) was added to dilute the solution, and the mixture was extracted with ethyl acetate (3 x 40 mL). The organic phase was washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by reverse-phase column chromatography (MeCN in H2O: 0% to 35%) to give intermediate 5-3 (350 mg). LCMS: MS m / z (ESI): 342.0 [M+H] + .

[0268] 5.3 Synthesis of intermediate 5-4:

[0269] Intermediate 1-8 (200 mg) was dissolved in dioxane (3 mL) and water (0.6 mL), and intermediate 5-3 (273 mg), potassium carbonate (166 mg), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (29 mg) were added. The mixture was stirred at 110 °C for 12 h under nitrogen. The reaction was cooled to room temperature, and the mixture was extracted with ethyl acetate. The organic phase was combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by Prep-TLC (PE:EA = 1:1) to give intermediate 5-4 (30 mg). LCMS: MS m / z (ESI): 420.0 [M+H] + .

[0270] 5.4 Synthesis of compound 005:

[0271] Intermediate 5-4 (30 mg) was dissolved in dichloromethane (1 mL) at room temperature, and boron tribromide (2 mL, 1M) was added dropwise at 0 °C. The reaction was allowed to warm to room temperature and stirred for 2 h. Methanol was added dropwise to quench the reaction, and the pH was adjusted to 7 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (10 mL x 3), and the organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by high-performance liquid chromatography to give the target product 5-amino-4-(3-hydroxy-2,6-dimethylphenyl)-2,8-dimethyl-2,4,7,8-tetrahydro-1,2,4,7,8,9-hexaazabenzo[cd]cyclopenta[h]azulene-3,6-dione (compound 005) (4.54 mg).

[0272] 1H NMR (400 MHz, DMSO) δ 9.59 (s, 1H), 9.14 (s, 1H), 7.44 (s, 1H), 7.09 (d, J = 8.3 Hz, 1H), 6.90 (d, J = 8.3 Hz, 1H), 4.02 (s, 3H), 3.72 (s, 3H), 1.86 (s, 3H), 1.79 (s, 3H). LCMS: MS m / z (ESI): 406.0 [M+H] + .

[0273] 5.5 Chiral resolution of compound 005:

[0274] Compound 005 was resolved by SFC chiral column (Chiralpak® IC, 250 x 4.6 mm, 5 pm, 40 °C, 2 mL / min, 40 °C, 40 bar, 220 nm, 10% MeOH, 90% CO2) Mobile phase A: Supercritical CO2, mobile phase B: methanol containing 0.1% 7.0 mol / L Ammonia in MEOH; A:B = 70:30), to give two isomers.

[0275] Compound 005-P1: (Rt = 3.14 min)

[0276] 1 H NMR (400 MHz, DMSO) δ 9.59 (s, 1H), 9.14 (s, 1H), 7.44 (s, 1H), 7.09 (d, J = 8.3 Hz, 1H), 6.90 (d, J = 8.3 Hz, 1H), 4.02 (s, 3H), 3.72 (s, 3H), 1.86 (s, 3H), 1.79 (s, 3H). LCMS: MS m / z (ESI): 406.0 [M+H] +

[0277] Compound 005-P2: (Rt = 5.11 min)

[0278] 1 H NMR (400 MHz, DMSO) δ 9.59 (s, 1H), 9.14 (s, 1H), 7.44 (s, 1H), 7.09 (d, J = 8.3 Hz, 1H), 6.90 (d, J = 8.3 Hz, 1H), 4.02 (s, 3H), 3.72 (s, 3H), 1.86 (s, 3H), 1.79 (s, 3H). LCMS: MS m / z (ESI): 406.0 [M+H] +

[0279] Example 6 5-Amino-4-(3-hydroxy-2,6-dimethylphenyl)-2-methyl-2,7-dihydro-3H-1,2,4,7,10- pentazabenzocycloalka[cd,h]pera-3,6(4H)-dione (Compound 006)

[0280] 6.1 Synthesis of Intermediate 6-2:

[0281] Intermediate 6-2 (30 mg) was dissolved in dichloromethane (2.0 mL) at room temperature, and boron tribromide (2.0 mL, 1 M) was added dropwise. The reaction system was stirred at room temperature for 2 hours. The reaction solution was quenched with methanol, and the pH was adjusted to 7 with saturated sodium bicarbonate solution and extracted with dichloromethane (3 x 5 mL). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography to give 5-amino-4-(3-hydroxy-2,6-dimethylphenyl)-2-methyl-2,7-dihydro-3H-1,2,4,7,10-pentazabenzocycloalka[cd,h]pera-3,6(4H)-dione (Compound 006) (1.62 mg).

[0282] 1 H NMR (400 MHz, DMSO) δ 9.39 (s, 1H), 8.91 (s, 1H), 8.13 (d, J = 5.6 Hz, 1H), 7.27 (d, J = 8.6 Hz, 1H), 7.08 (d, J = 8.6 Hz, 1H), 7.00 (d, J = 5.6 Hz, 1H), 4.11 (s, 3H), 3.84 (s, 3H), 1.92 (s, 3H), 1.83 (s, 3H).

[0283] 6.2 Synthesis of Compound 006:

[0284] Intermediate 6-2 (30 mg) was dissolved in dichloromethane (2.0 mL) at room temperature, and boron tribromide (2.0 mL, 1 M) was added dropwise. The reaction system was stirred at room temperature for 2 hours. The reaction solution was quenched with methanol, and the pH was adjusted to 7 with saturated sodium bicarbonate solution and extracted with dichloromethane (3 x 5 mL). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography to give 5-amino-4-(3-hydroxy-2,6-dimethylphenyl)-2-methyl-2,7-dihydro-3H-1,2,4,7,10-pentazabenzocycloalka[cd,h]pera-3,6(4H)-dione (Compound 006) (1.62 mg).

[0285] 1H NMR (400 MHz, DMSO) δ 9.38 (s, 1H), 8.90 (s, 1H), 8.13 (d, J = 5.6 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 7.00 (d, J = 5.6 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 4.12 (s, 3H), 1.87 (s, 3H), 1.80 (s, 3H). LCMS: MS m / z (ESI): 403.1 [M+H] + .

[0286] 6.3 Chiral resolution of compound 006:

[0287] Compound 006 was resolved by SFC chiral column (Chiralpak IC, 4.6 x 250 mm, 5 pm, 40 °C, 2 mL / min, 40 bar, 220 nm, 30% MeOH, 70% CO2) Mobile phase A: Supercritical CO2, mobile phase B: methanol containing 0.1% 7.0 mol / L Ammonia in MEOH; A:B = 65:35), to give two isomers.

[0288] Compound 006-P1: (Rt = 5.64 min)

[0289] 1 H NMR (400 MHz, DMSO) δ 9.38 (s, 1H), 8.90 (s, 1H), 8.13 (d, J = 5.6 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 7.00 (d, J = 5.6 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 4.12 (s, 3H), 1.87 (s, 3H), 1.80 (s, 3H). LCMS: MS m / z (ESI): 403.1 [M+H] + .

[0290] Compound 006-P2: (Rt = 8.89 min)

[0291] 1 H NMR (400 MHz, DMSO) δ 9.38 (s, 1H), 8.90 (s, 1H), 8.13 (d, J = 5.6 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 7.00 (d, J = 5.6 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 4.12 (s, 3H), 1.87 (s, 3H), 1.80 (s, 3H). LCMS: MS m / z (ESI): 403.1 [M+H] + .

[0292] Example 7 5-amino-4-(3-hydroxy-2,6-dimethylphenyl)-2-methyl-2,7-dihydro-3H-1,2,4,7,9- pentazabicyclo[cd,h]azulene-3,6(4H)-dione (Compound 007)

[0293] 7.1 Synthesis of Intermediate 7-2:

[0294] Intermediate 1-8 (230 mg) was dissolved in dioxane (2 mL), pinacol diborane (348 mg), potassium acetate (134 mg), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (34 mg) was added, and the reaction was stirred at 120 °C for 16 h after purging with nitrogen three times. The reaction was cooled to room temperature, and concentrated under reduced pressure. The residue was purified by Prep-TLC (PE:EA = 3:2) to give Intermediate 7-2 (117 mg). LCMS: MS m / z (ESI): 483.1 [M+H] + .

[0295] 7.2 Synthesis of Intermediate 7-3:

[0296] Intermediate 7-2 (33 mg) was dissolved in dioxane (1 mL) and water (0.2 mL), 4-iodopyridin-3-amine (12 mg), potassium carbonate (19 mg), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (4 mg) was added, and the reaction was stirred at 110 °C for 16 h after purging with nitrogen three times. The reaction was cooled to room temperature, and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE:EA = 1:1) to give Intermediate 7-3 (14 mg). LCMS: MS m / z (ESI): 417.1 [M+H] + .

[0297] 7.3 Synthesis of Compound 007:

[0298] Intermediate 7-3 (14 mg) was dissolved in dichloromethane (1 mL) at room temperature, and boron tribromide (1 mL, 1 M) was added at 0 °C. The reaction system was stirred at room temperature for 1 hour. The reaction was stopped, and methanol was added to quench the reaction. The reaction solution was adjusted to pH 7 with saturated sodium bicarbonate solution and extracted with ethyl acetate (10 mL x 3). The organic phase was combined and dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography to obtain the target product 5-amino-4-(3-hydroxy-2,6-dimethylphenyl)-2-methyl-2,7-dihydro-3H-1,2,4,7,9-pentaazabenzocycloalka[cd,h]azulene-3,6(4H)-dione (Compound 007) (1.06 mg).

[0299] 1 H NMR (400 MHz, DMSO) δ 9.21 (s, 1H), 8.94 (s, 1H), 8.31 (s, 1H), 8.03 (d, J = 4.8 Hz, 1H), 7.67 (d, J = 4.8 Hz, 1H), 7.09 (d, J = 8.0 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H), 4.13 (s, 3H), 1.88 (s, 3H), 1.80 (s, 3H). LCMS: MS m / z (ESI): 403.1 [M+H] + .

[0300] Example 8 8-amino-7-(3-hydroxy-2,6-dimethylphenyl)-1,5-dimethyl-5,7,10,11- tetrahydro-1H-1,2,4,5,7,10-hexazacyclopenta[7,8]cycloocta[1,2,3-cd]indole-6,9-dione (Compound 008)

[0301] 8.1 Synthesis of intermediate 8-2:

[0302] Intermediate 1-8 (500 mg) was dissolved in dioxane (20.0 mL) and water (2.0 mL) at room temperature, 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-5- carbonitrile (461 mg), potassium carbonate (273 mg) and [1,1'-bis(diphenylphosphino) ferrocene]dichloropalladium (73 mg) were added, the reaction solution was purged with argon for three times, and the reaction solution was reacted at 110 °C for 12 hours. Water (100.0 mL) was added to the reaction solution, and the organic phase was extracted with ethyl acetate (3 x 100 mL), and the organic phase was combined and washed with saturated brine (2 x 100 mL), and dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (PE:EA = 1:0~2:1) to obtain intermediate 8-2 (330 mg). LCMS: MS m / z (ESI): 462.1 [M+1] + .

[0303] 8.2 Synthesis of intermediate 8-3:

[0304] Intermediate 8-2 (330 mg) and cobalt dichloride hexahydrate (467 mg) were dissolved in methanol (10.0 mL), and sodium borohydride (136 mg) was added at 0 °C, and the reaction solution was reacted at 25 °C for 2 hours. Water (50.0 mL) was added to the reaction solution, and the organic phase was extracted with ethyl acetate (3 x 50 mL), and the organic phase was combined and washed with saturated brine (2 x 50 mL), and dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain intermediate 8-3 (300 mg). LCMS: MS m / z (ESI): 466.1 [M+1] + .

[0305] 8.3 Synthesis of intermediate 8-4:

[0306] Intermediate 8-3 (300 mg) was dissolved in a mixed solvent of methanol (5.0 mL), tetrahydrofuran (5.0 mL) and water (5.0 mL) at room temperature, and lithium hydroxide monohydrate (270 mg) was added, and the reaction solution was reacted at 50 °C for 12 hours. Water (50.0 mL) was added to the reaction solution, and the organic phase was extracted with ethyl acetate (3 x 50 mL), and the organic phase was combined and washed with saturated brine (2 x 50 mL), and dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (PE:EA = 1:0~1:1) to obtain intermediate 8-4 (120 mg). LCMS: MS m / z (ESI): 434.1 [M+H] + .

[0307] 8.4 Synthesis of compound 008:

[0308] Intermediate 8-4 (120 mg) was dissolved in dichloromethane (2.0 mL) at room temperature, and boron tribromide (2 M, 1.4 mL) was added. The reaction solution was reacted at 25 °C for 1 hour. Methanol was added to quench the reaction, and the pH was adjusted to 7 with a saturated sodium bicarbonate solution. The organic phase was extracted with ethyl acetate (3 x 10.0 mL), washed with saturated brine (2 x 10.0 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, diluted with N,N-dimethylformamide (2.0 mL), and purified by high-performance liquid chromatography to obtain the target product 8-amino-7-(3-hydroxy-2,6-dimethylphenyl)-1,5-dimethyl-5,7,10,11-tetrahydro-1H-1,2,4,5,7,10-hexazacyclopenta[7,8]cycloocta[1,2,3-cd]indole-6,9-dione (Compound 008) (35.63 mg).

[0309] 1 H NMR (400 MHz, DMSO) δ 9.58 (s, 1H), 8.34 (t, J = 7.5 Hz, 1H), 7.59 (s, 1H), 7.08 (d, J = 8.2 Hz, 1H), 6.89 (d, J = 8.2 Hz, 1H), 6.18 (s, 2H), 4.64 (s, 1H), 4.20 (s, 1H), 4.16 (s, 3H), 3.89 (s, 3H), 1.90 (s, 3H), 1.82 (s, 3H). LCMS: MS m / z (ESI): 420.0 [M+H] + .

[0310] Example 9 5-Amino-2-methyl-4-(5-methyl-1H-indazol-4-yl)-2,7-dihydro-3H-1,2,4,7-tetraazadibenzo[cd,h]azulene-3,6(4H)-dione (Compound 009)

[0311] According to the synthetic method of Reference Example 1, 3-methoxy-2,6-dimethylaniline in Step 1.3 was replaced with 5-methyl-1H-indazol-4-amine, and the final target compound 5-amino-2-methyl-4-(5-methyl-1H-indazol-4-yl)-2,7-dihydro-3H-1,2,4,7-tetraazadibenzo[cd,h]azulene-3,6(4H)-dione (Compound 009) was obtained.

[0312] 1H NMR (400 MHz, DMSO) δ 13.27 (s, 1H), 9.02 (s, 1H), 7.93 - 7.87 (m, 1H), 7.84 (s, 1H), 7.65 (d, J = 8.6 Hz, 1H), 7.44 (d, J = 8.6 Hz, 1H), 7.16 - 7.06 (m, 2H), 6.97 - 6.88 (m, 1H), 4.10 (s, 3H), 2.12 (s, 3H). LCMS: MS m / z (ESI): 412.1 [M+H] + .

[0313] Example 10 5-Amino-4-(3-hydroxy-2,6-dimethylphenyl)-2-methyl-2,7-dihydro-3H- 2,4,7-triazadibenzo[cd,h]azoline-3,6(4H)-dione (Compound 010)

[0314] 10.1 Synthesis of Intermediate 10-2:

[0315] Ethyl 3-bromo-lH-pyrrole-2-carboxylate (5.00 g) was dissolved in tetrahydrofuran (20.0 mL), sodium hydride (60%, 1.47 g) was added at 0 °C, stirred at room temperature for 10 min, methyl iodide (5.22 g) was added, and the mixture was stirred at 50 °C for 16 h under nitrogen protection. The reaction solution was added to ice water (100 mL) to quench, extracted with ethyl acetate (150 mL x 3), the combined organic phase was washed with saturated sodium chloride solution (100 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE:EA = 30:1-20:1) to give Intermediate 10-2 (3.94 g). LCMS: MS m / z (ESI): 232.0 [M+H] + .

[0316] 10.2 Synthesis of Intermediate 10-3:

[0317] Intermediate 10-2 (3.90 g) and 3-methoxy-2,6-dimethylaniline (4.05 g) were dissolved in dioxane (30.0 mL) at room temperature, and trimethylaluminum (1.6 M, 33.5 mL) was added at 0 °C. The reaction was carried out at 120 °C for 1 h under nitrogen protection. The reaction was quenched by adding methanol (150 mL) at 0 °C, and then concentrated under reduced pressure after the quenching was completed. The solution was diluted with water (100 mL) and extracted with ethyl acetate (150 mL x 3). The combined organic phase was washed with saturated sodium chloride solution (100 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography on silica gel to obtain intermediate 10-3 (5.27 g). LCMS: MS m / z (ESI): 337.1 [M+H] + .

[0318] 10.3 Synthesis of intermediate 10-4:

[0319] Intermediate 10-3 (1.00 g) was dissolved in dimethyl sulfoxide (10.0 mL) at room temperature, and methyl 2-cyanoacetate (441 mg), potassium carbonate (820 mg), and cuprous iodide (113 mg) were added successively. The reaction was carried out at 85 °C for 12 h after the system was replaced with nitrogen three times. The reaction was diluted with water (20 mL) and extracted with ethyl acetate (50 mL x 3). The combined 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 crude product was purified by slurry with petroleum ether (30 mL) to obtain intermediate 10-4 (970 mg). LCMS: MS m / z (ESI): 356.2 [M+H] + .

[0320] 10.4 Synthesis of intermediate 10-5:

[0321] Intermediate 10-4 (420 mg) was dissolved in acetonitrile (5.0 mL) at room temperature, and N-bromosuccinimide (210 mg) was added at 0 °C. The reaction was carried out at 25 °C for 12 h. The reaction was diluted with water (50 mL) and extracted with a mixed solution of ethyl acetate and tetrahydrofuran (1:1, 100 mL x 3). The organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by prep-TLC (PE:EA = 4:1) to obtain intermediate 10-5 (500 mg). LCMS: MS m / z (ESI): 434.1 [M+H] + .

[0322] 10.5 Synthesis of intermediate 10-6:

[0323] Intermediate 10-5 (2.63 g) was dissolved in 1,4-dioxane (30 mL) at room temperature, (2- aminophenyl)boronic acid (1.25 g), 3-(tert-butyl)-4-(2,6-dimethoxyphenyl)-2,3- dihydrobenzo[d][1,3]oxaphosphole (200 mg), potassium carbonate (1.67 g), [1,1'- bis(diphenylphosphino)ferrocene]palladium dichloride (221 mg) and water (6 mL) were added successively, and the mixture was purged with nitrogen three times, and reacted at 100 °C for 4 hours. The reaction solution was cooled to room temperature, diluted with water (30 mL), extracted with ethyl acetate (2 x 25 mL), and the combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (EA:PE = 0:1 to 1:2) to obtain intermediate 10-6 (1.31 g). LCMS: MS m / z (ESI): 447.2 [M+H] + .

[0324] 10.6 Synthesis of intermediate 10-7:

[0325] Intermediate 10-6 (650 mg) was dissolved in 1,4-dioxane (12 mL) at room temperature, and trimethylaluminum (1.6 M, 2.7 mL) was added, and the mixture was reacted at 100 °C for 1.5 hours. After the reaction was completed, the mixture was cooled to room temperature, quenched with methanol (20 mL), concentrated under reduced pressure, diluted with water (30 mL), and extracted with ethyl acetate (2 x 30 mL). The combined organic phase was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (EA:PE = 0:1 to 1:3) to obtain intermediate 10-7 (888 mg). LCMS: MS m / z (ESI): 415.2 [M+H] + .

[0326] 10.7 Synthesis of compound 010:

[0327] Intermediate 10-7 (288 mg) was dissolved in anhydrous dichloromethane (8 mL) at room temperature, and boron tribromide (1 M, 3.5 mL) was added, and the mixture was reacted at room temperature for 1 hour. The pH was adjusted to 8 to 9 with a saturated sodium bicarbonate solution, extracted with ethyl acetate (3 x 10 mL), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by high-performance liquid chromatography to obtain the target product 5-amino-4-(3-hydroxy-2,6-dimethylphenyl)-2-methyl-2,7-dihydro-3H-2,4,7- triazabenzocd,h]azulene-3,6(4H)-dione (compound 010) (142 mg).

[0328] 1H NMR (400 MHz, DMSO) δ 9.50 (s, 1H), 8.68 (s, 1H), 7.74 (s, 1H), 7.46 - 7.40 (m, 1H), 7.05 (d, J = 8.2 Hz, 1H), 7.01 - 6.78 (m, 4H), 3.88 (s, 3H), 1.87 (s, 3H), 1.79 (s, 3H). LCMS: MS m / z (ESI): 401.2 [M+H] + .

[0329] 10.8 Chiral resolution of compound 010:

[0330] Compound 010 was resolved by SFC chiral column (Chiralpak IC, 4.6 x 250 mm, 5 pm, 40 °C, 4 mL / min, 40% MeOH with 0.1% 7.0 mol / L Ammonia in MEOH, 220 nm) Mobile phase A: Supercritical CO2, mobile phase B: Ethanol, containing 0.1% 7.0 mol / L Ammonia in MEOH; A:B = 60:40), to give two isomers.

[0331] Compound 010-P1: (Rt = 4.14 min)

[0332] 1 H NMR (400 MHz, DMSO) δ 9.50 (s, 1H), 8.68 (s, 1H), 7.74 (s, 1H), 7.43 (d, J = 7.8 Hz, 1H), 7.06 (d, J = 8.2 Hz, 1H), 7.02 - 6.79 (m, 4H), 3.88 (s, 3H), 1.87 (s, 3H), 1.81 (s, 3H). LCMS: MS m / z (ESI): 401.2 [M+H] + .

[0333] Compound 010-P2: (Rt = 6.84 min)

[0334] 1 H NMR (400 MHz, DMSO) δ 9.50 (s, 1H), 8.68 (s, 1H), 7.74 (s, 1H), 7.43 (d, J = 7.7 Hz, 1H), 7.05 (d, J = 8.2 Hz, 1H), 7.01 - 6.78 (m, 4H), 3.88 (s, 3H), 1.87 (s, 3H), 1.79 (s, 3H). LCMS: MS m / z (ESI): 401.2 [M+H] + .

[0335] Example 11 5-Amino-4-(3-hydroxy-2,6-dimethylphenyl)-2,8-dimethyl-2,4,7,8- tetrahydro-2,4,7,8,9-pentaazabenzo[cd]cyclopenta[h]azulene-3,6-dione (Compound 011)

[0336] 11.1 Synthesis of Intermediate 11-2:

[0337] Intermediate 10-5 (2.6 g) was dissolved in 1,4-dioxane (30 mL) at room temperature, and then intermediate 5-3 (2.45 g), 3-(tert-butyl)-4-(2,6-dimethoxyphenyl)-2,3- dihydrobenzo[2,1-d][1,3]oxaphosphole (396 mg), potassium carbonate (1.66 g), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium (438 mg) and water (6 mL) were added successively, and the mixture was reacted at 100 °C for 4 h. The reaction solution was cooled to room temperature, diluted with water (30 mL), extracted with ethyl acetate (2 x 25 mL), and the combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column (PE:EA = 1; 0-2:1) to obtain intermediate 11-2 (1.42 g). LCMS: MS m / z (ESI): 651.4 [M+H] + .

[0338] 11.2 Synthesis of Intermediate 11-3:

[0339] Intermediate 11-2 (940 mg) was dissolved in 1,4-dioxane (6 mL) at room temperature, and then hydrochloric acid dioxane solution (4 M, 8 mL) was added, and the mixture was reacted at room temperature for 1 h. The pH was adjusted to 8-9 with saturated sodium bicarbonate solution, diluted with water (20 mL), extracted with ethyl acetate (2 x 20 mL), and the combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column (DCM:MeOH = 60:1-20:1) to obtain intermediate 11-3 (514 mg). LCMS: MS m / z (ESI): 451.2 [M+H] + .

[0340] 11.3 Synthesis of Intermediate 11-4:

[0341] Intermediate 11-3 (514 mg) was dissolved in 1,4-dioxane (10 mL) at room temperature, and potassium carbonate (1.11 g) was added. The mixture was reacted at 120 °C for 1 hour. After cooling to room temperature, the solution was diluted with water (30 mL), extracted with ethyl acetate (2 × 30 mL), and the combined organic phases were washed with saturated brine (20 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (DCM:MeOH = 1:0–50:1) to give intermediate 11-4 (340 mg). LCMS: MS m / z (ESI): 419.2 [M+H] + .

[0342] 11.4 Synthesis of Compound 011:

[0343] Intermediate 11-4 (116 mg) was dissolved in anhydrous dichloromethane (6 mL) at room temperature. Boron tribromide (1 M, 1.4 mL) was slowly added under an ice-water bath, and the reaction was carried out at room temperature for 1 hour. The pH was adjusted to 8-9 with saturated sodium bicarbonate solution, diluted with water (20 mL), and extracted with ethyl acetate (2 × 20 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by high performance liquid chromatography to obtain the target product 5-amino-4-(3-hydroxy-2,6-dimethylphenyl)-2,8-dimethyl-2,4,7,8-tetrahydro-2,4,7,8,9-pentaazabenzo[cd]cyclopenta[h]azine-3,6-dione (compound 011) (85 mg). 1 H NMR(400MHz,DMSO)δ9.50(s,1H),8.82(s,1H),7.31(s,1H),7.26(s,1H),7.05(d,J=8.2Hz ,1H),6.86(d,J=8.2Hz,1H),3.82(s,3H),3.66(s,3H),1.86(s,3H),1.78(s,3H).LCMS:MS m / z(ESI):405.2[M+H] + .

[0344] Chiral resolution of compound 011, 11.5:

[0345] Compound 011 was separated by an SFC chiral column. Mobile phase A: Supercritical CO2, mobile phase B: isopropanol, containing 0.1% 7.0 mol / L Ammonia in MEOH (A:B = 60:40), yielded two isomers.

[0346] Compound 011-P1: (Rt = 4.04 min)

[0347] 1 H NMR (400 MHz, DMSO) δ 9.50 (s, 1H), 8.82 (s, 1H), 7.31 (s, 1H), 7.26 (s, 1H), 7.05 (d, J = 8.2 Hz, 1H), 6.86 (d, J = 8.2 Hz, 1H), 3.82 (s, 3H), 3.66 (s, 3H), 1.86 (s, 3H), 1.78 (s, 3H). LCMS: MS m / z (ESI): 405.2 [M+H] + .

[0348] Compound 011-P2: (Rt = 6.48 min)

[0349] 1 H NMR (400 MHz, DMSO) δ 9.50 (s, 1H), 8.82 (s, 1H), 7.31 (s, 1H), 7.26 (s, 1H), 7.05 (d, J = 8.2 Hz, 1H), 6.86 (d, J = 8.2 Hz, 1H), 3.82 (s, 3H), 3.66 (s, 3H), 1.86 (s, 3H), 1.78 (s, 3H). LCMS: MS m / z (ESI): 405.2 [M+H] + .

[0350] Example 12 3-Amino-2-(3-hydroxy-2,6-dimethylphenyl)-7-methoxy-12-methyl- 2,5,6,12-tetrahydro-2,5,8,11,12-pentaazabenzo[7,8]cycloocta[l,2,3-cd]indene-l,4- dione (Compound 014)

[0351] 12.1 Synthesis of Intermediate 14-2:

[0352] Intermediate 1-8 (600 mg) was dissolved in dichloromethane (10 mL), boron tribromide (1 M, 3.57 mL) was added at 0 °C, and the reaction was allowed to proceed at room temperature for 30 min. The reaction was quenched by adding saturated sodium bicarbonate solution (10 mL) at 0 °C, and extracted with dichloromethane (10 mL x 3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash column (ACN / H2O: 0-60%) to give Intermediate 14-2 (200 mg). LCMS: MS m / z (ESI): 491.2 [M+H] + .

[0353] 12.2 Synthesis of Intermediate 14-3:

[0354] Intermediate 14-2 (180 mg), (3-cyano-2-methoxypyridin-4-yl)boronic acid (98 mg), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (26 mg) and potassium carbonate (152 mg) were dissolved in 1,4-dioxane (2 mL) and water (0.5 mL) and reacted at 100 °C for 16 hours. The reaction solution was cooled to room temperature, quenched with water (5 mL) and extracted with ethyl acetate (5 mL x 3). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (EA:PE = 0:1 ~ 1:1) to obtain intermediate 14-3 (50 mg). LCMS: MS m / z (ESI): 475.3 [M+H] + .

[0355] 12.3 Synthesis of intermediate 14-4:

[0356] Intermediate 14-3 (40 mg) was dissolved in tetrahydrofuran (1 mL) and methanol (1 mL), and cobalt dichloride hexahydrate (38 mg) was added. Sodium borohydride (16 mg) was added at 0 °C, and the reaction was carried out at room temperature for 2 hours. The reaction was quenched with water (5 mL) and extracted with dichloromethane (5 mL x 3). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and the residue was concentrated and purified by pre-TLC (MeOH:DCM = 1:10) to obtain intermediate 14-4 (8 mg). LCMS: MS m / z (ESI): 479.1 [M+H] + .

[0357] 12.4 Synthesis of compound 014:

[0358] Intermediate 14-4 (8 mg) was dissolved in a mixed solution of tetrahydrofuran (1 mL), methanol (1 mL) and water (1 mL), and lithium hydroxide (4 mg) was added. The reaction was carried out at 50 °C for 1 hour. Water (5 mL) was added to the reaction solution, and the reaction was extracted with ethyl acetate (5 mL x 3). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by pre-TLC (EA:PE = 2:1) to obtain the target product 3-amino-2-(3-hydroxy-2,6-dimethylphenyl)-7-methoxy-12-methyl-2,5,6,12-tetrahydro-2,5,8,11,12-pentaazabenzo[7,8]cycloocta[1,2,3-cd]indene-1,4-dione (compound 014) (1.62 mg). 1H NMR (400 MHz, MeOD) δ 8.12 (d, J = 5.4 Hz, 1H), 7.35 (d, J = 5.4 Hz, 1H), 7.12 (d, J = 8.3 Hz, 1H), 6.90 (d, J = 8.3 Hz, 1H), 4.60 - 4.45 (m, 2H), 4.31 (s, 3H), 4.01 (s, 3H), 1.97 (s, 3H), 1.92 (s, 3H). LCMS: MS m / z (ESI): 447.2 [M+H] + .

[0359] Example 13 5-amino-4-(3-hydroxy-2,6-dimethylphenyl)-1,2-dimethyl-2,7-dihydro-3H- 2,4,7-triazadibenzo[cd,h]azulene-3,6(4H)-dione (Compound 018)

[0360] 13.1 Synthesis of Intermediate 18-2:

[0361] Intermediate 10-7 (496 mg) was dissolved in methanol (10 mL) at room temperature, cooled to -50 °C and stirred for 10 min, then liquid bromine (1.2 mL) was added and the reaction was carried out at -50 °C for 20 min. The reaction was quenched by adding saturated sodium sulfite solution (2 x 25 mL) and extracted with ethyl acetate (2 x 25 mL), the organic phase was combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give crude intermediate 18-2 (565 mg). LCMS: MS m / z (ESI): 495.1 [M+H] + .

[0362] 13.2 Synthesis of Intermediate 18-3:

[0363] Intermediate 18-2 (154 mg) was dissolved in 1,4-dioxane (6 mL) at room temperature, then trimethylboroxine (78 mg), potassium fluoride (54 mg), [1,1'- bis(diphenylphosphino)ferrocene]palladium dichloride (23 mg) and water (1.5 mL) were added successively, the flask was purged with nitrogen for 3 times, and the reaction was carried out at 100 °C for 1 h. The reaction was cooled to room temperature, diluted with water (20 mL) and extracted with ethyl acetate (3 x 15 mL), the organic phase was combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated, the residue was separated and purified by silica gel column chromatography (EA: PE = 0: 1 ~ 1: 2) to give intermediate 18-3 (102 mg). LCMS: MS m / z (ESI): 429.2 [M+H] + .

[0364] 13.3 Synthesis of Compound 018:

[0365] Intermediate 18-3 (102 mg) was dissolved in dry dichloromethane (8 mL) at room temperature, and boron tribromide (1 M, 1.2 mL) was added. The reaction was stirred at room temperature for 1 h. The pH was adjusted to 8-9 with saturated sodium bicarbonate solution, and the organic phase was extracted with ethyl acetate (3 x 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by high-performance liquid chromatography to give the target product 5-amino-4-(3-hydroxy-2,6-dimethylphenyl)-1,2-dimethyl-2,7-dihydro-3H-2,4,7-triazadibenzo[cd,h]azulene-3,6(4H)-dione (Compound 018) (70 mg). 1 H NMR (400 MHz, DMSO) δ 9.55 (s, 1H), 8.48 (s, 1H), 7.24 (d, J = 7.6 Hz, 1H), 7.11 - 6.99 (m, 3H), 6.97 (td, J = 7.3, 1.8 Hz, 1H), 6.87 (d, J = 8.3 Hz, 1H), 3.93 (s, 3H), 2.49 (s, 3H), 1.85 (s, 3H), 1.78 (s, 3H). LCMS: MS m / z (ESI): 415.2 [M+H] + .

[0366] 13.4 Chiral resolution of Compound 018:

[0367] Compound 018 was chiral resolution by SFC (Chiralpak IC column, 4.6 x 250 mm, 5 pm, 40 °C, 1 mL / min, 40 bar, 220 nm, mobile phase A: Supercritical CO2, mobile phase B: Ethanol, containing 0.1% 7.0 mol / L Ammonia in MeOH; A:B = 65:35). Two isomers were obtained.

[0368] Compound 018-P1: (Rt = 3.84 min)

[0369] 1 H NMR (400 MHz, DMSO) δ 9.55 (s, 1H), 8.48 (s, 1H), 7.24 (d, J = 7.6 Hz, 1H), 7.11 - 6.99 (m, 3H), 6.97 (td, J = 7.3, 1.8 Hz, 1H), 6.87 (d, J = 8.3 Hz, 1H), 3.93 (s, 3H), 2.49 (s, 3H), 1.85 (s, 3H), 1.78 (s, 3H). LCMS: MS m / z (ESI): 415.2 [M+H] + .

[0370] Compound 018-P2: (Rt = 6.89 min)

[0371] 1 H NMR (400 MHz, DMSO) δ 9.49 (s, 1H), 8.47 (s, 1H), 7.24 (dd, J = 7.7, 1.6 Hz, 1H), 7.11 - 6.99 (m, 3H), 7.02 - 6.93 (m, 1H), 6.86 (d, J = 8.2 Hz, 1H), 3.93 (s, 3H), 2.49 (s, 3H), 1.86 (s, 3H), 1.78 (s, 3H). LCMS: MS m / z (ESI): 415.2 [M+H] + .

[0372] Example 14 5-Amino-l-ethyl-4-(3-hydroxy-2,6-dimethylphenyl)-2-methyl-2,7- dihydro-3H-2,4,7-triazadibenzo[cd,h]azoline-3,6(4H)-dione (Compound 019)

[0373] 14.1 Synthesis of Intermediate 19-2:

[0374] Intermediate 18-2 (150 mg) was dissolved in water (0.2 mL) and dioxane (2.0 mL) at room temperature, potassium vinyltrifluoroborate (48.9 mg), potassium carbonate (84 mg) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (44 mg) were added successively, and the mixture was replaced with nitrogen for three times and reacted at 120 °C for 12 hours. The reaction solution was diluted with water (10.0 mL), extracted with a mixture of ethyl acetate and tetrahydrofuran (1:1, 30.0 mL x 3), and the organic phase was combined, washed with saturated brine (10.0 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by prep-TLC (DCM:MeOH = 50:1) to obtain intermediate 19-2 (100 mg). LCMS: MS m / z (ESI): 441.1 [M+H] + .

[0375] 14.2 Synthesis of Intermediate 19-3:

[0376] Intermediate 19-2 (100 mg) was dissolved in tetrahydrofuran (2.0 mL) at room temperature, and palladium-carbon (10%, 50 mg) was added, and the mixture was replaced with hydrogen for three times and reacted at 25 °C for 12 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (dichloromethane:methanol = 100:1 ~ 15:1) to obtain intermediate 19-3 (60 mg). LCMS: MS m / z (ESI): 443.2 [M+H] + .

[0377] Synthesis of Compound 019, 14.3:

[0378] Intermediate 19-3 (400 mg) was dissolved in dichloromethane (1.0 mL) at room temperature, and boron tribromide (1 M, 1.0 mL) was slowly added at 0 °C. The reaction was carried out at 0 °C for 1 hour. The pH was adjusted to 7-8 with saturated sodium bicarbonate solution, and the reaction solution was diluted with water (30.0 mL). The solution was extracted with dichloromethane (30.0 mL × 3), and the combined organic phases were washed with saturated brine (30.0 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by prep-TLC (DCM:MeOH = 40:1) to obtain the target product 5-amino-1-ethyl-4-(3-hydroxy-2,6-dimethylphenyl)-2-methyl-2,7-dihydro-3H-2,4,7-triazadibenzo[cd,h]azine-3,6(4H)-dione (compound 019) (30 mg). 1 H NMR (400MHz, DMSO) δ9.51 (s, 1H), 8.45 (s, 1H), 7.22 (d, J = 7.5Hz, 1H), 7.09–6.97 (m, 4H), 6.86 (d, J = 8. 2Hz,1H),3.95(s,3H),2.90(q,J=7.4Hz,2H),1.86(s,3H),1.78(s,3H),1.32(t,J=7.4Hz,3H).LCMS:MS m / z(ESI):429.2[M+H] + .

[0379] Chiral resolution of compound 019, 14.4:

[0380] Compound 019 was chirally separated by SFC ( Mobile phase A: Supercritical CO2, mobile phase B: methanol, containing 0.1% 7.0 mol / L Ammonia in MeOH (A:B = 70:30), yielded two isomers.

[0381] Compound 019-P1: (Rt = 3.62 min)

[0382] 1H NMR (400 MHz, DMSO) δ 9.52 (s, 1H), 8.46 (s, 1H), 7.22 (d, J = 7.7 Hz, 1H), 7.10 - 6.97 (m, 4H), 6.87 (d, J = 8.1 Hz, 1H), 3.95 (s, 3H), 2.90 (q, J = 7.4 Hz, 2H), 1.86 (s, 3H), 1.78 (s, 3H), 1.32 (t, J = 7.4 Hz, 3H). LCMS: MS m / z (ESI): 429.2 [M+H] + .

[0383] Compound 019-P2: (Rt = 5.88 min)

[0384] 1 H NMR (400 MHz, DMSO) δ 9.52 (s, 1H), 8.46 (s, 1H), 7.22 (d, J = 7.7 Hz, 1H), 7.10 - 6.97 (m, 4H), 6.87 (d, J = 8.1 Hz, 1H), 3.95 (s, 3H), 2.90 (q, J = 7.4 Hz, 2H), 1.86 (s, 3H), 1.78 (s, 3H), 1.32 (t, J = 7.4 Hz, 3H). LCMS: MS m / z (ESI): 429.2 [M+H] + .

[0385] Example 15 5-amino-8-(3-((dimethylamino)methyl)phenyl)-4-(3-hydroxy-2,6- dimethylphenyl)-2-methyl-2,7-dihydro-3H-1,2,4,7-tetraazabenzo[cd]azulene-3,6(4H)- dione (Compound 023)

[0386] 15.1 Synthesis of Intermediate 23-2:

[0387] Intermediate 23-2: 3-(3-((dimethylamino)methyl)phenyl)acrylaldehyde 3-ethynylbenzaldehyde (2 g) was dissolved in super dry dichloromethane (40 mL), dimethylamine (2 M, 15.4 mL) and acetic acid (0.1 mL) were added, stirred at room temperature for 30 min, sodium triacetoxyborohydride (13.1 g) was added slowly at 0 °C, reacted at 25 °C for 12 h. Cooled to 0 °C, adjusted pH to 8 with saturated sodium bicarbonate, extracted with ethyl acetate (3 x 40 mL), the organic phase was combined and washed with saturated brine (3 x 30 mL), dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (MeOH:DCM = 0:1 ~ 1:10) to give intermediate 23-2 (1 g). LCMS: MS m / z (ESI): 160.2 [M+H] +.

[0388] 15.2 Synthesis of intermediate 23-3:

[0389] Intermediate 23-3 (2 g) was dissolved in N,N-dimethylformamide (20 mL), and malononitrile (780 mg), Ligand L1 (158 mg, synthesis method see Synthesis, 2024, 56, 975-988), cuprous iodide (56 mg) and cesium carbonate (3.8 g) were added in turn, and the reaction solution was replaced with argon three times, and the reaction solution was reacted at 90 °C for 12 hours. After cooling to room temperature, water (100 mL) was added to the reaction solution, and extracted with ethyl acetate (3 x 20 mL). The organic phase was combined and washed with saturated brine (3 x 60 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 1:0 ~ 3:2) to obtain intermediate 23-4 (1.4 g). LCMS: MS m / z (ESI): 324.2 [M+H] + .

[0390] 15.3 Synthesis of intermediate 23-4:

[0391] Intermediate 23-3 (2 g) was dissolved in N,N-dimethylformamide (20 mL), and malononitrile (780 mg), Ligand L1 (158 mg, synthesis method see Synthesis, 2024, 56, 975-988), cuprous iodide (56 mg) and cesium carbonate (3.8 g) were added in turn, and the reaction solution was replaced with argon three times, and the reaction solution was reacted at 90 °C for 12 hours. After cooling to room temperature, water (100 mL) was added to the reaction solution, and extracted with ethyl acetate (3 x 20 mL). The organic phase was combined and washed with saturated brine (3 x 60 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 1:0 ~ 3:2) to obtain intermediate 23-4 (1.4 g). LCMS: MS m / z (ESI): 324.2 [M+H] + .

[0392] 15.4 Synthesis of intermediate 23-5:

[0393] Intermediate 23-4 (1.6 g) was dissolved in acetonitrile (16 mL), and N-iodosuccinimide (1.1 g) and fluoroboric acid (2.1 g) were added successively. The reaction solution was replaced with nitrogen three times, and heated to 80°C for 2 hours. The reaction solution was cooled to room temperature, and then adjusted to pH 7-8 with saturated sodium bicarbonate at 0°C, and extracted with ethyl acetate (3 x 20 mL). The organic phase was combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by reverse phase column chromatography (H2O:MeCN = 1:0-3:1) to obtain intermediate 23-5 (580 mg). LCMS: MS m / z (ESI): 450.0 [M+H] + .

[0394] 15.5 Synthesis of intermediate 23-6:

[0395] Intermediate 23-5 (340 mg) was dissolved in tetrahydrofuran (4 mL), and intermediate 23-2 (241 mg), triethylamine (230 mg), cuprous iodide (14 mg), and dichlorobis(triphenylphosphine)palladium (53 mg) were added successively. The reaction solution was replaced with nitrogen three times, and heated to 70°C for 12 hours. Water (10 mL) was added for dilution, and extracted with ethyl acetate (3 x 10 mL). 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 purified by column chromatography (PE:EA = 1:0-3:1) to obtain intermediate 23-6 (300 mg). LCMS: MS m / z (ESI): 481.2 [M+H] + .

[0396] 15.6 Synthesis of intermediate 23-7:

[0397] Intermediate 23-6 (100 mg) was dissolved in concentrated sulfuric acid (2 mL), and heated to 40°C for 2 hours. The reaction solution was cooled to 0°C, and adjusted to pH 7-8 with saturated sodium bicarbonate, and extracted with ethyl acetate (3 x 10 mL). The organic phase was combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (EA:MeOH = 1:1-5:1) to obtain intermediate 23-7 (60 mg). LCMS: MS m / z (ESI): 499.3 [M+H] + .

[0398] 15.7 Synthesis of compound 023:

[0399] Intermediate 23-7 (30 mg) was dissolved in dichloromethane (1 mL), and boron tribromide (1 M, 0.5 mL) was slowly added at 0 °C. The reaction was stirred at 25 °C for 1 h. Methanol (2 mL) was added at 0 °C to quench the reaction, and the reaction was concentrated under reduced pressure. The residue was diluted with N,N-dimethylformamide (1 mL) and purified by high-performance liquid chromatography to give the target compound 5-amino-8-(3-((dimethylamino)methyl)phenyl)-4-(3-hydroxy-2,6-dimethylphenyl)-2-methyl-2,7-dihydro-3H-1,2,4,7-tetraazabenzo[cd]azulene-3,6(4H)-dione (Compound 023) (18.97 mg). 1 H NMR (400 MHz, DMSO) δ 9.57 (s, 1H), 7.88 (s, 1H), 7.52-7.43 (m, 2H), 7.43-7.31 (m, 2H), 7.08 (d, J = 8.2 Hz, 1H), 6.89 (d, J = 8.2 Hz, 1H), 5.69 (s, 1H), 3.98 (s, 3H), 3.65 (s, 2H), 2.33 (s, 6H), 1.87 (s, 3H), 1.80 (s, 3H). LCMS: MS m / z (ESI): 485.2 [M+H] + .

[0400] Example 16 5-amino-4-(3-hydroxy-2,6-dimethylphenyl)-2-methyl-8-(2-(trifluoromethyl)pyrimidin-5-yl)-2,7-dihydro-3H-1,2,4,7-tetraazabenzo[cd]azulene-3,6(4H)-dione (Compound 046)

[0401] 16.1 Synthesis of intermediate 46-2:

[0402] Intermediate 23-5 (136 mg), trimethylsilyl acetylene (149 mg), dichlorobis(triphenylphosphine)palladium (42.5 mg), cuprous iodide (11.5 mg), triphenylphosphine (31.8 g) were dissolved in anhydrous tetrahydrofuran (3 mL). After the air in the flask was replaced with nitrogen three times, triethylamine (91.9 mg) was added, and the reaction was stirred at 45 °C for 1 h. After the reaction was cooled to room temperature, the insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (EA / PE: 0%~20%) to give intermediate 46-2 (72.0 mg). LCMS: MS m / z (ESI): 420.2 [M+H] + .

[0403] 16.2 Synthesis of intermediate 46-3:

[0404] Intermediate 46-2 (72.0 mg) was dissolved in methanol (3 mL), anhydrous potassium carbonate (46.9 mg) was added, and the reaction was stirred at 25 °C for 1 h. The insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography on silica gel (EA / PE: 0%~30%) to obtain intermediate 46-3 (50.6 mg). LCMS: MS m / z (ESI): 348.1 [M+H] + .

[0405] 16.3 Synthesis of intermediate 46-4:

[0406] Intermediate 46-3 (38.0 mg), 5-bromo-2-(trifluoromethyl)pyrimidine (35.1 mg), dichlorobispalladium (23.1 mg), cuprous iodide (3.80 mg), triphenylphosphine (10.5 mg) were dissolved in N,N-dimethylformamide (3 mL). After being replaced with nitrogen for 3 times, triethylamine (3.03 mg) was added, and the reaction was heated to 100 °C for 1 h. After the reaction was cooled to room temperature, the insoluble matter was removed by filtration, and the filtrate was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography on silica gel (EA / PE: 0%~36%) to obtain intermediate 46-4 (20.5 mg). LCMS: MS m / z (ESI): 494.2 [M+H] + .

[0407] 16.4 Synthesis of intermediate 46-5:

[0408] Intermediate 46-4 (26.0 mg) was dissolved in concentrated sulfuric acid (2 mL), and the reaction was stirred at 45 °C for 3 h. After the reaction was cooled to room temperature, the reaction solution was slowly dropped into a saturated sodium bicarbonate solution, the pH was adjusted to 8, and the reaction was extracted with ethyl acetate (3 x 5.0 mL). The organic phase was washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by Prep-TLC (ethyl acetate: petroleum ether = 1:1) to obtain intermediate 46-5 (18.2 mg). LCMS: MS m / z (ESI): 512.1 [M+H] + .

[0409] 16.5 Synthesis of compound 046:

[0410] Intermediate 46-5 (18.2 mg) was dissolved in dichloromethane (3 mL), and a solution of boron tribromide in dichloromethane (1 M, 0.18 mL) was added dropwise. The reaction was stirred at 25 °C for 1 h. The reaction was cooled to 0 °C, and the pH was adjusted to 7 with saturated sodium bicarbonate. The organic phase was extracted with ethyl acetate (3 x 5 mL), combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (1 mL) and purified by high performance liquid chromatography to give the target compound 5-amino-4-(3-hydroxy-2,6-dimethylphenyl)-2-methyl-8-(2-(trifluoromethyl)pyrimidin-5-yl)-2,7-dihydro-3H-1,2,4,7-tetraazabenzo[cd]azulene-3,6(4H)-dione (Compound 046) (2.26 mg). 1 H NMR (400 MHz, DMSO) δ 10.34 (s, 1H), 9.41 (s, 2H), 7.09 (d, J = 8.2 Hz, 1H), 6.91 (d, J = 8.2 Hz, 1H), 6.01 (s, 1H), 4.19 (s, 3H), 1.88 (s, 3H), 1.80 (s, 3H). 19 F NMR (376 MHz, DMSO) δ -68.34. LCMS: MS m / z (ESI): 498.1 [M+H] + .

[0411] Example 175-amino-4-(3-hydroxy-2,6-dimethylphenyl)-2,9-dimethyl-2,4,7,9-tetrahydro-1,2,4,7,9,10-hexaazabenzo[cd]cyclopenta[h]azulene-3,6-dione (Compound 049)

[0412] 17.1 Synthesis of Intermediate 49-2:

[0413] Intermediate 49-2 (4.3 g) was obtained by dissolving 3-bromo-4-nitro-pyrazole (5.0 g) in N,N-dimethylformamide (30.0 mL) at room temperature, adding potassium carbonate (4.32 g) and iodomethane (4.43 g), and stirring at 25 °C for 2 h. Water (100.0 mL) was added to the reaction mixture, and the organic phase was extracted with ethyl acetate (3 x 100 mL), combined, washed with saturated brine (2 x 100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA = 1:0 to 10:1) to give the target compound. + .

[0414] 17.2 Synthesis of Intermediate 49-3:

[0415] Intermediate 49-2 (3.3 g) was dissolved in ethanol (33.0 mL) and water (33.0 mL) at room temperature, ammonium chloride (5.14 g) and iron powder (5.37 g) were added, and the reaction was carried out at 70 °C for 2 h. The reaction solution was filtered, the filter cake was washed with ethyl acetate (3 x 50 mL), and the filtrate was concentrated under reduced pressure to obtain intermediate 49-3 (2.0 g). LCMS: MS m / z (ESI): 176.0 [M+H] + .

[0416] 17.3 Synthesis of intermediate 49-4:

[0417] Intermediate 49-3 (2 g) was dissolved in ethanol (20.0 mL) and water (20.0 mL), di-tert-butyl dicarbonate (7.63 g) and sodium bicarbonate (3.72 g) were added, and the reaction was carried out at 25 °C for 16 h. Water (100.0 mL) was added to the reaction solution, which was extracted with ethyl acetate (3 x 100 mL), the organic phases were combined and washed with saturated brine (2 x 100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (PE:EA = 1:0~5:1) to obtain intermediate 49-4 (2.7 g). LCMS: MS m / z (ESI): 276.0 [M+H] + .

[0418] 17.4 Synthesis of intermediate 49-5:

[0419] Intermediate 49-4 (100 mg) was dissolved in dioxane (2.0 mL) and water (0.2 mL) at room temperature, intermediate 7-2 (208 mg), potassium carbonate (99 mg) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (26 mg) were added in turn, replaced with nitrogen for three times, and the reaction was carried out at 100 °C for 12 h. Water (20 mL) was added to the reaction solution, which was extracted with ethyl acetate (3 x 20 mL), the organic phases were combined and washed with saturated brine (2 x 20 mL), dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (PE:EA = 1:0~1:1) to obtain intermediate 49-5 (100 mg). LCMS: MS m / z (ESI): 552.2 [M+H] + .

[0420] 17.5 Synthesis of intermediate 49-6:

[0421] Intermediate 49-5 (100 mg) was dissolved in hydrochloric acid in methanol (4 M, 2.0 mL) at room temperature and reacted for 1 hour at 25 °C. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate (10 mL), adjusted to pH 7-8 with a saturated sodium bicarbonate solution, extracted with ethyl acetate (3 x 10 mL), the organic phases were combined and washed with saturated brine (2 x 10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain intermediate 49-6 (80 mg). LCMS: MS m / z (ESI): 452.2 [M+H] + .

[0422] 17.6 Synthesis of intermediate 49-7:

[0423] Intermediate 49-6 (80 mg) was dissolved in 1,4-dioxane (2.0 mL) at room temperature, trimethylaluminum (1.6 M, 0.3 mL) was added, and the reaction was carried out at 100 °C for 12 hours. Methanol (10 mL) was added to quench the reaction, the reaction solution was concentrated under reduced pressure, ethyl acetate (10 mL) and water (10 mL) were added, stirred for 10 minutes, extracted with ethyl acetate (3 x 10 mL), the organic phases were combined and washed with saturated brine (2 x 10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by pre-TLC (DCM:MeOH = 20:1) to obtain intermediate 49-7 (20 mg). LCMS: MS m / z (ESI): 420.2 [M+H] + .

[0424] 17.7 Synthesis of compound 049:

[0425] Intermediate 49-7 (20 mg) was dissolved in dichloromethane (1.0 mL) at room temperature, boron tribromide (1 M, 0.25 mL) was added, and the reaction was carried out at 25 °C for 1 hour. The reaction solution was quenched by adding a saturated sodium bicarbonate solution (10.0 mL), extracted with ethyl acetate (3 x 10.0 mL), the organic phase was washed with saturated brine (2 x 10.0 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, the residue was dissolved in N,N-dimethylformamide (1.0 mL), and purified by high-performance liquid chromatography to obtain the target product 5-amino-4-(3-hydroxy-2,6-dimethylphenyl)-2,9-dimethyl-2,4,7,9-tetrahydro-1,2,4,7,9,10-hexaazabenzo[cd]cyclopenta[h]azulene-3,6-dione (compound 049) (1.25 mg). 1H NMR (400 MHz, MeOD) δ 7.20 (s, 1H), 7.11 (d, J = 8.2 Hz, 1H), 6.90 (d, J = 8.2 Hz, 1H), 4.17 (s, 3H), 3.80 (s, 3H), 1.97 (s, 3H), 1.92 (s, 3H). LCMS: MS m / z (ESI): 406.2 [M+H] + .

[0426] Example 18 5-Amino-4-(3-hydroxy-2,6-dimethylphenyl)-1,2,8-trimethyl-2,4,7,8- tetrahydro-2,4,7,8,9-pentaazabenzo[cd]cyclopenta[h]azulene-3,6-dione (Compound 050)

[0427] 18.1 Synthesis of Intermediate 50-2:

[0428] Intermediate 50-2 (10 g) was dissolved in ethanol (100 mL) at room temperature, sodium ethoxide in ethanol (0.5 N, 100 mL) was added under argon protection, then the temperature was raised to 60 °C for 16 hours. Water (100.0 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 x 100.0 mL). The organic phase was washed with saturated brine (2 x 100.0 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was slurried with petroleum ether (50.0 mL) and ethyl acetate (50.0 mL), filtered, and the filter cake was dried under vacuum to give Intermediate 50-3 (3.2 g). LCMS: MS m / z (ESI): 169.1 [M+H] + .

[0429] 18.2 Synthesis of Intermediate 50-3:

[0430] Intermediate 50-2 (10 g) was dissolved in ethanol (100 mL) at room temperature, sodium ethoxide in ethanol (0.5 N, 100 mL) was added under argon protection, then the temperature was raised to 60 °C for 16 hours. Water (100.0 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 x 100.0 mL). The organic phase was washed with saturated brine (2 x 100.0 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was slurried with petroleum ether (50.0 mL) and ethyl acetate (50.0 mL), filtered, and the filter cake was dried under vacuum to give Intermediate 50-3 (3.2 g). LCMS: MS m / z (ESI): 169.1 [M+H] + .

[0431] 18.3 Synthesis of Intermediate 50-4:

[0432] Intermediate 50-3 (4.8 g) was dissolved in water (48 mL) at room temperature, hydrogen bromide (7.68 mL) was added, the mixture solution was cooled to -5 °C, a solution of sodium nitrite (5.9 g) in water (4.8 mL) was added dropwise slowly, and the reaction was stirred at -5 °C for 30 min, cuprous bromide (12.3 g) was added, the reaction was stirred at room temperature for 30 min, then the reaction was stirred at 100 °C in an oil bath for 2 h. The reaction was cooled to room temperature, extracted with ethyl acetate (3 x 100 mL), the organic phase was washed with saturated brine (2 x 100.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 20:1 to 5:1) to give intermediate 50-4 (925 mg). LCMS: MS m / z (ESI): 232.0 [M+H] + .

[0433] 18.4 Synthesis of intermediate 50-5:

[0434] Intermediate 50-4 (900.0 mg) was dissolved in tetrahydrofuran (9.00 mL) at room temperature, sodium hydride (232.6 mg) was added, and the reaction was stirred for 30 min. Iodomethane (825.6 mg) was added, and the reaction was stirred at 50 °C for 16 h. The reaction was cooled to room temperature, water (20.0 mL) was added, and the reaction was extracted with ethyl acetate (3 x 20.0 mL). The organic phase was washed with saturated brine (2 x 20.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 50:1 to 10:1) to give intermediate 50-5 (825 mg). LCMS: MS m / z (ESI): 246.0 [M+H] + .

[0435] 18.5 Synthesis of intermediate 50-6:

[0436] Intermediate 50-5 (350 mg) and 3-methoxy-2,6-dimethylaniline (322 mg) were dissolved in dioxane (3.50 mL) at room temperature, and trimethylaluminum (1.6 M, 8.88 mL) was added. The reaction was stirred at 120 °C in a sealed tube for 3 h under argon protection. The reaction was cooled to room temperature, diluted with methanol (10.0 mL), and quenched with water (10.0 mL). The reaction was extracted with dichloromethane (3 x 10.0 mL), and the organic phase was washed with saturated brine (2 x 10.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give intermediate 50-6 (349 mg). LCMS: MS m / z (ESI): 351.1 [M+H]+ .

[0437] 18.6 Synthesis of intermediate 50-7:

[0438] Intermediate 50-6 (1.0 g), methyl 2-cyanoacetate (564 mg), Ligand L1 (152 mg, synthesis method see Synthesis, 2024, 56, 975-988), cuprous iodide (27.1 mg) and cesium carbonate (2.78 g) were dissolved in N,N-dimethylformamide (20 mL) and reacted at 90 °C for 12 hours under nitrogen protection. Water (15 mL) was added to the reaction solution, extracted with ethyl acetate (5 x 30 mL), washed with saturated brine (3 x 50 mL), dried over anhydrous sodium sulfate, and the residue was concentrated and purified by column chromatography (EA / PE = 0:1~1:1) to obtain intermediate 50-7 (600 mg). LCMS: MS m / z (ESI): 370.2 [M+H] + .

[0439] 18.7 Synthesis of intermediate 50-8:

[0440] Intermediate 50-7 (600 mg) was dissolved in N,N-dimethylformamide (5 mL), and iodine (495 mg) was added at 0 °C. The reaction mixture was reacted at 0 °C for 30 minutes. Water (5 mL) was added to the reaction solution, and purification was performed by reverse phase flash column chromatography (ACN / H2O = 0:1~3:1) to obtain intermediate 50-8 (360 mg). LCMS: MS m / z (ESI): 496.2 [M+H] + .

[0441] 18.8 Synthesis of intermediate 50-9:

[0442] Intermediate 50-8 (360 mg), intermediate 5-3 (273 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (53.1 mg), phosphine ligand (CAS NO. 1268693-24-8, 48.0 mg) and potassium carbonate (201 mg) were dissolved in 1,4-dioxane (2 mL) and water (0.5 mL), and reacted at 100 °C for 1 hour by microwave. Water (5 mL) was added to the reaction solution to quench the reaction, extracted with ethyl acetate (3 x 5 mL), and the organic phase was washed with saturated brine (3 x 10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (EA / PE = 0:1~2:1) to obtain intermediate 50-9 (20.0 mg). LCMS: MS m / z (ESI): 565.3 [M+H] + .

[0443] 18.9 Synthesis of compound 050:

[0444] The remaining synthesis method refers to the steps 17.5 (hydrochloric acid methanol solution for Boc protection group removal), 17.6 (amine ester exchange ring closure catalyzed by trimethylaluminum) and 17.7 (boron tribromide for demethylation) of Example 17 (compound 049), and the product is purified by high performance liquid chromatography, and finally the target compound 5-amino-4-(3-hydroxy-2,6-dimethylphenyl)-1,2,8-trimethyl-2,4,7,8-tetrahydro-2,4,7,8,9-pentaazabenzo[cd]cyclopenta[h]azulene-3,6-dione (compound 050) is obtained. 1 H NMR (400 MHz, DMSO) δ 9.54 (s, 1H), 8.79 (s, 1H), 8.51 (s, 2H), 7.38 (s, 1H), 7.04 (d, J = 8.2 Hz, 1H), 6.86 (d, J = 8.2 Hz, 1H), 3.84 (s, 3H), 3.69 (s, 3H), 2.34 (s, 3H), 1.85 (s, 3H), 1.77 (s, 3H). LCMS: MS m / z (ESI): 419.2 [M+H] + .

[0445] Example 19 5-amino-4-(3-hydroxy-2,6-dimethylphenyl)-2,8,10-trimethyl-2,4,7,8-tetrahydro-1,2,4,7,8,9-hexaazabenzo[cd]cyclopenta[h]azulene-3,6-dione (compound 051)

[0446] 19.1 Synthesis of intermediate 51-2:

[0447] 1,3-dimethyl-1H-pyrazole-5-amine (2.0 g) was dissolved in tetrahydrofuran (20.0 mL) at room temperature, di-tert-butyl dicarbonate (5.89 g) and 4-dimethylaminopyridine (220 mg) were added, and reacted at 60°C for 2 hours. The reaction was stopped, concentrated under reduced pressure, diluted with ethanol (20 mL) and 20% NaOH solution (6 mL), and stirred at 25°C for 3 hours. The reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (3x100.0 mL). The organic phase was combined and washed with saturated brine (2x100.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol = 20:1~1:1) to obtain intermediate 51-2 (3.6 g). LCMS: MS m / z (ESI): 212.1 [M+H] + .

[0448] 19.2 Synthesis of Intermediate 51-3:

[0449] Intermediate 51-2 (3.6 g) was dissolved in N,N-dimethylformamide (36.0 mL) at room temperature, N-bromosuccinimide (3.64 g) was added, and the reaction was allowed to react at 25 °C for 2 hours. Water (100 mL) was added to the reaction solution, which was extracted with ethyl acetate (3 x 100.0 mL). The organic phase was combined and washed with saturated brine (2 x 100.0 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated and purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 10:1 to 1:1) to obtain Intermediate 51-3 (3.2 g). LCMS: MS m / z (ESI): 290.0 [M+H] + .

[0450] 19.3 Synthesis of Intermediate 51-4:

[0451] Intermediate 51-3 (500 mg) was dissolved in 1,4-dioxane (5.0 mL) at room temperature, pinacol diboronic acid (570 mg), potassium acetate (340 mg), palladium acetate (160 mg), and tricyclohexylphosphine (100 mg) were added, the reaction was replaced with nitrogen three times, and the reaction was allowed to react at 90 °C for 2 hours. The reaction solution was cooled to room temperature and filtered, and the filtrate was concentrated under reduced pressure to obtain Intermediate 51-4 (crude 800 mg), which was used directly in the next reaction.

[0452] 19.4 Synthesis of Intermediate 51-5:

[0453] Intermediate 51-4 (500 mg) was dissolved in 1,4-dioxane (5.0 mL) and water (0.5 mL) at room temperature, Intermediate 1-8 (300 mg), potassium carbonate (250 mg), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (50 mg) were added, the reaction was replaced with nitrogen three times, and the reaction was allowed to react at 120 °C for 12 hours. The reaction solution was cooled to room temperature, diluted with water (100 mL), extracted with ethyl acetate (2 x 100.0 mL), and the organic phase was combined, washed with saturated brine (2 x 100.0 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 10:1 to 1:1) to obtain Intermediate 51-5 (300 mg). LCMS: MS m / z (ESI): 566.3 [M+H] + .

[0454] 19.5 Synthesis of Compound 051:

[0455] The remaining synthesis was carried out according to the procedure of Example 17 (compound 049) step 17.5 (hydrochloric acid methanol solution deprotection of Boc group), step 17.6 (trimethylaluminum catalyzed amine trans-esterification ring closure) and step 17.7 (boron tribromide demethylation), the product was purified by high performance liquid chromatography to give the target compound 5-amino-4-(3-hydroxy-2,6-dimethylphenyl)-2,8,10- trimethyl-2,4,7,8-tetrahydro-l,2,4,7,8,9-hexaazabenzo[cd]cyclopenta[h]azulene-3,6-dione (compound 051). 1 H NMR (400 MHz, DMSO) δ 9.58 (s, 1H), 9.03 (s, 1H), 7.09 (d, J = 8.3 Hz, 1H), 6.89 (d, J = 8.3 Hz, 1H), 4.03 (s, 3H), 3.64 (s, 3H), 2.28 (s, 3H), 1.86 (s, 3H), 1.79 (s, 3H). LCMS: MS m / z (ESI): 420.2 [M+H] + .

[0456] 19.6 Chiral resolution of compound 051:

[0457] Compound 051 was chiral resolution by SFC (Supercritical CO2, mobile phase B: methanol, containing 0.1% 7.0 mol / L Ammonia in MeOH) to give two isomers.

[0458] Compound 051-P1: (Rt = 3.04 min)

[0459] 1 H NMR (400 MHz, DMSO) δ 9.58 (s, 1H), 9.03 (s, 1H), 7.09 (d, J = 8.3 Hz, 1H), 6.89 (d, J = 8.3 Hz, 1H), 4.03 (s, 3H), 3.64 (s, 3H), 2.28 (s, 3H), 1.86 (s, 3H), 1.79 (s, 3H). LCMS: MS m / z (ESI): 420.2 [M+H] + .

[0460] Compound 051-P2: (Rt = 5.48 min)

[0461] 1 ​H NMR (400 MHz, DMSO) δ 9.58 (s, 1H), 9.03 (s, 1H), 7.09 (d, J = 8.3 Hz, 1H), 6.89 (d, J = 8.3 Hz, 1H), 4.03 (s, 3H), 3.64 (s, 3H), 2.28 (s, 3H), 1.86 (s, 3H), 1.79 (s, 3H). LCMS: MS m / z (ESI): 420.2 [M+H] + .

[0462] Example 20 5-Amino-1-chloro-4-(3-hydroxy-2,6-dimethylphenyl)-2,8-dimethyl- 2,4,7,8-tetrahydro-2,4,7,8,9-pentaazabenzo[cd]cyclopenta[h]azulene-3,6-dione (Compound 052)

[0463] 20.1 Synthesis of Intermediate 52-2:

[0464] Intermediate 11-4 (107 mg) was dissolved in anhydrous dichloromethane (3 mL) and stirred at -60 °C after argon replacement, dichlorosulfoxyl (69 mg) was added dropwise slowly, and the reaction was carried out at -60 °C for 15 min. After the reaction was completed, the reaction solution was stirred in an ice water bath, and saturated aqueous sodium bicarbonate solution was added dropwise slowly until the pH was 8-9. Water (20 mL) was added for dilution, and dichloromethane (2 x 20 mL) was used for extraction. The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated and purified by Prep-TLC (PE:EA = 1:1) to obtain Intermediate 52-2 (51 mg). LCMS: MS m / z (ESI): 453.2 [M+H] + .

[0465] 20.2 Synthesis of Compound 052:

[0466] Intermediate 52-2 (51 mg) was dissolved in anhydrous dichloromethane (5 mL) at room temperature, and boron tribromide (1 M, 0.6 mL) was added. The reaction was carried out at room temperature for 1 h. Saturated sodium bicarbonate solution was added to adjust the pH to 8-9, and ethyl acetate (2 x 20 mL) was used for extraction. The combined organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography to obtain the target compound 5-amino-1-chloro-4-(3-hydroxy-2,6-dimethylphenyl)-2,8-dimethyl-2,4,7,8-tetrahydro-2,4,7,8,9-pentaazabenzo[cd]cyclopenta[h]azulene-3,6-dione (Compound 052) (11.3 mg). 1H NMR (400 MHz, DMSO) δ 9.66 (s, 1H), 8.97 (s, 1H), 7.63 (s, 1H), 7.06 (d, J = 8.3 Hz, 1H), 6.88 (d, J = 8.3 Hz, 1H), 3.85 (s, 3H), 3.70 (s, 3H), 1.85 (s, 3H), 1.78 (s, 3H). LCMS: MS m / z (ESI): 439.1 [M+H] + .

[0467] Example 21 5-Amino-4-(3-hydroxy-2,6-dimethylphenyl)-2,8,10-trimethyl-2,4,7,8- tetrahydro-2,4,7,8,9-pentaazabenzo[cd]cyclopenta[h]azulene-3,6-dione (Compound 053)

[0468] 21.1 Synthesis of Intermediate 53-2:

[0469] Intermediate 10-5 (1.0 g) was dissolved in 1,4-dioxane (10.0 mL) at room temperature, pinacol borane (884 mg), triethylamine (1.16 g), Xphos (109 mg), tris(dibenzylideneacetone)dipalladium (210 mg) were added, purged with argon for three times, and reacted at 95 °C for 1 hour. After cooling to room temperature, the reaction solution was diluted with water (30.0 mL), and a solid precipitated. After filtration, the filter cake was dried and purified by column chromatography (petroleum ether: ethyl acetate = 10:1 ~ 1:1) to obtain intermediate 53-2 (960 mg). LCMS: MS m / z (ESI): 482.2 [M+H] + .

[0470] 21.2 Synthesis of Intermediate 53-3:

[0471] Intermediate 53-2 (59 mg) was dissolved in 1,4-dioxane (2.0 mL) at room temperature, water (0.2 mL), intermediate 51-3 (30 mg), potassium carbonate (28 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (7 mg) and ligand 3-(tert-butyl)-4-(2,6-dimethoxyphenyl)-2,3-dihydrobenzo[d][1,3]oxazaphosphole (3 mg) were added successively, and the mixture was purged with argon for 3 times, and then reacted at 85 °C for 4 h. The reaction mixture was cooled to room temperature, quenched with water (10.0 mL), extracted with ethyl acetate (3 x 10.0 mL), and the organic phase was washed with saturated brine (2 x 10.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 10:1 ~ 1:1) to give intermediate 53-3 (10 mg). LCMS: MS m / z (ESI): 565.3 [M+H] + .

[0472] 21.3 Synthesis of compound 053:

[0473] The remaining synthesis methods refer to the steps 17.5 (hydrochloric acid methanol solution for Boc protection), 17.6 (amine ester exchange ring closure) and 17.7 (boron tribromide for demethylation) of Example 17 (compound 049). The product was purified by high performance liquid chromatography to finally obtain the target compound 5-amino-4-(3-hydroxy-2,6-dimethylphenyl)-2,8,10- trimethyl-2,4,7,8-tetrahydro-2,4,7,8,9-pentaazabenzo[cd]cyclopenta[h]azulene-3,6-dione (compound 053). LCMS: MS m / z (ESI): 419.2.

[0474] 21.4 Chiral resolution of compound 053:

[0475] Compound 053 was chiral resolution by SFC ( Mobile phase A: Supercritical CO2, mobile phase B: ethanol containing 0.1% 7.0 mol / L Ammonia in EtOH; A:B = 85:15), to obtain two isomers 053-P1 and 053-P2. Compound 053-P1: (Rt = 2.14 min)

[0476] 1H NMR (400 MHz, DMSO) δ 9.50 (s, 1H), 8.73 (s, 1H), 7.16 (s, 1H), 7.05 (d, J = 8.2 Hz, 1H), 6.86 (d, J = 8.2 Hz, 1H), 3.85 (s, 3H), 3.59 (s, 3H), 2.14 (s, 3H), 1.86 (s, 3H), 1.78 (s, 3H). LCMS: MS m / z (ESI): 419.2.

[0477] Compound 053-P2: (Rt = 4.38 min)

[0478] 1 H NMR (400 MHz, DMSO) δ 9.50 (s, 1H), 8.73 (s, 1H), 7.16 (s, 1H), 7.05 (d, J = 8.2 Hz, 1H), 6.86 (d, J = 8.2 Hz, 1H), 3.85 (s, 3H), 3.59 (s, 3H), 2.14 (s, 3H), 1.86 (s, 3H), 1.78 (s, 3H). LCMS: MS m / z (ESI): 419.2.

[0479] Example 22 5-Amino-4-(7-fluoro-lH-indazol-4-yl)-2,8-dimethyl-2,4,7,8- tetrahydro-l,2,4,7,8,9-hexazabenzo[cd]cyclopenta[h]azulen-3,6-dione (Compound 054)

[0480] 22.1 Synthesis of Intermediate 54-2:

[0481] 4-bromo-7-fluoro-lH-indazole (10.0 g), 3,4-dihydro-2H-pyran (DHP) (7.82 g) were dissolved in dichloromethane (100 mL), p-toluenesulfonic acid (810 mg) was added portionwise at 0 °C, the reaction was stirred at 0 °C for 1 hour until the reaction solution turned black. The reaction solution was added with water (100 mL), extracted with ethyl acetate (150 mL x 3), the combined organic phase was washed with saturated sodium chloride solution (100 mL x 3), dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated under reduced pressure, the crude product was purified by silica gel column chromatography (PE:EA = 30:1-20:1) to give intermediate 54-2 (13.3 g). LCMS: MS m / z (ESI): 299.0 [M+H] + .

[0482] 22.2 Synthesis of Intermediate 54-3:

[0483] Intermediate 54-2 (13.3 g) was dissolved in dioxane (150 mL) at room temperature, benzylamine (9.53 g), palladium acetate (2.01 g), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (7.70 g), cesium carbonate (43.3 g) were added, and the mixture was stirred at 110 °C for 12 h under nitrogen protection. Water (100 mL) was added to dilute the reaction mixture, which was extracted with ethyl acetate (150 mL x 3). The combined organic phase was washed with saturated sodium chloride solution (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (PE:EA = 10:1-4:1) to give intermediate 54-3 (12.3 g). LCMS: MS m / z (ESI): 326.2 [M+H] + .

[0484] 22.3 Synthesis of intermediate 54-4:

[0485] Intermediate 54-3 (2.3 g) was dissolved in methanol (12.0 mL) at room temperature, and palladium on carbon (10%, 500 mg) was added. After purging with hydrogen gas for 3 times, the reaction system was stirred at 30 °C under hydrogen gas overnight. The reaction solution was filtered to remove the palladium on carbon, and the filtrate was concentrated under reduced pressure to give intermediate 54-4 (1.48 g). LCMS: MS m / z (ESI): 236.2 [M+H] + .

[0486] 22.4 Synthesis of intermediate 54-5:

[0487] Intermediate 1-3 (10.0 g) was dissolved in N,N-dimethylformamide (10 mL) at room temperature, and benzyl bromide (8.7 g) and N,N-diisopropylethylamine (7.1 g) were added. The reaction was stirred at 25 °C for 2 days. Water (30.0 mL) was added to dilute the reaction mixture, which was extracted with ethyl acetate (2 x 40.0 mL). The organic phase was washed with saturated sodium chloride solution (3 x 40.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was slurried with petroleum ether (100.0 mL), and the obtained solid was dried under vacuum to give intermediate 54-5 (7.1 g). LCMS: MS m / z (ESI): 325.0 [M+H] + .

[0488] 22.5 Synthesis of intermediate 54-6:

[0489] Intermediate 54-5 (20.6 g) was dissolved in methanol (50 mL) and tetrahydrofuran (50 mL) at room temperature, lithium hydroxide (7.6 g) was added, water (50 mL) was added at 0 °C, and the reaction was stirred at 25 °C for 2 h. The reaction solution was concentrated under reduced pressure to remove methanol and tetrahydrofuran from the reaction solution, and the remaining aqueous solution was adjusted to pH 2-3 with 4M HC1, and a white solid was precipitated. The solid was collected by suction filtration, and the obtained solid was dried under vacuum to obtain intermediate 54-6 (18.5 g). LCMS: MS m / z (ESI): 311.0 [M+H] + .

[0490] 22.6 Synthesis of intermediate 54-7:

[0491] Intermediate 54-4 (1.28 g) and intermediate 54-6 (1.86 g) were dissolved in acetonitrile (12.0 mL) at room temperature, N,N,N',N'-tetramethylchloroformamidium hexafluorophosphate (2.29 g) and N-methylimidazole (1.34 g) were added, and the reaction was carried out at 25 °C for 12 h. Water (50.0 mL) was added for dilution, and extraction was performed with ethyl acetate (100 mL x 3), and the combined organic phase was washed with saturated brine (50.0 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA = 10:1-4:1) to obtain intermediate 54-7 (2.93 g). LCMS: MS m / z (ESI): 528.1 [M+H] + .

[0492] 22.7 Synthesis of intermediate 54-8:

[0493] Intermediate 54-7 (2.8 g) was dissolved in dimethyl sulfoxide (30.0 mL) at room temperature, 2-cyanoacetic acid methyl ester (788 mg), potassium carbonate (1.46 g), and cuprous iodide (202 mg) were added in sequence, and the reaction was carried out under nitrogen protection at 85 °C for 4 h. Water (60.0 mL) was added for dilution, and extraction was performed with a mixed solution of ethyl acetate and tetrahydrofuran (1:1, 100 mL x 3), and the combined organic phase was washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 10:1-3:1) to obtain intermediate 54-8 (2.05 g). LCMS: MS m / z (ESI): 547.1 [M+H] + .

[0494] 22.8 Synthesis of intermediate 54-9:

[0495] Intermediate 54-8 (500 mg) was dissolved in methanol (4.00 mL) at room temperature, palladium on carbon (10%, 100 mg) was added, after three times replacement with hydrogen, the reaction system was reacted under hydrogen at 30 °C for 12 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by prep-TLC separation (PE:EA = 3:1) to obtain intermediate 54-9 (400 mg). LCMS: MS m / z (ESI): 457.1 [M+H] + .

[0496] 22.9 Synthesis of intermediate 54-10:

[0497] Intermediate 54-9 (200 mg) was dissolved in chloroform (2.0 mL) at room temperature, N-phenyl bis(trifluoromethanesulfonyl) imide (223 mg), triethylamine (63 mg) and 4-dimethylamino pyridine (5 mg) were added, and reacted at 75 °C for 3 hours. Diluted with water (10.0 mL), extracted with ethyl acetate (20.0 mL x 3), the combined organic phase was washed with saturated sodium chloride solution (20.0 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 10:1-4:1) to obtain intermediate 54-10 (220 mg). LCMS: MS m / z (ESI): 589.1 [M+H] + .

[0498] 22.10 Synthesis of intermediate 54-11:

[0499] Intermediate 54-10 (100 mg) was dissolved in dioxane (2.0 mL) and water (0.2 mL), intermediate 5-3 (69 mg), potassium carbonate (47 mg) and [1,1'-bis(diphenylphosphino) ferrocene] palladium dichloride (12 mg) were added, replaced with nitrogen for three times, and reacted at 110 °C for 12 hours. Cooled to room temperature, diluted with water (10.0 mL), extracted with ethyl acetate (20.0 mL x 3). The combined organic phase was washed with saturated sodium chloride solution (20.0 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE:EA = 1:1) to obtain intermediate 54-11 (53 mg). LCMS: MS m / z (ESI): 636.2 [M+H] + .

[0500] 22.11 Synthesis of intermediate 54-12:

[0501] Intermediate 54-11 (50 mg) was dissolved in dichloromethane (1.0 mL) at room temperature, and dioxane hydrochloride solution (4 M, 1.0 mL) was added. The reaction mixture was reacted at 25 °C for 1 hour. The reaction solution was poured into saturated sodium bicarbonate solution (10.0 mL), the pH was adjusted to 6–7, and the mixture was extracted with ethyl acetate (20.0 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give intermediate 54-12 (33 mg). LCMS: MS m / z (ESI): 452.1 [M + H] + .

[0502] Synthesis of compound 054 (22.12):

[0503] Intermediate 54-12 (30 mg) and cesium carbonate (64 mg) were dissolved in 1,4-dioxane (2.0 mL) at room temperature, purged three times with nitrogen, and reacted at 120 °C for 12 hours. After cooling to room temperature, the reaction solution was diluted with water (10.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to obtain the target compound 5-amino-4-(7-fluoro-1H-indazol-4-yl)-2,8-dimethyl-2,4,7,8-tetrahydro-1,2,4,7,8,9-hexaazabenzo[cd]cyclopenta[h]azine-3,6-dione (compound 054) (3.13 mg). 1 HNMR (400MHz, DMSO) δ14.00(s,1H),9.14(s,1H),8.10(s,1H),7.45(s,1H),7.41–7.36(m,1H),7.18–7.14(m,1H),4.01(s,3H),3.73(s,3H). 19 F NMR(377MHz,DMSO)δ-129.51.LCMS:MS m / z(ESI):420.1[M+H] + .

[0504] Example 23 5-Amino-4-(4-fluoro-3-hydroxy-2,6-dimethylphenyl)-2,8-dimethyl-2,4,7,8-tetrahydro-1,2,4,7,8,9-hexaazabenzo[cd]cyclopentazo[h]azine-3,6-dione (Compound 055)

[0505] 23.1 Synthesis of intermediate 55-2:

[0506] Dissolve 4-fluoro-3-methoxyaniline (5 g) in acetic acid (50 mL), then add N-bromosuccinimide (13.9 g), stir at 25 °C for 2 hours. Dilute the reaction solution with water (30 mL), extract with ethyl acetate (3 x 40 mL), wash the combined organic phases with saturated brine (3 x 30 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purify the residue by silica gel column chromatography (PE:EA = 1:0 ~ 10:1) to isolate and purify to obtain intermediate 55-2 (4.5 g). LCMS: MS m / z (ESI): 299.9 [M+H] + .

[0507] 23.2 Synthesis of intermediate 55-3:

[0508] Dissolve intermediate 55-2 (4.2 g) in 1,4-dioxane (50 mL) and water (5 mL), add 2,4,6-trimethylboroxine (2.6 g), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (1.0 g), and cesium carbonate (13.7 g) in sequence, replace with nitrogen three times, and react the reaction solution at 100 °C for 12 hours. Cool to room temperature, dilute the reaction solution with water (30 mL), extract with ethyl acetate (3 x 40 mL). Wash the organic phase with saturated brine (3 x 30 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the residue by silica gel column chromatography (PE:EA = 1:0 ~ 5:1) to obtain intermediate 55-3 (1.1 g). LCMS: MS m / z (ESI): 170.1 [M+H] + .

[0509] 23.3 Synthesis of compound 055:

[0510] Reference the remaining steps to the synthesis of Example 24 (compound 056), replace intermediate 56-5 in step 24.5 with intermediate 55-3, and finally obtain the target compound 5-amino-4-(4-fluoro-3-hydroxy-2,6-dimethylphenyl)-2,8-dimethyl-2,4,7,8-tetrahydro-1,2,4,7,8,9-hexaazabenzo[cd]cyclopenta[h]azulene-3,6-dione (compound 055). 1 H NMR (400 MHz, DMSO) δ 9.65 (s, 1H), 9.15 (s, 1H), 7.44 (s, 1H), 7.14 (d, J = 11.3 Hz, 1H), 4.02 (s, 3H), 3.72 (s, 3H), 1.88 (s, 3H), 1.84 (s, 3H). 19 F NMR (377 MHz, DMSO) δ -133.88. LCMS: MS m / z (ESI): 424.2 [M+H] + .

[0511] 23.4 Chiral resolution of compound 055:

[0512] Compound 055 was chiral resolution by SFC (Chiralpak® IC, 4.6 x 150 mm, 5 pm, 40 °C, 1 mL / min, 40 bar, 220 nm, 10% MeOH, 90% CO2) Mobile phase A: Supercritical CO2, mobile phase B: methanol containing 0.1% 7.0 mol / L Ammonia in MEOH, A:B = 70:30), to give two isomers.

[0513] Compound 055-P1: (Rt = 6.77 min)

[0514] 1 H NMR (400 MHz, DMSO) d 9.65 (s, 1H), 9.15 (s, 1H), 7.44 (s, 1H), 7.14 (d, J = 11.3 Hz, 1H), 4.02 (s, 3H), 3.72 (s, 3H), 1.88 (s, 3H), 1.84 (s, 3H). 19 F NMR (376 MHz, DMSO) d -133.88. LCMS: MS m / z (ESI): 424.2 [M+H] + .

[0515] Compound 055-P2: (Rt = 10.02 min)

[0516] 1 H NMR (400 MHz, DMSO) d 9.65 (s, 1H), 9.15 (s, 1H), 7.44 (s, 1H), 7.14 (d, J = 11.4 Hz, 1H), 4.02 (s, 3H), 3.72 (s, 3H), 1.88 (s, 3H), 1.84 (s, 3H). 19 F NMR (376 MHz, DMSO) d -133.88. LCMS: MS m / z (ESI): 424.2 [M+H] + .

[0517] Example 24 5-Amino-4-(3-fluoro-5-hydroxy-2,6-dimethylphenyl)-2,8-dimethyl- 2,4,7,8-tetrahydro-l,2,4,7,8,9-hexazabenzo[cd]cyclopenta[h]azulene-3,6-dione (Compound 056)

[0518] 24.1 Synthesis of intermediate 56-2:

[0519] Dissolve 3-fluoro-5-methoxyaniline (10.0 g) in N,N-dimethylformamide (200 mL) at room temperature, add N-chlorosuccinimide (9.47 g), and react at 25°C for 12 hours. Dilute the reaction mixture with water (200 mL), extract with ethyl acetate (3 x 200 mL), combine the organic phases, wash with saturated brine (100 mL), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Purify the residue by silica gel column chromatography (PE:EA = 10:1 to 1:1) to obtain intermediate 56-2 (4.0 g). 1 H NMR (400 MHz, DMSO) δ 6.15-6.14 (m, 1H), 6.11-6.07 (m, 1H), 5.57 (s, 2H), 3.75 (s, 3H).

[0520] 24.2 Synthesis of intermediate 56-3:

[0521] Dissolve intermediate 56-2 (4.0 g) in acetonitrile (100 mL), add N-bromosuccinimide (16.3 g), and react at 25°C for 12 hours. Dilute the reaction mixture with water (100 mL), extract with ethyl acetate (3 x 100 mL), wash the organic phase with saturated brine (100 mL), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography (PE:EA = 10:1 to 1:1) to obtain intermediate 56-3 (7.5 g). LCMS: MS m / z (ESI): 333.8 [M+H] + .

[0522] 24.3 Synthesis of intermediate 56-4:

[0523] Dissolve intermediate 56-3 (7.0 g) in 1,4-dioxane (20 mL) and water (2 mL), add trimethylboroxine (5.3 g), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (770 mg), and potassium carbonate (8.75 g) in sequence, and react at 100°C for 12 hours. Dilute the reaction mixture with water (100 mL), extract with ethyl acetate (3 x 100 mL), combine the organic phases, wash with saturated brine (150 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purify the residue by silica gel column chromatography (PE:EA = 20:1 to 1:1) to obtain intermediate 56-4 (3.67 g). LCMS: MS m / z (ESI): 204.1 [M+H] + .

[0524] 24.4 Synthesis of intermediate 56-5:

[0525] Intermediate 56-4 (3.67 g) and ammonium acetate (22.8 g) were dissolved in methanol (20 mL) at room temperature, palladium on carbon (10%, 3.7 g) was added, the reaction system was subjected to microwave reaction at 110 °C for 2 hours under argon protection. Cooled to room temperature, the reaction solution was diluted with water (200 mL), extracted with ethyl acetate (3 x 200 mL), the organic phase was washed with saturated brine (2 x 100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (PE:EA = 40:1~30:1) to obtain intermediate 56-5 (2.1 g). LCMS: MS m / z (ESI): 170.1 [M+H] + .

[0526] 24.5 Synthesis of intermediate 56-6:

[0527] Intermediate 54-6 (3.85 g) was dissolved in acetonitrile (30 mL), N,N,N',N'-tetramethylchloroformamidium hexafluorophosphate (5.2 g), azidomethyl imidazole (3.06 g) and intermediate 56-5 (2.1 g) were added, and reacted at 25 °C for 16 hours. The reaction solution was diluted with water (100 mL), extracted with ethyl acetate (3 x 100 mL), the organic phase was washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (PE:EA = 10:1~1:1) to obtain intermediate 56-6 (4.0 g). LCMS: MS m / z (ESI): 462.1 [M+H] + .

[0528] 24.6 Synthesis of intermediate 56-7:

[0529] Intermediate 56-6 (4.0 g) and methyl 2-cyanoacetate (1.28 g) were dissolved in dimethyl sulfoxide (20 mL) at room temperature, cuprous iodide (330 mg) and potassium carbonate (2.4 g) were added, replaced with nitrogen three times, and reacted at 85 °C for 4 hours. The reaction solution was diluted with water (100 mL), extracted with ethyl acetate (3 x 100 mL), the organic phase was washed with saturated brine (2 x 100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (PE:EA = 10:1~3:1) to obtain intermediate 56-7 (2.2 g). LCMS: MS m / z (ESI): 481.1 [M+H] + .

[0530] 24.7 Synthesis of intermediate 56-8:

[0531] Intermediate 56-7 (2.2 g) was dissolved in tetrahydrofuran (20 mL) at room temperature, palladium on carbon (10%, 700 mg) was added, and the reaction was replaced with hydrogen three times and reacted at 65 °C for 12 hours under hydrogen atmosphere. The reaction was filtered and concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (PE:EA = 10:1 ~ 3:1) to obtain intermediate 56-8 (1.5 g). LCMS: MS m / z (ESI): 391.1 [M+H] + .

[0532] 24.8 Synthesis of intermediate 56-9:

[0533] Intermediate 56-8 (1.5 g) was dissolved in chloroform (20 mL) at room temperature, N-phenyl bis(trifluoromethanesulfonyl)imide (2.0 g), 4-dimethylaminopyridine (50 mg), and triethylamine (580 mg) were added, and the reaction was reacted at 75 °C for 3 hours. Water (100 mL) was added to the reaction solution to dilute, extracted with dichloromethane (3 x 100 mL), and the organic phase was washed with saturated brine (2 x 100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (PE:EA = 10:1 ~ 8:1) to obtain intermediate 56-9 (1.7 g). LCMS: MS m / z (ESI): 523.1 [M+H] + .

[0534] 24.9 Synthesis of intermediate 56-10:

[0535] Intermediate 56-9 (200 mg) was dissolved in 1,4-dioxane (2 mL) at room temperature, intermediate 5-3 (260 mg), potassium carbonate (160 mg), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (30 mg) were added, replaced with nitrogen three times, and reacted at 110 °C for 1 hour by microwave. The reaction was cooled to room temperature, diluted with water (10 mL), extracted with ethyl acetate (3 x 10 mL), and the organic phase was washed with saturated brine (2 x 10 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (PE:EA = 10:1 ~ 3:1) to obtain intermediate 56-10 (200 mg). LCMS: MS m / z (ESI): 570.2 [M+H] + .

[0536] 24.10 Synthesis of intermediate 56-11:

[0537] Intermediate 56-10 (200 mg) was dissolved in hydrochloric acid dioxane solution (4 M, 6 mL) at room temperature, and the reaction was carried out at 25 °C for 12 h. The reaction solution was concentrated under reduced pressure to obtain intermediate 56-11 (150 mg). LCMS: MS m / z (ESI): 470.2 [M+H] + .

[0538] 24.11 Synthesis of intermediate 56-12:

[0539] Intermediate 56-11 (150 mg) was dissolved in 1,4-dioxane (5 mL) at room temperature, and cesium carbonate (350 mg) was added. The reaction was carried out at 120 °C for 12 h. After cooling to room temperature, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (DCM:MeOH = 50:1 ~ 20:1) to obtain intermediate 56-12 (110 mg). LCMS: MS m / z (ESI): 438.2 [M+H] + .

[0540] 24.12 Synthesis of compound 056:

[0541] Intermediate 56-12 (110 mg) was dissolved in dichloromethane (5 mL) at room temperature, and boron tribromide solution (1 M, 0.25 mL) was added. The reaction was carried out at 25 °C for 1 h. Saturated sodium bicarbonate solution (10 mL) was added to quench, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. N,N-dimethylformamide (1 mL) was added to dilute, and high-performance liquid chromatography was used for purification to obtain the target compound 5-amino-4-(3-fluoro-5-hydroxy-2,6-dimethylphenyl)-2,8-dimethyl-2,4,7,8-tetrahydro-1,2,4,7,8,9-hexazabenzo[cd]cyclopenta[h]azulene-3,6-dione (compound 056) (16 mg). 1 HNMR (400 MHz, DMSO) δ 10.11 (s, 1H), 9.17 (s, 1H), 7.44 (s, 1H), 6.78 (d, J = 11.1 Hz, 1H), 4.02 (s, 3H), 3.72 (s, 3H), 1.77 (s, 3H), 1.74 (s, 3H). 19 F NMR (377 MHz, DMSO) δ -117.70. LCMS: MS m / z (ESI): 424.1 [M+H] + .

[0542] Example 25 5-Amino-4-(2,6-dichloro-3-hydroxyphenyl)-2,8-dimethyl-2,4,7,8- tetrahydro-l,2,4,7,8,9-hexazabenzo[cd]cyclopenta[h]azulene-3,6-dione (Compound 057)

[0543] 25.1 Synthesis of Intermediate 57-2:

[0544] Intermediate 57-2 (2 g) was dissolved in ethyl acetate (40 mL) at room temperature, wet palladium on carbon (200 mg, 10%) was added, and the mixture was stirred at 40 °C for 12 h. The reaction was cooled to room temperature and filtered through celite. The filtrate was concentrated under reduced pressure to give Intermediate 57-3 (1.6 g). LCMS: MS m / z (ESI): 192.0 [M+H] + .

[0545] 25.2 Synthesis of Intermediate 57-3:

[0546] Intermediate 57-2 (2 g) was dissolved in ethyl acetate (40 mL) at room temperature, wet palladium on carbon (200 mg, 10%) was added, and the mixture was stirred at 40 °C for 12 h. The reaction was cooled to room temperature and filtered through celite. The filtrate was concentrated under reduced pressure to give Intermediate 57-3 (1.6 g). LCMS: MS m / z (ESI): 192.0 [M+H] + .

[0547] 25.3 Synthesis of Compound 057:

[0548] The remaining steps were performed according to the synthesis of Example 24 (Compound 056), with Intermediate 56-5 in step 24.5 replaced by Intermediate 57-3, to give the target compound 5-amino-4-(2,6-dichloro-3-hydroxyphenyl)-2,8-dimethyl-2,4,7,8- tetrahydro-l,2,4,7,8,9-hexazabenzo[cd]cyclopenta[h]azulene-3,6-dione (Compound 057). 1H NMR (400 MHz, DMSO) δ 10.95 (s, 1H), 9.20 (s, 1H), 8.14 (br s, 2H), 7.53 (d, J = 9.0 Hz, 1H), 7.45 (s, 1H), 7.19 (d, J = 9.0 Hz, 1H), 4.02 (s, 3H), 3.72 (s, 3H). LCMS: MS m / z (ESI): 446.1 [M+H] + .

[0549] 25.4 chiral resolution of compound 057:

[0550] Compound 057 was chiral resolution by SFC ( Mobile phase A: Supercritical CO2, mobile phase B: methanol, containing 0.1% 7.0 mol / L Ammonia in MEOH, A:B = 65:35), two isomers were obtained.

[0551] Compound 057-P1: (Rt = 2.96 min)

[0552] 1 H NMR (400 MHz, DMSO) δ 10.95 (s, 1H), 9.20 (s, 1H), 8.14 (br s, 2H), 7.53 (d, J = 9.0 Hz, 1H), 7.45 (s, 1H), 7.19 (d, J = 9.0 Hz, 1H), 4.02 (s, 3H), 3.72 (s, 3H). LCMS: MS m / z (ESI): 446.1 [M+H] + .

[0553] Compound 057-P2: (Rt = 4.09 min)

[0554] 1 H NMR (400 MHz, DMSO) δ 10.95 (s, 1H), 9.20 (s, 1H), 8.14 (br s, 2H), 7.53 (d, J = 9.0 Hz, 1H), 7.45 (s, 1H), 7.19 (d, J = 9.0 Hz, 1H), 4.02 (s, 3H), 3.72 (s, 3H). LCMS: MS m / z (ESI): 446.1 [M+H] + .

[0555] Synthesis of compound 024, 044, 048 and 058 of example 26

[0556] The synthesis of compound 024 and 048 was carried out according to the procedure described in Reference Example 15 (synthesis of compound 023) by replacing the intermediate 23-2 in step 15.5 with the corresponding alkynyl starting material. The synthesis of compound 044 was carried out according to the procedure described in Reference Example 22 (synthesis of compound 054). The synthesis of compound 058 was carried out according to the procedure described in Reference Example 12 (synthesis of compound 014). The characterization data of the compounds are shown in Table 1.

[0557] Table 1

[0558] The compounds listed in Table 2 were prepared essentially according to the same procedures as in Examples 1 to 25, using starting materials that were either commercially available or prepared according to literature procedures. Table 2 gives the names and structures of these compounds.

[0559] Table 2

[0560] Example 1 PKMYT1 enzymatic activity inhibition experiment The inhibition of PKMYT1 kinase by the compounds was detected by ADP-Glo assay. First, prepare the reaction buffer (Assay buffer): 50 mM HEPES, 10 mM MgCl, 1 mM EGTA, 0.01% Brij-35, 2 mM DTT, then dilute MYT1 enzyme (Carna, 05-176, final concentration 20 nM) and reaction substrate (final concentration 40 mM ATP and final concentration 40 nM unactivated CDK1, Signalchem C22-14G) with the reaction buffer respectively. Dilute the test compound 3-fold gradient into 10 concentrations, with the starting concentration of 3 mM. Transfer 50 nL of the diluted compound into a 384-well plate, transfer 5 pL of MYT1 enzyme solution into a 384-well plate, and incubate at 25°C for 10 minutes. Transfer 5 pL of reaction substrate solution into a 384-well plate, and incubate at 25°C for 180 minutes. Then transfer 5 pL of ADP-Glo Reagent (Promega, V9101) into a 384-well plate, and incubate at 25°C for 40 minutes. Finally, transfer 10 pL of ADP-Glo Detection Reagent into a 384-well plate, and incubate at 25°C for 40 minutes. Use an enzyme label instrument (BMG) to measure the luminescence intensity of the sample. Use XLfit 5.5.0 software to establish a non-linear regression equation, and perform concentration-response curve fitting and IC50 calculation. 50 The experimental results are shown in Table 3.

[0561] Table 3 Test results of compounds for PKMYT1 enzymatic activity

[0562] Example 2: Inhibition of tumor cell proliferation

[0563] Prepare a 10,000 cells / mL suspension of HCC1569 cells (ATCC, CRL-2330) and transfer 195 μL to a 96-well transwell flat bottom cell culture plate (Corning, #3603) and incubate overnight at 37°C, 5% CO2. Dilute the test compound stock solution with DMSO to an intermediate concentration and dilute by 1:3 to 10 concentration points. Transfer 5 μL of the diluted compound solution to the wells of the overnight incubated cells, with an initial maximum concentration of 10 μM. Incubate at 37°C, 5% CO2for 7 days. On the eighth day, remove the cell culture plate from the incubator and allow it to return to room temperature. Add 100 μL of Celltiter-Glo reagent (Promega, G7573), shake for 2 minutes to mix thoroughly, and then incubate at room temperature for 30 minutes in the dark. Perform quantification using a BMG microplate reader (BMG, PHERAstar FSX). Use XLfit 5.5.0 software to establish a non-linear regression equation for concentration-response curve fitting and IC50 determination. The test results are shown in Table 4.

[0564] Table 4: Test results of the inhibitory activity of compounds on HCC1569 cell proliferation

[0565] Example 3: Pharmacokinetic experiment in mice

[0566] Experimental materials: CD-1 mice were purchased from Zhejiang VITROLIFE Experimental Animal Technology Co., Ltd., Sibeifeng (Beijing) Biotechnology Co., Ltd., and Sibeifeng (Suzhou) Biotechnology Co., Ltd. DMSO, Solutol, PEG400, acetonitrile, methanol, VETPGS, Labrasol, etc. were purchased from Sigma-Aldrich, J&K Scientific, etc.

[0567] Experimental equipment: LC-MS / MS system was Waters Acquity UPLC class I plus connected with AB Sciex Triple Quad 6500+, and the chromatographic column was Agilent Poroshell 120EC-C18 4μm (50×2.1mm) or ACQUITY UPLC HSS T3 1.8μm (2.1×50mm). All data were collected and processed by Analyst software, and the pharmacokinetic parameters were calculated using Phoenix WinNonlin Build 8.3.

[0568] Experimental method: Female CD-I mice (20-30 g, 6-8 weeks) were randomly divided into 2 groups according to body weight, 3 mice in each group. The first group was given the test compound by tail vein injection, the dose was 1 mg / kg or 0.5 mg / kg, and the solvent was 5% DMSO + 5% Solutol + 90% Saline solution; the second group was given the test compound orally, the dose was 2 mg / kg or 5 mg / kg, and the solvent was shown in Table 5. The first group of animals was normally fed and watered before the experiment, and the second group of animals was fasted overnight before the experiment, and the food was added 2 hours after administration. The mice were collected at 0.083 (only intravenous injection group), 0.25, 0.5, 1, 2, 4, 8 and 24 hours before and after administration. The collected whole blood samples were placed in K2EDTA anticoagulant tubes, centrifuged (4000g, 5min, 4℃) to prepare plasma, and the plasma samples were stored in a ultra-low temperature refrigerator at -75±15℃ until detection. The mouse plasma samples were added with internal standard compound acetonitrile solution and vortexed for 0.5 min, then centrifuged at 3900 rpm for 15 min, the supernatant was transferred and diluted 3 times with water solution, and 2 μL was injected into the LC-MS / MS system for quantitative analysis. The female CD-I mouse plasma standard curve (linear range: 0.5-1000 ng / mL) and quality control samples (1, 2, 5, 50, 400, 800 ng / mL) were determined simultaneously. Part of the pharmacokinetic test results are shown in Table 5.

[0569] Table 5 Pharmacokinetic test results of mice

[0570] Example 4 In vivo efficacy experiment of mice

[0571] HCC1569 is a human breast cancer cell. A model was established using NOD SCID female mice, 0.2 mL (3×10 6 HCC1569 cells were subcutaneously inoculated on the right back of each mouse, and when the average tumor volume reached 100-200 mm 3 , the mice were grouped and administered, and the test compound was administered orally every day. The tumor diameter was measured twice a week and at the end of administration. The formula for calculating the tumor volume was V=0.5a×b 2 , where a and b represent the long diameter and short diameter of the tumor, respectively. The antitumor effect of the compound was evaluated by tumor growth inhibition rate (TGI). TGI (%) = [1-(average tumor volume at the end of administration of a certain treatment group-average tumor volume at the beginning of administration of the treatment group) / (average tumor volume at the end of treatment of the vehicle control group-average tumor volume at the beginning of treatment of the vehicle control group)]×100 (%). The body weight change rate (%) = [BW t / BW0-1]×100 (%), where BW tBW0 is the initial average body weight of the mice of the group at the time of grouping and dosing. The reference compound is RP-6306, the synthesis method of which can be found in the literature J. Med. Chem. 2022, 65, 15, 10251-10284.

[0572] The test results are shown in Figures 1, 2 and Figures 3, 4 and Tables 6 and 7. It can be seen from the test results that the compound of the present application can achieve similar or better tumor inhibition effect at a daily dose equivalent to or less than the reference compound, while having less impact on animal body weight and higher safety advantage.

[0573] Table 6 Pharmacodynamic experiment 1 of mouse HCC1569 model

[0574] Table 7 Pharmacodynamic experiment 2 of mouse HCC1569 model

Claims

Compounds of formula (I): or a pharmaceutically acceptable salt thereof, wherein E 1 and E 2 are each independently selected from O and S; Ring A is a 5-membered heteroaromatic ring; R 1 selected from the group consisting of hydrogen, C 1-10 1-6alkyl, C 3-10 2-6alkenyl, C 1-4 2-6alkynyl, C 3-10 3-6cycloalkyl, heterocyclyl, -C 1-4 2-6alkylene-heterocyclyl, CN, NO2, -C(=O)R A1 , -C(=O)OR A1 , -C(=O)NR A1 R B1 , -S(=O) r R A1 , -S(=O)(=NR E1 )R B1 , -S(=O) r NR A1 R B1 , and -S(=O)(=NR E1 )NR A1 R B1 , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is unsubstituted or substituted with at least one substituent independently selected from R X1 ; 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, heterocyclyl, -C 1-4 alkylene-heterocyclyl, CN, NO2, -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, and heterocyclyl is unsubstituted or substituted with at least one substituent selected independently from R X2 ; W is absent, or is CR 3 R 3 ' R 3 and R 3 are independently selected from the group consisting of 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, heterocyclyl, -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 substituent independently selected from R X3 ; R 4 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, heterocyclyl, -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 substituent independently selected from R X4 ; 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, heterocyclyl, -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 substituent independently selected from R X5 ; 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, heterocyclyl, -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 substituent independently selected from R X6 ; 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, heterocyclyl, -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 Each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is unsubstituted or is selected independently from R. X7 Substituents of the substituents; 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, heterocyclyl, -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 substituent independently selected from R X8 ; 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, heterocyclyl, -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 substituent independently selected from R X9 ; or R 8 and R 9 together with the atom to which they are attached form a C 5-6 hydrocarbon ring or a 5-6 membered heterocyclic or heteroaromatic ring containing 1, 2, or 3 heteroatoms each independently selected from the group consisting of oxygen, sulfur, and nitrogen, which ring is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X8 ; R 10 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, heterocyclyl, -C 1-4 alkylene-heterocyclyl, CN, NO2, aryl, -C 1-4 alkylene-aryl, heteroaryl, -C 1-4 alkylene-heteroaryl, -NR A10 R B10 , -OR A10 , -SR A10 , -C(=O)R A10 , -C(=NR E10 )R A10 , -C(=N-OR B10 )R A10 , -C(=O)OR A10 , -OC(=O)R A10 , -C(=O)NR A10 R B10 , -NR A10 C(=O)R B10 , -C(=NR E10 )NR A10 R B10 , -NR A10 C(=NR E10 )R B10 , -OC(=O)NR A10 R B10 , -NR A10 C(=O)OR B10 , -NR A10 C(=O)NR A10 R B10 , -NR A10 C(=S)NR A10 R B10 , -NR A10 C(=NR E10 )NR A10 R B10 , -S(=O) r R A10 , -S(=O)(=NR E10 )R B10 , -N=S(=O)R A10 R B10 , -S(=O)2OR A10 , -OS(=O)2R A10 , -NR A10 S(=O) r R B10 , -NR A10 S(=O)(=NR E10 )R B10 , -S(=O) r NR A10 R B10 , -S(=O)(=NR E10 )NR A10 R B10 , -NR A10 S(=O)2NR A10 R B10 and -NR A10 S(=O)(=NR E10 )NR A10 R B10 wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from R X10 ; R 11 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, heterocyclyl, -C 1-4 alkylene-heterocyclyl, CN, NO2, aryl, -C 1-4 alkylene-aryl, heteroaryl, -C 1-4 alkylene-heteroaryl, -NR A11 R B11 , -OR A11 , -SR A11 , -C(=O)R A11 , -C(=NR E11 )R A11 , -C(=N-OR B11 )R A11 , -C(=O)OR A11 , -OC(=O)R A11 , -C(=O)NR A11 R B11 , -NR A11 C(=O)R B11 , -C(=NR E11 )NR A11 R B11 , -NR A11 C(=NR E11 )R B11 , -OC(=O)NR A11 R B11 , -NR A11 C(=O)OR B11 , -NR A11 C(=O)NR A11 R B11 , -NR A11 C(=S)NR A11 R B11 , -NR A11 C(=NR E11 )NR A11 R B11 , -S(=O) r R A11 , -S(=O)(=NR E11 )R B11 , -N=S(=O)R A11 R B11 , -S(=O)2OR A11 , -OS(=O)2R A11 -NR A11 S(=O) r R B11 -NR A11 S(=O)(=NR E11 )R B11 -S (=O) r NR A11 R B11 -S(=O)(=NR) E11 )NR A11 R B11 -NR A11 S(=O)2NR A11 R B11 and -NR A11 S(=O)(=NR E11 )NR A11 R B11 Each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is unsubstituted or is selected independently from R. X11 Substituents of the substituents; or R 10 and R 11 together with the atoms to which they are attached form a C 3-10 monocyclic hydrocarbon ring or 4-12 membered heterocyclic ring containing 1, 2, or 3 heteroatoms or a 6-10 membered aromatic ring or 5-10 membered heteroaromatic ring containing 1, 2, or 3 heteroatoms, wherein each heteroatom is independently selected from the group consisting of oxygen, sulfur, nitrogen, and phosphorus, which ring is substituted with h substituents independently selected from the group consisting of R 12 ; R 12 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, heterocyclyl, -C 1-4 alkylene-heterocyclyl, CN, NO2, aryl, -C 1-4 alkylene-aryl, heteroaryl, -C 1- 4alkylene-heteroaryl, -NR A12 R B12 , -OR A12 , -SR A12 , -C(=O)R A12 , -C(=NR E12 )R A12 , -C(=N-OR B12 )R A12 , -C(=O)OR A12 , -OC(=O)R A12 , -C(=O)NR A12 R B12 , -NR A12 C(=O)R B12 , -C(=NR E12 )NR A12 R B12 , -NR A12 C(=NR E12 )R B12 , -OC(=O)NR A12 R B12 , -NR A12 C(=O)OR B12 , -NR A12 C(=O)NR A12 R B12 , -NR A12 C(=S)NR A12 R B12 , -NR A12 C(=NR E12 )NR A12 R B12 , -S(=O) r R A12 , -S(=O)(=NR E12 )R B12 , -N=S(=O)R A12 R B12 , -S(=O)2OR A12 , -OS(=O)2R A12 , -NR A12 S(=O) r R B12 , -NR A12 S(=O)(=NR E12 )R B12 , -S(=O) r NR A12 R B12 , -S(=O)(=NR E12 )NR A12 R B12 , -NR A12 S(=O)2NR A12 R B12 , and -NR A12 S(=O)(=NR E12 )NR A12 R B12 wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is unsubstituted or substituted by at least one substituent independently selected from R X12 ; is a single or double bond; each R A1 , R A2 , R A3 , R A4 , R A5 , R A6 , R A7 , R A8 , R A9 , R A10 , R A11 , R A12 , R B1 , R B2 , R B3 , R B4 , R B5 , R B6 , R B7 , R B8 , R B9 , R B10 , R B11 and R B12 are independently selected from hydrogen, C 1-10 1-6alkyl, C 2-10 1-6alkenyl, C 2-10 1-6alkynyl, C 3-10 3-6cycloalkyl, -C 1-4 1-6alkylene-C 3-10 3-6cycloalkyl, heterocyclyl, -C 1-4 1-6alkylene-heterocyclyl, aryl, -C 1-4 1-6alkylene-aryl, heteroaryl and -C 1-4 1-6alkylene-heteroaryl, wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from R X ; 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 " or "R A10 and R B10 " or "R A11 and R B11 " or "R A12 and R B12 " together with the single or multiple atoms to which they are attached 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 substituents selected from R X ; each R E1 , R E2 , R E3 , R E4 , R E5 , R E6 , R E7 , R E8 , R E9 , R E10 , R E11 and R E12 are independently selected from hydrogen, C 1-10 1-6alkyl, 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 alkyl is unsubstituted or substituted by at least one substituent independently selected from R X ; each R X , R X1 , R X2 , R X3 , R X4 , R X5 , R X6 , R X7 , R X8 , R X9 , R X10 , R X11 and R X12 are independently selected from halo, C 1-10 1-6alkyl, C 2-10 2-6alkenyl, C 2-10 2-6alkynyl, C 3-10 3-6cycloalkyl, -C 1-4 1-6alkylene-C 3-10 3-6cycloalkyl, heterocyclyl, -C 1-4 1-6alkylene-heterocyclyl, aryl, -C 1-4 1-6alkylene-aryl, heteroaryl, -C 1-4 1-6alkylene-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 Each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is unsubstituted or is selected independently from R. Y Substituents of the substituents; each R a1 and R b1 is independently selected from the group consisting of 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, heterocyclyl, -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 substituent independently selected from the group consisting of R Y ; or R a1 and R b1 together with the single or multiple atoms to which they are attached 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 substituents selected from R Y ; each R c1 and R d1 is independently selected from the group consisting of 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, heterocyclyl, -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 substituent independently selected from R Y ; or each R c1 and R d1 together with the single or multiple carbon atom to which they are attached 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 groups independently selected from R Y ; Each R e1 Independently selected from hydrogen and C 1-10 Alkyl group, 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 is selected independently from R Y Substituents of the substituents; Each R Y Independently selected from halogens, 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 (heterocyclic), -O (C 1-4 alkylene-heterocyclic groups), -SH, -S(C 1-10 alkyl), -S(C 3-10 cycloalkyl), -S(C 1-4 Alkylene-C 3-10 cycloalkyl), -S (heterocyclic), -S (C 1-4 alkylene-heterocyclic groups), -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 (heterocyclic) and -NH (C 1-4 (alkylene-heterocyclic group); g is selected from 0, 1, and 2; h 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. The compound of claim 1, wherein R 1 selected from the group consisting of hydrogen, C 1-10 alkyl and C 3-10 cycloalkyl, wherein alkyl and cycloalkyl are unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X1 ; R is selected from the group consisting of hydrogen and C 1 alkyl, wherein alkyl and cycloalkyl are unsubstituted or substituted with at least one substituent independently selected from the group consisting of R 1-10 alkyl, wherein alkyl and cycloalkyl are unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X1 alkyl, wherein alkyl and cycloalkyl are unsubstituted or substituted with at least one substituent independently selected from the group consisting of R 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 alkyl is unsubstituted or substituted by at least one substituent independently selected from R X2 ; R is selected from -NR 2 R is selected from -NR A2 R B2 and hydrogen, in particular -NH2. The compound of any one of claims 1-3, wherein W is absent. The compound of any one of claims 1-3, wherein W is CR 3 R 3 ' wherein, R 3 and R 3 are independently selected from the group consisting of hydrogen, C 1-10 alkyl and C 3-10 cycloalkyl, wherein alkyl and cycloalkyl are unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X3 ; Preferably, R 3 and R 3 'Independently selected from hydrogen C 1-10 Alkyl group, wherein the alkyl group is unsubstituted or is selected independently from R. X3 Substituents are substituted. The compound of any one of claims 1-5, wherein each R is independently selected from the group consisting of halogen, C 4 alkyl, C 1-10 alkenyl, C 3-10 alkynyl, cycloalkyl, CN, -NR A4 R B4 , -OR A4 , -SR A4 , and -C(=O)R A4 , wherein each alkyl, alkenyl, alkynyl, and cycloalkyl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X4 ; R is independently selected from the group consisting of F, CI, Br, CN, and C 4 alkyl, wherein said alkyl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R 1-10 alkyl, wherein said alkyl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X4 alkyl, wherein said alkyl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R More preferably, each R 4 is independently selected from F, CI, methyl and ethyl. The compound of any one of claims 1-6, wherein R 5 selected from the group consisting of halogen and C 1-10 alkyl, wherein alkyl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X5 alkyl, wherein alkyl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R Preferably, R 5 is selected from CI and methyl. The compound of any one of claims 1-7, wherein R 6 selected from hydrogen, halogen, C 1-10 alkyl, CN, NO2, -NR A6 R B6 and -OR A6 wherein alkyl is unsubstituted or substituted with at least one substituent independently selected from R X6 ; Preferably, R 6 is hydrogen or F, in particular hydrogen. The compound of any one of claims 1-8, wherein R 7 selected from hydrogen, halogen, C 1-10 alkyl, CN, NO2, -NR A7 R B7 and -OR A7 wherein alkyl is unsubstituted or substituted with at least one substituent independently selected from R X7 ; Preferably, R 7 is hydrogen or F, in particular hydrogen. The compound of any one of claims 1-9, wherein R 8 selected from halogen, C 1-10 alkyl, CN, NO2, -NR A8 R B8 and -OR A8 ; Preferably, R 8 is -OH. The compound of any one of claims 1-10, wherein R 9 selected from the group consisting of halogen and C 1-10 alkyl, wherein alkyl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X9 alkyl, wherein alkyl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R Preferably, R 9 is selected from CI and methyl. The compound of any one of claims 1-9, wherein R 8 and R 9 together with the atom to which they are attached form a 5-membered heterocyclic or 5-membered heteroaromatic ring containing 1, 2, or 3 heteroatoms, each independently selected from oxygen, sulfur, and nitrogen, which ring is unsubstituted or substituted with at least one substituent independently selected from R X8 ; R 8 and R 9 together with the atoms to which they are attached form a pyrazole ring; the ring is unsubstituted or substituted with at least one substituent independently selected from R X8 . The compound of any one of claims 1-12, wherein R 10 selected from C 1-10 alkyl, aryl, -C 1-4 alkylene-aryl, heteroaryl, and -C 1-4 alkylene-heteroaryl, wherein each alkyl, alkylene, aryl, and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from R X10 ; Preferably, R 10 The group is selected from methyl, phenyl, pyrazolyl, pyridyl, and pyrimidinyl, wherein the methyl, phenyl, pyrazolyl, pyridyl, and pyrimidinyl groups are unsubstituted or are selected independently from R. X10 Substituents of the substituents; More preferably, R 10 selected from methyl, phenyl, The compound of any one of claims 1-13, wherein R 11 selected from the group consisting of hydrogen, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, -C 1-4 alkylene-C 3-10 cycloalkyl, CN and NO2, wherein each alkyl, alkylene and cycloalkyl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X11 ; Preferably, R 11 is hydrogen. The compound of any one of claims 1-12, wherein R 10 and R 11 together with the atom to which they are attached form a 6-10 membered aromatic ring or a 5-10 membered heteroaromatic ring containing 1, 2, or 3 heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen, and phosphorus, which ring is substituted with h substituents independently selected from the group consisting of R 12 ; R 10 and R 11 together with the atoms to which they are attached form a phenyl ring, pyridine, pyrazole, imidazole or benzimidazole, wherein the phenyl ring, pyridine, pyrazole and benzimidazole are substituted with h substituents independently selected from R 12 ; More preferably, R 10 and R 11 together with the atom to which they are attached form the following structure: The compound of any one of claims 1-15, wherein R 12 selected from halogen, C 1-10 alkyl, C 3-10 cycloalkyl, -C 1-4 alkylene-C 3-10 cycloalkyl, CN, NO2, -NR A12 R B12 and -OR A12 wherein each alkyl, alkylene and cycloalkyl is unsubstituted or substituted with at least one substituent independently selected from R X12 ; R is selected from the group consisting of halogen, -CN, C 12 alkyl, -OH and -0(C 1-10 alkyl), wherein each alkyl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R 1-10 alkyl, -OH and -0(C X12 alkyl), wherein each alkyl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R More preferably, R 12 is selected from F, methyl and methoxy. The compound of any one of claims 1-16, wherein Ring A is selected from pyrrole and pyrazole. A compound of claim 1 having the structure of formula (la), (la-1), or (lla): A compound, or pharmaceutically acceptable salt thereof, wherein the compound is selected from: A pharmaceutical composition comprising a compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. Use of a compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 20, in the manufacture of a medicament for the treatment of a disease, disorder, or condition selected from a disease of abnormal cell proliferation. Use of a compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 20, in the manufacture of a medicament for the treatment of 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 tumor of hematological origin selected from the group consisting of bladder cancer, endometrial cancer, lung squamous cell carcinoma, 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, stomach cancer, cervical cancer, thyroid cancer, prostate cancer, and skin cancer; (b) a hematopoietic tumor of lymphoid lineage selected from the group consisting of leukemia, acute lymphoblastic leukemia, acute lymphoblastic T-cell leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, and Burkitt's lymphoma; (c) a hematopoietic tumor of myeloid lineage selected from the group consisting of acute and chronic myelogenous leukemia, myelodysplastic syndrome, and promyelocytic leukemia; (d) a tumor of mesenchymal origin selected from the group consisting of fibrosarcoma and rhabdomyosarcoma; (e) a tumor of the central and peripheral nervous system selected from the group consisting of astrocytoma, neuroblastoma, glioma, and schwannoma; or (f) melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderma pigmentosum, keratoactanthoma, thyroid follicular cancer, or Kaposi's sarcoma; More preferably, the cancer is selected from melanoma, colon cancer, lung cancer, pancreatic cancer, prostate cancer, bladder cancer, head cancer, neck cancer, breast cancer, cervical cancer, ovarian cancer and leukemia.

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