WO2025247067A1 - Kif18a inhibitor - Google Patents

Abstract

The present invention relates to the field of medicinal chemistry and particularly to a class of compounds or pharmaceutically acceptable salts as Kif18A inhibitors, preparation methods therefor, pharmaceutical compositions thereof, and use thereof in the treatment of a Kif18A-related disease.

Description

Kif18A inhibitors Technical Field

This invention relates to the field of medicinal chemistry, and particularly to a class of compounds or pharmaceutically acceptable salts used as Kif18A inhibitors, methods for their preparation, pharmaceutical compositions thereof, and their use in the treatment of Kif18A-related diseases.

Background Technology

Genomic instability is a key characteristic of most tumors, often accompanied by multiple loss and duplication of entire chromosomes. In tumor cells, abnormalities in chromosome number and structure typically originate from mutations in DNA repair genes (such as BRCA1/2) and cell cycle regulatory genes (such as TP53). Abnormal karyotypes also make tumor cells exceptionally sensitive to mitotic interference. Over the past few decades, many mitotic-targeting drugs have been developed for cancer treatment. Among these, paclitaxel derivatives (such as paclitaxel and docetaxel) are the most prominent and widely used to treat various human malignancies, including ovarian, breast, lung, and prostate cancer. Despite the wide applicability and good efficacy of antimitotic drugs, prevalent side effects and drug resistance still limit their success in cancer treatment. Therefore, the development of next-generation antimitotic drugs with fewer drug resistance issues and better safety profiles is urgently needed.

The kinesin superfamily is a class of molecular motors found in eukaryotic cells. Within the cell, they move along microtubules by hydrolyzing ATP, thus playing a role in processes such as mitosis, meiosis, and protein transport. During mitosis, kinesins play crucial roles in spindle assembly, chromosome separation, and movement.

Human kinin family member 18A (Kif18A) belongs to the kinin-8 family. Kif18A is thought to regulate the dynamics of kinetochore microtubules, controlling proper chromosome positioning and spindle tension during mitosis to ensure the equal distribution of sister chromatids to two daughter cells. Tumor cells are genomically unstable and therefore more dependent on the function of Kif18A. Studies of cells with genome-wide aberrant proliferation, a common feature in human cancers, have shown that the growth of abnormal tetraploid cells is significantly inhibited when Kif18A is depleted, while the growth of normal diploid cells is not significantly affected. Furthermore, mice with Kif18A knocked out through transgenesis can still survive to adulthood, suggesting that the development of inhibitors targeting Kif18A may have good safety profiles. Therefore, identifying inhibitors of Kif18A ATPase activity is a promising approach for developing novel anticancer agents.

Summary of the Invention

On the one hand, compounds of formula (I) are provided:

Or its pharmaceutically acceptable salt.

in,

Ring B is selected from 5-membered heterocyclic aromatic rings;

Q is selected from M is selected from N and CH; U and V are each independently selected from O, S, L is selected from chemical bonds, -O-, -S-, -NR ^6- , and _C1-2 alkylene groups; wherein each These represent the connection sites;

^A1 is selected from N and C(R ⁷ );

^A2 is selected from N and C(R ⁸ );

^A3 is selected from N and C( ^R9 );

L ¹ is selected from -(CR ^C R ^D ) _t -S(=O) _r -, -(CR ^C R ^D ) _t -NR ^F S(=O) _r -, and -(CR ^C R ^D ) _t -S(=O) _r NR ^F -;

^L2 is selected from _C1-6 alkylene groups;

^X1 is selected from N and C (R ¹⁰ );

^X2 is selected from N and C(R ¹¹ );

^X3 is selected from N and C(R ¹² );

^R1 is selected from _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, _C3-10 cycloalkyl, _-C1-4 alkylene- _C3-10 cycloalkyl, heterocyclic, -C1-4 alkylene-heterocyclic, aryl, _-C1-4 alkylene-aryl, heteroaryl, _-C1-4 alkylene- _heteroaryl , -NR ^A1 R ^B1 , -OR A1, -SR A1, -C(=O)R ^A1 , -C(=NR ^E1 )R ^A1 , -C(=N-OR ^B1 )R ^A1 , -C(=O)OR ^A1 , -OC(=O)R ^A1 , -C(=O)NR ^A1 R ^B1 , -NR ^F1 C ⁽ =O)R ^A1 , -C(=NR ^E1 )NR ^{A1 R B1 ,} -NR ^F1 C(=NR ^E1) )R ^A1 , -OC(=O)NR ^A1 R ^B1 , -NR ^F1 C(=O)OR ^A1 , -NR ^F1 C(=O)NR ^A1 R ^B1 , -NR ^F1 C(=S)NR ^A1 R ^B1 , -NR ^F1 C(=NR ^E1 )NR ^A1 R ^B1 , -S(=O) _r R ^A1 , -S(=O)(=NR ^E1 )R ^A1 , -N＝S(＝O)R ^A1 R ^B1 , -S(＝O) ₂ OR ^A1 , -OS(＝O) ₂ R ^A1 , -NR ^F1 S(＝O) _r R ^A1 , -NR ^F1 S(＝O)(＝NR ^E1 )R ^A1 , -S(＝O) _r NR ^A1 R ^B1 , -S(＝O)(＝NR ^E1 )NR ^A1 R ^B1 , -NR ^F1 S(=O) ₂ NR ^{A1 RB1} and -NR ^F1 S(＝O)(＝NR ^E1 )NR ^{A1 RB1} , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl group is unsubstituted or substituted by at least one substituent independently selected from ^RX1 ;

Each ^R2 is independently selected from halogens, _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, _C3-10 cycloalkyl, _-C1-4 alkylene- _C3-10 cycloalkyl, heterocyclic, -C1-4 alkylene-heterocyclic, aryl, _-C1-4 alkylene-aryl, _heteroaryl , _-C1-4 alkylene-heteroaryl, CN, _NO2 , ^-NRA2RB2 , ^-ORA2 , -SRA2, -C(=O) ^RA2 , -C( ₌ O) ^ORA2 , ^-OC (=O) ^RA2 , -C(=O) ^NRA2RB2 , ^-NRA2C (=O) ^RB2 , -NRA2C(= ^NRE2 ) ^RB2 , ^-OC (= ^{O)NRA2RB2 , -NRA2C (} =O ^{) ORB2} , -NR ^A2 C(=O)NR ^A2 R ^B2 , -NR ^A2 C(=S)NR ^A2 R ^B2 , -NR ^A2 C(=NR ^E2 )NR ^A2 R ^B2 , -S(=O) _r R ^A2 , -S(=O)(=NR ^E2 )R ^B2 , -N=S(=O)R ^A2 R ^B2 , -S(=O) ₂ OR ^A2 , -OS(=O) ₂ R ^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) ₂ NR ^A2 R ^B2 and -NR ^A2 S(=O)(=NR ^E2 )NR ^A2 R ^B2 Each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is either unsubstituted or substituted by at least one substituent independently selected from ^RX2 ;

^R3 is selected from hydrogen, halogens, CN, _NO2 , -NR ^A3RB3 , -OR ^A3 , ^{-SR A3 ,} -C(=O) ^RA3 , -C(=O)OR ^A3 , -OC(=O) ^RA3 , -C(=O) ^{NR A3RB3} and -NR ^A3C (=O) ^RB3 ;

Each ^R4 is independently selected from halogens, _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, _C3-10 cycloalkyl, -C1-4 alkylene- _C3-10 cycloalkyl, _heterocyclic , -C1-4 alkylene-heterocyclic, CN, _NO2 , -NR _A4 ^RB4 , -OR ^A4 , -SR ^A4 , -C(=O)R ^A4 , -C(=O)OR ^A4 , ^-OC (=O)R ^A4 , -C(=O)NR ^{A4 RB4} , -NR ^A4 C(=O) ^RB4 , -NR ^A4 C(=NR ^E4 ) ^RB4 , -OC(=O)NR ^{A4 RB4} , -NR ^A4 C(=O)OR ^B4 , -NR ^A4 C(=O)NR ^{A4 RB4} , -NR ^A4 C(=S) ^{NR A4 RB4} -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) ₂ OR ^A4 , -OS(＝O) ₂ R ^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) ₂ NR ^A4 R ^B4 and -NR ^A4 S(＝O)(＝NR ^E4 )NR ^A4 R ^B4 , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl and heterocyclic group is unsubstituted or substituted by at least one substituent independently selected from ^RX4 ;

Or any two R ^4s together with the carbon atoms attached to them form a saturated or unsaturated 3-7 membered ring containing 0, 1, 2 or 3 heteroatoms, wherein the heteroatoms are independently selected from oxygen, sulfur, nitrogen and phosphorus, and the ring is either unsubstituted or substituted by 1, 2 or 3 R ^X4 substituents.

^R4a and ^R4b are each independently selected from hydrogen and ^R4 ;

Or R ^4a and R ^4b together with the carbon atoms attached to them form a saturated or unsaturated 3-7 membered ring containing 0, 1, 2 or 3 heteroatoms, wherein the heteroatoms are independently selected from oxygen, sulfur, nitrogen and phosphorus, and the ring is either unsubstituted or substituted by 1, 2 or 3 R ^X4 substituents.

R ^5a and R ^5b are each independently selected from hydrogen, halogen, _C1-10 alkyl and _C3-10 cycloalkyl, wherein the alkyl and cycloalkyl are unsubstituted or substituted by at least one substituent independently selected from R ^X5 ;

Or R ^5a and R ^5b together with the carbon atoms attached to them form a saturated or unsaturated 3-7 membered ring containing 0, 1, 2 or 3 heteroatoms, wherein the heteroatoms are independently selected from oxygen, sulfur, nitrogen and phosphorus, and the ring is either unsubstituted or substituted by 1, 2 or 3 R ^X5 substituents.

^R6 is selected from hydrogen and _C1-10 alkyl groups, wherein the alkyl group is unsubstituted or substituted by at least one substituent selected independently from R ^X6 ;

R ⁷ is selected from halogens, _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, _C3-10 cycloalkyl, _-C1-4 alkylene- _C3-10 cycloalkyl, heterocyclic, -C1-4 alkylene-heterocyclic, aryl, _-C1-4 alkylene-aryl, heteroaryl, _-C1-4 alkylene-heteroaryl, CN, NO ₂ , -NR ^A7 _RB7 , -OR A7, -SR ^A7 , -C(=O)R ^A7 , -C(=O)OR ^A7 , -OC(=O)R ^A7 , -C(=O)NR ^{A7 RB7} , -NR ^A7 C(=O)R ^B7 , -NR ^A7 C(=NR ^E7 )R ^B7 , -OC(=O)NR ^{A7 RB7} , -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) ₂ OR ^A7 , -OS(=O) ₂ R ^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) ₂ NR ^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 either unsubstituted or substituted by at least one substituent independently selected from ^RX7 .

^R8 is selected from halogens, _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, _C3-10 cycloalkyl, _-C1-4 alkylene- _C3-10 cycloalkyl, heterocyclic, -C1-4 alkylene-heterocyclic, aryl, _-C1-4 alkylene-aryl, heteroaryl, _-C1-4 alkylene-heteroaryl, CN, NO2, -NR ^A8 _RB8 , -OR _A8 , -SR ^A8 , -C(=O)R ^A8 , ^-C (=O)OR A8, -OC(=O)R ^A8 , -C(=O)NR ^{A8 RB8} , -NR ^A8 C(=O) ^{R B8 ,} -NR ^A8 C(=NR ^E8 )R ^B8 , -OC(=O)NR ^{A8 RB8} , -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) ₂ OR ^A8 , -OS(=O) ₂ R ^A8 , -NR ^A8 S(=O) _r ^RB8 , -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) ₂ NR ^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 either unsubstituted or substituted by at least one substituent independently selected from ^RX8 .

Alternatively, ^R7 and ^R8, together with the atoms attached to them, form a _C5-10 hydrocarbon ring or a 5-10 membered heterocycle or a 5-10 membered heteroaromatic ring containing 1, 2, or 3 heteroatoms, wherein the hydrocarbon ring, heterocycle, and heteroaromatic ring are monocyclic or bicyclic, the heteroatoms in the heterocycle are independently selected from oxygen, sulfur, nitrogen, and phosphorus, and the heteroatoms in the heteroaromatic ring are independently selected from oxygen, sulfur, and nitrogen; the ring is unsubstituted or substituted by at least one substituent independently selected from R ^X8 ;

R ⁹ is selected from halogens, _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, _C3-10 cycloalkyl, _-C1-4 alkylene- _C3-10 cycloalkyl, heterocyclic, -C1-4 alkylene-heterocyclic, aryl, _-C1-4 alkylene-aryl, heteroaryl, _-C1-4 alkylene-heteroaryl, CN, NO ₂ , -NR ^A9 _RB9 , -OR A9, -SR ^A9 , -C(= ^O )R A9, ^-C (=O)OR A9, -OC(=O)R ^A9 , -C(=O)NR ^{A9 RB9} , -NR ^A9 C(=O)R ^B9 , -NR ^A9 C(=NR ^E9 )R ^B9 , -OC(=O)NR ^{A9 RB9} , -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) ₂ OR ^A9 , -OS(=O) ₂ R ^A9 , -NR ^A9 S(=O) _r ^RB9 , -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) ₂ NR ^A9 R ^B9 and -NR ^A9 S(=O)(=NR ^E9 )NR ^A9 R ^B9 Each alkyl, alkylene, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is either unsubstituted or substituted by at least one substituent independently selected from ^RX9 ;

^R10 is selected from halogens, _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, _C3-10 cycloalkyl, _-C1-4 alkylene- _C3-10 cycloalkyl, heterocyclic, -C1-4 alkylene-heterocyclic, aryl, _-C1-4 alkylene-aryl, heteroaryl, _-C1-4 alkylene-heteroaryl, CN, _NO2 , -NR ^A10 _RB10 , -OR A10, -SR ^A10 , -C(=O)R ^A10 , -C(=O)OR ^A10 , -OC(=O)R ^A10 , -C(=O)NR ^{A10 RB10} , -NR ^A10 C( ^{=O)RB10, -NR A10 C(=NR E10)RB10 , -OC ( = O} )NR ^{A10 RB10} , -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) ₂ OR ^A10 , -OS(＝O) ₂ R ^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) ₂ NR ^{A10 RB10} and -NR ^A10 S(＝O)(＝NR ^E10 )NR ^{A10 RB10} , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl group is unsubstituted or substituted by at least one substituent independently selected from ^RX10 ;

R ¹¹ is selected from halogens, _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, _C3-10 cycloalkyl, _-C1-4 alkylene- _C3-10 cycloalkyl, heterocyclic, -C1-4 alkylene-heterocyclic, aryl, _-C1-4 alkylene-aryl, heteroaryl, _-C1-4 alkylene-heteroaryl, CN, NO ₂ , -NR ^A11 _RB11 , -OR ^A11 , -SR ^A11 , -C(=O)R ^A11 , -C(=O)OR ^{A11, -OC(=O)R A11 ,} -C(=O)NR ^{A11 RB11} , -NR ^{A11 C} (=O) ^RB11 , -NR ^A11 C(=NR ^E11 ) ^RB11 , -OC(=O)NR ^{A11 RB11} ,-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) ₂ OR ^A11 , -OS(＝O) ₂ R ^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) ₂ NR ^A11 R ^B11 and -NR ^A11 S(＝O)(＝NR ^E11 )NR ^A11 R ^B11 , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl group is unsubstituted or substituted by at least one substituent independently selected from ^RX11 ;

Alternatively, ^R10 and ^R11, together with the atoms attached to them, form a _C5-10 hydrocarbon ring or a 5-10 membered heterocycle or a 5-10 membered heteroaromatic ring containing 1, 2 or 3 heteroatoms, wherein the hydrocarbon ring, heterocycle and heteroaromatic ring are monocyclic or bicyclic, the heteroatoms in the heterocycle are independently selected from oxygen, sulfur, nitrogen and phosphorus, and the heteroatoms in the heteroaromatic ring are independently selected from oxygen, sulfur and nitrogen; the ring is unsubstituted or substituted by at least one substituent independently selected from R ^X11 ;

^R12 is selected from halogens, _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, _C3-10 cycloalkyl, _-C1-4 alkylene- _C3-10 cycloalkyl, heterocyclic, -C1-4 alkylene-heterocyclic, aryl, _-C1-4 alkylene-aryl, heteroaryl, _-C1-4 alkylene-heteroaryl, CN, NO2, -NR ^A12 _RB12 , -OR _A12 , -SR ^A12 , -C(=O) ^RA12 , ^-C (=O)OR ^A12 , -OC(=O)RA12, -C(=O)NR ^{A12 RB12} , -NR ^A12 C(=O ^{)RB12 ,} -NR ^A12 C(=NR ^E12 ) ^RB12 , -OC(= ^O )NR ^{A12 RB12} , -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) ₂ OR ^A12 , -OS(＝O) ₂ R ^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, heterocyclic, aryl and heteroaryl group is unsubstituted or substituted by at least one substituent independently selected from ^RX12 ;

Each ^RF , ^RF1 , RA1, ^RA2 , ^RA3 , ^RA4 , RA7, ^RA8 , ^RA9 , ^RA10 , ^RA11 , ^RA12 , ^RB1 , ^RB2 , ^RB3 , ^RB4 , RB7, ^RB8 , ^RB9 , ^RB10 , ^RB11 , ^{and RB12 is} independently selected from hydrogen, _C1-10 alkyl, ^C2-10 _alkenyl , ^C2-10 alkynyl, _C3-10 cycloalkyl, _-C1-4 alkylene- _C3-10 cycloalkyl, heterocyclic, _-C1-4 alkylene-heterocyclic, _aryl , _-C1-4 alkylene-aryl, heteroaryl _, and -C _1-4 alkylene-heteroaryl, wherein each alkyl, alkylene, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl and heteroaryl group is unsubstituted or substituted by at least one substituent independently selected from R ^X ;

Or “ ^RA1 and ^RB1 ” or “ ^RA2 and ^RB2 ” or “ ^RA3 and RB3” or “RA4 and ^RB4 ” or “ ^RA7 and ^RB7 ” or “ ^RA8 and ^RB8 ” or “ ^RA9 and ^RB9 ” or “ ^RA10 and ^RB10 ” or “ ^RA11 and ^RB11 ” or “ ^RA12 and ^RB12 ” together with one or more atoms attached to them constitute a 4-12 membered heterocycle containing 0, 1 or 2 additional independent heteroatoms selected from oxygen, sulfur, nitrogen and phosphorus, which is either unsubstituted or substituted ^with 1, 2 or 3 substituents selected ^{from RX} ;

Each ^RC and ^RD is independently selected from hydrogen, halogen, _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, _C3-10 cycloalkyl, _-C1-4 alkylene- _C3-10 cycloalkyl, heterocyclic, -C1-4 alkylene-heterocyclic, aryl, _-C1-4 alkylene-aryl, _heteroaryl and _-C1-4 alkylene-heteroaryl, wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl is unsubstituted or substituted by at least one substituent independently selected from ^RX ;

Alternatively, each “ ^RC and ^RD ” together with one or more carbon atoms attached to them forms a 3-12 membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, which is either unsubstituted or substituted with 1, 2 or 3 substituents independently selected from ^RX .

Each ^RE1 , ^RE2 , ^RE4 , ^RE7 , ^RE8 , ^RE9 , ^RE10 , ^RE11 and ^RE12 is independently selected from hydrogen, _C1-10 alkyl, CN, _NO2 , -S(=O) _rRa1 , -C(=O) ^Ra1 , -C(=O) ^ORa1 , ^{-C (} =O) ^NRa1Rb1 and -S(=O) ^rNRa1Rb1 , wherein the alkyl group is unsubstituted or substituted _by at least one substituent independently selected from ^{RX ;}

Each ^RX , ^RX1 , ^RX2 , RX4, ^RX5 , ^RX6 , ^RX7 , ^RX8 , ^RX9 , ^RX10 , ^RX11 , ^{and RX12 is} independently selected from halogens, _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, _C3-10 cycloalkyl, _-C1-4 alkylene- _C3-10 cycloalkyl, heterocyclic, _{-C1-4 alkylene-heterocyclic, aryl, -C1-4 alkylene} -aryl, heteroaryl, _-C1-4 alkylene-heteroaryl, CN, _NO2 , -( ^CRc1Rd1 ) ^uNRa1Rb1 , _- ( ^CRc1Rd1 ) ^{uORb1 ,} _- ( ^CRc1Rd1 ) _uC ( _＝ ^O ) ^Ra1 , - ^{( CRc1Rd1 ) u} C(＝NR ^e1 )R ^a1 , -(CR ^c1 R ^d1 ) _u C(＝O)OR ^b1 , -(CR ^c1 R ^d1 ) _u OC(＝O)R ^b1 , -(CR ^c1 R ^d1 ) _u C(＝O)NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _u NR ^a1 C(＝O)R ^b1 , -(CR ^c1 R ^d1 ) _u C(＝NR ^e1 )NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _u NR ^a1 C(＝NR ^e1 )R ^b1 , -(CR ^c1 R ^d1 ) _u OC(＝O)NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _u NR ^a1 C(＝O)OR ^b1 , -(CR ^c1 R ^d1 ) _u NR ^a1 C(＝O)NR ^a1 R ^b1 ,-(CR ^c1 R ^d1 ) _u NR ^a1 C(＝S)NR ^a1 R ^b1 ,-(CR ^c1 R ^d1 ) _u NR ^a1 C(＝NR ^e1 )NR ^a1 R ^b1 ,-(CR ^c1 R ^d1 ) _u S(＝O) _r R ^b1 ,-(CR ^c1 R ^d1 ) _u S(＝O)(＝NR ^e1 )R ^b1 ,-(CR ^c1 R ^d1 ) _u N＝S(＝O)R ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _u S(＝O) ₂ OR ^b1 , -(CR ^c1 R ^d1 ) _u OS(＝O) ₂ R ^b1 , -(CR ^c1 R ^d1 ) _u NR ^a1 S(＝O) _r R ^b1 , -(CR ^c1 R ^d1 ) _u NR ^a1 S(＝O)(＝NR ^e1 )R ^b1 、-(CR ^c1 R ^d1 ) _u S(＝O) _r NR ^a1 R ^b1 、-(CR ^c1 R ^d1 ) _u S(＝O)(＝NR ^e1 )NR ^a1 R ^b1 、-(CR ^c1 R ^d1 ) _u NR ^a1 S(＝O) ₂ NR ^a1 R ^b1 and -(CR ^c1 R ^d1 ) _u NR ^a1 S(＝O)(＝NR ^e1 )NR ^a1 R ^b1 , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl group is unsubstituted or substituted by at least one substituent independently selected from R ^Y ;

Each ^Ra1 and ^Rb1 is independently selected from hydrogen, _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, _C3-10 cycloalkyl, _-C1-4 alkylene- _C3-10 cycloalkyl, heterocyclic, -C1-4 alkylene-heterocyclic, aryl, _-C1-4 alkylene-aryl, heteroaryl and _-C1-4 alkylene-heteroaryl, wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, _aryl and heteroaryl is unsubstituted or substituted by at least one substituent independently selected from R ^Y ;

Or ^Ra1 and ^Rb1 together with one or more atoms attached to them form a 4-12 membered heterocycle containing 0, 1 or 2 additional independent heteroatoms selected from oxygen, sulfur, nitrogen and phosphorus, which is either unsubstituted or substituted with 1, 2 or 3 substituents selected from R ^Y.

Each ^Rc1 and ^Rd1 is independently selected from hydrogen, halogen, _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, C3-10 cycloalkyl, _-C1-4 alkylene- _C3-10 cycloalkyl, heterocyclic, _-C1-4 alkylene-heterocyclic, aryl, _-C1-4 alkylene-aryl, _heteroaryl and _-C1-4 alkylene-heteroaryl, wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl is unsubstituted or substituted by at least one substituent independently selected from R ^Y ;

Alternatively, each ^Rc1 and ^Rd1 together with one or more carbon atoms attached to them can form a 3-12 membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, which is either unsubstituted or substituted with 1, 2 or 3 substituents independently selected from R and ^Y.

Each ^Re1 is independently selected from hydrogen, _C1-10 alkyl, CN, _NO2 , -S(=O) _rRa1 ^, -C ⁽ =O) ^Ra1 , -C(=O) ^ORa1 , -C(=O) ^NRa1Rb1 and _-S (=O) ^rNRa1Rb1 , wherein the alkyl group is unsubstituted or substituted ^by at least one substituent independently selected from ^RY ;

Each R ^Y is independently selected from halogen, _NO₂ , -CN, _C1-10 alkyl, -OH, -O ( _C1-10 alkyl), -O ( _C3-10 cycloalkyl), -O ( _C1-4 alkylene- _C3-10 cycloalkyl), -O (heterocyclic), -O ( _C1-4 alkylene-heterocyclic), -SH, -S ( _C1-10 alkyl), -S ( _C3-10 cycloalkyl), -S ( _C1-4 alkylene- _C3-10 cycloalkyl), -S (heterocyclic), -S ( _C1-4 alkylene-heterocyclic), _-NH₂ , -NH (C1-10 alkyl), -N ( _C1-10 alkyl), -NH ( _C3-10 cycloalkyl), _-NH ( _C1-4 alkylene- _C3-10 cycloalkyl), -NH (heterocyclic), and -NH ( _C1-10 alkyl). _1-4 -alkylene-heterocyclic groups);

d is selected from 0, 1, 2, 3, and 4;

m is selected from 0, 1, 2, 3, and 4;

n is selected from 0, 1, 2, and 3;

p is an integer selected from 0 to 13;

Each r is independently selected from 1 and 2;

Each t is independently selected from 0, 1, 2, 3, and 4;

Each u is independently selected from 0, 1, 2, 3, and 4.

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

In another aspect, the use of the compounds of the present invention or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof in the preparation of medicaments for treating diseases, symptoms or conditions selected from diseases of abnormal cell proliferation is provided.

Attached Figure Description

Figure 1 shows the effect of compound 007 on tumor volume in a mouse OVCAR3 model.

Figure 2 shows that compound 007 has little effect on the body weight of the mouse OVCAR3 model.

Detailed Implementation

The following specific embodiments illustrate the technical content of the present invention. Those skilled in the art can easily understand other advantages and effects of the present invention through the content disclosed in the specification. The present invention can also be implemented or applied through other different specific embodiments. Those skilled in the art can make various modifications and changes without departing from the spirit of the present invention.

definition

Unless otherwise defined below, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. The term "technique" as used herein refers to techniques commonly understood in the art, including variations and equivalent substitutions that are obvious to one of ordinary skill in the art. While it is believed that the following terms will be readily understood by one of ordinary skill in the art, the following definitions are set forth to better illustrate the invention. When a trade name appears herein, it refers to the corresponding product or its active ingredient. All patents, published patent applications, and publications cited herein are incorporated herein by reference.

The term "Kif18A inhibitor" refers to an inhibitor of Kif18A ATPase activity. Those skilled in the art will understand that this term does not limit the mode of action of the inhibitor. For example, the inhibitor can bind to Kif18A through any suitable site, wherein the site may be selected, for example, from ATP-binding sites, allosteric sites, and combinations thereof. As another example, the inhibitor can act on Kif18A that is not bound to microtubules, and/or can act on the Kif18A-microtubule complex.

When a quantity, concentration, or other numerical value or parameter is described as a range, preferred range, or preferred upper or lower limit, it should be understood as equivalent to specifically disclosing any range formed by combining any upper or preferred value with any lower or preferred value, whether or not the range is explicitly stated. Unless otherwise stated, the numerical ranges listed herein are intended to include the endpoints of the range as well as all integers and fractions (decimals) within the range. For example, the expression " _C1 - _C10 " or " _C1-10 " covers the range of 1 to 10 carbon atoms and should be understood to also cover any subranges within it and each point value, such as _C2-3 , _C2-4 , _C2-5 , _C3-4 , _C3-5 , _C3-6 , _C3-7 , _C1-2 , _C1-3 , _C1-4 , _C1-5 , _C1-6 , _C1-7 , _C1-8 , _{C1-9 , etc.} , as well as _C1 , _C2 , _C3 , _C4 , _C5 , _C6 , _C7 , _C8 , _C9 , _C10 , etc. The expressions "C ₃ - C ₁₀ " or "C _3-10 " should also be understood in a similar way, for example, they can encompass C _3-4 , C _3-5 , C _3-6 , C _3-7 , C _3-8 , C _4-5 , C _4-6 , C ₄ -C ₇ , C ₅ -C _6, etc., as well as C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ , C ₁₀ , etc. The expression "C _6-14 " should also be understood in a similar way, for example, it can encompass C _6-10 , C _6-13 , C _10-13 , etc., as well as C ₆ , C ₁₀ , C ₁₃ , etc. For example, the expression "3-14 yuan" should be understood as encompassing any subrange and each point value, such as 3-4, 3-5, 3-6, 3-7, 3-8, 4-5, 4-6, 4-7, 5-6, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 yuan, etc. The expressions "3-12 yuan,""5-14yuan,""3-7yuan," and "4-8 yuan" should be understood in a similar way. The expression "p is an integer selected from 0 to 13" means that p is any integer from 0 to 13; for example, p can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13. Other similar expressions, such as p1 and p2, should also be understood in a similar way.

When any variable (e.g., ^RX ) appears more than once in the composition or structure of a compound, its definition is independent for each occurrence in each case. For example, the statement "each ^RX is independently selected" means that if there are multiple ^RX , the options for each ^RX substituent are independent of each other in each case. Other variables or expressions such as ^R2 , ^R4 , ^RF , RF1, ^RA1 , ^RA2 , ^RA3 , ^RA4 , ^RA7 , ^RA8 , RA9, ^RA10 , RA11, ^RA12 , ^RB1 , ^RB2 , ^RB3 , ^RB4 , ^RB7 , ^RB8 , ^RB9 , ^RB10 , ^RB11 , ^RB12 , ^RC , ^RD , ^RE1 , ^RE2 , ^RE4 , ^RE7 , RE8, ^RE9 , ^RE10 , ^RE11 , ^RE12 , ^RX , ^{RX1 , RX2} , ^{RX4 , RX5 , RX6 , RX7} , ^RX8 , ^RX9 , ^RX10 , ^{RX11 , RX12 Ra1} , ^Rb1 , ^Rc1 , ^Rd1 , ^Re1 , and ^RY should also be understood in a similar way.

Unless the context clearly specifies otherwise, the singular forms such as “a kind” and “the kind” include the plural forms. The expressions “a kind or more” or “at least one” can mean 1, 2, 3, 4, 5, 6, 7, 8, 9, or more. In one embodiment, “at least one” means 1, 2, 3, or 4.

The terms “optional” or “optional” mean that the events described below may occur but are not guaranteed to occur, and the description includes the possibility that the events or situations described therein may or may not occur.

The terms “substitution” and “substituted” refer to the selective replacement of one or more (e.g., one, two, three, or four) hydrogen atoms on a specified atom by a designated group, provided that the substitution does not exceed the normal valence of the specified atom in the present case and that the substitution forms a stable compound. Combinations of substituents and/or variables are permitted only if such combinations form a stable compound. When describing the absence of a substituent, it should be understood that the substituent can be one or more hydrogen atoms, provided that the structure allows the compound to reach a stable state.

Unless otherwise specified, as used herein, the connection point of a substituent may be any suitable location of the substituent. When the bond of a substituent is such that it is a bond that passes through the ring and connects two atoms, such a substituent may be bonded to either cyclic atom in the substituted ring.

The expressions “comprising,” “including,” “containing,” and “having” are open-ended and do not exclude additional unlisted elements, steps, or components. The expression “consisting of…” does not include any unspecified elements, steps, or components. The expression “substantially consisting of…” means that the scope is limited to the specified elements, steps, or components, as well as optional elements, steps, or components that do not materially affect the essential and novel features of the claimed subject matter. It should be understood that the expression “comprising” includes both the expressions “substantially consisting of…” and “consisting of…”.

The terms “halogen” or “halogenated” should be understood to refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) atoms, preferably fluorine, chlorine or bromine atoms.

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

The term "alkyl" refers to a saturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms, connected to the rest of the molecule by a single bond. Alkyl groups include straight-chain alkyl groups and branched-chain alkyl groups. Alkyl groups can contain 1-10 carbon atoms and are called _C1-10 alkyl groups, such as _C1-6 alkyl, _C1-4 alkyl, _C1-3 alkyl, _C1-2 alkyl, _C3 alkyl, _C4 alkyl, and _C3-6 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, etc. Non-limiting examples of branched alkyl groups include, but are not limited to, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl.

A divalent group is a group obtained by removing a hydrogen atom from an atom with free valence electrons in a corresponding monovalent group. A divalent group has two connection sites that attach to the rest of the molecule, and these two connection sites can be located on the same atom or two different atoms of the divalent group.

"alkylene" or "alkylidene" refers to a saturated divalent hydrocarbon group. Alkylenes include straight-chain or branched alkylenes. Examples of straight-chain alkylenes include, but are not limited to, methylene ( _-CH₂- ), -( _CH₂ ) _₂- , -( _CH₂ ) _₃- , -( _CH₂ ) _₄- , -( _CH₂ ) _₅- , -( _CH₂ ) _₆- , etc. Examples of branched 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 )- _, and -CH _{( C2H5 )} -( _CH2 ) _{2- .} -, -CH ₂ -CH(C ₂ H ₅ )-CH ₂ -, -C(CH ₃ ) ₂ -(CH ₂ ) ₂ -, -CH ₂ -C(CH ₃ ) ₂ -CH ₂ -, -CH(CH ₃ )-(CH ₂ ) ₃ -, -CH ₂ -CH(CH ₃ )-(CH ₂ ) ₂ -, -CH(C ₅ H ₁₁ )-, -C(C ₂ H ₅ )(C ₃ H ₇ )-, -C(CH ₃ )(C ₄ H ₉ )-, -CH(C ₄ H ₉ )-CH ₂ -, -C(C ₂ H ₅ ) ₂ -CH ₂ -, -C(CH ₃ )(C ₃ H ₇ )-CH ₂ -, -CH(C ₂ H ₅ )-CH(C ₂ H ₅ )-, -CH(CH ₃ )-CH(C ₃ H ₇ )-, -C(CH ₃ ) ₂ -C(CH ₃ ) ₂ -, -CH(C ₃ H ₇ )-(CH ₂ ) ₂ -, -CH ₂ -CH(C ₃ H ₇ )-CH ₂ -, -CH(C ₂ H ₅ )-C(CH ₃ ) ₂ -, -C(CH ₃ ) ₂ -CH(CH ₃ )-CH ₂ -, -CH(CH ₃ )-C(CH ₃ ) ₂ -CH ₂ -, -CH(C ₂ H ₅ )-CH(CH ₃ )-CH ₂ -, -CH(CH ₃ )-CH(C ₂ H ₅ )-CH ₂ -, -CH(CH ₃ )-CH ₂ -CH(C ₂ H ₅ )-, -CH(CH ₃ )-C(CH ₃ ) ₂ -CH ₂ -, -(CH(CH ₃ )) ₃ -, -C(CH ₃ ) ₂ -(CH ₂ ) ₃ -, -CH(C ₂ H ₅ )-(CH ₂ ) ₃ -, -CH ₂ -CH(C ₂ H ₅ )-(CH ₂ ) ₂ -, -CH ₂ -CH(CH ₃ )-CH(CH ₃ )-CH ₂ -, -(CH(CH ₃ )) ₂ -(CH ₂ ) ₂ -, -CH(CH ₃ )-(CH ₂ ) ₂ -CH(CH ₃ )-, -(CH ₂ ) ₂ -CH(CH ₃ )-(CH ₂ ) ₂ -, -CH ₂ -CH(CH ₃ )-(CH ₂ ) ₃ -, -CH(CH ₃ )-(CH ₂ ) ₄ -, etc.

The term "alkenyl" refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms, having at least one double bond. Alkenyl groups can have 2-8 carbon atoms, i.e., "C _2-8 alkenyl," such as C _2-4 alkenyl and C _3-4 alkenyl. Non-limiting examples of alkenyl groups include, but are not limited to, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, etc.

The term "alkynyl" refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms, having at least one triple bond. Alynyl groups can have 2-8 carbon atoms, i.e., "C _2-8 alkynyl," such as C _2-4 alkynyl and C _3-4 alkynyl. Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl, propynyl-1-alkynyl, propynyl-2-alkynyl, butynyl-1-alkynyl, butynyl-2-alkynyl, butynyl-3-alkynyl, etc.

The term "cyclic hydrocarbon group" refers to a saturated or unsaturated non-aromatic cyclic hydrocarbon group consisting of carbon and hydrogen atoms, preferably containing one or two rings. The cyclic hydrocarbon group can be monocyclic, fused polycyclic, bridged, or spirocyclic. The cyclic hydrocarbon group can have 3-10 carbon atoms, i.e., "C _3-10 cyclic hydrocarbon group," such as C _3-8 , C ₅ , C ₆ , and C ₇ cyclic hydrocarbon groups. Non-limiting examples of cyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclic [2.2.1]heptyl, and spiro[3.3]heptyl. In some embodiments, the C atoms in the cyclic hydrocarbon group are optionally substituted with oxo groups. In some embodiments, the C atoms in the cyclic hydrocarbon group are optionally substituted with imino groups. In some embodiments, the imino group is unsubstituted (=NH) or substituted with groups described in the context. In some embodiments, the imino group is substituted with -OR, where R is H or a C _1-10 alkyl group.

The terms “cycloalkyl” and “cycloalkyl” have the same meaning herein and are used interchangeably. A cycloalkyl group refers to a saturated cyclic hydrocarbon group. A cycloalkyl group may have 3, 4, 5, 6, 7, 8, 9, or 10 cyclic carbon atoms (C _3-10 ). Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, and bicyclo[2.1.1]hexyl.

The term "heterocyclic group" or "heterocyclic hydrocarbon group" refers to a monocyclic or bicyclic cyclic system (3-14-membered, 7-14-membered, 3-8-membered, 3-7-membered, 4-6-membered, 5-6-membered) having, for example, 3-14 (e.g., 7-14, 3-8, 3-7, 4-6-membered, or 5-6-membered) ring atoms, wherein at least one ring atom (e.g., 1, 2, or 3) is a heteroatom selected from oxygen, sulfur, nitrogen, and phosphorus, and the remaining ring atoms are carbon atoms. The cyclic system can be saturated (also understood as the corresponding "heterocyclic alkyl") or unsaturated (i.e., having one or more double and/or triple bonds within the ring). Optionally, the heterocyclic group can be benzofused. The "heterocyclic group" or "heterocyclic hydrocarbon group" is not aromatic. In some embodiments, the C, N, S, and P atoms in the heterocycle are optionally substituted with oxygen. In some embodiments, the C, S, and P atoms in the heterocycle are optionally substituted with imino groups. In some embodiments, the imino group is unsubstituted (=NH) or substituted with a group described in the context. In some embodiments, the imino group is substituted with -OR, where R is H or a _C1-10 alkyl group.

The heterocyclic group can be, for example, a four-membered ring, such as azahexacyclobutane or oxacyclobutane; or a five-membered ring, such as tetrahydrofuranyl, dioxolinyl, pyrrolyl, imidazoalkyl, pyrazolyl, pyrrolinyl, oxopyrrolyl, or 2-oxoimidazolidin-1-yl; or a six-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithiaalkyl, thiomorpholinyl, piperazine, 1,1-dioxo-1,2-thiazin-2-yl, or trithiaalkyl; or a seven-membered ring, such as diazacyclobutane. Base ring.

Heterocyclic groups can be bicyclic, without limitation, such as five-membered fused five-membered rings, like octahydrocyclopentane[c]pyrrolithyl; or five-membered fused six-membered bicyclic rings, like octahydropyrrolo[1,2-b]pyrazinyl.

As mentioned above, heterocycles can be unsaturated, meaning they can contain one or more double bonds without limitation. For example, unsaturated heterocycles containing nitrogen atoms can be 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-pyrroleyl, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl, or 4H-[1,4]thiazinyl rings. Unsaturated heterocycles containing oxygen atoms can be 2H-pyran, 4H-pyran, or 2,3-dihydrofuran. Unsaturated heterocycles containing sulfur atoms can be 2H-thiaran or 4H-thiaran. Heterocycles can be benzofused without limitation, such as dihydroisoquinoline rings.

Exemplary bicyclic heterocyclic rings also include:

The term "aryl" refers to an aromatic ring group consisting of an all-carbon monocyclic or fused polycyclic (e.g., bicyclic) ring with a conjugated π-electron system. For example, an aryl group can have 6-14 carbon atoms, suitably 6-10, and more preferably 6 or 10. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracene.

The term "heteroaryl" should be understood to preferably refer to a monovalent monocyclic, bicyclic, or tricyclic aromatic ring system having 5, 6, 7, 8, 9, or 10 ring atoms ("5-10 heteroaryl"), particularly 5, 6, 9, or 10 ring atoms, and the ring atoms contain at least one (suitably 1-4, more preferably 1, 2, or 3) heteroatoms that may be the same or different, said heteroatoms being, for example, oxygen, nitrogen, or sulfur. Furthermore, in each case, the heteroaryl group may be benzofused. Specifically, the heteroaryl group is selected from thienyl, furanyl, pyrroleyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, etc., and their benzo[derivatives], such as benzofuranyl, benzothienyl, benzooxazolyl, benzoisooxazolyl, benzoimidazolyl, benzotriazolyl, indazole, indolyl, isindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and their benzo[derivatives], such as quinolinyl, quinazolinyl, isoquinolinyl, etc.; or azocinyl, inazinyl, purinyl, etc., and their benzo[derivatives]; or cyclolinyl, phthalazinyl, quinazolinyl, quinoxolinyl, naphridinyl, carbazole, acridinyl, etc.

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

The compounds of this invention encompass pharmaceutically acceptable salts, stereoisomers, solvates, polymorphs, tautomers, isotopic compounds, metabolites, or prodrugs.

The compounds of this invention can exist in specific geometric or stereoisomeric forms. All such compounds are contemplated. For example, the compounds of this invention may contain E or Z configurations of carbon-carbon or carbon-nitrogen double bonds, where “E” indicates that, according to the Cahn-Ingold-Prelog preference rule, the preferred substituent is on the opposite side of the carbon-carbon or carbon-nitrogen double bond, and “Z” indicates that the preferred substituent is on the same side of the carbon-carbon or carbon-nitrogen double bond. The compounds of this invention may also exist as mixtures of “E” and “Z” isomers. Isomeric forms also include cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this invention. Purification and separation of such substances can be achieved using standard techniques known in the art.

Optically pure enantiomers can be obtained by resolving racemic mixtures using conventional methods, such as by forming diastereomer salts using optically active acids or bases, or by forming covalent diastereomers. Mixtures of diastereomers can be separated into individual diastereomers based on their physical and/or chemical differences using methods known in the art (e.g., by chromatography or fractional crystallization). An optically active enantiomer base or acid is then released from the separated diastereomer salt. Another method for separating racemic enantiomers uses chiral chromatography (e.g., chiral HPLC columns), where the separated chiral isomers may be conventionally derivatized or not 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 underivatized chiral isomers. Similarly, optically pure compounds of the present invention can be obtained via chiral synthesis using optically active starting materials.

The compounds of the present invention can exist in the form of solvates (preferably hydrates), wherein the compounds of the present invention contain a solvent, particularly, for example, water, methanol, or ethanol, as a structural element of the lattice of the compound. The amount of polar solvent, particularly water, can be present in stoichiometric or non-stoichiometric proportions.

This invention also covers all possible crystalline forms or polymorphs of the compounds of this invention, which may be a single polymorph or a mixture of more than one polymorph in any proportion.

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

The scope of this invention also includes metabolites of the compounds of this invention, i.e., substances formed in the body when the compounds of this invention are administered. Such products can be generated, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc., of the administered compounds.

The present invention further includes, within its scope, prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention that may have little or no pharmacological activity themselves, which, when administered to or onto the body, can be converted, for example, by hydrolysis and cleavage into the compounds of the present invention having the desired activity.

The term “polymorph” or “polymorphic material” refers to a single polymorph or a mixture of more than one polymorph in any proportion.

The term "crystal form" or "crystal" refers to any solid substance that exhibits a three-dimensional arrangement, as opposed to amorphous solid substances, and produces characteristic X-ray powder diffraction patterns with clearly defined peaks.

The term "amorphous" refers to any solid substance that is not ordered in three dimensions.

The term "pharmaceutically acceptable" means that, within the normal range of medical judgment, contact with a patient's tissues will not cause inappropriate toxicity, irritation, allergic reactions, etc.

The term "pharmaceutically acceptable carrier" refers to substances that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. "Pharmaceutically acceptable carriers" include, but are not limited to, glidants, sweeteners, diluents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersants, disintegrants, stabilizers, solvents, or emulsifiers.

The terms “active ingredient,” “therapeutic agent,” “active substance,” or “active agent” refer to a chemical entity that can effectively treat or prevent a target disorder, disease, or symptom.

For the purposes of pharmaceuticals, pharmaceutical units, or active ingredients, the terms "effective amount," "therapeutic effective amount," or "preventive effective amount" refer to a sufficient quantity of a drug or agent that provides acceptable side effects while achieving the desired therapeutic effect. The determination of the effective amount varies from person to person, depending on the individual's age and general condition, as well as the specific active substance. The appropriate effective amount in a given case can be determined by a person skilled in the art based on routine testing.

The term "individual" includes humans or non-human animals. Exemplary human individuals include individuals suffering from a disease (such as the disease described herein) (referred to as patients) or normal individuals. In this invention, "non-human animals" includes all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock, and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

Compound of formula (I)

In one aspect, the present invention provides compounds having the structure of formula (I):

Or its pharmaceutically acceptable salt.

in,

Ring B is selected from 5-membered heterocyclic aromatic rings;

Q is selected from M is selected from N and CH; U and V are each independently selected from O, S, L is selected from chemical bonds, -O-, -S-, -NR ^6- , and _C1-2 alkylene groups; wherein each These represent the connection sites;

^A1 is selected from N and C(R ⁷ );

^A2 is selected from N and C(R ⁸ );

^A3 is selected from N and C( ^R9 );

L ¹ is selected from -(CR ^C R ^D ) _t -S(=O) _r -, -(CR ^C R ^D ) _t -NR ^F S(=O) _r -, and -(CR ^C R ^D ) _t -S(=O) _r NR ^F -;

^L2 is selected from _C1-6 alkylene groups;

^X1 is selected from N and C (R ¹⁰ );

^X2 is selected from N and C(R ¹¹ );

^X3 is selected from N and C(R ¹² );

^R1 is selected from _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, _C3-10 cycloalkyl, _-C1-4 alkylene- _C3-10 cycloalkyl, heterocyclic, -C1-4 alkylene-heterocyclic, aryl, _-C1-4 alkylene-aryl, heteroaryl, _-C1-4 alkylene- _heteroaryl , -NR ^A1 R ^B1 , -OR A1, -SR A1, -C(=O)R ^A1 , -C(=NR ^E1 )R ^A1 , -C(=N-OR ^B1 )R ^A1 , -C(=O)OR ^A1 , -OC(=O)R ^A1 , -C(=O)NR ^A1 R ^B1 , -NR ^F1 C ⁽ =O)R ^A1 , -C(=NR ^E1 )NR ^{A1 R B1 ,} -NR ^F1 C(=NR ^E1) )R ^A1 , -OC(=O)NR ^A1 R ^B1 , -NR ^F1 C(=O)OR ^A1 , -NR ^F1 C(=O)NR ^A1 R ^B1 , -NR ^F1 C(=S)NR ^A1 R ^B1 , -NR ^F1 C(=NR ^E1 )NR ^A1 R ^B1 , -S(=O) _r R ^A1 , -S(=O)(=NR ^E1 )R ^A1 , -N＝S(＝O)R ^A1 R ^B1 , -S(＝O) ₂ OR ^A1 , -OS(＝O) ₂ R ^A1 , -NR ^F1 S(＝O) _r R ^A1 , -NR ^F1 S(＝O)(＝NR ^E1 )R ^A1 , -S(＝O) _r NR ^A1 R ^B1 , -S(＝O)(＝NR ^E1 )NR ^A1 R ^B1 , -NR ^F1 S(=O) ₂ NR ^{A1 RB1} and -NR ^F1 S(＝O)(＝NR ^E1 )NR ^{A1 RB1} , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl group is unsubstituted or substituted by at least one substituent independently selected from ^RX1 ;

Each ^R2 is independently selected from halogens, _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, _C3-10 cycloalkyl, _-C1-4 alkylene- _C3-10 cycloalkyl, heterocyclic, -C1-4 alkylene-heterocyclic, aryl, _-C1-4 alkylene-aryl, _heteroaryl , _-C1-4 alkylene-heteroaryl, CN, _NO2 , ^-NRA2RB2 , ^-ORA2 , -SRA2, -C(=O) ^RA2 , -C( ₌ O) ^ORA2 , ^-OC (=O) ^RA2 , -C(=O) ^NRA2RB2 , ^-NRA2C (=O) ^RB2 , -NRA2C(= ^NRE2 ) ^RB2 , ^-OC (= ^{O)NRA2RB2 , -NRA2C (} =O ^{) ORB2} , -NR ^A2 C(=O)NR ^A2 R ^B2 , -NR ^A2 C(=S)NR ^A2 R ^B2 , -NR ^A2 C(=NR ^E2 )NR ^A2 R ^B2 , -S(=O) _r R ^A2 , -S(=O)(=NR ^E2 )R ^B2 , -N=S(=O)R ^A2 R ^B2 , -S(=O) ₂ OR ^A2 , -OS(=O) ₂ R ^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) ₂ NR ^A2 R ^B2 and -NR ^A2 S(=O)(=NR ^E2 )NR ^A2 R ^B2 Each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is either unsubstituted or substituted by at least one substituent independently selected from ^RX2 ;

^R3 is selected from hydrogen, halogens, CN, _NO2 , -NR ^A3RB3 , -OR ^A3 , ^{-SR A3 ,} -C(=O) ^RA3 , -C(=O)OR ^A3 , -OC(=O) ^RA3 , -C(=O) ^{NR A3RB3} and -NR ^A3C (=O) ^RB3 ;

Each ^R4 is independently selected from halogens, _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, _C3-10 cycloalkyl, -C1-4 alkylene- _C3-10 cycloalkyl, _heterocyclic , -C1-4 alkylene-heterocyclic, CN, _NO2 , -NR _A4 ^RB4 , -OR ^A4 , -SR ^A4 , -C(=O)R ^A4 , -C(=O)OR ^A4 , ^-OC (=O)R ^A4 , -C(=O)NR ^{A4 RB4} , -NR ^A4 C(=O) ^RB4 , -NR ^A4 C(=NR ^E4 ) ^RB4 , -OC(=O)NR ^{A4 RB4} , -NR ^A4 C(=O)OR ^B4 , -NR ^A4 C(=O)NR ^{A4 RB4} , -NR ^A4 C(=S) ^{NR A4 RB4} -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) ₂ OR ^A4 , -OS(＝O) ₂ R ^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) ₂ NR ^A4 R ^B4 and -NR ^A4 S(＝O)(＝NR ^E4 )NR ^A4 R ^B4 , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl and heterocyclic group is unsubstituted or substituted by at least one substituent independently selected from ^RX4 ;

Or any two R ^4s together with the carbon atoms attached to them form a saturated or unsaturated 3-7 membered ring containing 0, 1, 2 or 3 heteroatoms, wherein the heteroatoms are independently selected from oxygen, sulfur, nitrogen and phosphorus, and the ring is either unsubstituted or substituted by 1, 2 or 3 R ^X4 substituents.

^R4a and ^R4b are each independently selected from hydrogen and ^R4 ;

Or R ^4a and R ^4b together with the carbon atoms attached to them form a saturated or unsaturated 3-7 membered ring containing 0, 1, 2 or 3 heteroatoms, wherein the heteroatoms are independently selected from oxygen, sulfur, nitrogen and phosphorus, and the ring is either unsubstituted or substituted by 1, 2 or 3 R ^X4 substituents.

R ^5a and R ^5b are each independently selected from hydrogen, halogen, _C1-10 alkyl and _C3-10 cycloalkyl, wherein the alkyl and cycloalkyl are unsubstituted or substituted by at least one substituent independently selected from R ^X5 ;

Or R ^5a and R ^5b together with the carbon atoms attached to them form a saturated or unsaturated 3-7 membered ring containing 0, 1, 2 or 3 heteroatoms, wherein the heteroatoms are independently selected from oxygen, sulfur, nitrogen and phosphorus, and the ring is either unsubstituted or substituted by 1, 2 or 3 R ^X5 substituents.

^R6 is selected from hydrogen and _C1-10 alkyl groups, wherein the alkyl group is unsubstituted or substituted by at least one substituent selected independently from R ^X6 ;

R ⁷ is selected from halogens, _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, _C3-10 cycloalkyl, _-C1-4 alkylene- _C3-10 cycloalkyl, heterocyclic, -C1-4 alkylene-heterocyclic, aryl, _-C1-4 alkylene-aryl, heteroaryl, _-C1-4 alkylene-heteroaryl, CN, NO ₂ , -NR ^A7 _RB7 , -OR A7, -SR ^A7 , -C(=O)R ^A7 , ^-C (=O)OR A7, -OC(=O)R ^A7 , -C(=O)NR ^{A7 RB7} , -NR ^A7 C(=O)R ^B7 , -NR ^A7 C(=NR ^E7 )R ^B7 , -OC(=O)NR ^{A7 RB7} , -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) ₂ OR ^A7 , -OS(=O) ₂ R ^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) ₂ NR ^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 either unsubstituted or substituted by at least one substituent independently selected from ^RX7 .

^R8 is selected from halogens, _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, _C3-10 cycloalkyl, _-C1-4 alkylene- _C3-10 cycloalkyl, heterocyclic, -C1-4 alkylene-heterocyclic, aryl, _-C1-4 alkylene-aryl, heteroaryl, _-C1-4 alkylene-heteroaryl, CN, NO2, -NR ^A8 _RB8 , -OR _A8 , -SR ^A8 , -C(=O)R ^A8 , ^-C (=O)OR A8, -OC(=O)R ^A8 , -C(=O)NR ^{A8 RB8} , -NR ^A8 C(=O) ^{R B8 ,} -NR ^A8 C(=NR ^E8 )R ^B8 , -OC(=O)NR ^{A8 RB8} , -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) ₂ OR ^A8 , -OS(=O) ₂ R ^A8 , -NR ^A8 S(=O) _r ^RB8 , -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) ₂ NR ^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 either unsubstituted or substituted by at least one substituent independently selected from ^RX8 .

Alternatively, ^R7 and ^R8, together with the atoms attached to them, form a _C5-10 hydrocarbon ring or a 5-10 membered heterocycle or a 5-10 membered heteroaromatic ring containing 1, 2, or 3 heteroatoms, wherein the hydrocarbon ring, heterocycle, and heteroaromatic ring are monocyclic or bicyclic, the heteroatoms in the heterocycle are independently selected from oxygen, sulfur, nitrogen, and phosphorus, and the heteroatoms in the heteroaromatic ring are independently selected from oxygen, sulfur, and nitrogen; the ring is unsubstituted or substituted by at least one substituent independently selected from R ^X8 ;

R ⁹ is selected from halogens, _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, _C3-10 cycloalkyl, _-C1-4 alkylene- _C3-10 cycloalkyl, heterocyclic, -C1-4 alkylene-heterocyclic, aryl, _-C1-4 alkylene-aryl, heteroaryl, _-C1-4 alkylene-heteroaryl, CN, NO ₂ , -NR ^A9 _RB9 , -OR A9, -SR ^A9 , -C(= ^O )R A9, ^-C (=O)OR A9, -OC(=O)R ^A9 , -C(=O)NR ^{A9 RB9} , -NR ^A9 C(=O)R ^B9 , -NR ^A9 C(=NR ^E9 )R ^B9 , -OC(=O)NR ^{A9 RB9} , -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) ₂ OR ^A9 , -OS(=O) ₂ R ^A9 , -NR ^A9 S(=O) _r ^RB9 , -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) ₂ NR ^A9 R ^B9 and -NR ^A9 S(=O)(=NR ^E9 )NR ^A9 R ^B9 Each alkyl, alkylene, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is either unsubstituted or substituted by at least one substituent independently selected from ^RX9 ;

^R10 is selected from halogens, _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, _C3-10 cycloalkyl, _-C1-4 alkylene- _C3-10 cycloalkyl, heterocyclic, -C1-4 alkylene-heterocyclic, aryl, _-C1-4 alkylene-aryl, heteroaryl, _-C1-4 alkylene-heteroaryl, CN, _NO2 , -NR ^A10 _RB10 , -OR A10, -SR ^A10 , -C(=O)R ^A10 , -C(=O)OR ^A10 , -OC(=O)R ^A10 , -C(=O)NR ^{A10 RB10} , -NR ^A10 C( ^{=O)RB10, -NR A10 C(=NR E10)RB10 , -OC ( = O} )NR ^{A10 RB10} , -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) ₂ OR ^A10 , -OS(＝O) ₂ R ^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) ₂ NR ^{A10 RB10} and -NR ^A10 S(＝O)(＝NR ^E10 )NR ^{A10 RB10} , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl group is unsubstituted or substituted by at least one substituent independently selected from ^RX10 ;

R ¹¹ is selected from halogens, _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, _C3-10 cycloalkyl, _-C1-4 alkylene- _C3-10 cycloalkyl, heterocyclic, -C1-4 alkylene-heterocyclic, aryl, _-C1-4 alkylene-aryl, heteroaryl, _-C1-4 alkylene-heteroaryl, CN, NO ₂ , -NR ^A11 _RB11 , -OR ^A11 , -SR ^A11 , -C(=O)R ^A11 , -C(=O)OR ^{A11, -OC(=O)R A11 ,} -C(=O)NR ^{A11 RB11} , -NR ^{A11 C} (=O) ^RB11 , -NR ^A11 C(=NR ^E11 ) ^RB11 , -OC(=O)NR ^{A11 RB11} ,-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) ₂ OR ^A11 , -OS(＝O) ₂ R ^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) ₂ NR ^A11 R ^B11 and -NR ^A11 S(＝O)(＝NR ^E11 )NR ^A11 R ^B11 , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl group is unsubstituted or substituted by at least one substituent independently selected from ^RX11 ;

Alternatively, ^R10 and ^R11, together with the atoms attached to them, form a _C5-10 hydrocarbon ring or a 5-10 membered heterocycle or a 5-10 membered heteroaromatic ring containing 1, 2 or 3 heteroatoms, wherein the hydrocarbon ring, heterocycle and heteroaromatic ring are monocyclic or bicyclic, the heteroatoms in the heterocycle are independently selected from oxygen, sulfur, nitrogen and phosphorus, and the heteroatoms in the heteroaromatic ring are independently selected from oxygen, sulfur and nitrogen; the ring is unsubstituted or substituted by at least one substituent independently selected from R ^X11 ;

^R12 is selected from halogens, _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, _C3-10 cycloalkyl, _-C1-4 alkylene- _C3-10 cycloalkyl, heterocyclic, -C1-4 alkylene-heterocyclic, aryl, _-C1-4 alkylene-aryl, heteroaryl, _-C1-4 alkylene-heteroaryl, CN, NO2, -NR ^A12 _RB12 , -OR _A12 , -SR ^A12 , -C(=O) ^RA12 , ^-C (=O)OR ^A12 , -OC(=O)RA12, -C(=O)NR ^{A12 RB12} , -NR ^A12 C(=O ^{)RB12 ,} -NR ^A12 C(=NR ^E12 ) ^RB12 , -OC(= ^O )NR ^{A12 RB12} , -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) ₂ OR ^A12 , -OS(＝O) ₂ R ^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, heterocyclic, aryl and heteroaryl group is unsubstituted or substituted by at least one substituent independently selected from ^RX12 ;

Each ^RF , ^RF1 , RA1, ^RA2 , ^RA3 , ^RA4 , RA7, ^RA8 , ^RA9 , ^RA10 , ^RA11 , ^RA12 , ^RB1 , ^RB2 , ^RB3 , ^RB4 , RB7, ^RB8 , ^RB9 , ^RB10 , ^RB11 , ^{and RB12 is} independently selected from hydrogen, _C1-10 alkyl, ^C2-10 _alkenyl , ^C2-10 alkynyl, _C3-10 cycloalkyl, _-C1-4 alkylene- _C3-10 cycloalkyl, heterocyclic, _-C1-4 alkylene-heterocyclic, _aryl , _-C1-4 alkylene-aryl, heteroaryl _, and -C _1-4 alkylene-heteroaryl, wherein each alkyl, alkylene, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl and heteroaryl group is unsubstituted or substituted by at least one substituent independently selected from R ^X ;

Or “ ^RA1 and ^RB1 ” or “ ^RA2 and ^RB2 ” or “ ^RA3 and ^RB3 ” or “RA4 and RB4” or “ ^RA7 and ^RB7 ” or “ ^RA8 and ^RB8 ” or “ ^RA9 and ^RB9 ” or “ ^RA10 and ^RB10 ” or “ ^RA11 and ^RB11 ” or “ ^RA12 and ^RB12 ” together with one or more atoms attached to them constitute a 4-12 membered heterocycle containing 0, 1 or 2 additional independent heteroatoms selected from oxygen, sulfur, nitrogen and phosphorus, which is either unsubstituted or substituted ^with 1, 2 or 3 substituents selected ^{from RX} ;

Each ^RC and ^RD is independently selected from hydrogen, halogen, _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, _C3-10 cycloalkyl, _-C1-4 alkylene- _C3-10 cycloalkyl, heterocyclic, -C1-4 alkylene-heterocyclic, aryl, _-C1-4 alkylene-aryl, _heteroaryl and _-C1-4 alkylene-heteroaryl, wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl is unsubstituted or substituted by at least one substituent independently selected from ^RX ;

Alternatively, each “ ^RC and ^RD ” together with one or more carbon atoms attached to them forms a 3-12 membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, which is either unsubstituted or substituted with 1, 2 or 3 substituents independently selected from ^RX .

Each ^RE1 , ^RE2 , ^RE4 , ^RE7 , ^RE8 , ^RE9 , ^RE10 , ^RE11 and ^RE12 is independently selected from hydrogen, _C1-10 alkyl, CN, _NO2 , -S(=O) _rRa1 , -C(=O) ^Ra1 , -C(=O) ^ORa1 , ^{-C (} =O) ^NRa1Rb1 and -S(=O) ^rNRa1Rb1 , wherein the alkyl group is unsubstituted or substituted _by at least one substituent independently selected from ^{RX ;}

Each ^RX , ^RX1 , ^RX2 , RX4, ^RX5 , ^RX6 , ^RX7 , ^RX8 , ^RX9 , ^RX10 , ^RX11 , ^{and RX12 is} independently selected from halogens, _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, _C3-10 cycloalkyl, _-C1-4 alkylene- _C3-10 cycloalkyl, heterocyclic, _{-C1-4 alkylene-heterocyclic, aryl, -C1-4 alkylene} -aryl, heteroaryl, _-C1-4 alkylene-heteroaryl, CN, _NO2 , -( ^CRc1Rd1 ) ^uNRa1Rb1 , _- ( ^CRc1Rd1 ) ^{uORb1 ,} _- ( ^CRc1Rd1 ) _uC ( _＝ ^O ) ^Ra1 , - ^{( CRc1Rd1 ) u} C(＝NR ^e1 )R ^a1 , -(CR ^c1 R ^d1 ) _u C(＝O)OR ^b1 , -(CR ^c1 R ^d1 ) _u OC(＝O)R ^b1 , -(CR ^c1 R ^d1 ) _u C(＝O)NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _u NR ^a1 C(＝O)R ^b1 , -(CR ^c1 R ^d1 ) _u C(＝NR ^e1 )NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _u NR ^a1 C(＝NR ^e1 )R ^b1 , -(CR ^c1 R ^d1 ) _u OC(＝O)NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _u NR ^a1 C(＝O)OR ^b1 , -(CR ^c1 R ^d1 ) _u NR ^a1 C(＝O)NR ^a1 R ^b1 ,-(CR ^c1 R ^d1 ) _u NR ^a1 C(＝S)NR ^a1 R ^b1 ,-(CR ^c1 R ^d1 ) _u NR ^a1 C(＝NR ^e1 )NR ^a1 R ^b1 ,-(CR ^c1 R ^d1 ) _u S(＝O) _r R ^b1 ,-(CR ^c1 R ^d1 ) _u S(＝O)(＝NR ^e1 )R ^b1 ,-(CR ^c1 R ^d1 ) _u N＝S(＝O)R ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _u S(＝O) ₂ OR ^b1 , -(CR ^c1 R ^d1 ) _u OS(＝O) ₂ R ^b1 , -(CR ^c1 R ^d1 ) _u NR ^a1 S(＝O) _r R ^b1 , -(CR ^c1 R ^d1 ) _u NR ^a1 S(＝O)(＝NR ^e1 )R ^b1 、-(CR ^c1 R ^d1 ) _u S(＝O) _r NR ^a1 R ^b1 、-(CR ^c1 R ^d1 ) _u S(＝O)(＝NR ^e1 )NR ^a1 R ^b1 、-(CR ^c1 R ^d1 ) _u NR ^a1 S(＝O) ₂ NR ^a1 R ^b1 and -(CR ^c1 R ^d1 ) _u NR ^a1 S(＝O)(＝NR ^e1 )NR ^a1 R ^b1 , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl group is unsubstituted or substituted by at least one substituent independently selected from R ^Y ;

Each ^Ra1 and ^Rb1 is independently selected from hydrogen, _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, _C3-10 cycloalkyl, _-C1-4 alkylene- _C3-10 cycloalkyl, heterocyclic, -C1-4 alkylene-heterocyclic, aryl, _-C1-4 alkylene-aryl, heteroaryl and _-C1-4 alkylene-heteroaryl, wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, _aryl and heteroaryl is unsubstituted or substituted by at least one substituent independently selected from R ^Y ;

Or ^Ra1 and ^Rb1 together with one or more atoms attached to them form a 4-12 membered heterocycle containing 0, 1 or 2 additional independent heteroatoms selected from oxygen, sulfur, nitrogen and phosphorus, which is either unsubstituted or substituted with 1, 2 or 3 substituents selected from R ^Y.

Each ^Rc1 and ^Rd1 is independently selected from hydrogen, halogen, _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, C3-10 cycloalkyl, _-C1-4 alkylene- _C3-10 cycloalkyl, heterocyclic, _-C1-4 alkylene-heterocyclic, aryl, _-C1-4 alkylene-aryl, _heteroaryl and _-C1-4 alkylene-heteroaryl, wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl is unsubstituted or substituted by at least one substituent independently selected from R ^Y ;

Alternatively, each ^Rc1 and ^Rd1 together with one or more carbon atoms attached to them can form a 3-12 membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, which is either unsubstituted or substituted with 1, 2 or 3 substituents independently selected from R and ^Y.

Each ^Re1 is independently selected from hydrogen, _C1-10 alkyl, CN, _NO2 , -S(=O) _rRa1 ^, -C ⁽ =O) ^Ra1 , -C(=O) ^ORa1 , -C(=O) ^NRa1Rb1 and _-S (=O) ^rNRa1Rb1 , wherein the alkyl group is unsubstituted or substituted ^by at least one substituent independently selected from ^RY ;

Each R ^Y is independently selected from halogen, _NO₂ , -CN, _C1-10 alkyl, -OH, -O ( _C1-10 alkyl), -O ( _C3-10 cycloalkyl), -O ( _C1-4 alkylene- _C3-10 cycloalkyl), -O (heterocyclic), -O ( _C1-4 alkylene-heterocyclic), -SH, -S ( _C1-10 alkyl), -S ( _C3-10 cycloalkyl), -S ( _C1-4 alkylene- _C3-10 cycloalkyl), -S (heterocyclic), -S ( _C1-4 alkylene-heterocyclic), _-NH₂ , -NH (C1-10 alkyl), -N ( _C1-10 alkyl), -NH ( _C3-10 cycloalkyl), _-NH ( _C1-4 alkylene- _C3-10 cycloalkyl), -NH (heterocyclic), and -NH ( _C1-10 alkyl). _1-4 -alkylene-heterocyclic groups);

d is selected from 0, 1, 2, 3, and 4;

m is selected from 0, 1, 2, 3, and 4;

n is selected from 0, 1, 2, and 3;

p is an integer selected from 0 to 13;

Each r is independently selected from 1 and 2;

Each t is independently selected from 0, 1, 2, 3, and 4;

Each u is independently selected from 0, 1, 2, 3, and 4.

In one embodiment, u is 0. In one embodiment, d is 0. In one embodiment, d is 1.

In one embodiment, each ^RA1 , ^RA2 , RA3, ^RA4 , ^RA7 , RA8, ^RA9 , ^RA10 , ^RA11 , ^RA12 , ^RB1 , ^RB2 , ^RB3 , RB4, ^RB7 , ^RB8 , ^RB9 , ^RB10 , ^{RB11 and RB12 is} independently selected from hydrogen and _C1-10 alkyl groups, wherein each alkyl group is unsubstituted or substituted ^with at least one substituent independently selected ^{from RX} .

In one embodiment, each ^RE1 , ^RE2 , ^RE4 , ^RE7 , ^RE8 , ^RE9 , ^RE10 , ^RE11 and ^RE12 is independently selected from hydrogen and _C1-10 alkyl groups, wherein the alkyl group is unsubstituted or substituted by at least one substituent independently selected from ^RX .

In one embodiment, each ^RX , ^RX1 , ^RX2 , ^RX4 , ^RX5 , ^RX6 , ^RX7 , ^RX8 , ^RX9 , ^RX10 , ^RX11 , and ^RX12 is independently selected from halogens, _C1-10 alkyl groups, _C3-10 cycloalkyl groups, _-C1-4 alkylene _{- C3-10} cycloalkyl groups, heterocyclic groups, _-C1-4 alkylene-heterocyclic groups, CN, _NO2 , -( ^CRc1Rd1 ) _tNRa1Rb1 ^, -( ^{CRc1Rd1 ) tORb1} , -( ^CRc1Rd1 ) _tC (= ^O ) ^Ra1 , -( ^{CRc1Rd1 )} _tC (=O) ^{ORb1 ,} -( ^{CRc1Rd1 )} _tOC ( ^{= O )} R _... ^d1 ) _t C(＝O)NR ^a1 R ^b1 and -(CR ^c1 R ^d1 ) _t NR ^a1 C(＝O)R ^b1 , particularly selected from halogens, C _1-10 alkyl groups, CN, NO ₂ , -(CR ^c1 R ^d1 ) _t NR ^a1 R ^b1 and -(CR ^c1 R ^d1 ) _t OR ^b1 , wherein each alkyl, alkylene, cycloalkyl and heterocyclic group is unsubstituted or substituted by at least one substituent independently selected from ^RY .

In one embodiment, each ^Ra1 and ^Rb1 is independently selected from hydrogen and _C1-10 alkyl groups, wherein each alkyl group is unsubstituted or substituted by at least one substituent independently selected from ^Ry .

In one embodiment, each ^Rc1 and ^Rd1 is independently selected from hydrogen, halogens and _C1-10 alkyl groups, wherein each alkyl group is unsubstituted or substituted by at least one substituent independently selected from ^Ry .

In one embodiment, each R ^Y is independently selected from halogen, NO ₂ , -CN, _C1-10 alkyl, -OH, -O ( _C1-10 alkyl), -NH ₂ , -NH ( _C1-10 alkyl), and -N ( _C1-10 alkyl) ₂ , preferably selected from halogen, NO ₂ , -CN, and _C1-10 alkyl.

In one embodiment, ^R1 is selected from _C3-10 cycloalkyl, _-C1-4 alkylene- _C3-10 cycloalkyl, heterocyclic, _-C1-4 alkylene-heterocyclic, -NR ^A1 R ^B1 , -OR ^A1 , -SR ^A1 , -C(=O)R ^A1 , -C(=O)OR ^A1 , -OC(=O)R ^A1 , -C(=O)NR ^A1 R ^B1 , -NR ^F1 C(=O)R ^A1 , -OC(=O)NR ^A1 R ^B1 , -NR ^F1 C(=O)OR ^A1 , -NR ^F1 C(=O)NR ^A1 R ^B1 , -S(=O) _r R ^A1 , -S(=O) _2OR ^A1 , -OS(=O) ₂ R ^A1 , -NR ^F1S (=O) _r R ^A1 , -S(=O) _rNR ^A1 R ^B1 and -NR ^F1 S(＝O) ₂ NR ^A1 R ^B1 , wherein each alkylene, cycloalkyl, and heterocyclic group is unsubstituted or substituted with at least one substituent independently selected from ^RX1 . In one embodiment, ^RF1 is selected from hydrogen and _C1-10 alkyl, particularly hydrogen. In one embodiment, ^R1 is selected from _C3-10 cycloalkyl, _-C1-4 alkylene- _C3-10 cycloalkyl, heterocyclic group, and _-C1-4 alkylene-heterocyclic group, wherein each alkylene, cycloalkyl, and heterocyclic group is unsubstituted or substituted with at least one substituent independently selected from ^RX1 . In one embodiment, ^R1 is selected from _C3-10 cycloalkyl, preferably _C4-6 cycloalkyl, particularly _C4 or _C6 cycloalkyl, especially _C4 cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with at least one substituent independently selected from ^RX1 . In one embodiment, ^RX1 is selected from halogens and _C1-10 alkyl, preferably F.

In one implementation, ^R1 is selected from

In one embodiment, each ^R2 is independently selected from halogens, _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, _C3-10 cycloalkyl, -C1-4 alkylene- _C3-10 cycloalkyl, _heterocyclic , _-C1-4 alkylene-heterocyclic, CN, _NO2 , ^-NRA2RB2 , -ORA2, ^-SRA2 , -C(=O) ^RA2 , ^-C (=O) ^ORA2 , -OC(=O) ^RA2 , ^{-C(=O)NRA2RB2 , -NRA2C} (=O) ^RB2 , ^-OC (=O) ^{NRA2RB2, -NRA2C(=O)ORB2 , -NRA2C} ( ^{= O} ) ^NRA2RB2 , ^-S (=O) ^rRA2 , -N= ^S (=O ⁾ _RA2RB2 The ^groups are -S(=O) _₂ORA₂ , ^-OS (=O) _₂RA₂ , -NRA₂S(=O) ^rRB₂ , _-S (=O) ^rNRA₂RB₂ , and ^-NRA₂S (=O) _{₂NRA₂RB₂} , wherein each _alkyl , ^alkylene , ^alkenyl , alkynyl, cycloalkyl, and heterocyclic group is unsubstituted or substituted ^by at least one substituent independently selected from ^RX₂ . In one embodiment, ^R₂ is selected from halogens, CN, _NO₂ , and C₁ _-10 alkyl groups, wherein the alkyl group is unsubstituted or substituted ^by at least one substituent independently selected from ^RX₂ .

In one embodiment, ^L1 is -(CR ^CRD ) _t ^{- NRFS} (=O) _r- . In one embodiment, t is 0. In one embodiment, r is 2. In one embodiment, ^RF is H. In one embodiment, ^L1 is -NHS(=O) _2- . In one embodiment, ^L2 is selected from _C1-6 alkylene, preferably _C1-3 alkylene, particularly methylene or ethylene. In one embodiment, ^L2 is methylene. In one embodiment, ^L2 is ethylene. In one embodiment, ^R3 is selected from hydrogen, halogen, CN, _NO2 , ^-NRA3RB3 , ^{-ORA3 and -SRA3} , preferably selected from hydrogen, halogen and ^-ORA3 . In one embodiment, ^R3 is hydrogen. In one embodiment, ^R3 is F. In one embodiment, ^R3 is ^-ORA3 , wherein ^RA3 is preferably H.

In one embodiment, ^L1 is -NHS(=O) _2- , ^L2 is ethylene, and ^R3 is hydrogen, and formula (I) has the structure of formula (II-1):

^R1 , ^R2 , ^A1 , ^A2 , ^A3 , ring B, Q, d, ^X1 , ^X2 , ^X3 are as defined in equation (I).

In one embodiment, ^L1 is -NHS(=O) _2- , ^L2 is ethylene, and ^R3 is -OH, and formula (I) has the structure of formula (II-2):

^R1 , ^R2 , ^A1 , ^A2 , ^A3 , ring B, Q, d, ^X1 , ^X2 , ^X3 are as defined in equation (I).

In one embodiment, ^L1 is -NHS(=O) _2- , ^L2 is methylene, and ^R3 is hydrogen, and formula (I) has the structure of formula (II-3) as follows:

^R1 , ^R2 , ^A1 , ^A2 , ^A3 , ring B, Q, d, ^X1 , ^X2 , ^X3 are as defined in equation (I).

In one embodiment, each ^R4 is independently selected from halogens, _C1-10 alkyl groups, _C3-10 cycloalkyl groups, _-C1-4 alkylene- _{C3-10 cycloalkyl} groups, heterocyclic groups, _-C1-4 alkylene-heterocyclic groups, CN, _NO2 , ^-NRA4RB4 , ^-ORA4 , -C(=O) ^RA4 , -C(=O) ^ORA4 , -OC(=O) ^RA4 , -C(=O) ^NRA4RB4 , ^{-NRA4C(=O)RB4 , -S} (=O) ^rRA4 , -S(=O) _2ORA4 , _-OS (=O) ^2RA4 , ^-NRA4S (=O) ^rRB4 , _-S ( ₌ O) _rNRA4RB4 , wherein each alkyl, alkylene, ^cycloalkyl , and ^heterocyclic group is unsubstituted or is selected ^from at least one of the halogens ^{. X4} can be substituted by a substituent; or any two ^R4s together with the carbon atoms attached to them can form a saturated or unsaturated 5-membered ring containing 0, 1, 2 or 3 heteroatoms, wherein the heteroatoms are independently selected from oxygen, sulfur, nitrogen and phosphorus, and the ring is either unsubstituted or substituted by 1, 2 or 3 R ^X4 substituents.

In one embodiment, each ^R4 is independently selected from halogens, _C1-10 alkyl groups, _C3-10 cycloalkyl groups, heterocyclic groups, CN, _NO2 , ^-NRA4RB4 , ^-ORA4 , -OC(= ^O ) ^RA4 , -NRA4C(=O) ^RB4 , -OS(=O) ^2RA4 , and ^-NRA4S (=O) _rRB4 , wherein _each ^alkyl , cycloalkyl, and heterocyclic group is unsubstituted or substituted ^with at least one substituent independently selected from ^RX4 . In one embodiment, each ^RA4 and ^RB4 is independently selected from hydrogen and _C1-10 alkyl groups, wherein each alkyl group is unsubstituted or substituted with at least one substituent independently selected from ^RX4 . In one embodiment, each ^R4 is independently selected from halogens, _{C1-10 alkyl} groups, _C3-10 cycloalkyl groups, CN, and _NO2 , preferably from halogens and _C3-10 cycloalkyl groups, wherein each alkyl and cycloalkyl group is unsubstituted or substituted by at least one substituent independently selected from ^R4 . In one embodiment, each ^R4 is independently selected from halogens. In a particular embodiment, ^R4 is F.

In one embodiment, any two ^R4 atoms, together with the carbon atoms attached to them, form a _C5-6 hydrocarbon ring, particularly a _C5 hydrocarbon ring, which is either unsubstituted or substituted by one, two, or three ^R4 substituents. In another embodiment, any two ^R4 atoms, together with the carbon atoms attached to them, form a saturated _C5 hydrocarbon ring, which is either unsubstituted or substituted by one, two, or three ^R4 substituents.

In one embodiment, ^R4a and ^R4b are each independently selected from hydrogen, halogen, CN, _NO2 , _C1-10 alkyl, _C3-10 cycloalkyl, _-C1-4 alkylene- _C3-10 cycloalkyl, heterocyclic, and _-C1-4 alkylene-heterocyclic, wherein each alkyl, alkylene, cycloalkyl, and heterocyclic group is unsubstituted or substituted with at least one substituent independently selected from R ^X4 . In one embodiment, ^R4a and ^R4b are each independently selected from hydrogen, halogen, _C1-10 alkyl, _C3-10 cycloalkyl, and _-C1-4 alkylene- _C3-10 cycloalkyl, preferably from hydrogen, halogen, and _C3-10 cycloalkyl, wherein each alkyl, alkylene, and cycloalkyl is unsubstituted or substituted with at least one substituent independently selected from R ^X4 . In one embodiment, ^R4a and ^R4b are each independently selected from hydrogen and halogen. In one embodiment, ^R4a and ^R4b are hydrogen. In one embodiment, ^R4a and ^R4b are F. In one embodiment, ^R4a is selected from _C3-10 cycloalkyl groups, and ^R4b is selected from hydrogen and halogens; wherein the cycloalkyl group is unsubstituted or substituted with at least one substituent independently selected from R ^X4 . In one embodiment, ^R4a is cyclopropyl, which is unsubstituted or substituted with at least one substituent independently selected from R ^X4 , and ^R4b is H or F.

In one embodiment, ^R4a and ^R4b, together with the carbon atoms attached to them, form a saturated or unsaturated 3-7 membered hydrocarbon ring, which is either unsubstituted or substituted by one, two, or three ^RX4 substituents. In another embodiment, ^R4a and ^R4b, together with the carbon atoms attached to them, form a saturated 3-membered hydrocarbon ring, which is either unsubstituted or substituted by one, two, or three ^RX4 substituents.

In one embodiment, ^R5a and ^R5b are each independently selected from hydrogen, halogen, and _C1-10 alkyl, wherein the alkyl group is unsubstituted or substituted with at least one substituent independently selected from R ^X5 . In one embodiment, ^R5a and ^R5b are each independently selected from hydrogen and halogen. In one embodiment, ^R5a and ^R5b are each independently selected from H and F. In one embodiment, ^R5a and ^R5b are F. In one embodiment, ^R5a and ^R5b are each independently selected from _C1-10 alkyl. In one embodiment, ^R5a and ^R5b are methyl.

In one embodiment, ^R5a and ^R5b, together with the carbon atoms attached to them, form a saturated or unsaturated 3-7 membered hydrocarbon ring, which is either unsubstituted or substituted by one, two, or three ^RX5 substituents. In another embodiment, ^R5a and ^R5b, together with the carbon atoms attached to them, form a saturated 3-membered hydrocarbon ring, which is either unsubstituted or substituted by one, two, or three ^RX5 substituents.

In one implementation, ^R6 is hydrogen.

In one embodiment, ^A1 is C( ^R7 ). In one embodiment, ^R7 is hydrogen.

In one embodiment, ^A2 is C( ^R8 ). In one embodiment, ^R8 is hydrogen.

In one implementation, in formula (I) The structure is

In one implementation, ^A3 is N.

In one embodiment, ^A3 is C( ^R9 ). In one embodiment, ^R9 is hydrogen.

In one embodiment, ^R7 and ^R8, together with the atoms attached to them, form a 5-6 membered heteroaromatic ring containing one, two, or three heteroatoms, particularly a 5-membered heteroaromatic ring, wherein the heteroatoms in the heteroaromatic ring are independently selected from oxygen, sulfur, and nitrogen; the heteroaromatic ring is either unsubstituted or substituted with at least one substituent independently selected from R ^X8 . In one embodiment, ^R7 and ^R8 , together with the atoms attached to them, form a thiazole or a furan.

In one implementation, in formula (I) The structure is

In one embodiment, ^X1 is C( ^R10 ). In another embodiment, ^R10 is hydrogen.

In one embodiment, ^X2 is C( ^R11 ). In another embodiment, ^R11 is hydrogen.

In one embodiment, ^X3 is C( ^R12 ). In another embodiment, ^R12 is hydrogen.

In one embodiment, ^R10 and ^R11 , together with the atoms attached to them, form a _C5-6 hydrocarbon ring, particularly a _C5 hydrocarbon ring; the hydrocarbon ring is unsubstituted or substituted with at least one substituent independently selected from ^RX11 . In one embodiment, ^R10 and ^R11, together with the atoms attached to them, form a 5-6 membered heterocycle containing one, two, or three heteroatoms, particularly a 5-membered heterocycle, wherein the heteroatoms in the heterocycle are independently selected from oxygen, sulfur, and nitrogen; the heterocycle is unsubstituted or substituted with at least one substituent independently selected from ^RX11 . In one embodiment, ^R10 and ^R11 , together with the atoms attached to them, form a 5-6 membered heteroaromatic ring containing one, two, or three heteroatoms, particularly a 5-membered heteroaromatic ring, wherein the heteroatoms in the heteroaromatic ring are independently selected from oxygen, sulfur, and nitrogen; the heteroaromatic ring is unsubstituted or substituted with at least one substituent independently selected from ^RX11 .

In one implementation, in formula (I) The structure is In one implementation, in formula (I) The structure is In one implementation, in formula (I) The structure is

In one embodiment, Q has the structure of equation (i), equation (ii), equation (iii), or equation (iv):

in,

p1 is an integer selected from 0 to 13;

p2 is an integer selected from 0 to 11;

L, M, ^R4 , ^R4a , ^R4b , ^R5a , ^R5b , m, n are defined as in equation (I).

In one implementation, M is N.

In one embodiment, L is selected from chemical bonds and -O-, especially -O-. In one embodiment, the chemical bond is a single bond.

In one implementation, the structure of equation (i) is selected from:

Among them, ^R4a , ^R4b , ^R4c , ^R4d , ^R4e , ^R4f , ^R4g , ^R4h , ^R4i , ^R4j , ^R4k and ^R4l are each independently selected from hydrogen and ^R4 .

In one embodiment, one of “R ^4c and R ^4d ” and one of “R ⁴ⁱ and R ^4j ” together with the carbon atoms attached to them form a saturated C ₅ hydrocarbon ring, which is either unsubstituted or substituted by one, two or three ^RX4 substituents.

In one implementation, the structure of formula (ii) is selected from:

Wherein, ^R4c , ^R4d , ^R4e , ^R4f , ^R4g , ^R4h , ^R4i , ^R4j , ^R4k , and ^R4l are each independently selected from hydrogen and ^R4 . In one embodiment, the structure of formula (iii) is selected from:

Among them, ^R4c , ^R4d , ^R4e , ^R4f , ^R4g , ^R4h , ^R4i , ^R4j , ^R4k and ^R4l are each independently selected from hydrogen and ^R4 .

In one implementation, the structure of formula (iv) is selected from:

Among them, ^R4c , ^R4d , ^R4e , ^R4f , ^R4g , ^R4h , ^R4i , ^R4j , ^R4k and ^R4l are each independently selected from hydrogen and ^R4 .

In one implementation, m is 1 or 2.

In one implementation, n is 0 or 1.

In one implementation, p is 0 or 1.

In one implementation, p1 is 0.

In one implementation, p2 is 0.

In one implementation scheme, Q is selected from: Preferably selected from In one implementation scheme, Q is In one implementation scheme, Q is In one implementation scheme, Q is

In one embodiment, ring B is selected from a nitrogen-containing 5-membered heteroaromatic ring.

In one implementation scheme, ring B is selected from... The structure is substituted by d independent substituents selected from ^R2 ; where "---" indicates the site where ring B connects to a ring containing ^A1 , ^A2 , and ^A3 , while "---" indicates another site where ring B connects to other parts of the molecule. In one embodiment, ring B is... In one implementation, in formula (I) The structure is

In one embodiment, formula (I) has the structure of formula (III):

in,

^B1 is selected from N( ^R2a ), N, O, S and C( ^R2a );

^B2 is selected from N( ^R2b ), N, O, S and C( ^R2b );

^B3 is selected from N( ^R2c ), N, O, S and C( ^R2c );

B ² is selected from N(R ^2d ), N, O, S and C(R ^2d );

^B5 is selected from N( ^R2e ), N, O, S and C( ^R2e );

^R2a , ^R2b , ^R2c , ^R2d , and ^R2e are each independently selected from hydrogen and ^R2 ;

To maintain ring B as an aromatic single or double bond;

^R1 , ^R2 , ^R3 , ^A1 , ^A2 , ^A3 , Q, ^L1 , ^L2 , ^X1 , ^X2 , ^X3 are as defined in equation (I).

In one embodiment, formula (III) has the structure of formula (III-1) or formula (III-2).

In one implementation, in formula (I) The structure is ^R1 is ^R3 is hydrogen.

In one implementation, in formula (I) The structure is ^R1 is ^R3 is hydrogen, Q is... In one implementation, in formula (I) The structure is ^R1 is ^R3 is hydrogen, Q is...

In one embodiment, ^L1 is -NHS(=O) _2- , ^L2 is methylene or ethylene, and ^R3 is hydrogen, F, or -OH. In one embodiment, ^L2 is methylene and ^R3 is hydrogen. In one embodiment, ^L2 is ethylene and ^R3 is hydrogen.

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

PROTAC compounds and antibody-drug conjugates (ADCs)

In another aspect, the present invention provides a PROTAC compound comprising the compound of the present invention, an E3 ubiquitin ligase-binding ligand, and a linker connecting the compound of the present invention and the E3 ubiquitin ligase-binding ligand. The compound of the present invention can act as a ligand to bind to Kif18A. In one embodiment, the PROTAC compound can be used to promote the degradation of Kif18A via UPS.

In another aspect, the present invention provides an antibody-drug conjugate comprising the compound of the present invention, an antibody capable of binding to a target, and a connector linking the compound of the present invention and the antibody.

Pharmaceutical compositions and pharmaceutical preparations

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

The pharmaceutical compositions of the present invention can be administered in any manner, provided they achieve the effect of preventing, alleviating, preventing, or treating symptoms in humans or animals. For example, various suitable dosage forms can be prepared depending on the route of administration. For example, they can be administered to patients orally or parenterally in conventional formulations. These conventional formulations include, for example, capsules, microcapsules, tablets, granules, powders, lozenges, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions, and emulsions.

The dosage of the compound administered to the subject can be adjusted to a considerable extent. The dosage can be varied depending on the specific route of administration and the subject's needs, and can be determined by a healthcare professional.

Treatment methods and uses

According to certain embodiments of the present invention, the present invention or its pharmaceutically acceptable salts, stereoisomers, solvates, polymorphs, tautomers, isotopic compounds, metabolites or prodrugs, or pharmaceutical compositions of the present invention may be used to prevent or treat Kif18A-mediated diseases, or diseases that respond to the inhibition of Kif18A, including but not limited to diseases of abnormal cell proliferation, such as cancer and autoimmune diseases.

Therefore, in another aspect, the present invention also provides the use of the compounds of the present invention or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof in the preparation of medicaments for treating diseases, symptoms or conditions selected from diseases of abnormal cell proliferation, wherein the compounds or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof are optionally used in combination with a second therapeutic agent.

In another aspect, the present invention provides compounds of the present invention or pharmaceutically acceptable salts thereof, or pharmaceutical compositions of the present invention, optionally in combination with a second therapeutic agent, for the treatment of diseases of abnormal cell proliferation.

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

In one embodiment, the disease, condition, or symptom is selected from: cancerous proliferative diseases (e.g., cancer); non-cancer proliferative diseases (e.g., benign skin hyperplasia (e.g., psoriasis), restenosis, and benign prostatic hyperplasia (BPH)); pancreatitis; kidney disease; pain; inhibition of sperm development; prevention of blastocyst implantation; treatment of diseases related to angiogenesis or vascularization (e.g., tumor angiogenesis, acute and chronic inflammatory diseases such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema, and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, senile dementia). Age-related diseases include: macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma, and ovarian, breast, lung, pancreatic, prostate, colon, and epidermoid carcinoma; asthma; neutrophil chemotaxis (e.g., reperfusion injury from myocardial infarction and stroke, and inflammatory arthritis); septic shock; T-cell-mediated diseases in which immunosuppression is valuable (e.g., prevention of organ transplant rejection, graft-versus-host disease, lupus, multiple sclerosis, and rheumatoid arthritis); atherosclerosis; inhibition of keratinocytes responding to a mixture of growth factors; chronic obstructive pulmonary disease (COPD) and other diseases.

In one embodiment, the disease, condition, or symptom is cancer, for example selected from: (a) solid tumors or hematopoietic tumors selected from the following cancers: bladder cancer, endometrial cancer, squamous cell carcinoma of the lung, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, small cell lung cancer, esophageal cancer, gallbladder cancer, brain cancer, head and neck cancer, ovarian cancer, pancreatic cancer, gastric cancer, cervical cancer, thyroid cancer, prostate cancer, and skin cancer; (b) hematopoietic tumors selected from the following lymphoid systems: leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma. (c) Lymphoma, non-Hodgkin's lymphoma, pilocellular lymphoma, and Burkert's lymphoma; (d) hematopoietic tumors of the following bone marrow lineages: acute and chronic myeloid leukemia, myelodysplastic syndromes, and promyelocytic leukemia; (e) stromal tumors of the following fibrosarcoma and rhabdomyosarcoma; (f) tumors of the central and peripheral nervous systems of the following astrocytoma, neuroblastoma, glioma, and schwannoma; or (f) melanoma, seminoma, teratoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, follicular thyroid carcinoma, or Kaposi's sarcoma.

In one embodiment, the disease, condition, or symptom 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. In a particular embodiment, the disease, condition, or symptom is ovarian cancer.

combination therapy

The compounds of the present invention or their pharmaceutically acceptable salts, or the pharmaceutical compositions of the present invention, may be used alone or in combination with other therapeutic agents.

For example, the use of adjuvants can enhance the therapeutic effect of the compounds of this invention (e.g., the therapeutic benefit of using an adjuvant alone is minimal, but when used in combination with another drug, it can enhance the individual's therapeutic benefit), or, for example, the combination of the compounds of this invention with another equally effective therapeutic agent can enhance the individual's therapeutic benefit. For example, in the treatment of cancer, using the compounds of this invention in combination with another drug for treating cancer may enhance clinical benefit. Combined therapies include, but are not limited to, physical therapy, psychotherapy, radiotherapy, chemotherapy agents, small molecule targeted therapies (e.g., kinase inhibitors, immune agonists), immunotherapy (e.g., anti-PD-1, anti-PDL-1, CAR-T cells), etc. Regardless of the disease, condition, or illness, the two therapies should have an additive or synergistic effect on the individual's therapeutic benefit.

In one embodiment, the other therapeutic agent is selected from inhibitors of members of the kinesin superfamily, such as kinesin spindle protein (KSP, also known as kinesin Eg5) inhibitors. In one embodiment, the other therapeutic agent is selected from centromere-associated protein E (CENP-E) inhibitors.

Beneficial effects

The novel small molecule Kif18A inhibitor provided by this invention exhibits outstanding Kif18A inhibitory activity and cell proliferation inhibitory activity.

Therefore, the compounds of the present invention are capable of preventing or treating Kif18A-mediated diseases, or diseases that respond to the inhibition of Kif18A, including but not limited to diseases of abnormal cell proliferation such as cancer and autoimmune diseases, and have good prospects for development into drugs.

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

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

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

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

(4) Excellent safety profile (low toxicity and/or fewer side effects to non-target normal cells or tissues, and a wider therapeutic window).

Example

To more clearly illustrate the objectives and technical solutions of this invention, the invention will be further described below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Specific experimental methods not mentioned in the following embodiments were performed according to conventional experimental methods.

Instruments, materials and reagents

Unless otherwise specified, all instruments and reagents used in the examples are commercially available. Reagents may be used directly without further purification.

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). Semi-preparative HPLC: Column: Waters SunFire ^™ C18 10μm OBD 19*250mm; Mobile phase A: _H₂O (containing 0.1% formic acid); Mobile phase B: _CH₃CN .

NMR: Bruker Avance III 400M

OVCAR3 cells were obtained from ATCC CAT#HTB-161.

Synthesis scheme

Compounds of formula (I) or pharmaceutically acceptable salts thereof can be synthesized by various methods, some exemplary methods of which are provided below and in examples. Other synthetic methods can be readily devised by those skilled in the art based on the information disclosed herein.

In the reactions described below, it may be necessary to protect the active groups to prevent them from participating in other undesirable reactions. These groups include hydroxyl, amino, imine, thiol-containing, or carboxyl groups, which may be present in the final product. Commonly used protecting groups can be found in T.W. Greene and P.G.M. Wuts in "Protective Groups in Organic Chemistry," John Wiley and Sons, 1991.

The synthetic schemes for all compounds of this invention are illustrated by the following schemes and examples. The raw materials used are derived from commercially available products or can be prepared according to existing processes or the methods exemplified herein.

As shown in Synthesis Scheme 1, the compound of formula (I) can be prepared and synthesized from compounds M1 and M2, which are known in the literature or understood by those skilled in the art, by various methods. For example, compounds M1 and M2 are cyclized to obtain the compound of formula (I). Here ^{, y1} and ^y2 are the reactive groups of the cyclization reaction, for example, a 1,3-dipolar group and an alkynyl group, respectively, wherein the 1,3-dipolar group is, for example, an azide group.

Synthesis Scheme 1

In one embodiment, the cyclization reaction is a click reaction. In one embodiment, the click reaction is CuAAC (copper-catalyzed alkyne-azide cycloaddition). In one embodiment, the cyclization reaction is carried out in the presence of a copper reagent, such as _CuSO₄ with a reducing agent (e.g., sodium ascorbate), or CuBr or CuOAc. In one embodiment, the cyclization reaction is carried out in a tert-butanol-water mixed solvent, and optionally under heating conditions.

Another synthetic route for compound (I) is shown in synthetic scheme 2. Compounds M1 and M3 are used as starting materials, and a cyclization reaction yields compound M4. Here, ^w1 is a leaving group, selected for example from halogens, OTf, and especially halogens. M4 is reacted with reagent ^R2 via nucleophilic substitution or coupling to yield compound (I). The coupling reaction is, for example, the Ullmann reaction or the Buchwald reaction.

Synthesis Scheme 2

In one embodiment, the coupling reaction is carried out in the presence of a copper reagent, such as CuI, in a solvent such as DMF or DMSO, and can be catalyzed by an amino acid or a ligand (e.g., an amine), and optionally in the presence of a base, and optionally under heating conditions.

Intermediate compounds can be prepared using known methods, such as reacting a corresponding amine compound with an azide reagent in the presence of a diazotizing reagent to prepare a compound with an azide group (compound M1 or compound M2), where the diazotizing reagent is, for example, tert-butyl nitrite, and the azide reagent is, for example, TMSN _3. Alternatively, compounds with an alkynylating group can be reacted with a corresponding leaving group with an alkynylating reagent to prepare an alkynylating compound (compound M1 or compound M2), where the leaving group is, for example, a halogen, and the alkynylating reagent is, for example, trimethylsilylacetylene.

In some cases, the order of the above reaction schemes can be changed to promote the reaction or avoid unwanted reaction products. The following examples are provided to provide a more complete understanding of the invention. These examples are merely illustrative and should not be construed as limiting the invention in any way.

Example 1: N-(4-(4-(1-(3,3-difluorocyclobutyl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-1,2,3-triazol-1-yl)-3- (6-azaspiro[2.5]octane-6-yl)phenyl)ethanesulfonamide (Compound 001)

1.1 Synthesis of intermediates 1-2:

2-Fluoro-4-iodo-1-nitrobenzene (1 g), 6-azaspiro[2.5]octane hydrochloride (720 mg), and diisopropylethylamine (2.9 g) were dissolved in NMP (5 mL) and reacted at 100 °C with stirring for 16 hours. The reaction mixture was poured into ice water (20 mL) and extracted with ethyl acetate (3 × 20 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 silica gel column chromatography (EA/PE: 0–5%) to give intermediate 1-2 (1.2 g). LCMS: MS m/z (ESI): 358.9 [M+H] ⁺ .

1.2 Synthesis of intermediates 1-3:

Intermediate 1-2 (1.4 g) was dissolved in a mixed solvent of ethanol/tetrahydrofuran/water (40 mL/40 mL/20 mL) at room temperature. Reduced iron powder (1.1 g) and ammonium chloride (1.05 g) were added, and the mixture was stirred at 60 °C for 2 hours. The reaction solution was filtered, and the filtrate was diluted with water (100 mL), extracted with ethyl acetate (3 × 100 mL), and the combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain intermediate 1-3 (crude product, 1.2 g), which was used directly in subsequent reactions. LCMS: MS m/z (ESI): 329.0 [M+H] ⁺ .

1.3 Synthesis of intermediates 1-4:

Intermediate 1-3 (0.1 g) was dissolved in acetonitrile (2 mL), and tert-butyl nitrite (47 mg) and trimethyl azidosilane (53 mg) were added dropwise at 0 °C. The mixture was stirred at room temperature for 1 hour. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (2 × 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (EA in PE: 0–2%) to give intermediate 1-4 (67 mg). LCMS: MS m/z (ESI): 355.2 [M+H] ⁺ .

1.4 Synthesis of intermediates 1-5:

4,4-Difluorocyclobut-1-ol (850 mg) and triphenylphosphine (6.20 g) were added to a toluene (20.0 mL) solution of 1.38 g of 6-bromopyridazine-3(2H)-one at room temperature. The mixture was stirred at 120 °C for 10 minutes under nitrogen protection, followed by the addition of diisopropyl azodicarbonate (4.80 g). The reaction was then stirred at 120 °C for 4 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA in PE: 0–50%) to obtain crude intermediate 1-5 (2.50 g).

Synthesis of intermediates 1-6:

At room temperature, 72.0 mg of bis(triphenylphosphine)-palladium dichloride, 346 mg of triethylamine, 359 mg of triphenylphosphine, and 130 mg of cuprous iodide were added to a tetrahydrofuran (10.0 mL) solution of intermediate 1-5 (1.0 g). After three purgings with nitrogen and stirring at room temperature for 10 minutes, 503 mg of trimethylsilylacetylene was added. The reaction was carried out under nitrogen protection at 70 °C with stirring for 3 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (EA in PE: 0–20%) to obtain intermediate 1-6 (300 mg). LCMS: MS m/z (ESI): 283.0 [M+H] ⁺ .

1.6 Synthesis of intermediates 1-7:

At room temperature, a saturated potassium carbonate solution (1.00 mL) was added dropwise to a methanol (5.00 mL) solution of intermediate 1-6 (300 mg). The reaction mixture was stirred at room temperature for 30 minutes under nitrogen protection. A saturated sodium chloride aqueous solution (20.0 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 × 20.0 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 1-7 (200 mg). LCMS: MS m/z (ESI): 211.0 [M+H] ⁺ .

1.7 Synthesis of intermediates 1-8:

Intermediate 1-4 (337 mg), anhydrous copper sulfate (15.0 mg), and sodium L-ascorbate (189 mg) were added to a mixed solvent (10.0 mL/10.0 mL) of water and tert-butanol for intermediate 1-7 (200 mg) at room temperature. The reaction mixture was stirred at 60 °C for 2 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (EA in PE: 0–50%) to obtain intermediate 1-8 (220 mg). LCMS: MS m/z (ESI): 565.1 [M+H] ⁺ .

1.8 Synthesis of Compound 001:

At room temperature, sarcosine (16.0 mg), cuprous iodide (17.0 mg), and potassium phosphate (94.0 mg) were added to a solution of 29.0 mg ethanesulfonamide in 5.00 mL of N,N-dimethylformamide. The mixture was stirred at 50 °C for 5 minutes under nitrogen protection. Then, intermediate 1-8 (50.0 mg) was added to the reaction system. The mixture was heated and stirred at 100 °C for 2 hours under nitrogen protection. Cool to room temperature, add water (10 mL) to the reaction solution, extract with ethyl acetate (2 × 10 mL), combine the organic phases, wash with a mixture of ammonia/saturated ammonium chloride (V/V = 1/10, 2 × 10 mL), dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by high performance liquid chromatography (SunFire Prep C18 OBD 10 μm, 19*250 mm, mobile phase A: _H₂O containing 0.1% formic acid, mobile phase B: _CH₃CN , A/B = 60% - 5% gradient) to obtain the target product N-(4-(4-(1-(3,3-difluorocyclobutyl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-1,2,3-triazol-1-yl)-3-(6-azaspiro[2.5]octane-6-yl)phenyl)ethanesulfonamide (compound 001) (10.96 mg). ¹ H NMR (400MHz, DMSO) δ10.18(s,1H),9.15(s,1H),8.08(d,J＝9.6Hz,1H),7.56(d,J＝8.6Hz,1H),7.17–7.11(m,2H),7.04(dd,J＝8.6,2.3Hz,1H), 5.37–5.27(m,1H),3.20(q,J＝7.3Hz,2H),3.15–3.05(m,4H),2.68(t,J＝5.3Hz,4H),1.30(s,4H),1.23(t,J＝7.3Hz,3H),0.25(s,4H).LCMS:MS m/z(ESI):546.2[M+H] ⁺ .

Example 2: N-(4-(4-(1-(3,3-difluorocyclobutyl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-1,2,3-triazol-1-yl)-3- (6-azaspiro[2.5]octane-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (Compound 002)

2.1 Synthesis of Compound 002:

At room temperature, sarcosine (32.0 mg), cuprous iodide (34.0 mg), and potassium phosphate (188 mg) were added to a solution of 2-hydroxyethane-1-sulfonamide (67.0 mg) in N,N-dimethylformamide (5.00 mL). The mixture was stirred at 50 °C for 5 minutes under nitrogen protection, and then intermediate 1-8 (100 mg) was added. The reaction was continued at 100 °C for 2 hours under nitrogen protection. After cooling to room temperature, water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (2 × 10 mL). The organic phases were combined, washed with a mixture of ammonia and saturated ammonium chloride (V/V = 1/10, 2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was subjected to preparative high-performance liquid chromatography (SunFire Prep C18 OBD 10 μm, 19*250 mm, mobile phase A: _H₂O containing 0.1% formic acid, mobile phase B: CH₃ ₎ using a preparative high-performance liquid chromatography (SPLC) method. CN, A/B = 80% - 5% gradient change) purification, to obtain the target product N-(4-(4-(1-(3,3-difluorocyclobutyl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-1,2,3-triazol-1-yl)-3-(6-azaspiro[2.5]octane-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (compound 002) (13.95 mg). ¹ H NMR (400MHz, DMSO) δ9.15(s,1H),8.08(d,J＝9.6Hz,1H),7.54(d,J＝8.6Hz,1H),7.13(d,J＝9.6Hz,1H),7.11(d,J＝2.2Hz,1H),7.01(dd,J＝8.6,2.2 Hz,1H),5.35–5.30(m,1H),3.77(t,J＝6.5Hz,2H),3.30–3.27(m,2H),3.2 0–3.01(m,4H),2.68(t,J＝5.2Hz,4H),1.31(s,4H),0.25(s,4H).LCMS:MS m/z(ESI):562.2[M+H] ⁺ .

Example 3: N-(4-(4-(1-(4,4-difluorocyclohexyl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-1,2,3-triazol-1-yl)-3- (6-azaspiro[2.5]octane-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (Compound 003)

3.1 Synthesis of intermediate 3-2:

At room temperature, 4,4-difluorocyclohexane-1-ol (780 mg) and triphenylphosphine (4.50 g) were added to a toluene (25.0 mL) solution of 1.00 g of 6-bromopyridazine-3(2H)-one. The mixture was stirred at 120 °C for 10 minutes under nitrogen protection, and then DIAD (3.47 g) was added. The mixture was stirred at 120 °C for 2 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA/PE: 0–30%) to give intermediate 3-2 (1.50 g).

3.2 Synthesis of intermediate 3-3:

At room temperature, bis(diphenylphosphine)palladium dichloride (72.0 mg), triethylamine (346 mg), triphenylphosphine (359 mg), and cuprous iodide (130 mg) were added to a tetrahydrofuran (10.0 mL) solution of intermediate 3-2 (1.50 g). After three nitrogen purgings and stirring at room temperature for 10 minutes, trimethylsilylacetylene (503 mg) was added. The reaction was carried out under nitrogen protection at 70 °C with stirring for 5 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (EA in PE: 0–20%) to give intermediate 3-3 (700 mg). LCMS: MS m/z (ESI): 352.4 [M+ACN+H] ⁺ .

3.3 Synthesis of intermediates 3-4:

A saturated potassium carbonate solution (1.00 mL) was added dropwise to a methanol (5.00 mL) solution of intermediate 3-3 (350 mg) at room temperature. The reaction mixture was stirred at room temperature for 30 minutes under nitrogen protection. A saturated sodium chloride aqueous solution (20.0 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 × 20.0 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give intermediate 3-4 (250 mg). LCMS: MS m/z (ESI): 239.4 [M+H] ⁺ .

3.4 Synthesis of Compound 003:

Referring to the synthesis method of Example 1, intermediates 1-7 in step 1.7 were replaced with intermediates 3-4, and ethanesulfonamide in step 1.8 was replaced with 2-hydroxyethane-1-sulfonamide, to obtain the target compound N-(4-(4-(1-(4,4-difluorocyclohexyl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-1,2,3-triazol-1-yl)-3-(6-azaspiro[2.5]octane-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (compound 003). ¹ H NMR (400MHz, DMSO) δ9.09 (s, 1H), 8.03 (d, J = 9.6Hz, 1H), 7.56 (d, J = 8.5Hz, 1H), 7.13 (d, J = 9.6Hz, 1H), 7.10 (d, J = 2.2Hz, 1H), 7.01 (d, J = 8.7Hz, 1H),5.09–5.05(m,1H),3.77(t,J＝6.5Hz,2H),3.33–3.27(m,2H),2.66(t,J＝5.1Hz,4H),2.21–1.85(m,8H),1.31(s,4H),0.25(s,4H).LCMS:MS m/z(ESI):590.3[M+H] ⁺ .

Example 4: N-(4-(4-(1-(4,4-difluorocyclohexyl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-1,2,3-triazol-1-yl)-3- (6-azaspiro[2.5]octane-6-yl)phenyl)-2-fluoroethane-1-sulfonamide (Compound 004)

4.1 Synthesis of intermediate 4-2:

At room temperature, sarcosine (500 mg), cuprous iodide (530.0 mg), and potassium phosphate (3.0 g) were added to a solution of 1.05 g of 2-hydroxyethane-1-sulfonamide in 30.00 mL of N,N-dimethylformamide. The mixture was heated and stirred at 50 °C for 5 minutes under nitrogen protection, followed by the addition of intermediate 1-2 (1.0 g). The reaction was continued at 100 °C for 3 hours under nitrogen protection. The reaction solution was diluted with 10.0 mL of saturated sodium chloride aqueous solution and extracted with ethyl acetate (3 × 10.0 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (EA/PE: 0–50%) to give intermediate 4-2 (800 mg). LCMS: MS m/z (ESI): 356.2 [M+H] ⁺ .

4.2 Synthesis of intermediate 4-3:

Intermediate 4-2 (500 mg) was dissolved in anhydrous dichloromethane (20 mL) under nitrogen protection. The solution was cooled to 0 °C, and DAST (700 mg) was added. The mixture was then slowly heated to room temperature and stirred for 8 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (EA/PE: 0–30%) to obtain intermediate 4-3 (150 mg). LC-MS: MS m/z (ESI): 358.0 [M+H] ⁺ .

4.3 Synthesis of intermediate 4-4:

Reduced iron powder (160 mg) and ammonium chloride (160 mg) were added to a mixed solution of intermediate 4-3 (100 mg) in ethanol/tetrahydrofuran/water (10 mL/10 mL/5 mL) at room temperature. The mixture was stirred at 60 °C for 2 hours under nitrogen protection. The reaction solution was poured into a saturated sodium chloride solution (100 mL) and extracted with ethyl acetate (3 × 100 mL). The organic phases were combined, 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 in PE: 0–20%) to obtain intermediate 4-4 (81 mg). LCMS: MS m/z (ESI): 328.4 [M+H] ⁺ .

4.4 Synthesis of intermediates 4-5:

Intermediate 4-4 (100 mg) was dissolved in acetonitrile (5 mL), cooled to 0 °C under nitrogen protection, and tert-butyl nitrite (47 mg) and trimethyl azidosilane (53 mg) were added dropwise to the reaction solution. The mixture was then stirred at room temperature for 1 hour. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (2 × 20 mL). The organic phases were combined, 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 in PE: 0–10%) to obtain intermediate 4-5 (80 mg). LCMS: MS m/z (ESI): 354.4 [M+H] ⁺ .

4.5 Synthesis of Compound 004:

Anhydrous copper sulfate (4.52 mg) and sodium L-ascorbate (30.9 mg) were added to a mixed solution of intermediates 3-4 (50 mg), intermediates 4-5 (33.6 mg), water (1.00 mL), and tert-butanol (1.00 mL) at room temperature. The reaction mixture was stirred at 60 °C for 2 hours under nitrogen protection. Water (20.0 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 × 40.0 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by high-performance liquid chromatography (HPLC) to obtain the target product N-(4-(4-(1-(4,4-difluorocyclohexyl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-1,2,3-triazol-1-yl)-3-(6-azaspiro[2.5]octane-6-yl)phenyl)-2-fluoroethane-1-sulfonamide (compound 004) ( ^6.88 mg). NMR (400MHz, DMSO) δ10.29(s,1H),9.09(s,1H),8.03(d,J＝9.6Hz,1H),7.58(d,J＝8.6 Hz,1H),7.16–7.09(m,2H),7.03(dd,J＝8.6,2.3Hz,1H),5.09–5.05(m,1H),4.84(t,J ＝5.1Hz,1H),4.72(t,J＝5.1Hz,1H),3.70(t,J＝5.1Hz,1H),3.64(t,J＝5.1Hz,1H),2.6 6(t,J＝5.2Hz,4H),2.20–1.99(m,6H),1.92(s,2H),1.31(s,4H),0.25(s,4H).LCMS:MS m/z(ESI):592.4[M+H] ⁺ .

Example 5 N-(4-(4-(1-(3,3-difluorocyclobutyl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-1,2,3-triazol-1-yl) -3-((4,4-difluorocyclohexyl)oxy)phenyl)ethanesulfonamide (Compound 005)

5.1 Synthesis of intermediate 5-2:

5-Iodo-2-nitrophenol (1.20 g) was dissolved in dichloromethane (20.0 mL) at room temperature, and 4,4-difluorocyclohexane-1-ol (689 mg) and triphenylphosphine (1.78 g) were added. DIAD (1.18 g) was added under nitrogen protection, and the reaction was carried out for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (EA/PE: 0–10%) to give intermediate 5-2 (1.50 g, crude product).

5.2 Synthesis of intermediate 5-3:

Intermediate 5-2 (1.30 g) was dissolved in a mixed solvent of tetrahydrofuran/ethanol/water (V/V/V = 4/2/1, 20.0 mL) at room temperature. Iron powder (1.94 g) and ammonium chloride (1.82 g) were added, and the mixture was stirred at 75 °C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (EA in PE: 0–20%) to obtain intermediate 5-3 (550 mg). LCMS: MS m/z (ESI): 354.0 [M+H] ⁺ .

5.3 Synthesis of intermediate 5-4:

At room temperature, tert-butyl nitrite (242 mg) and azidotrimethylsilane (275 mg) were added to a solution of intermediate 5-3 (550 mg) in acetonitrile (15.0 mL), and the mixture was stirred at 50 °C for 2 hours. Water (20 mL) was added to the reaction mixture, and the solution was extracted with ethyl acetate (2 × 20 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated by silica gel column chromatography to obtain intermediate 5-4 (550 mg).

5.4 Synthesis of intermediate 5-5:

Intermediate 1-7 (121 mg), anhydrous copper sulfate (19.0 mg), and sodium L-ascorbate (127 mg) were added to a mixed solution of intermediate 5-4 (220 mg) in water (6.5 mL) and tert-butanol (6.5 mL) at room temperature. The mixture was stirred at 60 °C for 2 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the residue was purified by thin-layer preparative chromatography (EA in PE: 20%) to obtain intermediate 5-5 (200 mg). LCMS: MS m/z (ESI): 590.0 [M+H] ⁺ .

Synthesis of Compound 005:

DMEDA (12.0 mg), cuprous iodide (52.0 mg), potassium phosphate (144 mg), and intermediate 5-5 (80.0 mg) were added to a solution of 44.0 mg ethanesulfonamide in N,N-dimethylformamide (3.00 mL) at room temperature. The mixture was then microwaved at 120 °C for 1 hour. The reaction was stopped, and water (10 mL) was added to the reaction solution. The solution was then extracted with ethyl acetate (3 × 20.0 mL). The organic phases were combined and washed successively with ammonia (8%-10%, 3×20.0 mL) and saturated saline (3×20.0 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by high performance liquid chromatography to obtain the target product N-(4-(4-(1-(3,3-difluorocyclobutyl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-1,2,3-triazol-1-yl)-3-((4,4-difluorocyclohexyl)oxy)phenyl)ethanesulfonamide (compound 005) (9.79 mg). ¹ H NMR (400MHz, DMSO) δ10.24(s,1H),8.94(s,1H),8.08(d,J＝9.6Hz,1H),7.65(d,J＝8.6Hz,1H),7.16(d,J＝2.2Hz,1H),7.13(d,J＝9.6Hz,1H),7.00(d d,J＝8.6,2.2Hz,1H),5.30–5.21(m,1H),4.67(s,1H),3.21(q,J＝7.3Hz,2 H),3.17–3.02(m,4H),1.90–1.84(m,8H),1.23(t,J＝7.3Hz,3H).LCMS:MS m/z(ESI):571.2[M+H] ⁺ .

Example 6 N-(4-(4-(1-(3,3-difluorocyclobutyl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-1,2,3-triazol-1-yl) -3-((4,4-difluorocyclohexyl)oxy)phenyl)-2-hydroxyethane-1-sulfonamide (Compound 006)

Referring to the synthesis method of Example 5, the ethanesulfonamide in step 5.5 was replaced with 2-hydroxyethyl-1-sulfonamide to obtain the target product N-(4-(4-(1-(3,3-difluorocyclobutyl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-1,2,3-triazol-1-yl)-3-((4,4-difluorocyclohexyl)oxy)phenyl)-2-hydroxyethane-1-sulfonamide (compound 006). ¹ H NMR (400MHz, DMSO) δ8.94(s,1H),8.08(d,J＝9.6Hz,1H),7.64(d,J＝8.6Hz,1H),7.13(d,J＝9.8Hz,2H),6.99(d,J＝8.6Hz ,1H),5.30–5.21(m,1H),4.66(s,1H),3.78(t,J＝6.4Hz,2H),3.32–3.31(m,2H),3.17–3.01(m,4H),1.95–1.76(m,8H). LCMS:MS m/z(ESI):587.1[M+H] ⁺ .

Example 7 N-(3-(8,8-difluoro-3-azabicyclo[3.2.1]octane-3-yl)-4-(4-(1-(3,3-difluorocyclobutyl)-6-oxo- 1,6-dihydropyridazin-3-yl)-1H-1,2,3-triazol-1-yl)phenyl)ethanesulfonamide (compound 007)

7.1 Synthesis of intermediate 7-2:

At room temperature, 210 mg of 8,8-difluoro-3-azabicyclo[3.2.1]octane and 924 mg of DIEA were added to a DMSO solution of 381 mg of 2-fluoro-4-iodo-1-nitrobenzene (381 mg) in 5.00 mL. The mixture was then sealed and stirred at 80 °C for 16 hours. After cooling to room temperature, the mixture was diluted with 20.0 mL of saturated sodium chloride aqueous solution and extracted with ethyl acetate (3 × 20.0 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give intermediate 7-2 (550 mg, crude product), which was used directly in the next reaction. LCMS: MS m/z (ESI): 394.9 [M+H] ⁺ .

7.2 Synthesis of intermediate 7-3:

Intermediate 7-2 (550 mg) was dissolved in a mixed solvent of tetrahydrofuran/ethanol/water (4:2:1, 10.0 mL) at room temperature. Iron powder (782 mg) and ammonium chloride (749 mg) were added, and the mixture was stirred at 80 °C for 2 hours under nitrogen protection. The reaction solution was cooled to room temperature, diluted with saturated sodium chloride aqueous solution (20.0 mL), and extracted with ethyl acetate (3 × 20.0 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 preparative thin-layer chromatography (PE:EA = 4:1) to obtain intermediate 7-3 (300 mg). LCMS: MS m/z (ESI): 364.9 [M+H] ⁺ .

7.3 Synthesis of intermediate 7-4:

At room temperature, 71.0 mg of azide-trimethylsilane and 64.0 mg of tert-butyl nitrite were added to a 3.00 mL solution of intermediate 7-3 (150 mg). The mixture was stirred at 50 °C for 2 hours under nitrogen protection. The reaction solution was cooled to room temperature, diluted with 20.0 mL of water, and extracted with ethyl acetate (3 × 20.0 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give intermediate 7-4 (150 mg). LCMS: MS m/z (ESI): 391.0 [M+H] ⁺ .

7.4 Synthesis of intermediate 7-5:

Intermediate 1-7 (81 mg) was dissolved in a water/tert-butanol (1:1, 5.00 mL) mixture at room temperature. Intermediate 7-4 (150 mg), anhydrous copper sulfate (12.0 mg), and sodium L-ascorbate (84.0 mg) were added. The mixture was stirred at 60 °C for 2 hours under nitrogen protection. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (PE:EA = 4:1) (SunFire Prep C18 OBD 10 μm, 19*250 mm, mobile phase A: _H₂O containing 0.1% formic acid, mobile phase B: _CH₃CN , A/B = 70%–5% gradient) to obtain intermediate 7-5 (100 mg). LCMS: MS m/z (ESI): 601.0 [M+H] ^⁺ .

7.5 Synthesis of Compound 007:

At room temperature, (1S,2S)-N ^<sub>1 ,N₂-dimethylcyclohexane-1,2-diamine (12.0 mg), cuprous iodide (32.0 mg), potassium phosphate (35.0 mg), and intermediate 7-5 (50.0 mg) were added to a solution of ethanesulfonamide (27.0 mg) in N, ^N -dimethylformamide (2.0 mL). The mixture was reacted at 120 °C for 1 hour under microwave conditions. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography to obtain the target product N-(3-(8,8-difluoro-3-azabicyclo[3.2.1]octane-3-yl)-4-(4-(1-(3,3-difluorocyclobutyl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-1,2,3-triazol-1-yl)phenyl)ethanesulfonamide (compound 007) (16.18 mg). ¹ H NMR (400MHz, DMSO) δ10.13(s,1H),9.12(s,1H),8.10(d,J＝9.6Hz,1H),7.48(d,J＝8.6 Hz,1H),7.23(d,J＝2.2Hz,1H),7.14(d,J＝9.6Hz,1H),7.11(dd,J＝8.6,2.2Hz,1H),5. 30–5.25(m,1H),3.21(q,J＝7.3Hz,2H),3.15–3.03(m,4H),2.99(d,J＝11.0Hz,2H),2. 59(d,J＝11.0Hz,2H),2.21(s,2H),1.61–1.53(m,4H),1.23(t,J＝7.3Hz,3H).LCMS:MS m/z(ESI):582.1[M+H] ⁺ .

Example 8 N-(3-(3-azabicyclo[3.2.1]octane-3-yl)-4-(4-(1-(3,3-difluorocyclobutyl)-6-oxo-1,6-dihydropyridazin- 3-yl)-1H-1,2,3-triazol-1-yl)phenyl)ethanesulfonamide (compound 008)

Referring to the synthesis method of Example 7, 8,8-difluoro-3-azabicyclo[3.2.1]octane in step 7.1 was replaced with 8-azabicyclo(3.2.1)octane, and the remaining steps were the same as in Example 7. Finally, the target compound N-(3-(3-azabicyclo[3.2.1]octan-3-yl)-4-(4-(1-(3,3-difluorocyclobutyl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-1,2,3-triazol-1-yl)phenyl)ethanesulfonamide (compound 008) was obtained. ¹ H NMR (400MHz, DMSO) δ10.16 (s, 1H), 8.98 (s, 1H), 8.10 (d, J = 9.6Hz, 1H), 7.42 ( d,J＝8.5Hz,1H),7.17–7.12(m,2H),7.02(dd,J＝8.5,2.2Hz,1H),5.35–5.25(m ,1H),3.17(q,J＝7.4Hz,2H),3.13–3.01(m,4H),2.66(d,J＝10.4Hz,2H),2.50 –2.42(m,2H),2.07(s,2H),1.52–1.36(m,6H),1.22(t,J＝7.4Hz,3H).LCMS:MS m/z(ESI):546.1[M+H] ⁺ .

Example 9: N-(3-(3-azabicyclo[3.2.1]octane-3-yl)-4-(4-(1-(3,3-difluorocyclobutyl)-6-oxo-1,6-dihydropyridazin -3-yl)-1H-1,2,3-triazol-1-yl)phenyl)-2-hydroxyethane-1-sulfonamide (Compound 009)

Referring to the synthesis method of Example 7, 8,8-difluoro-3-azabicyclo[3.2.1]octane in step 7.1 was replaced with 8-azabicyclo(3.2.1)octane, and ethanesulfonamide in step 7.5 was replaced with 2-hydroxyethyl-1-sulfonamide, finally yielding the target compound N-(3-(3-azabicyclo[3.2.1]octan-3-yl)-4-(4-(1-(3,3-difluorocyclobutyl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-1,2,3-triazol-1-yl)phenyl)-2-hydroxyethane-1-sulfonamide (compound 009). ¹ H NMR (400MHz, DMSO) δ8.98(s,1H),8.10(d,J＝9.6Hz,1H),7.41(d,J＝8.5Hz,1H),7.14(d,J＝9.6Hz,2H),7.01(dd,J＝8.5,2.3Hz,1H),5.32–5.25(m,1H) ,3.77(t,J＝6.6Hz,2H),3.30(t,J＝6.6Hz,2H),3.19–3.04(m,4H),2.67(d, J＝10.5Hz,2H),2.50–2.42(m,2H),2.07(s,2H),1.53–1.36(m,6H).LCMS:MS m/z(ESI):562.1[M+H] ⁺ .

Example 10 N-(7-(4-(1-(3,3-difluorocyclobutyl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-1,2,3-triazol-1-yl)-6- (6-azaspiro[2.5]octane-6-yl)-2,3-dihydro-1H-inden-4-yl)ethanesulfonamide (Compound 010)

Synthesis of intermediate 10-2 (10.1):

Triethylsilane (12.7 g) was added to a TFA (160 mL) solution of 4-bromo-6-fluoro-2,3-dihydro-1H-inden-1-one (10.0 g, 43.7 mmol) at room temperature, and the mixture was purged three times with argon. The reaction mixture was stirred at 25 °C for 12 hours. The reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The organic phases were combined, washed with saturated sodium chloride aqueous solution (3 × 50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (EA in PE: 0–10%) to give intermediate 10⁻² (7.00 g). ¹ H NMR (400MHz, DMSO) δ: 7.22 (d, J = 8.8 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 2.95 (t, J = 7.2 Hz, 2H), 2.78 (t, J = 7.2 Hz, 2H), 2.04–2.00 (m, 2H).

Synthesis of intermediate 10-3 (10.2):

Acetic anhydride (6.66 mL) was added to a solution of intermediate 10⁻² (500 mg) in acetic acid (6.66 mL) at room temperature. The mixture was cooled to 0 °C, and fuming nitric acid (0.850 mL) was added. The reaction mixture was stirred at 25 °C for 2 hours. The reaction solution was diluted with water (5 mL), extracted with ethyl acetate (3 × 10 mL), the organic phases were combined, washed with saturated sodium chloride aqueous solution (3 × 10 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (EA in PE: 0–10%) to give intermediate 10⁻³ (180 mg).

Synthesis of intermediate 10-4 (10.3):

At room temperature, 6-azaspiro[2.5]octane hydrochloride (45.5 mg) and DIEA (199 mg) were added to a solution of intermediate 10⁻³ (80.0 mg) in NMP (3.00 mL). The reaction mixture was stirred at 80 °C for 2 hours. The reaction solution was diluted with water (5 mL), extracted with ethyl acetate (3 × 10 mL), the organic phases were combined, washed with saturated sodium chloride aqueous solution (3 × 10 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (EA in PE: 0–10%) to give intermediate 10⁻⁴ (100 mg). LCMS: MS m/z (ESI): 351.0 [M+H] ^⁺ .

Synthesis of compound 010, 10.4:

Referring to the synthesis method of Example 1, intermediate 1-2 in step 1.2 was replaced with intermediate 10-4, and the remaining steps were the same as in Example 1, finally yielding the target compound N-(7-(4-(1-(3,3-difluorocyclobutyl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-1,2,3-triazol-1-yl)-6-(6-azaspiro[2.5]octane-6-yl)-2,3-dihydro-1H-indene-4-yl) ethanesulfonamide (compound 010). ¹ H NMR (400MHz, DMSO) δ9.62(s,1H),8.96(s,1H),8.09(d,J＝9.7Hz,1H),7.13(d,J＝9.6Hz,1H),7.09(s,1H),5.33–5.24(m,1H),3.22–3.04(m,6H),2. 94(t,J＝7.4Hz,2H),2.76(t,J＝7.4Hz,2H),2.64(t,J＝5.3Hz,4H),1.99(p,J＝7.4Hz,2H),1.25(t,J＝7.3Hz,3H),1.21(s,4H),0.21(s,4H).LCMS:MS m/z(ESI):586.2[M+H] ⁺ .

Example 11 N-(3-(8,8-difluoro-3-azabicyclo[3.2.1]octane-3-yl)-4-(4-(1-(3,3-difluorocyclobutyl)-6-oxo -1,6-dihydropyridazin-3-yl)-1H-1,2,3-triazol-1-yl)phenyl)-2-hydroxyethane-1-sulfonamide (Compound 011)

Referring to the synthesis method of Example 7, the ethanesulfonamide in step 7.5 was replaced with 2-hydroxyethyl-1-sulfonamide to obtain the target compound N-(3-(8,8-difluoro-3-azabicyclo[3.2.1]octane-3-yl)-4-(4-(1-(3,3-difluorocyclobutyl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-1,2,3-triazol-1-yl)phenyl)-2-hydroxyethane-1-sulfonamide (compound 011). ¹ H NMR (400MHz, DMSO) δ9.10 (s, 1H), 8.10 (d, J = 9.6Hz, 1H), 7.44 (d, J = 8.5Hz, 1H), 7. 18(d,J＝2.3Hz,1H),7.14(d,J＝9.6Hz,1H),7.06(dd,J＝8.6,2.2Hz,1H),5.35–5.2 3(m,1H),3.77(t,J＝6.5Hz,2H),3.28(t,J＝6.5Hz,2H),3.18–3.04(m,5H),3.00(d ,J＝11.0Hz,2H),2.58(d,J＝11.0Hz,2H),2.20(s,2H),1.63–1.50(m,4H).LCMS:MS m/z(ESI):598.1[M+H] ⁺ .

Example 12 N-(3-(3-azabicyclo[3.2.1]octane-3-yl)-4-(4-(1-(3,3-difluorocyclobutyl)-6-oxo-1,6-dihydropyridazin -3-yl)-1H-1,2,3-triazol-1-yl)phenyl)methanesulfonamide (compound 024)

Referring to the synthesis method of Example 7, 8,8-difluoro-3-azabicyclo[3.2.1]octane in step 7.1 was replaced with 8-azabicyclo(3.2.1)octane, and ethanesulfonamide in step 7.5 was replaced with methanesulfonamide, finally yielding the target compound N-(3-(3-azabicyclo[3.2.1]octan-3-yl)-4-(4-(1-(3,3-difluorocyclobutyl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-1,2,3-triazol-1-yl)phenyl)methanesulfonamide (compound 024). ¹ H NMR (400MHz, DMSO) δ10.08(s,1H),8.99(s,1H),8.11(d,J＝9.6Hz,1H),7.45(d,J＝8.5Hz,1H),7.18–7.11(m,2H),7.04(dd,J＝8.5,2.3Hz,1 H),5.35–5.25(m,1H),3.20–3.05(m,4H),3.09(s,3H),2.68(d,J＝10.4Hz,2H),2.50–2.43(m,2H),2.07(s,2H),1.52–1.37(m,6H).LCMS:MS m/z(ESI):532.2[M+H] ⁺ .

Example 13 N-(3-(8,8-difluoro-3-azabicyclo[3.2.1]octane-3-yl)-4-(4-(1-(3,3-difluorocyclobutyl)-6-oxo -1,6-dihydropyridazin-3-yl)-1H-1,2,3-triazol-1-yl)phenyl)methanesulfonamide (Compound 025)

Referring to the synthesis method of Example 7, the ethanesulfonamide in step 7.5 was replaced with methanesulfonamide to obtain the target compound N-(3-(8,8-difluoro-3-azabicyclo[3.2.1]octane-3-yl)-4-(4-(1-(3,3-difluorocyclobutyl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-1,2,3-triazol-1-yl)phenyl)methanesulfonamide (compound 025). ¹ H NMR(400MHz, DMSO)δ9.10(s,1H),8.10(d,J＝9.6Hz,1H),7.46(d,J＝8.4Hz,1H),7.21–7.11(m,2H),7.08(d,J＝8.2Hz,1H),5.33–5.2 3(m,1H),3.18–3.06(m,4H),3.06(s,3H),3.00(d,J＝11.0Hz,2H),2.59(d,J＝11.0Hz,2H),2.20(s,2H),1.61–1.51(m,4H).LCMS:MS m/z(ESI):568.1[M+H] ⁺ .

The compounds listed in Table 1 were prepared in essentially the same manner as in Examples 1-13, using commercially available starting materials or those prepared according to literature methods. Table 1 provides the names and structures of the compounds.

Table 1

Example 1: Kif18A enzyme activity inhibition experiment

Inhibition of Kif18A ATPase activity was determined by ADP-Glo assay. The recombinant human Kif18A protein fragment (M1-V374, N-terminal His tag) was obtained via an E. coli expression system and purified by affinity chromatography (Reference: Locke, Julia, et al. "Structural basis of human kinesin-8 function and inhibition." Proceedings of the National Academy of Sciences 114.45(2017):E9539-E9548.). 4 nM of the purified Kif18A protein fragment was mixed with reaction buffer [(15 mM Tris, pH 7.5), ₁₀ mM MgCl2, 0.01% Pluronic F-68 (Life Technologies Inc), 2% DMSO, 1 μM paclitaxel (Cytoskeleton Inc), 30 μg/mL porcine microtubules (Cytoskeleton Inc)] at room temperature. The test compound was serially diluted 3-fold to 10 concentrations. 0.25 μL of each diluted compound was added to 2.5 μL of reaction buffer and incubated at room temperature for 10 minutes. 2.5 μL of 30 μM ATP was added to the reaction buffer to initiate the enzymatic reaction, and the reaction was allowed to proceed for 15 minutes at room temperature. ADP-Glo reagent was added to the reaction system according to the instructions, and the luminescence intensity of the sample was measured using a microplate reader (from BMG). A nonlinear regression equation was established using XLfit 5.5.0 software, the concentration-response curve was fitted, and the _IC50 was calculated. The experimental results are shown in Table 2.

Table 2. Results of enzyme activity testing for compound Kif18A

Example 2: Cell Proliferation Experiment

OVCAR3 cells (from ATCC) were seeded in 96-well plates at the optimal concentration for a 4-day cell growth assay. On the second day, the test compound or DMSO was serially diluted 3-fold from the initial 10 μM and added to the cells for co-incubation. After incubation at 37°C for 4 days, ADP-Glo reagent was added to each well, and the cells were incubated at room temperature for 30 minutes. The luminescence intensity of the samples was then measured using a microplate reader (from BMG). A nonlinear regression equation was established using XLfit 5.5.0 software to fit the concentration-response curve, and the _IC50 was calculated. The experimental results are shown in Table 3.

Table 3. Results of cell inhibitory activity assay for compound OVCAR3

Example 3: Pharmacokinetic Experiment in Mice

Experimental materials: CD-1 mice were purchased from Zhejiang Vital River Laboratory Animal Technology Co., Ltd., Spifort (Beijing) Biotechnology Co., Ltd., and Spifort (Suzhou) Biotechnology Co., Ltd. DMSO, Solutol, PEG400, acetonitrile, methanol, and VETPGS were purchased from Sigma-Aldrich, etc.

Experimental equipment: The LC-MS/MS system was a Waters Acquity UPLC class I plus tandem with an AB Sciex Triple Quad 6500+, and the chromatographic column was an Agilent Poroshell 120EC-C18 4μm (50×2.1mm). All data were acquired and processed using Analyst software, and pharmacokinetic parameters were calculated using Phoenix Build 8.3.

Experimental Methods: Six female CD-1 mice (20–30 g, 6–8 weeks old) were randomly divided into two groups of three mice each, based on their body weight. Group 1 received the test compound via tail vein injection at a dose of 1 mg/kg or 0.5 mg/kg, in a solution of 5% DMSO + 5% Solutol + 90% Saline. Group 2 received the test compound orally at a dose of 2 mg/kg or 5 mg/kg, in a solution of 5% DMSO/20% PEG400/75% (15% VETPGS aqueous solution). Group 1 mice were fed and watered normally before the experiment, while Group 2 mice were fasted overnight and fed 2 hours after administration. Blood samples were collected from the dorsal paw vein before administration and at 0.083 (for the intravenous injection group only), 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration. Whole blood samples were collected and placed in _K2 ·EDTA anticoagulant tubes. Plasma was prepared by centrifugation (4000g, 5min, 4℃). Plasma samples were stored at -75±15℃ until analysis. Mouse plasma samples were added to acetonitrile solution containing an internal standard compound and vortexed for 0.5min, followed by centrifugation at 3900rpm for 15min. The supernatant was transferred and diluted 3-fold with aqueous solution. 2μL of the supernatant was injected into an LC-MS/MS system for quantitative analysis. A standard curve of female CD-1 mouse plasma (linear range: 0.5–1000 ng/mL) and quality control samples (1, 2, 5, 50, 400, 800 ng/mL) were used to determine sample concentrations. Partial pharmacokinetic results are shown in Table 4.

Table 4 Results of mouse pharmacokinetics tests

As shown in Table 4, the compounds of this application possess excellent pharmacokinetic properties. The _Cmax , T1 _/2 , and AUC _last of compound 001 are all higher than those of compound 002, indicating that the pharmacokinetic properties of ethylsulfonamide are further superior to those of 2-hydroxyethylsulfonamide.

Example 4: In vivo efficacy study in mice

OVCAR3 is a human ovarian cancer cell line. A model was established using BALB/c nude female mice. 0.2 mL (10 × ^10⁶ cells) of OVCAR3 cells were subcutaneously inoculated into the right posterior dorsal region of each mouse. Treatment was initiated when the average tumor volume reached 100-150 ^mm³ , with five animals per group. The test compound was administered orally daily. Tumor diameter was measured twice weekly and at the endpoint of treatment. The tumor volume was calculated using the formula: V = 0.5a × b², where a and b represent the major and minor diameters of the tumor, respectively. The tumor-suppressive efficacy of the compound was evaluated using the tumor growth inhibition rate (TGI). TGI (%) = [1 - (average tumor volume at the end of treatment in a certain treatment group - average tumor volume at the start of treatment in that treatment group) / (average tumor volume at the end of treatment in the solvent control group - average tumor volume at the start of treatment in the solvent control group)] × 100 (%). Animal body weight change rate (%) = [ _BWt / _BW0 - 1] × 100 (%), where _BWt is the average body weight of mice in a certain treatment group at the time of measurement, and _BW0 is the initial average body weight of mice in that group at the time of administration. The reference compound is the Kif18A inhibitor AMG650 (CAS#: 2410796-79-9), and its synthesis method is based on patent WO2020132648. The test results are shown in Table 5 and Figures 1 and 2. The compound of this application achieved excellent tumor inhibition effect and had little impact on animal body weight, demonstrating good safety.

Table 5. Pharmacological effects in mouse OVCAR3 model

Claims (20)

Compounds of formula (I):
Or its pharmaceutically acceptable salt. in, Ring B is selected from 5-membered heterocyclic aromatic rings; Q is selected from M is selected from N and CH; U and V are each independently selected from O, S, L is selected from chemical bonds, -O-, -S-, -NR ^6- , and _C1-2 alkylene groups; wherein each These represent the connection sites; ^A1 is selected from N and C(R ⁷ ); ^A2 is selected from N and C(R ⁸ ); ^A3 is selected from N and C( ^R9 ); L ¹ is selected from -(CR ^C R ^D ) _t -S(=O) _r -, -(CR ^C R ^D ) _t -NR ^F S(=O) _r -, and -(CR ^C R ^D ) _t -S(=O) _r NR ^F -; ^L2 is selected from _C1-6 alkylene groups; ^X1 is selected from N and C (R ¹⁰ ); ^X2 is selected from N and C(R ¹¹ ); ^X3 is selected from N and C(R ¹² ); ^R1 is selected from _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, _C3-10 cycloalkyl, _-C1-4 alkylene- _C3-10 cycloalkyl, heterocyclic, -C1-4 alkylene-heterocyclic, aryl, _-C1-4 alkylene-aryl, heteroaryl, _-C1-4 alkylene- _heteroaryl , -NR ^A1 R ^B1 , -OR A1, -SR A1, -C(=O)R ^A1 , -C(=NR ^E1 )R ^A1 , -C(=N-OR ^B1 )R ^A1 , -C(=O)OR ^A1 , -OC(=O)R ^A1 , -C(=O)NR ^A1 R ^B1 , -NR ^F1 C ⁽ =O)R ^A1 , -C(=NR ^E1 )NR ^{A1 R B1 ,} -NR ^F1 C(=NR ^E1) )R ^A1 , -OC(=O)NR ^A1 R ^B1 , -NR ^F1 C(=O)OR ^A1 , -NR ^F1 C(=O)NR ^A1 R ^B1 , -NR ^F1 C(=S)NR ^A1 R ^B1 , -NR ^F1 C(=NR ^E1 )NR ^A1 R ^B1 , -S(=O) _r R ^A1 , -S(=O)(=NR ^E1 )R ^A1 , -N＝S(＝O)R ^A1 R ^B1 , -S(＝O) ₂ OR ^A1 , -OS(＝O) ₂ R ^A1 , -NR ^F1 S(＝O) _r R ^A1 , -NR ^F1 S(＝O)(＝NR ^E1 )R ^A1 , -S(＝O) _r NR ^A1 R ^B1 , -S(＝O)(＝NR ^E1 )NR ^A1 R ^B1 , -NR ^F1 S(=O) ₂ NR ^{A1 RB1} and -NR ^F1 S(＝O)(＝NR ^E1 )NR ^{A1 RB1} , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl group is unsubstituted or substituted by at least one substituent independently selected from ^RX1 ; Each ^R2 is independently selected from halogens, _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, _C3-10 cycloalkyl, _-C1-4 alkylene- _C3-10 cycloalkyl, heterocyclic, -C1-4 alkylene-heterocyclic, aryl, _-C1-4 alkylene-aryl, _heteroaryl , _-C1-4 alkylene-heteroaryl, CN, _NO2 , ^-NRA2RB2 , ^-ORA2 , -SRA2, -C(=O) ^RA2 , -C( ₌ O) ^ORA2 , ^-OC (=O) ^RA2 , -C(=O) ^NRA2RB2 , ^-NRA2C (=O) ^RB2 , -NRA2C(= ^NRE2 ) ^RB2 , ^-OC (= ^{O)NRA2RB2 , -NRA2C (} =O ^{) ORB2} , -NR ^A2 C(=O)NR ^A2 R ^B2 , -NR ^A2 C(=S)NR ^A2 R ^B2 , -NR ^A2 C(=NR ^E2 )NR ^A2 R ^B2 , -S(=O) _r R ^A2 , -S(=O)(=NR ^E2 )R ^B2 , -N=S(=O)R ^A2 R ^B2 , -S(=O) ₂ OR ^A2 , -OS(=O) ₂ R ^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) ₂ NR ^A2 R ^B2 and -NR ^A2 S(=O)(=NR ^E2 )NR ^A2 R ^B2 Each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is either unsubstituted or substituted by at least one substituent independently selected from ^RX2 ; ^R3 is selected from hydrogen, halogens, CN, _NO2 , -NR ^A3RB3 , -OR ^A3 , ^{-SR A3 ,} -C(=O) ^RA3 , -C(=O)OR ^A3 , -OC(=O) ^RA3 , -C(=O) ^{NR A3RB3} and -NR ^A3C (=O) ^RB3 ; Each ^R4 is independently selected from halogens, _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, _C3-10 cycloalkyl, -C1-4 alkylene- _C3-10 cycloalkyl, _heterocyclic , -C1-4 alkylene-heterocyclic, CN, _NO2 , -NR _A4 ^RB4 , -OR ^A4 , -SR ^A4 , -C(=O)R ^A4 , -C(=O)OR ^A4 , ^-OC (=O)R ^A4 , -C(=O)NR ^{A4 RB4} , -NR ^A4 C(=O) ^RB4 , -NR ^A4 C(=NR ^E4 ) ^RB4 , -OC(=O)NR ^{A4 RB4} , -NR ^A4 C(=O)OR ^B4 , -NR ^A4 C(=O)NR ^{A4 RB4} , -NR ^A4 C(=S) ^{NR A4 RB4} -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) ₂ OR ^A4 , -OS(＝O) ₂ R ^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) ₂ NR ^A4 R ^B4 and -NR ^A4 S(＝O)(＝NR ^E4 )NR ^A4 R ^B4 , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl and heterocyclic group is unsubstituted or substituted by at least one substituent independently selected from ^RX4 ; Or any two R ^4s together with the carbon atoms attached to them form a saturated or unsaturated 3-7 membered ring containing 0, 1, 2 or 3 heteroatoms, wherein the heteroatoms are independently selected from oxygen, sulfur, nitrogen and phosphorus, and the ring is either unsubstituted or substituted by 1, 2 or 3 R ^X4 substituents. ^R4a and ^R4b are each independently selected from hydrogen and ^R4 ; Or R ^4a and R ^4b together with the carbon atoms attached to them form a saturated or unsaturated 3-7 membered ring containing 0, 1, 2 or 3 heteroatoms, wherein the heteroatoms are independently selected from oxygen, sulfur, nitrogen and phosphorus, and the ring is either unsubstituted or substituted by 1, 2 or 3 R ^X4 substituents. R ^5a and R ^5b are each independently selected from hydrogen, halogen, _C1-10 alkyl and _C3-10 cycloalkyl, wherein the alkyl and cycloalkyl are unsubstituted or substituted by at least one substituent independently selected from R ^X5 ; Or R ^5a and R ^5b together with the carbon atoms attached to them form a saturated or unsaturated 3-7 membered ring containing 0, 1, 2 or 3 heteroatoms, wherein the heteroatoms are independently selected from oxygen, sulfur, nitrogen and phosphorus, and the ring is either unsubstituted or substituted by 1, 2 or 3 R ^X5 substituents. ^R6 is selected from hydrogen and _C1-10 alkyl groups, wherein the alkyl group is unsubstituted or substituted by at least one substituent selected independently from R ^X6 ; R ⁷ is selected from halogens, _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, _C3-10 cycloalkyl, _-C1-4 alkylene- _C3-10 cycloalkyl, heterocyclic, -C1-4 alkylene-heterocyclic, aryl, _-C1-4 alkylene-aryl, heteroaryl, _-C1-4 alkylene-heteroaryl, CN, NO ₂ , -NR ^A7 _RB7 , -OR A7, -SR ^A7 , -C(=O)R ^A7 , ^-C (=O)OR A7, -OC(=O)R ^A7 , -C(=O)NR ^{A7 RB7} , -NR ^A7 C(=O)R ^B7 , -NR ^A7 C(=NR ^E7 )R ^B7 , -OC(=O)NR ^{A7 RB7} , -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) ₂ OR ^A7 , -OS(=O) ₂ R ^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) ₂ NR ^A7 R ^B7 and -NR ^A7 S(=O)(=NR ^E7 )NR ^A7 R ^B7 Each alkyl, alkylene, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is either unsubstituted or substituted by at least one substituent independently selected from ^RX7 . ^R8 is selected from halogens, _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, _C3-10 cycloalkyl, _-C1-4 alkylene- _C3-10 cycloalkyl, heterocyclic, -C1-4 alkylene-heterocyclic, aryl, _-C1-4 alkylene-aryl, heteroaryl, _-C1-4 alkylene-heteroaryl, CN, NO2, -NR ^A8 _RB8 , -OR _A8 , -SR ^A8 , -C(=O)R ^A8 , ^-C (=O)OR A8, -OC(=O)R ^A8 , -C(=O)NR ^{A8 RB8} , -NR ^A8 C(=O) ^{R B8 ,} -NR ^A8 C(=NR ^E8 )R ^B8 , -OC(=O)NR ^{A8 RB8} , -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) ₂ OR ^A8 , -OS(=O) ₂ R ^A8 , -NR ^A8 S(=O) _r ^RB8 , -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) ₂ NR ^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 either unsubstituted or substituted by at least one substituent independently selected from ^RX8 . Alternatively, ^R7 and ^R8, together with the atoms attached to them, form a _C5-10 hydrocarbon ring or a 5-10 membered heterocycle or a 5-10 membered heteroaromatic ring containing 1, 2, or 3 heteroatoms, wherein the hydrocarbon ring, heterocycle, and heteroaromatic ring are monocyclic or bicyclic, the heteroatoms in the heterocycle are independently selected from oxygen, sulfur, nitrogen, and phosphorus, and the heteroatoms in the heteroaromatic ring are independently selected from oxygen, sulfur, and nitrogen; the ring is unsubstituted or substituted by at least one substituent independently selected from R ^X8 ; R ⁹ is selected from halogens, _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, _C3-10 cycloalkyl, _-C1-4 alkylene- _C3-10 cycloalkyl, heterocyclic, -C1-4 alkylene-heterocyclic, aryl, _-C1-4 alkylene-aryl, heteroaryl, _-C1-4 alkylene-heteroaryl, CN, NO ₂ , -NR ^A9 _RB9 , -OR A9, -SR ^A9 , -C(= ^O )R A9, ^-C (=O)OR A9, -OC(=O)R ^A9 , -C(=O)NR ^{A9 RB9} , -NR ^A9 C(=O)R ^B9 , -NR ^A9 C(=NR ^E9 )R ^B9 , -OC(=O)NR ^{A9 RB9} , -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) ₂ OR ^A9 , -OS(=O) ₂ R ^A9 , -NR ^A9 S(=O) _r ^RB9 , -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) ₂ NR ^A9 R ^B9 and -NR ^A9 S(=O)(=NR ^E9 )NR ^A9 R ^B9 Each alkyl, alkylene, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is either unsubstituted or substituted by at least one substituent independently selected from ^RX9 ; ^R10 is selected from halogens, _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, _C3-10 cycloalkyl, _-C1-4 alkylene- _C3-10 cycloalkyl, heterocyclic, -C1-4 alkylene-heterocyclic, aryl, _-C1-4 alkylene-aryl, heteroaryl, _-C1-4 alkylene-heteroaryl, CN, _NO2 , -NR ^A10 _RB10 , -OR A10, -SR ^A10 , -C(=O)R ^A10 , -C(=O)OR ^A10 , -OC(=O)R ^A10 , -C(=O)NR ^{A10 RB10} , -NR ^A10 C( ^{=O)RB10, -NR A10 C(=NR E10)RB10 , -OC ( = O} )NR ^{A10 RB10} , -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) ₂ OR ^A10 , -OS(＝O) ₂ R ^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) ₂ NR ^{A10 RB10} and -NR ^A10 S(＝O)(＝NR ^E10 )NR ^{A10 RB10} , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl group is unsubstituted or substituted by at least one substituent independently selected from ^RX10 ; R ¹¹ is selected from halogens, _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, _C3-10 cycloalkyl, _-C1-4 alkylene- _C3-10 cycloalkyl, heterocyclic, -C1-4 alkylene-heterocyclic, aryl, _-C1-4 alkylene-aryl, heteroaryl, _-C1-4 alkylene-heteroaryl, CN, NO ₂ , -NR ^A11 _RB11 , -OR ^A11 , -SR ^A11 , -C(=O)R ^A11 , -C(=O)OR ^{A11, -OC(=O)R A11 ,} -C(=O)NR ^{A11 RB11} , -NR ^{A11 C} (=O) ^RB11 , -NR ^A11 C(=NR ^E11 ) ^RB11 , -OC(=O)NR ^{A11 RB11} ,-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) ₂ OR ^A11 , -OS(＝O) ₂ R ^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) ₂ NR ^A11 R ^B11 and -NR ^A11 S(＝O)(＝NR ^E11 )NR ^A11 R ^B11 , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl group is unsubstituted or substituted by at least one substituent independently selected from ^RX11 ; Alternatively, ^R10 and ^R11, together with the atoms attached to them, form a _C5-10 hydrocarbon ring or a 5-10 membered heterocycle or a 5-10 membered heteroaromatic ring containing 1, 2 or 3 heteroatoms, wherein the hydrocarbon ring, heterocycle and heteroaromatic ring are monocyclic or bicyclic, the heteroatoms in the heterocycle are independently selected from oxygen, sulfur, nitrogen and phosphorus, and the heteroatoms in the heteroaromatic ring are independently selected from oxygen, sulfur and nitrogen; the ring is unsubstituted or substituted by at least one substituent independently selected from R ^X11 ; ^R12 is selected from halogens, _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, _C3-10 cycloalkyl, _-C1-4 alkylene- _C3-10 cycloalkyl, heterocyclic, -C1-4 alkylene-heterocyclic, aryl, _-C1-4 alkylene-aryl, heteroaryl, _-C1-4 alkylene-heteroaryl, CN, NO2, -NR ^A12 _RB12 , -OR _A12 , -SR ^A12 , -C(=O) ^RA12 , ^-C (=O)OR ^A12 , -OC(=O)RA12, -C(=O)NR ^{A12 RB12} , -NR ^A12 C(=O ^{)RB12 ,} -NR ^A12 C(=NR ^E12 ) ^RB12 , -OC(= ^O )NR ^{A12 RB12} , -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) ₂ OR ^A12 , -OS(＝O) ₂ R ^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, heterocyclic, aryl and heteroaryl group is unsubstituted or substituted by at least one substituent independently selected from ^RX12 ; Each ^RF , ^RF1 , RA1, ^RA2 , ^RA3 , ^RA4 , RA7, ^RA8 , ^RA9 , ^RA10 , ^RA11 , ^RA12 , ^RB1 , ^RB2 , ^RB3 , ^RB4 , RB7, ^RB8 , ^RB9 , ^RB10 , ^RB11 , ^{and RB12 is} independently selected from hydrogen, _C1-10 alkyl, ^C2-10 _alkenyl , ^C2-10 alkynyl, _C3-10 cycloalkyl, _-C1-4 alkylene- _C3-10 cycloalkyl, heterocyclic, _-C1-4 alkylene-heterocyclic, _aryl , _-C1-4 alkylene-aryl, heteroaryl _, and -C _1-4 alkylene-heteroaryl, wherein each alkyl, alkylene, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl and heteroaryl group is unsubstituted or substituted by at least one substituent independently selected from R ^X ; Or “ ^RA1 and ^RB1 ” or “ ^RA2 and ^RB2 ” or “ ^RA3 and ^RB3 ” or “RA4 and RB4” or “ ^RA7 and ^RB7 ” or “ ^RA8 and ^RB8 ” or “ ^RA9 and ^RB9 ” or “ ^RA10 and ^RB10 ” or “ ^RA11 and ^RB11 ” or “ ^RA12 and ^RB12 ” together with one or more atoms attached to them constitute a 4-12 membered heterocycle containing 0, 1 or 2 additional independent heteroatoms selected from oxygen, sulfur, nitrogen and phosphorus, which is either unsubstituted or substituted ^with 1, 2 or 3 substituents selected ^{from RX} ; Each ^RC and ^RD is independently selected from hydrogen, halogen, _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, _C3-10 cycloalkyl, _-C1-4 alkylene- _C3-10 cycloalkyl, heterocyclic, -C1-4 alkylene-heterocyclic, aryl, _-C1-4 alkylene-aryl, _heteroaryl and _-C1-4 alkylene-heteroaryl, wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl is unsubstituted or substituted by at least one substituent independently selected from ^RX ; Alternatively, each “ ^RC and ^RD ” together with one or more carbon atoms attached to them forms a 3-12 membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, which is either unsubstituted or substituted with 1, 2 or 3 substituents independently selected from ^RX . Each ^RE1 , ^RE2 , ^RE4 , ^RE7 , ^RE8 , ^RE9 , ^RE10 , ^RE11 and ^RE12 is independently selected from hydrogen, _C1-10 alkyl, CN, _NO2 , -S(=O) _rRa1 , -C(=O) ^Ra1 , -C(=O) ^ORa1 , ^{-C (} =O) ^NRa1Rb1 and -S(=O) ^rNRa1Rb1 , wherein the alkyl group is unsubstituted or substituted _by at least one substituent independently selected from ^{RX ;} Each ^RX , ^RX1 , ^RX2 , RX4, ^RX5 , ^RX6 , ^RX7 , ^RX8 , ^RX9 , ^RX10 , ^RX11 , ^{and RX12 is} independently selected from halogens, _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, _C3-10 cycloalkyl, _-C1-4 alkylene- _C3-10 cycloalkyl, heterocyclic, _{-C1-4 alkylene-heterocyclic, aryl, -C1-4 alkylene} -aryl, heteroaryl, _-C1-4 alkylene-heteroaryl, CN, _NO2 , -( ^CRc1Rd1 ) ^uNRa1Rb1 , _- ( ^CRc1Rd1 ) ^{uORb1 ,} _- ( ^CRc1Rd1 ) _uC ( _＝ ^O ) ^Ra1 , - ^{( CRc1Rd1 ) u} C(＝NR ^e1 )R ^a1 , -(CR ^c1 R ^d1 ) _u C(＝O)OR ^b1 , -(CR ^c1 R ^d1 ) _u OC(＝O)R ^b1 , -(CR ^c1 R ^d1 ) _u C(＝O)NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _u NR ^a1 C(＝O)R ^b1 , -(CR ^c1 R ^d1 ) _u C(＝NR ^e1 )NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _u NR ^a1 C(＝NR ^e1 )R ^b1 , -(CR ^c1 R ^d1 ) _u OC(＝O)NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _u NR ^a1 C(＝O)OR ^b1 , -(CR ^c1 R ^d1 ) _u NR ^a1 C(＝O)NR ^a1 R ^b1 ,-(CR ^c1 R ^d1 ) _u NR ^a1 C(＝S)NR ^a1 R ^b1 ,-(CR ^c1 R ^d1 ) _u NR ^a1 C(＝NR ^e1 )NR ^a1 R ^b1 ,-(CR ^c1 R ^d1 ) _u S(＝O) _r R ^b1 ,-(CR ^c1 R ^d1 ) _u S(＝O)(＝NR ^e1 )R ^b1 ,-(CR ^c1 R ^d1 ) _u N＝S(＝O)R ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _u S(＝O) ₂ OR ^b1 , -(CR ^c1 R ^d1 ) _u OS(＝O) ₂ R ^b1 , -(CR ^c1 R ^d1 ) _u NR ^a1 S(＝O) _r R ^b1 , -(CR ^c1 R ^d1 ) _u NR ^a1 S(＝O)(＝NR ^e1 )R ^b1 、-(CR ^c1 R ^d1 ) _u S(＝O) _r NR ^a1 R ^b1 、-(CR ^c1 R ^d1 ) _u S(＝O)(＝NR ^e1 )NR ^a1 R ^b1 、-(CR ^c1 R ^d1 ) _u NR ^a1 S(＝O) ₂ NR ^a1 R ^b1 and -(CR ^c1 R ^d1 ) _u NR ^a1 S(＝O)(＝NR ^e1 )NR ^a1 R ^b1 , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl group is unsubstituted or substituted by at least one substituent independently selected from R ^Y ; Each ^Ra1 and ^Rb1 is independently selected from hydrogen, _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, _C3-10 cycloalkyl, _-C1-4 alkylene- _C3-10 cycloalkyl, heterocyclic, -C1-4 alkylene-heterocyclic, aryl, _-C1-4 alkylene-aryl, heteroaryl and _-C1-4 alkylene-heteroaryl, wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, _aryl and heteroaryl is unsubstituted or substituted by at least one substituent independently selected from R ^Y ; Or ^Ra1 and ^Rb1 together with one or more atoms attached to them form a 4-12 membered heterocycle containing 0, 1 or 2 additional heteroatoms selected from oxygen, sulfur, nitrogen and phosphorus, which is either unsubstituted or substituted with 1, 2 or 3 substituents selected from R ^Y. Each ^Rc1 and ^Rd1 is independently selected from hydrogen, halogen, _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, C3-10 cycloalkyl, _-C1-4 alkylene- _C3-10 cycloalkyl, heterocyclic, _-C1-4 alkylene-heterocyclic, aryl, _-C1-4 alkylene-aryl, _heteroaryl and _-C1-4 alkylene-heteroaryl, wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl is unsubstituted or substituted by at least one substituent independently selected from R ^Y ; Alternatively, each ^Rc1 and ^Rd1 together with one or more carbon atoms attached to them can form a 3-12 membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, which is either unsubstituted or substituted with 1, 2 or 3 substituents independently selected from R and ^Y. Each ^Re1 is independently selected from hydrogen, _C1-10 alkyl, CN, _NO2 , -S(=O) _rRa1 ^, -C ⁽ =O) ^Ra1 , -C(=O) ^ORa1 , -C(=O) ^NRa1Rb1 and _-S (=O) ^rNRa1Rb1 , wherein the alkyl group is unsubstituted or substituted ^by at least one substituent independently selected from ^RY ; Each R ^Y is independently selected from halogen, _NO₂ , -CN, _C1-10 alkyl, -OH, -O ( _C1-10 alkyl), -O ( _C3-10 cycloalkyl), -O ( _C1-4 alkylene- _C3-10 cycloalkyl), -O (heterocyclic), -O ( _C1-4 alkylene-heterocyclic), -SH, -S ( _C1-10 alkyl), -S ( _C3-10 cycloalkyl), -S ( _C1-4 alkylene- _C3-10 cycloalkyl), -S (heterocyclic), -S ( _C1-4 alkylene-heterocyclic), _-NH₂ , -NH (C1-10 alkyl), -N ( _C1-10 alkyl), -NH ( _C3-10 cycloalkyl), _-NH ( _C1-4 alkylene- _C3-10 cycloalkyl), -NH (heterocyclic), and -NH ( _C1-10 alkyl). _1-4 -alkylene-heterocyclic groups); d is selected from 0, 1, 2, 3, and 4; m is selected from 0, 1, 2, 3, and 4; n is selected from 0, 1, 2, and 3; p is an integer selected from 0 to 13; Each r is independently selected from 1 and 2; Each t is independently selected from 0, 1, 2, 3, and 4; Each u is independently selected from 0, 1, 2, 3, and 4. The compound of claim 1, wherein R ¹ is selected from C _3-10 cycloalkyl, -C _1-4 alkylene-C _3-10 cycloalkyl, heterocyclic and -C _1-4 alkylene-heterocyclic, wherein each alkylene, cycloalkyl and heterocyclic is unsubstituted or substituted by at least one substituent selected independently from R ^X1 ; Preferably, ^R1 is selected from _C4-6 cycloalkyl groups, wherein the cycloalkyl group is unsubstituted or substituted by at least one substituent independently selected from R ^X1 ; More preferably, ^R1 is selected from The compound of claim 1 or 2, wherein ^R2 is selected from halogens, CN, _NO2 and _C1-10 alkyl groups, wherein the alkyl group is unsubstituted or substituted by at least one substituent independently selected from R ^X2 . The compound of any one of claims 1-3, wherein ^L1 is -NHS(＝O) _2- ; and/or ^L2 is selected from _C1-3 alkylene groups, particularly methylene or ethylene. The compound of any one of claims 1-4, wherein ^R3 is selected from hydrogen, halogen, CN, _NO2 , ^-NRA3RB3 , ^{-ORA3 and -SRA3} ; Preferably, ^R3 is F, -hydrogen, or -OH, especially hydrogen or -OH. The compound of any one of claims 1-5, wherein Each ^R4 is independently selected from halogens, _C1-10 alkyl groups, _C3-10 cycloalkyl groups, CN and _NO2 , preferably from halogens and _{C3-10 cycloalkyl} groups, wherein each alkyl and cycloalkyl group is unsubstituted or substituted by at least one substituent independently selected from R ^X4 ; or any two ^R4 groups together with the carbon atoms attached to them form a _C5-6 hydrocarbon ring, which is unsubstituted or substituted by 1, 2 or 3 R ^X4 substituents; Preferably, ^R4 is F; or any two ^R4s together with the carbon atoms attached to them form a saturated _C5 hydrocarbon ring, which is unsubstituted or substituted by one, two or three ^R4 substituents. The compound of any one of claims 1-6, wherein Q has the following structure (i):
in, p1 is an integer selected from 0 to 13; Preferably, M is N; or Q has the structure of equation (iii) as follows:
in, p1 is an integer selected from 0 to 13; Preferably, L is -O-. The compound of claim 7, wherein ^R4a and ^R4b are each independently selected from hydrogen and halogen; preferably, ^R4a and ^R4b are hydrogen, or ^R4a and ^R4b are F; or ^R4a and ^R4b, together with the carbon atoms attached to them, form a saturated or unsaturated 3-7 membered hydrocarbon ring, which is either unsubstituted or substituted by one, two, or three R ^X4 substituents. The compound of any one of claims 1-8, wherein Q is selected from: The compound of any one of claims 1-9, wherein ^A1 is C( ^R7 ); wherein ^R7 is preferably hydrogen; and/or ^A2 is C( ^R8 ); wherein ^R8 is preferably hydrogen; and/or A ³ is N. The compound of any one of claims 1-9, wherein ^A1 is C( ^R7 ), ^A2 is C( ^R8 ); wherein ^R7 and ^R8, together with the atoms attached to them, form a 5-membered heteroaromatic ring containing 1, 2, or 3 heteroatoms, wherein the heteroatoms in the heteroaromatic ring are independently selected from oxygen, sulfur, and nitrogen; the heteroaromatic ring is unsubstituted or substituted with at least one substituent independently selected from R ^X8 ; and/or ^A3 is C( ^R9 ); wherein ^R9 is preferably hydrogen. The compound of any one of claims 1-9, wherein In formula (I) The structure is The compound of any one of claims 1-12, wherein ^X1 is C( ^R10 ); wherein ^R10 is preferably hydrogen; and/or ^X2 is C( ^R11 ); wherein ^R11 is preferably hydrogen; and/or ^X3 is C( ^R12 ); wherein ^R12 is preferably hydrogen. The compound of any one of claims 1-12, wherein ^X1 is C( ^R10 ), ^X2 is C( ^R11 ); wherein ^R10 and ^R11, together with the atoms attached to them, form a _C5 hydrocarbon ring or a 5-membered heterocycle or a 5-membered heteroaromatic ring containing 1, 2, or 3 heteroatoms, wherein the heteroatoms in the heterocycle and heteroaromatic ring are independently selected from oxygen, sulfur, and nitrogen; the ring is unsubstituted or substituted by at least one substituent independently selected from R ^X11 ; and/or ^X3 is C( ^R12 ); wherein ^R12 is preferably hydrogen. The compound of any one of claims 1-12, wherein In formula (I) The structure is The compound of any one of claims 1-15, wherein ring B is selected from... The compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

A pharmaceutical composition comprising a compound of any one of claims 1-17 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. Use of any compound of claims 1-17 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 18, in the preparation of a medicament for treating a disease, symptom, or condition selected from diseases of abnormal cell proliferation. Use of the compound of any one of claims 1-17 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 18, in the preparation of a medicament for treating a disease, symptom, or condition, wherein... The disease, symptom, or condition mentioned is cancer; Preferably, the cancer is selected from: (a) solid tumors or hematopoietic tumors selected from the following cancers: bladder cancer, endometrial cancer, squamous cell carcinoma of the lung, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, small cell lung cancer, esophageal cancer, gallbladder cancer, brain cancer, head and neck cancer, ovarian cancer, pancreatic cancer, gastric cancer, cervical cancer, thyroid cancer, prostate cancer, and skin cancer; (b) hematopoietic tumors selected from the following lymphoid systems: leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin lymphoma, and non-Hodgkin lymphoma. (c) Lymphoma, pilocellular lymphoma, and Burkert lymphoma; (d) hematopoietic tumors of the following bone marrow lineages: acute and chronic myeloid leukemia, myelodysplastic syndromes, and promyelocytic leukemia; (e) stromal tumors of the following fibrosarcoma and rhabdomyosarcoma; (f) tumors of the central and peripheral nervous systems of the following astrocytoma, neuroblastoma, glioma, and schwannoma; or (f) melanoma, seminoma, teratoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, follicular thyroid carcinoma, 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.