Compounds as Kif18A inhibitors

Abstract

The invention relates to the field of medicinal chemistry, in particular to a compound used as a Kif18A inhibitor or pharmaceutically acceptable salt, a preparation method of the compound, a pharmaceutical composition and application of the compound or the pharmaceutically acceptable salt to treatment of Kif18A related diseases.

Description

Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and in particular to a class of compounds or pharmaceutically acceptable salts used as Kif18A inhibitors, preparation methods and pharmaceutical compositions thereof, and use thereof in treating Kif18A-related diseases. Background Art

[0002] Genomic instability is an important feature of most tumors, which is usually accompanied by multiple losses and duplications of entire chromosomes. In tumor cells, abnormalities in chromosome number and structure usually come from mutations in DNA repair genes (such as BRCA1 / 2) and cell cycle regulatory genes (such as TP53). Abnormal karyotypes also make tumor cells particularly sensitive to interference with mitosis. In the past few decades, many drugs targeting mitosis have been developed for tumor treatment. Among them, taxanes (such as paclitaxel and docetaxel) are the most important class and are widely used in the treatment of various human malignancies including ovarian cancer, breast cancer, lung cancer and prostate cancer. Although anti-mitotic drugs have a wide range of applications and good efficacy, widespread side effects and drug resistance still limit their success in tumor treatment. Therefore, the next generation of anti-mitotic drugs with fewer drug resistance problems and better safety needs to be developed urgently.

[0003] The kinesin superfamily is a class of molecular motors found in eukaryotic cells. In cells, they move along microtubules by hydrolyzing ATP, thereby playing a role in mitosis, meiosis, and protein transport. During mitosis, kinesins play an important role in spindle assembly, chromosome separation, and movement.

[0004] Human kinesin family member 18A (Kif18A) belongs to the kinesin-8 family. Kif18A is believed to control correct chromosome positioning and spindle tension in mitosis by regulating the dynamic behavior of kinetochore microtubules, thereby ensuring that sister chromatids are evenly distributed to the two daughter cells. Tumor cells have unstable genomes and are therefore more dependent on the function of Kif18A protein. Studies on cells with abnormal whole-genome multiplication, which is common in human cancer, found that when Kif18A was depleted, the growth of abnormal tetraploid cells was significantly inhibited, while the growth of normal diploid cells was not significantly affected. In addition, mice with transgenic knockout of Kif18A can still survive to adulthood, indicating that the development of inhibitors targeting Kif18A may have good safety. Therefore, finding inhibitors of Kif18A ATPase activity is a promising approach to developing new anticancer agents. Summary of the invention

[0005] In one aspect, a compound of formula (I) is provided:

[0006]

[0007] or a pharmaceutically acceptable salt thereof,

[0008] in,

[0009] Ring A is selected from C 6-14 Aromatic rings and 5-14 membered heteroaromatic rings;

[0010] Ring B is selected from a 5-membered heteroaromatic ring;

[0011] Q is selected from wherein M is selected from N, CH and C; U and V are each independently selected from O, S, L is selected from a chemical bond, -O-, -S-, -NR 7 -、C 1-2 Alkylene and C 2-4 Alkyne; each Respectively represent the connection site;

[0012] X 1 , X 2 and X 3 Each independently selected from N and C(R 8 );

[0013] R 1 Selected from C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclyl, aryl, -C 1-4 Alkylene-aryl, heteroaryl, -C 1-4 Alkylene-heteroaryl, -NR A R B 、-OR A 、-SR A 、-C(=O)R A 、-C(=NR E )R A 、-C(=N-OR B )R A 、-C(=O)OR A 、-OC(=O)R A 、-C(=O)NR A R B 、-NR F C(=O)R A 、-C(=NRE )NR A R B 、-NR F C(=NR E )R A 、-OC(=O)NR A R B 、-NR F C(=O)OR A 、-NR F C(=O)NR A R B 、-NR F C(=S)NR A R B 、-NR F C(=NR E )NR A R B 、-S(=O) r R A 、-S(=O)(=NR E )R A 、-N=S(=O)R A R B 、-S(=O)2OR A 、-OS(=O)2R A 、-NR F S(=O) r R A 、-NR F S(=O)(=NR E )R A 、-S(=O) r NR A R B 、-S(=O)(=NR E )NR A R B 、-NR F S(=O)2NR A R B and-NR F S(=O)(=NR E )NR A R B , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R X1 Substituents are substituted;

[0014] R 2 Selected from -(CR C2 R D2 ) t -S(=O) r RA2 、-(CR C2 R D2 ) t -S(=O)(=NR E2 )R B2 、-(CR C2 R D2 ) t -N=S(=O)R A2 R B2 、-(CR C2 R D2 ) t -S(=O)2OR A2 、-(CR C2 R D2 ) t -OS(=O)2R A2 、-(CR C2 R D2 ) t -NR A2 S(=O) r R B2 、-(CR C2 R D2 ) t -NR A2 S(=O)(=NR E2 )R B2 、-(CR C2 R D2 ) t -S(=O) r NR A2 R B2 、-(CR C2 R D2 ) t -S(=O)(=NR E2 )NR A2 R B2 、-(CR C2 R D2 ) t -NR A2 S(=O)2NR A2 R B2 and-NR A2 S(=O)(=NR E2 )NR A2 R B2 ;

[0015] Each R 3 Independently selected from halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclyl, aryl, -C 1-4 Alkylene-aryl, heteroaryl, -C 1-4 Alkylene-heteroaryl, CN, NO2, -NR A3 R B3 、-OR A3 、-SR A3 、-C(=O)R A3 、-C(=O)OR A3 、-OC(=O)R A3 、-C(=O)NR A3 R B3 、-NR A3 C(=O)R B3 、-NR A3 C(=NR E3 )R B3 、-OC(=O)NR A3 R B3 、-NR A3 C(=O)OR B3 、-NR A3 C(=O)NR A3 R B3 、-NR A3 C(=S)NR A3 R B3 、-NR A3 C(=NR E3 )NR A3 R B3 、-S(=O) r R A3 、-S(=O)(=NR E3 )R B3 、-N=S(=O)R A3 R B3 、-S(=O)2OR A3 、-OS(=O)2R A3 、-NR A3 S(=O) r R B3 、-NR A3 S(=O)(=NR E3 )R B3 、-S(=O) r NR A3 R B3 、-S(=O)(=NR E3 )NR A3 R B3 、-NR A3 S(=O)2NR A3 RB3 and-NR A3 S(=O)(=NR E3 )NR A3 R B3 , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R X3 Substituents are substituted;

[0016] or R 1 With adjacent R 3 Together with the atoms to which they are attached, they form C 5-12 A hydrocarbon ring or a 5-12 membered heterocyclic ring containing 1, 2 or 3 heteroatoms, wherein the hydrocarbon ring and the heterocyclic ring are monocyclic or bicyclic, wherein the heteroatoms contained in the heterocyclic ring are independently selected from oxygen, sulfur, nitrogen and phosphorus; the ring is unsubstituted or substituted by at least one independently selected from R X3 Substituents are substituted;

[0017] Each R 4 Independently selected from halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclyl, aryl, -C 1-4 Alkylene-aryl, heteroaryl, -C 1-4 Alkylene-heteroaryl, CN, NO2, -NR A4 R B4 、-OR A4 、-SR A4 、-C(=O)R A4 、-C(=O)OR A4 、-OC(=O)R A4 、-C(=O)NR A4 R B4 、-NR A4 C(=O)R B4 、-NR A4 C(=NR E4 )R B4 、-OC(=O)NR A4 R B4 、-NR A4 C(=O)OR B4 、-NR A4 C(=O)NR A4 R B4 、-NR A4 C(=S)NR A4 R B4、-NR A4 C(=NR E4 )NR A4 R B4 、-S(=O) r R A4 、-S(=O)(=NR E4 )R B4 、-N=S(=O)R A4 R B4 、-S(=O)2OR A4 、-OS(=O)2R A4 、-NR A4 S(=O) r R B4 、-NR A4 S(=O)(=NR E4 )R B4 、-S(=O) r NR A4 R B4 、-S(=O)(=NR E4 )NR A4 R B4 、-NR A4 S(=O)2NR A4 R B4 and-NR A4 S(=O)(=NR E4 )NR A4 R B4 , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R X4 Substituents are substituted;

[0018] Each R 5 Independently selected from halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclic group, CN, NO2, -NR A5 R B5 、-OR A5 、-SR A5 、-C(=O)R A5 、-C(=O)OR A5 、-OC(=O)R A5 、-C(=O)NR A5 R B5 、-NR A5 C(=O)RB5 、-NR A5 C(=NR E5 )R B5 、-OC(=O)NR A5 R B5 、-NR A5 C(=O)OR B5 、-NR A5 C(=O)NR A5 R B5 、-NR A5 C(=S)NR A5 R B5 、-NR A5 C(=NR E5 )NR A5 R B5 、-S(=O) r R A5 、-S(=O)(=NR E5 )R B5 、-N=S(=O)R A5 R B5 、-S(=O)2OR A5 、-OS(=O)2R A5 、-NR A5 S(=O) r R B5 、-NR A5 S(=O)(=NR E5 )R B5 、-S(=O) r NR A5 R B5 、-S(=O)(=NR E5 )NR A5 R B5 、-NR A5 S(=O)2NR A5 R B5 and-NR A5 S(=O)(=NR E5 )NR A5 R B5 , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl and heterocyclyl is unsubstituted or substituted with at least one independently selected from R X5 Substituents are substituted;

[0019] R 5a and R 5b are each independently selected from hydrogen and R 5 ;

[0020] or R 5a and R 5bTogether with the carbon atoms to which they are attached, they form a saturated or unsaturated 3-7 membered ring containing 0, 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, which ring is unsubstituted or substituted with 1, 2 or 3 R X5 Substituent substitution;

[0021] R 6a and R 6b are independently selected from hydrogen, halogen, C 1-10 Alkyl and C 3-10 Cycloalkyl, wherein alkyl and cycloalkyl are unsubstituted or substituted with at least one independently selected from R X6 Substituents are substituted;

[0022] or R 6a and R 6b Together with the carbon atoms to which they are attached, they form a saturated or unsaturated 3-7 membered ring containing 0, 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, which ring is unsubstituted or substituted with 1, 2 or 3 R X6 Substituent substitution;

[0023] R 7 Selected from hydrogen and C 1-10 Alkyl, wherein the alkyl group is unsubstituted or substituted with at least one independently selected from R X7 Substituents are substituted;

[0024] Each R 8 independently selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclyl, aryl, -C 1-4 Alkylene-aryl, heteroaryl, -C 1-4 Alkylene-heteroaryl, CN, NO2, -NR A8 R B8 、-OR A8 、-SR A8 、-C(=O)R A8 、-C(=O)OR A8 、-OC(=O)R A8 、-C(=O)NR A8 R B8 、-NR A8 C(=O)R B8 、-NR A8 C(=NR E8 )R B8 、-OC(=O)NRA8 R B8 、-NR A8 C(=O)OR B8 、-NR A8 C(=O)NR A8 R B8 、-NR A8 C(=S)NR A8 R B8 、-NR A8 C(=NR E8 )NR A8 R B8 、-S(=O) r R A8 、-S(=O)(=NR E8 )R B8 、-N=S(=O)R A8 R B8 、-S(=O)2OR A8 、-OS(=O)2R A8 、-NR A8 S(=O) r R B8 、-NR A8 S(=O)(=NR E8 )R B8 、-S(=O) r NR A8 R B8 、-S(=O)(=NR E8 )NR A8 R B8 、-NR A8 S(=O)2NR A8 R B8 and-NR A8 S(=O)(=NR E8 )NR A8 R B8 , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R X8 Substituents are substituted;

[0025] Each R F , R A , R B , R A2 , R A3 , R A4 , R A5 , R A8 , R B2 , R B3 , R B4 , R B5 and R B8independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclyl, aryl, -C 1-4 Alkylene-aryl, heteroaryl and -C 1-4 Alkylene-heteroaryl, wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R X Substituents are substituted;

[0026] or "R A and R B ” or “R A2 and R B2 ” or “R A3 and R B3 ” or “R A4 and R B4 ” or “R A5 and R B5 ” or “R A8 and R B8 "Together with the atoms or atoms to which they are attached, they form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, which ring is unsubstituted or substituted with 1, 2 or 3 atoms selected from R X Substituents are substituted;

[0027] Each R C2 and R D2 independently selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclyl, aryl, -C 1-4 Alkylene-aryl, heteroaryl and -C 1-4 Alkylene-heteroaryl, wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R X Substituents are substituted;

[0028] Or each "R C2 and R D2"Together with the single or multiple carbon atoms to which they are attached, they form a 3-12 membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, which ring is unsubstituted or substituted with 1, 2 or 3 independently selected from R X Substituents are substituted;

[0029] Each R E , R E2 , R E3 , R E4 , R E5 and R E8 independently selected from hydrogen, C 1-10 Alkyl, CN, NO2, -S(=O) r R a1 、-C(=O)R a1 、-C(=O)OR a1 、-C(=O)NR a1 R b1 and -S(=O) r NR a1 R b1 , wherein the alkyl group is unsubstituted or substituted with at least one independently selected from R X Substituents are substituted;

[0030] Each R X , R X1 , R X3 , R X4 , R X5 , R X6 , R X7 and R X8 Independently selected from halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclyl, aryl, -C 1-4 Alkylene-aryl, heteroaryl, -C 1-4 Alkylene-heteroaryl, CN, NO2, -(CR c1 R d1 ) u NR a1 R b1 、-(CR c1 R d1 ) u OR b1 、-(CR c1 R d1 ) u C(=O)R a1 、-(CRc1 R d1 ) 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 Rb1 ,-(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)2OR b1 ,-(CR c1 R d1 ) u OS(=O)2R 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)2NR 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, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R Y Substituents are substituted;

[0031] Each R a1 and R b1 independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclyl, aryl, -C 1-4 Alkylene-aryl, heteroaryl and -C 1-4 Alkylene-heteroaryl, wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R Y Substituents are substituted;

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

[0033] Each R c1 and R d1 independently selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclyl, aryl, -C 1-4 Alkylene-aryl, heteroaryl and -C 1-4 Alkylene-heteroaryl, wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R Y Substituents are substituted;

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

[0035] Each R e1 independently selected from hydrogen, C 1-10 Alkyl, CN, NO2, -S(=O) r R a1 、-C(=O)R a1 、-C(=O)OR a1 、-C(=O)NR a1 R b1 and -S(=O) r NR a1 R b1 , wherein the alkyl group is unsubstituted or substituted with at least one independently selected from R Y Substituents are substituted;

[0036] Each R Y Independently selected from halogen, NO2, -CN, C 1-10 Alkyl, -OH, -O(C 1-10 Alkyl), -O(C 3-10 Cycloalkyl), -O(C 1-4 Alkylene-C 3-10 Cycloalkyl), -O(heterocyclyl), -O(C 1-4 Alkylene-heterocyclyl), -SH, -S(C 1-10 Alkyl), -S(C 3-10 Cycloalkyl), -S(C 1-4 Alkylene-C 3-10 Cycloalkyl), -S(heterocyclyl), -S(C 1-4 Alkylene-heterocyclyl), -NH2, -NH(C 1-10 Alkyl), -N(C 1-10 Alkyl)2, -NH(C 3-10 Cycloalkyl), -NH(C 1-4 Alkylene-C 3-10 Cycloalkyl), -NH(heterocyclyl) and -NH(C 1-4 alkylene-heterocyclyl);

[0037] g is selected from 0, 1, 2, 3 and 4;

[0038] d is selected from 0, 1, 2, 3 and 4;

[0039] m is selected from 0, 1, 2, 3 and 4;

[0040] n is selected from 0, 1, 2 and 3;

[0041] p is an integer selected from 0 to 13;

[0042] Each r is independently selected from 1 and 2;

[0043] Each t is independently selected from 0, 1, 2, 3 and 4;

[0044] Each u is independently selected from 0, 1, 2, 3 and 4.

[0045] In another aspect, a pharmaceutical composition is provided, comprising a preventively or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

[0046] In another aspect, there is provided a use of a compound of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition in the preparation of a medicament for treating a disease, disorder or condition selected from a cell proliferation disorder. DETAILED DESCRIPTION

[0047] Specific embodiments are provided below to illustrate the technical contents of the present invention. Those skilled in the art can easily understand other advantages and effects of the present invention through the contents disclosed in the specification. The present invention can also be implemented or applied through other different specific embodiments. Those skilled in the art can make various modifications and changes without departing from the spirit of the present invention.

[0048] definition

[0049] Unless otherwise defined below, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art. The technology used herein refers to the technology generally understood in the art, including variants and equivalent substitutions that are obvious to those skilled in the art. Although it is believed that the following terms are easily understood by those skilled in the art, the following definitions are set forth to better illustrate the present invention. When a trade name appears herein, it refers to the corresponding commodity or its active ingredient. All patents, published patent applications and publications cited herein are incorporated herein by reference.

[0050] The term "Kif18A inhibitor" is an inhibitor of Kif18A ATPase activity. It will be appreciated by those skilled in the art that this term does not limit the mode of action of the inhibitor. For example, the inhibitor may bind to Kif18A via any suitable site, wherein the site may be selected from, for example, an ATP binding site, an allosteric site, and a combination thereof. For another example, the inhibitor may act on Kif18A that is not bound to microtubules, and / or may act on Kif18A-microtubule complexes.

[0051] When a certain amount, concentration or other numerical value or parameter is described in the form of a range, a preferred range or a preferred upper limit or a preferred lower limit, it should be understood as being equivalent to specifically disclosing any range formed by combining any upper limit or preferred value with any lower limit or preferred value, whether or not the range is explicitly stated. Unless otherwise stated, the numerical ranges listed herein are intended to include the endpoints of the range and all integers and fractions (decimals) within the range. For example, the expression "C1-C 10 " or "C 1-10 " covers the range of 1-10 carbon atoms and should be understood to also cover any subranges and each point value therein, such as C 2-3 , C 2-4 , C 2-5 , C 3-4 , C 3-5 , C 3-6 , C 3-7 , C 1-2 , C 1-3 , C 1-4 , C 1-5 , C 1-6 , C 1-7 , C 1-8 , C1-9, etc., as well as C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 etc. The expression “C3-C 10 " or "C 3-10 " should also be understood in a similar way, for example, it can cover C 3-4 , C 3-5 , C 3-6 , C 3-7 , C 3-8 , C 4-5 , C 4-6 , C4-C7, C5-C6, etc. and C3, C4, C5, C6, C7, C8, C9, C 10 etc. Expression “C 6-14 " should also be understood in a similar way, for example, it can cover C 6-10 , C 6-13 , C 10-13 etc. and C6, C 10 , C 13Etc. For another example, the expression "3-14 yuan" should be understood to cover any sub-ranges therein and each point value, such as 3-4, 3-5, 3-6, 3-7, 3-8, 4-5, 4-6, 4-7, 5-6, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 yuan, etc. The expressions "3-12 yuan", "5-14 yuan", "3-7 yuan", "4-8 yuan" should also be understood in a similar manner. The expression "p is an integer selected from 0 to 13" means that p is any integer from 0 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 manner.

[0052] When any variable (such as R X ) occurs more than once in the composition or structure of a compound, its definition is independent at each occurrence. For example, the expression “each R X "Independently selected from" means that if there are multiple R X , then in each case each R X The substituents are independent of each other. Other variables or expressions such as R 3 , R 5 , R 8 , R A1 , R A2 , R A3 , R A5 , R A8 , R B1 , R B2 , R B3 , R B5 , R B8 , R C2 , R D2 , R E1 , R E2 , R E3 , R E5 , R E8 , R X , R X1 , R X3 , R X4 , R X5 , R X6 , R X7 , R X8 , R a1 , R b1 , R c1 , R d1 , R e1 and R Y It should be understood in a similar way.

[0053] Unless the context clearly dictates otherwise, singular forms such as "a", "an", and "the" include plural forms. The expression "one or more" or "at least one" may mean 1, 2, 3, 4, 5, 6, 7, 8, 9 or more. In one embodiment, "at least one" means 1, 2, 3 or 4.

[0054] The terms "optional" or "optionally" mean that the subsequently described event may occur but need not occur, and that the description includes instances where said event or circumstance occurs or does not occur.

[0055] The terms "substituted" and "substituted" refer to one or more (e.g., one, two, three or four) hydrogen atoms on the designated atom being replaced by a selection from the indicated group, provided that the normal atomic valence of the designated atom in the current situation is not exceeded and the substitution forms a stable compound. Combinations of substituents and / or variables are permitted only if such combinations form stable compounds. When a substituent is described as not present, it should be understood that the substituent can be one or more hydrogen atoms, provided that the structure can achieve a stable state of the compound.

[0056] Unless otherwise indicated, as used herein, the point of attachment of a substituent may be from any convenient position of the substituent. When a bond to a substituent is shown as passing through a bond connecting two atoms in a ring, then such a substituent may be bonded to any ring-forming atom in the substitutable ring.

[0057] The expressions "comprising," "including," "containing," and "having" are open ended and do not exclude additional unrecited elements, steps, or ingredients. The expression "consisting of excludes any element, step, or ingredient not specified. The expression "consisting essentially of means that the scope is limited to the specified elements, steps, or ingredients, as well as the optional presence of elements, steps, or ingredients that do not materially affect the basic and novel characteristics of the claimed subject matter. It should be understood that the expression "comprising" includes the expressions "consisting essentially of" and "consisting of.

[0058] The term "halo" or "halogen" or "halo" is understood to mean a fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) atom, preferably a fluorine, chlorine or bromine atom.

[0059] The term "hydrocarbyl" refers to a monovalent group derived from a hydrocarbon. Examples of hydrocarbyl groups include, but are not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, and aryl.

[0060] The term "alkyl" refers to a saturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, which is connected to the rest of the molecule by a single bond. Alkyl groups include straight-chain alkyl groups and branched-chain alkyl groups. Alkyl groups can contain 1 to 10 carbon atoms, referred to as C 1-10 Alkyl groups, such as C1-6 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl, C 1-2 Alkyl, C3 alkyl, C4 alkyl, C 3-6 Alkyl. Non-limiting examples of straight-chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, etc. Non-limiting examples of branched alkyl groups include, but are not limited to, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, etc.

[0061] A divalent group refers to a group obtained by removing a hydrogen atom from an atom with free valence electrons of a corresponding monovalent group. A divalent group has two attachment sites connected to the rest of the molecule, wherein the two attachment sites can be located on the same atom or two different atoms of the divalent group.

[0062] "Alkylene" or "alkylidene" refers to a saturated divalent hydrocarbon group. Alkylene includes straight chain or branched chain alkylene. Examples of straight chain alkylene include, but are not limited to, methylene (-CH2-), -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, etc. Examples of branched chain alkylene include, but are not limited to -CH(CH3)-, -CH(C2H5)-, -CH(CH3)-CH2-, -CH(C3H7)-, -CH(C2H5)-CH2-, -C(CH3)2-CH2-, -(CH(CH3))2-, -CH(CH3)-(CH2)2-, -CH2-CH(CH3)-CH2-, -CH(C4H9)-, -C(CH3)(C3H7)- , -C(C2H5)2-, -CH(C3H7)-CH2-, -CH(C2H5)-CH(CH3)-, -CH(C2H5)-(CH2)2-, -CH2-CH(C2H5)-CH2 -, -C(CH3)2-(CH2)2-, -CH2-C(CH3)2-CH2-, -CH(CH3)-(CH2)3-, -CH2-CH(CH3)-(CH2)2-, -CH(C5H 11)-, -C(C2H5)(C3H7)-, -C(CH3)(C4H9)-, -CH(C4H9)-CH2-, -C(C2H5)2-CH2-, -C (CH3)(C3H7)-CH2-, -CH(C2H5)-CH(C2H5)-, -CH(CH3)-CH(C3H7)-, -C(CH3)2-C( CH3)2-, -CH(C3H7)-(CH2)2-, -CH2-CH(C3H7)-CH2-, -CH(C2H5)-C(CH3)2-, -C(CH3)2-CH(CH3)-CH2-, -CH(CH3)-C(CH3)2-CH2-, -CH(C2H5)-CH(CH3)-CH2-, -CH( CH3)-CH(C2H5)-CH2-, -CH(CH3)-CH2-CH(C2H5)-, -CH(CH3)-C(CH3)2-CH2-, -(CH(CH3))3-, -C(CH3)2-(CH2)3-, -CH(C2H5)-(CH2)3-, -CH2-CH(C2H5)-(CH2)2-, -CH2-CH(CH3)-CH(CH3)-CH2-, -(CH(CH3))2-(CH2)2-, -CH(CH3)-(CH2)2-CH(CH3)-, -(CH2)2-CH(CH3)-(CH2)2-, -CH2-CH(CH3)-(CH2)3-, -CH(CH3)-(CH2)4-, etc.

[0063] The term "alkenyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one double bond. The alkenyl group may have 2 to 8 carbon atoms, i.e., "C 2-8 Alkenyl", such as C 2-4 Alkenyl, C 3-4 Alkenyl. Non-limiting examples of alkenyl groups include, but are not limited to, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, and the like.

[0064] The term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one triple bond. The alkynyl group may have 2 to 8 carbon atoms, i.e., "C 2-8 Alkynyl", such as C 2-4 Alkynyl, C 3-4 Alkynyl. Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, and the like.

[0065] "Alkynylidene" refers to an unsaturated divalent hydrocarbon group having at least one triple bond. Alkynylidene includes straight chain or branched chain alkynylene. Examples of straight chain alkynylene include, but are not limited to -C≡C-, -CH2-C≡C-, -(CH2)2-C≡C-, -(CH2)3-C≡C- and -CH(CH3)-C≡C-.

[0066] The term "cycloalkyl" refers to a saturated or unsaturated non-aromatic cyclic hydrocarbon group composed of carbon atoms and hydrogen atoms, preferably containing 1 or 2 rings. The cycloalkyl group can be a monocyclic, fused polycyclic, bridged or spirocyclic structure. The cycloalkyl group can have 3-10 carbon atoms, i.e., "C 3-10 Cycloalkyl", such as C 3-8 Cycloalkyl, C5 cycloalkyl, C6 cycloalkyl, C7 cycloalkyl. Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.1]heptyl and spiro[3.3]heptyl, etc. In some embodiments, the C atoms in the cycloalkyl are optionally substituted with oxo. In some embodiments, the C atoms in the cycloalkyl are optionally substituted with imino. In some embodiments, the imino is unsubstituted (=NH) or substituted with a group described in the context. In some embodiments, the imino is substituted with -OR, wherein R is H or C 1-10 alkyl.

[0067] The terms "cyclic alkyl" and "cycloalkyl" have the same meaning herein and can be used interchangeably. Cycloalkyl refers to a saturated cyclic hydrocarbon group. A cycloalkyl group can have 3, 4, 5, 6, 7, 8, 9 or 10 ring carbon atoms (C 3-10 ). Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, and bicyclo[2.1.1]hexyl. In some embodiments, the cycloalkyl group is C 3-7 Monocyclic or bicyclic cycloalkyl, preferably C 3-6 Monocyclic cycloalkyl, in particular cyclopropyl.

[0068] The term "heterocyclyl" or "heterocycloalkyl" refers to a monocyclic or bicyclic ring system (3-14-membered, 7-14-membered, 3-8-membered, 3-7-membered, 4-6-membered, 5-6-membered) having, for example, 3-14 ring atoms (e.g., 7-14, 3-8, 3-7, 4-6, or 5-6 ring atoms), wherein at least one ring atom (e.g., 1, 2, or 3) is a heteroatom selected from oxygen, sulfur, nitrogen, and phosphorus, and the remaining ring atoms are C. The ring system may be saturated (also understood as the corresponding "heterocycloalkyl") or unsaturated (i.e., having one or more double bonds and / or triple bonds in the ring). Optionally, the heterocyclyl may be benzo-fused. "Heterocyclyl" or "heterocycloalkyl" does not have aromaticity. In some embodiments, the C, N, S, and P atoms in the heterocycle are optionally substituted by oxo. In some embodiments, the C, S, and P atoms in the heterocycle are optionally substituted by imino. In some embodiments, the imino group is unsubstituted (=NH) or substituted with groups as described above or below. In some embodiments, the imino group is substituted with -OR, wherein R is H or C 1-10 alkyl.

[0069] The heterocyclic group can be, for example, a four-membered ring, such as azetidinyl, oxetanyl; or a five-membered ring, such as tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, oxopyrrolidinyl, 2-oxoimidazolidin-1-yl; or a six-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, 1,1-dioxo-1,2-thiazin-2-yl or trithianyl; or a seven-membered ring, such as diazepine, Base ring.

[0070] The heterocyclic group may be bicyclic, without limitation, for example, a five-membered and a five-membered ring, such as octahydrocyclopenta[c]pyrrolyl; or a five-membered and a six-membered bicyclic ring, such as octahydropyrrolo[1,2-b]pyrazinyl.

[0071] As mentioned above, the heterocycle may be unsaturated, i.e., it may contain one or more double bonds, without being limited thereto, for example, an unsaturated heterocycle containing a nitrogen atom may be a 1,6-dihydropyrimidine, a 1,2-dihydropyrimidine, a 1,4-dihydropyrimidine, a 1,6-dihydropyridine, a 1,2-dihydropyridine, a 1,4-dihydropyridine, a 2,3-dihydro-1H-pyrrole, a 3,4-dihydro-1H-pyrrole, a 2,5-dihydro-1H-pyrrolyl, a 4H-[1,3,4]thiadiazinyl, a 4,5-dihydrooxazolyl or a 4H-[1,4]thiazinyl ring, an unsaturated heterocycle containing an oxygen atom may be a 2H-pyran, a 4H-pyran, a 2,3-dihydrofuran, an unsaturated heterocycle containing a sulfur atom may be a 2H-thiopyran, a 4H-thiopyran. The heterocycle may be benzo-fused, without being limited thereto, for example, a dihydroisoquinolinyl ring.

[0072] Exemplary bicyclic heterocycles also include:

[0073]

[0074] The term "aryl" refers to an aromatic ring group of an all-carbon monocyclic or fused polycyclic (such as a bicyclic) ring having a conjugated π electron system. For example, an aryl group may have 6-14 carbon atoms, preferably 6-10, more preferably 6 or 10. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and the like.

[0075] The term "heteroaryl" is to be understood as preferably meaning a monovalent monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 7, 8, 9 or 10 ring atoms ("5-10 heteroaryl"), in particular 5 or 6 or 9 or 10 ring atoms, and containing at least one (suitably 1 to 4, more suitably 1, 2 or 3) heteroatom which may be identical or different, such as oxygen, nitrogen or sulfur. Furthermore, in each case the heteroaryl group may be benzo-fused. In particular, the heteroaryl group is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, and the like, and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, and benzo derivatives thereof, such as quinolyl, quinazolinyl, isoquinolyl, and the like; or azocinyl, indolizinyl, purinyl, and the like, and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, carbazolyl, acridinyl, and the like.

[0076] The pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof. The methods for preparing the pharmaceutically acceptable salts of the compounds of the present invention are known to those skilled in the art.

[0077] The compounds of the present invention encompass pharmaceutically acceptable salts, stereoisomers, solvates, polymorphs, tautomers, isotopic compounds, metabolites or prodrugs thereof.

[0078] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds. For example, the compounds of the present invention may exist in E or Z configurations of carbon-carbon double bonds or carbon-nitrogen double bonds, wherein "E" represents the preferred substituents on the opposite side of the carbon-carbon double bond or carbon-nitrogen double bond according to the Cahn-Ingold-Prelog priority rules, and "Z" represents the preferred substituents on the same side of the carbon-carbon double bond or carbon-nitrogen double bond. The compounds of the present invention may also exist in the form of mixtures of "E" and "Z" isomers. Isomer forms also include cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Purification and separation of such substances can be achieved by standard techniques known in the art.

[0079] Optically pure enantiomers can be obtained by resolving racemic mixtures according to conventional methods, for example, by forming diastereomeric salts using optically active acids or bases, or by forming covalent diastereomers. A mixture of diastereoisomers can be separated into single diastereomers based on their physical and / or chemical differences by methods known in the art (e.g., by chromatography or fractional crystallization). Then, the optically active enantiomer base or acid is released from the separated diastereomeric salts. Another method for separating racemic enantiomers can use chiral chromatography (e.g., chiral HPLC columns), and the separated chiral isomers can be subjected to conventional derivatization treatment or non-derivatization before separation, depending on which method can achieve more effective separation of chiral isomers. Enzymatic methods can also be used to separate derivatized or non-derivatized chiral isomers. Similarly, optically active raw materials can be used to obtain optically pure compounds of the present invention by chiral synthesis.

[0080] The compounds of the present invention may exist in the form of solvates (preferably hydrates), wherein the compounds of the present invention contain a solvent as a structural element of the crystal lattice of the compound, in particular water, methanol or ethanol. The amount of polar solvents, in particular water, may be present in a stoichiometric or non-stoichiometric ratio.

[0081] The present invention also encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be a single polymorph or a mixture of more than one polymorph in any ratio.

[0082] The compounds of the invention may exist in isotopically labeled or enriched form, containing one or more atoms having a different mass and mass number from the most common atomic mass in nature. Isotopes may be radioactive or non-radioactive isotopes. Isotopes of atoms such as hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine include, but are not limited to,2 H. 3 H. 13 C. 14 C. 15 N. 18 O. 32 P. 35 S. 18 F. 36 Cl and 125 I.

[0083] Also included within the scope of the present invention are metabolites of the compounds of the present invention, i.e., substances formed in vivo when the compounds of the present invention are administered. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymolysis, etc. of the administered compounds.

[0084] The present invention further includes within its scope prodrugs of the compounds of the invention, which are certain derivatives of the compounds of the invention that may themselves have little or no pharmacological activity but are converted, for example by hydrolytic cleavage, into compounds of the invention having the desired activity when administered into or onto the body.

[0085] The term "polymorph" or "polymorph" refers to a single polymorph or a mixture of more than one polymorph in any proportion.

[0086] The term "crystalline form" or "crystal" refers to any solid material that exhibits a three-dimensional ordering, in contrast to amorphous solid material, which produces a characteristic X-ray powder diffraction pattern with well-defined peaks.

[0087] The term "amorphous" refers to any solid material that has no order in three dimensions.

[0088] The term "pharmaceutically acceptable" means that it is within the scope of normal medical judgment and will not cause undue toxicity, irritation, allergic response, or the like in contact with the tissues of patients.

[0089] The term "pharmaceutically acceptable carrier" refers to those substances that have no significant irritation to organisms and do not impair the biological activity and performance of the active compound. "Pharmaceutically acceptable carrier" includes, but is not limited to, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersants, disintegrants, stabilizers, solvents or emulsifiers.

[0090] The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating or preventing a target disorder, disease, or condition.

[0091] With respect to a drug, drug unit or active ingredient, the term "effective amount", "therapeutically effective amount" or "prophylactically effective amount" refers to a sufficient amount of the drug or pharmaceutical agent that can achieve the desired effect with acceptable side effects. The determination of the effective amount varies from person to person, depending on the age and general condition of the individual and on the specific active substance. The appropriate effective amount in each case can be determined by a person skilled in the art based on routine experiments.

[0092] The term "subject" includes humans or non-human animals. Exemplary human subjects include human subjects (referred to as patients) suffering from diseases (e.g., diseases described herein) or normal subjects. "Non-human animals" in the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0093] Compounds of formula (I)

[0094] In one aspect, the present invention provides a compound having the structure of formula (I):

[0095]

[0096] or a pharmaceutically acceptable salt thereof,

[0097] in,

[0098] Ring A is selected from C 6-14 Aromatic rings and 5-14 membered heteroaromatic rings;

[0099] Ring B is selected from a 5-membered heteroaromatic ring;

[0100] Q is selected from wherein M is selected from N, CH and C; U and V are each independently selected from O, S, L is selected from a chemical bond, -O-, -S-, -NR 7 -、C 1-2 Alkylene and C 2-4 Alkyne; each Respectively represent the connection site;

[0101] X 1 , X 2 and X 3 Each independently selected from N and C(R 8 );

[0102] R 1 Selected from C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclyl, aryl, -C 1-4 Alkylene-aryl, heteroaryl, -C 1-4 Alkylene-heteroaryl, -NR A R B 、-OR A 、-SR A 、-C(=O)R A 、-C(=NR E )R A 、-C(=N-OR B )R A 、-C(=O)OR A 、-OC(=O)R A 、-C(=O)NR A R B 、-NR F C(=O)R A 、-C(=NR E )NR A R B 、-NR F C(=NR E )R A 、-OC(=O)NR A R B 、-NR F C(=O)OR A 、-NR F C(=O)NR A R B 、-NR F C(=S)NR A R B 、-NR F C(=NR E )NR A R B 、-S(=O) r R A 、-S(=O)(=NR E )R A 、-N=S(=O)R A R B 、-S(=O)2OR A 、-OS(=O)2R A 、-NR F S(=O) r R A 、-NR F S(=O)(=NR E )R A 、-S(=O) r NR A RB 、-S(=O)(=NR E )NR A R B 、-NR F S(=O)2NR A R B and-NR F S(=O)(=NR E )NR A R B , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R X1 Substituents are substituted;

[0103] R 2 Selected from -(CR C2 R D2 ) t -S(=O) r R A2 、-(CR C2 R D2 ) t -S(=O)(=NR E2 )R B2 、-(CR C2 R D2 ) t -N=S(=O)R A2 R B2 、-(CR C2 R D2 ) t -S(=O)2OR A2 、-(CR C2 R D2 ) t -OS(=O)2R A2 、-(CR C2 R D2 ) t -NR A2 S(=O) r R B2 、-(CR C2 R D2 ) t -NR A2 S(=O)(=NR E2 )R B2 、-(CR C2 R D2 ) t -S(=O) r NR A2 R B2 、-(CR C2 R D2 )t -S(=O)(=NR E2 )NR A2 R B2 、-(CR C2 R D2 ) t -NR A2 S(=O)2NR A2 R B2 and-NR A2 S(=O)(=NR E2 )NR A2 R B2 ;

[0104] Each R 3 Independently selected from halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclyl, aryl, -C 1-4 Alkylene-aryl, heteroaryl, -C 1-4 Alkylene-heteroaryl, CN, NO2, -NR A3 R B3 、-OR A3 、-SR A3 、-C(=O)R A3 、-C(=O)OR A3 、-OC(=O)R A3 、-C(=O)NR A3 R B3 、-NR A3 C(=O)R B3 、-NR A3 C(=NR E3 )R B3 、-OC(=O)NR A3 R B3 、-NR A3 C(=O)OR B3 、-NR A3 C(=O)NR A3 R B3 、-NR A3 C(=S)NR A3 R B3 、-NR A3 C(=NR E3 )NR A3 R B3 、-S(=O) r R A3、-S(=O)(=NR E3 )R B3 、-N=S(=O)R A3 R B3 、-S(=O)2OR A3 、-OS(=O)2R A3 、-NR A3 S(=O) r R B3 、-NR A3 S(=O)(=NR E3 )R B3 、-S(=O) r NR A3 R B3 、-S(=O)(=NR E3 )NR A3 R B3 、-NR A3 S(=O)2NR A3 R B3 and-NR A3 S(=O)(=NR E3 )NR A3 R B3 , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R X3 Substituents are substituted;

[0105] or R 1 With adjacent R 3 Together with the atoms to which they are attached, they form C 5-12 A hydrocarbon ring or a 5-12 membered heterocyclic ring containing 1, 2 or 3 heteroatoms, wherein the hydrocarbon ring and the heterocyclic ring are monocyclic or bicyclic, wherein the heteroatoms contained in the heterocyclic ring are independently selected from oxygen, sulfur, nitrogen and phosphorus; the ring is unsubstituted or substituted by at least one independently selected from R X3 Substituents are substituted;

[0106] Each R 4 Independently selected from halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclyl, aryl, -C 1-4 Alkylene-aryl, heteroaryl, -C 1-4 Alkylene-heteroaryl, CN, NO2, -NR A4 R B4 、-OR A4 、-SRA4 、-C(=O)R A4 、-C(=O)OR A4 、-OC(=O)R A4 、-C(=O)NR A4 R B4 、-NR A4 C(=O)R B4 、-NR A4 C(=NR E4 )R B4 、-OC(=O)NR A4 R B4 、-NR A4 C(=O)OR B4 、-NR A4 C(=O)NR A4 R B4 、-NR A4 C(=S)NR A4 R B4 、-NR A4 C(=NR E4 )NR A4 R B4 、-S(=O) r R A4 、-S(=O)(=NR E4 )R B4 、-N=S(=O)R A4 R B4 、-S(=O)2OR A4 、-OS(=O)2R A4 、-NR A4 S(=O) r R B4 、-NR A4 S(=O)(=NR E4 )R B4 、-S(=O) r NR A4 R B4 、-S(=O)(=NR E4 )NR A4 R B4 、-NR A4 S(=O)2NR A4 R B4 and-NR A4 S(=O)(=NR E4 )NR A4 R B4 , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R X4 Substituents are substituted;

[0107] Each R 5 Independently selected from halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclic group, CN, NO2, -NR A5 R B5 、-OR A5 、-SR A5 、-C(=O)R A5 、-C(=O)OR A5 、-OC(=O)R A5 、-C(=O)NR A5 R B5 、-NR A5 C(=O)R B5 、-NR A5 C(=NR E5 )R B5 、-OC(=O)NR A5 R B5 、-NR A5 C(=O)OR B5 、-NR A5 C(=O)NR A5 R B5 、-NR A5 C(=S)NR A5 R B5 、-NR A5 C(=NR E5 )NR A5 R B5 、-S(=O) r R A5 、-S(=O)(=NR E5 )R B5 、-N=S(=O)R A5 R B5 、-S(=O)2OR A5 、-OS(=O)2R A5 、-NR A5 S(=O) r R B5 、-NR A5 S(=O)(=NR E5 )R B5 、-S(=O) r NR A5 R B5 、-S(=O)(=NRE5 )NR A5 R B5 、-NR A5 S(=O)2NR A5 R B5 and-NR A5 S(=O)(=NR E5 )NR A5 R B5 , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl and heterocyclyl is unsubstituted or substituted with at least one independently selected from R X5 Substituents are substituted;

[0108] R 5a and R 5b are each independently selected from hydrogen and R 5 ;

[0109] or R 5a and R 5b Together with the carbon atoms to which they are attached, they form a saturated or unsaturated 3-7 membered ring containing 0, 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, which ring is unsubstituted or substituted with 1, 2 or 3 R X5 Substituent substitution;

[0110] R 6a and R 6b are independently selected from hydrogen, halogen, C 1-10 Alkyl and C 3-10 Cycloalkyl, wherein alkyl and cycloalkyl are unsubstituted or substituted with at least one independently selected from R X6 Substituents are substituted;

[0111] or R 6a and R 6b Together with the carbon atoms to which they are attached, they form a saturated or unsaturated 3-7 membered ring containing 0, 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, which ring is unsubstituted or substituted with 1, 2 or 3 R X6 Substituent substitution;

[0112] R 7 Selected from hydrogen and C 1-10 Alkyl, wherein the alkyl group is unsubstituted or substituted with at least one independently selected from R X7 Substituents are substituted;

[0113] Each R 8 independently selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclyl, aryl, -C 1-4 Alkylene-aryl, heteroaryl, -C 1-4 Alkylene-heteroaryl, CN, NO2, -NR A8 R B8 、-OR A8 、-SR A8 、-C(=O)R A8 、-C(=O)OR A8 、-OC(=O)R A8 、-C(=O)NR A8 R B8 、-NR A8 C(=O)R B8 、-NR A8 C(=NR E8 )R B8 、-OC(=O)NR A8 R B8 、-NR A8 C(=O)OR B8 、-NR A8 C(=O)NR A8 R B8 、-NR A8 C(=S)NR A8 R B8 、-NR A8 C(=NR E8 )NR A8 R B8 、-S(=O) r R A8 、-S(=O)(=NR E8 )R B8 、-N=S(=O)R A8 R B8 、-S(=O)2OR A8 、-OS(=O)2R A8 、-NR A8 S(=O) r R B8 、-NR A8 S(=O)(=NR E8 )R B8 、-S(=O) r NR A8 R B8 、-S(=O)(=NR E8 )NR A8 R B8 、-NR A8 S(=O)2NR A8 RB8 and-NR A8 S(=O)(=NR E8 )NR A8 R B8 , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R X8 Substituents are substituted;

[0114] Each R F , R A , R B , R A2 , R A3 , R A4 , R A5 , R A8 , R B2 , R B3 , R B4 , R B5 and R B8 independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclyl, aryl, -C 1-4 Alkylene-aryl, heteroaryl and -C 1-4 Alkylene-heteroaryl, wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R X Substituents are substituted;

[0115] or "R A and R B ” or “R A2 and R B2 ” or “R A3 and R B3 ” or “R A4 and R B4 ” or “R A5 and R B5 ” or “R A8 and R B8 "together with the atoms or atoms to which they are attached, they form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, which ring is unsubstituted or substituted with 1, 2 or 3 atoms selected from R X Substituents are substituted;

[0116] Each R C2 and R D2independently selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclyl, aryl, -C 1-4 Alkylene-aryl, heteroaryl and -C 1-4 Alkylene-heteroaryl, wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R X Substituents are substituted;

[0117] Or each "R C2 and R D2 "Together with the single or multiple carbon atoms to which they are attached, they form a 3-12 membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, which ring is unsubstituted or substituted with 1, 2 or 3 independently selected from R X Substituents are substituted;

[0118] Each R E , R E2 , R E3 , R E4 , R E5 and R E8 independently selected from hydrogen, C 1-10 Alkyl, CN, NO2, -S(=O) r R a1 、-C(=O)R a1 、-C(=O)OR a1 、-C(=O)NR a1 R b1 and -S(=O) r NR a1 R b1 , wherein the alkyl group is unsubstituted or substituted with at least one independently selected from R X Substituents are substituted;

[0119] Each R X , R X1 , R X3 , R X4 , R X5 , R X6 , R X7 and R X8 Independently selected from halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclyl, aryl, -C 1-4 Alkylene-aryl, heteroaryl, -C 1-4 Alkylene-heteroaryl, CN, NO2, -(CR c1 R d1 ) u NR a1 R b1 、-(CR c1 R d1 ) u OR b1 、-(CR c1 R d1 ) u C(=O)R a1 、-(CR c1 R d1 ) 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 NRa1 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)2OR b1 、-(CR c1 R d1 ) u OS(=O)2R 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 、-(CRc1 R d1 ) u S(=O)(=NR e1 )NR a1 R b1 、-(CR c1 R d1 ) u NR a1 S(=O)2NR 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, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R Y Substituents are substituted;

[0120] Each R a1 and R b1 independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclyl, aryl, -C 1-4 Alkylene-aryl, heteroaryl and -C 1-4 Alkylene-heteroaryl, wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R Y Substituents are substituted;

[0121] or R a1 and R b1 Together with the atoms to which they are attached, they form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, which ring is unsubstituted or substituted with 1, 2 or 3 atoms selected from R Y Substituents are substituted;

[0122] Each R c1 and R d1 independently selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclyl, aryl, -C 1-4 Alkylene-aryl, heteroaryl and -C 1-4 Alkylene-heteroaryl, wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R Y Substituents are substituted;

[0123] Or each R c1 and R d1 Together with the single or multiple carbon atoms to which they are attached, they form a 3-12 membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, which ring is unsubstituted or substituted with 1, 2 or 3 heteroatoms independently selected from R Y Substituents are substituted;

[0124] Each R e1 independently selected from hydrogen, C 1-10 Alkyl, CN, NO2, -S(=O) r R a1 、-C(=O)R a1 、-C(=O)OR a1 、-C(=O)NR a1 R b1 and -S(=O) r NR a1 R b1 , wherein the alkyl group is unsubstituted or substituted with at least one independently selected from R Y Substituents are substituted;

[0125] Each R Y Independently selected from halogen, NO2, -CN, C 1-10 Alkyl, -OH, -O(C 1-10 Alkyl), -O(C 3-10 Cycloalkyl), -O(C 1-4 Alkylene-C 3-10 Cycloalkyl), -O(heterocyclyl), -O(C 1-4 Alkylene-heterocyclyl), -SH, -S(C 1-10 Alkyl), -S(C 3-10 Cycloalkyl), -S(C 1-4 Alkylene-C 3-10 Cycloalkyl), -S(heterocyclyl), -S(C 1-4 Alkylene-heterocyclyl), -NH2, -NH(C 1-10 Alkyl), -N(C 1-10 Alkyl)2, -NH(C 3-10 Cycloalkyl), -NH(C 1-4 Alkylene-C3-10 Cycloalkyl), -NH(heterocyclyl) and -NH(C 1-4 alkylene-heterocyclyl);

[0126] g is selected from 0, 1, 2, 3 and 4;

[0127] d is selected from 0, 1, 2, 3 and 4;

[0128] m is selected from 0, 1, 2, 3 and 4;

[0129] n is selected from 0, 1, 2 and 3;

[0130] p is an integer selected from 0 to 13;

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

[0132] Each t is independently selected from 0, 1, 2, 3 and 4;

[0133] Each u is independently selected from 0, 1, 2, 3 and 4.

[0134] In one embodiment, r is 2. In one embodiment, u is 0. In one embodiment, g is 0. In one embodiment, g is 1. In one embodiment, d is 0. In one embodiment, d is 1.

[0135] In one embodiment, R 1 Selected from C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclyl, wherein each alkylene, cycloalkyl and heterocyclyl is unsubstituted or substituted with at least one independently selected from R X1 In one embodiment, each R X1 independently selected from F and methyl, wherein methyl is unsubstituted or substituted with at least one independently selected from R Y substituted by a substituent.

[0136] In one embodiment, R 1 is selected from nitrogen-containing heterocyclic groups, which are optionally substituted by at least one independently selected from R X1 In one embodiment, the nitrogen-containing heterocyclic group is selected from piperidinyl and morpholinyl. In one embodiment, the nitrogen-containing heterocyclic group is connected to the A ring via a nitrogen atom on the heterocyclic ring. In one embodiment, R 1 Selected from and in and Optionally, at least one independently selected from R X1 In one embodiment, R 1Selected from

[0137] In one embodiment, R 1 It is cyclohexyl.

[0138] In one embodiment, R 2 Selected from -S(=O) r NR A2 R B2 and-NR A2 S(=O) r R B2 , especially -NR A2 S(=O) r R B2 , where R A2 For H, R B2 Selected from C 1-3 Alkyl and C 3-6 Cycloalkyl, wherein each alkyl and cycloalkyl is unsubstituted or substituted with at least one independently selected from R X In one embodiment, r is 2. In one embodiment, R 2 Selected from -NH-S(=O)2-C 1-3 Alkyl, -NH-S(=O)2-C 1-3 Alkylene-OH, -NH-S(=O)2-C 1-3 Alkylene-F and -NH-S(=O)2-C 3-6 In another embodiment, R 2 Selected from -S(=O)2NH-C 1-3 Alkyl, -S(=O)2NH-C 1-3 Alkylene-OH, -S(=O)2NH-C 1-3 Alkylene-F and -S(=O)2NH-C 3-6 In one embodiment, R 2 Selected from

[0139] In one embodiment, each R 3 Independently selected from halogen, CN, NO2, C 1-10 Alkyl, -OR A3 、-C(=O)R A3 、-C(=O)NR A3 R B3 and-NR A3 C(=O)R B3 , wherein each alkyl group is unsubstituted or substituted with at least one independently selected from R X3 In one embodiment, R 3Selected from F, Cl, Br, methyl, methoxy, acetyl and

[0140] In one embodiment, R 1 With adjacent R 3 Together with the atoms to which they are attached, they form a C5 monocyclic hydrocarbon ring or a C 10-12 A bicyclic hydrocarbon ring or a 5-membered monocyclic heterocyclic ring or a 10-12-membered bicyclic heterocyclic ring containing 1, 2 or 3 heteroatoms, wherein the heteroatoms contained in the heterocyclic ring are independently selected from oxygen, sulfur and nitrogen; the ring is unsubstituted or substituted by at least one independently selected from R X3 In one embodiment, R 1 With adjacent R 3 Together with the atoms to which they are attached, they form or contain 1, 2 or 3 heteroatoms, wherein the heteroatoms contained in the heterocyclic ring are independently selected from oxygen, sulfur and nitrogen; the ring is unsubstituted or substituted with at least one independently selected from R X3 In one embodiment, R 1 With adjacent R 3 Together with the atoms to which they are attached, they form 2-oxaspiro[4.5]decane-3-ene, which is unsubstituted or substituted with at least one independently selected from R X3 substituted by a substituent.

[0141] In one embodiment, in formula (I) The structure is

[0142] In one embodiment, each R 4 independently selected from halogen, C 1-10 alkyl, CN and NO2, wherein each alkyl is unsubstituted or substituted with at least one independently selected from R X4 In a particular embodiment, each R 4 are independently selected from halogen.

[0143] In one embodiment, each R 5 Independently selected from halogen, C 1-10 Alkyl, C 3-10 Cycloalkyl, CN and NO2, wherein each alkyl and cycloalkyl is unsubstituted or substituted with at least one independently selected from R X5 In one embodiment, each R 5 In a particular embodiment, R 5 Methyl or F.

[0144] In one embodiment, R 5a and R 5b are independently selected from hydrogen, halogen and C 3-10Cycloalkyl, wherein each cycloalkyl is unsubstituted or substituted with at least one independently selected from R X5 In one embodiment, R 5a and R 5b is hydrogen or F. In one embodiment, R 5a and R 5b Together with the carbon atoms to which they are attached, they form a saturated 3-membered hydrocarbon ring which is unsubstituted or has 1, 2 or 3 R X5 Substituent substitution.

[0145] In one embodiment, R 6a and R 6b are independently selected from hydrogen, halogen and C 1-10 Alkyl, wherein the alkyl group is unsubstituted or substituted with at least one independently selected from R X6 In one embodiment, R 6a and R 6b Each is independently selected from H and F. In one embodiment, R 6a and R 6b is F. In one embodiment, R 6a and R 6b Each independently selected from C 1-10 In one embodiment, R 6a and R 6b It is methyl.

[0146] In one embodiment, R 7 Selected from hydrogen, C 1-4 Alkyl and C 1-4 Halogenated alkyl.

[0147] In one embodiment, X 2 It is N, X 1 and X 3 Each independently selected from C(R 8 In one embodiment, R 8 is H. In one embodiment, X 1 , X 2 and X 3 is C(R 8 ), where R 8 For H.

[0148] In one embodiment, Q has the structure of Formula (i), Formula (ii), Formula (iii) or Formula (iv):

[0149]

[0150] in,

[0151] p1 is an integer selected from 0 to 13;

[0152] p2 is an integer selected from 0 to 11;

[0153] L, M, R 5 , R 5a , R 5b , R 6a , R 6b , m, and n are as defined in formula (I).

[0154] In one embodiment, M is N. In one embodiment, L is selected from a chemical bond and -O-, in particular -O-.

[0155] In one embodiment, the structure of formula (i) is selected from:

[0156]

[0157] Among them, R 5a , R 5b , R 5c , R 5d , R 5e , R 5f , R 5g , R 5h , R 5i , R 5j , R 5k and R 5l are each independently selected from hydrogen and R 5 .

[0158] In one embodiment, the structure of formula (ii) is selected from:

[0159]

[0160] Among them, R 5c , R 5d , R 5e , R 5f , R 5g , R 5h , R 5i , R 5j , R 5k and R 5l are each independently selected from hydrogen and R 5 .

[0161] In one embodiment, the structure of formula (iii) is selected from:

[0162]

[0163] Among them, R 5c , R 5d , R 5e , R 5f , R 5g , R5h , R 5i , R 5j , R 5k and R 5l are each independently selected from hydrogen and R 5 .

[0164] In one embodiment, the structure of formula (iv) is selected from:

[0165]

[0166] Among them, R 5c , R 5d , R 5e , R 5f , R 5g , R 5h , R 5i , R 5j , R 5k and R 5l are each independently selected from hydrogen and R 5 .

[0167] In one embodiment, m is 1 or 2. In one embodiment, n is 0 or 1. In one embodiment, p is 0 or 1. In one embodiment, p1 is 0. In one embodiment, p2 is 0.

[0168] In one embodiment, Q is selected from:

[0169] In one embodiment, ring A is selected from phenyl, pyridine, pyridazine and pyrimidine, which are independently selected from R 3 In one embodiment, ring A is selected from The structure is independently selected from R 3 substituted by a substituent; wherein Represents ring A and R 1 The connection point, represents another point at which ring A is attached to the rest of the molecule. In one embodiment, ring A is selected from

[0170] In one embodiment, Ring A is selected from The structure is independently selected from R 3 substituted by a substituent; wherein Represents ring A and R 1 The connection point, Represents another point at which ring A is attached to the rest of the molecule.

[0171] In one embodiment, ring A is selected from a nitrogen-containing 5-membered heteroaromatic ring. In one embodiment, ring A is selected from

[0172] In one embodiment, ring B is selected from nitrogen-containing 5-membered heteroaryl rings. In one embodiment, ring B is selected from This structure is substituted with d substituents independently selected from R 4 ; wherein represents the site where ring B is connected to ring A, represents another site where ring B is connected to other parts of the molecule. In one embodiment, ring B is selected from

[0173] In one embodiment, ring A is selected from a benzene ring and a 6-membered heteroaryl ring; formula (I) has the structure of formula (II) as follows:

[0174]

[0175] wherein,

[0176] A 1 is selected from N and C(R 3a );

[0177] A 2 is selected from N and C(R 3b );

[0178] A 3 is selected from N and C(R 3c );

[0179] A 4 is selected from N and C(R 3d );

[0180] A 5 is selected from N and C(R 3e );

[0181] A 6 is selected from N and C(R 3f );

[0182] R 3a , R 3b , R 3c , R 3d , R 3e and R 3f are each independently selected from hydrogen and R 3 ;

[0183] B 1 is selected from N(R 4a ), N, O, S and C(R 4a );

[0184] B 2Selected from N(R 4b ), N, O, S, and C(R 4b );

[0185] B 3 Selected from N(R 4c ), N, O, S, and C(R 4c );

[0186] B 4 Selected from N(R 4d ), N, O, S, and C(R 4d );

[0187] B 5 Selected from N(R 4e ), N, O, S, and C(R 4e );

[0188] R 4a 、R 4b 、R 4c 、R 4d 和R 4e Are each independently selected from hydrogen and R 4 ;

[0189] Is a single bond or double bond that keeps ring A and ring B aromatic;

[0190] R 1 、R 2 、R 3 、R 4 、Q, X 1 、X 2 、X 3 As defined in formula (I).

[0191] In one embodiment, formula (II) has the structure of formula (IIa), (IIb), (IIc), (IId), (IIe), or (IIf) as follows.

[0192]

[0193] In one embodiment, the Structure in formula (II) is In one embodiment, formula (I) has the structure of formula (III) as follows:

[0194]

[0195] Wherein,

[0196] A 1 Selected from N(R 3a ), N, O, S, and C(R 3a );

[0197] A 2 selected from N(R 3b )、N、O、S and C(R 3b );

[0198] A 3 selected from N(R 3c )、N、O、S and C(R 3c );

[0199] A 4 selected from N(R 3d )、N、O、S and C(R 3d );

[0200] A 5 selected from N(R 3e )、N、O、S and C(R 3e );

[0201] R 3a 、R 3b 、R 3c 、R 3d and R 3e are each independently selected from hydrogen and R 3 ;

[0202] B 1 selected from N(R 4a )、N、O、S and C(R 4a );

[0203] B 2 selected from N(R 4b )、N、O、S and C(R 4b );

[0204] B 3 selected from N(R 4c )、N、O、S and C(R 4c );

[0205] B 4 selected from N(R 4d )、N、O、S and C(R 4d );

[0206] B 5 selected from N(R 4e )、N、O、S and C(R 4e );

[0207] R 4a 、R 4b 、R 4c 、R 4d and R 4e are each independently selected from hydrogen and R 4 ;

[0208] A single bond or double bond to keep ring A and ring B aromatic;

[0209] R 1 , R 2 , R 3 , R 4 , Q, X 1 , X 2 , X 3 As defined in formula (I).

[0210] In one embodiment, Ring A is thiazole or oxazole.

[0211] In one embodiment, Formula (III) has the structure of Formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe) or (IIIf) below.

[0212]

[0213]

[0214] In one embodiment, R 1 With R 3e Together with the atoms to which they are attached, they form C 5-12 A hydrocarbon ring or a 5-12 membered heterocyclic ring containing 1, 2 or 3 heteroatoms, wherein the hydrocarbon ring and the heterocyclic ring are monocyclic or bicyclic, wherein the heteroatoms contained in the heterocyclic ring are independently selected from oxygen, sulfur, nitrogen and phosphorus; the ring is unsubstituted or substituted by at least one independently selected from R X3 substituted by a substituent.

[0215] In one embodiment, R 1 With R 3e Together with the atoms to which they are attached, they form 2-oxaspiro[4.5]decane-3-ene, which is unsubstituted or substituted with at least one independently selected from R X3 substituted by a substituent.

[0216] In one embodiment, R 1 for R 2 for Q is

[0217] In one embodiment, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0218]

[0219]

[0220]

[0221] PROTAC compounds and antibody-drug conjugates (ADCs)

[0222] In another aspect, the present invention provides a PROTAC compound comprising a compound of the present invention, an E3 ubiquitin ligase binding ligand, and a linker connecting the compound of the present invention and the E3 ubiquitin ligase binding ligand. The compound of the present invention can be used as a ligand to bind to Kif18A. In one embodiment, the PROTAC compound can be used to promote the degradation of Kif18A by UPS.

[0223] In yet another aspect, the present invention provides an antibody-drug conjugate comprising a compound of the present invention, an antibody capable of binding to a target, and a linker connecting the compound of the present invention and the antibody.

[0224] Pharmaceutical compositions and pharmaceutical preparations

[0225] Another object of the present invention is to provide a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer, isotope compound, metabolite or prodrug thereof, and at least one pharmaceutically acceptable carrier.

[0226] The pharmaceutical composition of the present invention can be administered in any manner as long as it achieves the effect of preventing, alleviating, preventing or treating human or animal symptoms. For example, various suitable dosage forms can be prepared according to the route of administration. For example, it can be administered orally or parenterally to a patient in the form of a conventional preparation. The conventional preparations are such as capsules, microcapsules, tablets, granules, powders, lozenges, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions and emulsions.

[0227] The dosage of the compound administered to a subject can be adjusted to a considerable extent. The dosage can vary depending on the specific route of administration and the needs of the subject, and can be subject to the judgment of a healthcare professional.

[0228] Treatments and uses

[0229] According to certain embodiments of the present invention, the present invention or its pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer, isotope compound, metabolite or prodrug or the pharmaceutical composition of the present invention can be used to prevent or treat Kif18A-mediated diseases, or diseases responsive to the inhibition of Kif18A, including but not limited to abnormal cell proliferation diseases such as cancer and autoimmune diseases.

[0230] Therefore, in another aspect, the present invention also provides the use of the compound of the present invention or its pharmaceutically acceptable salt or the pharmaceutical composition of the present invention in the preparation of a medicament for treating a disease, disorder or condition, wherein the disease, disorder or condition is selected from a cell proliferation abnormality disease, and the compound or its pharmaceutically acceptable salt or pharmaceutical composition is optionally used in combination with a second therapeutic agent.

[0231] In another aspect, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present invention, optionally in combination with a second therapeutic agent, for use in treating a cell proliferation disorder.

[0232] In a further aspect, the present invention provides a method for treating a cell proliferation disorder, the method comprising administering to an individual in need thereof an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention, wherein the compound or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition is optionally used in combination with a second therapeutic agent.

[0233] In one embodiment, the disease, disorder or condition is selected from: a cancerous proliferative disease (e.g., cancer); a noncancerous proliferative disease (e.g., benign skin hyperplasia (e.g., psoriasis), restenosis, and benign prostatic hypertrophy (BPH)); pancreatitis; kidney disease; pain; hindering sperm development; preventing blastocyst implantation; treating diseases associated with angiogenesis or angiogenesis (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 macular degeneration, hemangiomas, gliomas, melanomas, Kaposi's sarcoma, and ovarian, breast, lung, pancreatic, prostate, colon, and epidermoid carcinomas); asthma; neutrophil chemotaxis (e.g., reperfusion injury in 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 erythematosus, multiple sclerosis, and rheumatoid arthritis); atherosclerosis; inhibition of keratinocyte responses to cocktails of growth factors; chronic obstructive pulmonary disease (COPD), and other diseases.

[0234] In one embodiment, the disease, disorder or condition is cancer, for example selected from: (a) a solid tumor or a blood-borne tumor selected from the following cancers: bladder cancer, endometrial cancer, squamous cell lung cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, small cell lung cancer, esophageal cancer, gallbladder cancer, brain cancer, head and neck cancer, ovarian cancer, pancreatic cancer, gastric cancer, cervical cancer, thyroid cancer, prostate cancer and skin cancer; (b) a hematopoietic tumor of the lymphoid lineage selected from the following: leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's (c) a hematopoietic neoplasm of the myeloid lineage selected from the group consisting of acute and chronic myeloid leukemias, myelodysplastic syndromes and promyelocytic leukemias; (d) a tumor of mesenchymal origin selected from the group consisting of fibrosarcoma and rhabdomyosarcoma; (e) a tumor of the central and peripheral nervous system selected from the group consisting of astrocytoma, neuroblastoma, glioma and schwannoma; or (f) a melanoma, a seminoma, a teratoma, an osteosarcoma, a xeroderma pigmentosum, a keratoacanthoma, a follicular thyroid carcinoma or a Kaposi's sarcoma.

[0235] In one embodiment, the disease, disorder or condition 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, disorder or condition is ovarian cancer.

[0236] Combination therapy

[0237] The compound of the present invention or its pharmaceutically acceptable salt or the pharmaceutical composition of the present invention can be used alone or in combination with other therapeutic agents.

[0238] For example, the use of an adjuvant can enhance the therapeutic effect of the compounds of the present invention (for example, the therapeutic benefit of using an adjuvant alone is minimal, but when used in combination with another drug, the therapeutic benefit of the individual can be enhanced), or, for example, the compound of the present invention combined with another therapeutic agent that also has therapeutic effects can enhance the therapeutic benefit of the individual. For example, when treating cancer, when using the compound of the present invention, the combined use of another drug for treating cancer may enhance the clinical benefit. Therapies that can be combined include but are not limited to physical therapy, psychotherapy, radiotherapy, chemotherapeutic agents, small molecule targeted therapeutic agents (such as kinase inhibitors, immune agonists), immunotherapy (anti-PD-1, anti-PDL-1, CAR-T cells), etc. Regardless of the disease, disorder or condition, the two therapies should have an additive effect or a synergistic effect to benefit the treatment of the individual.

[0239] In one embodiment, the other therapeutic agent is selected from inhibitors of members of the kinesin superfamily, such as inhibitors of kinesin spindle protein (KSP, also known as kinesin Eg5). In one embodiment, the other therapeutic agent is selected from inhibitors of centromere associated protein E (CENP-E).

[0240] Beneficial Effects

[0241] The novel small molecule Kif18A inhibitor provided by the present invention shows outstanding Kif18A inhibitory activity and cell proliferation inhibitory activity.

[0242] Therefore, the compounds of the present invention can prevent or treat diseases mediated by Kif18A, or diseases responsive to the inhibition of Kif18A, including but not limited to abnormal cell proliferation diseases such as cancer and autoimmune diseases, and have good prospects for development as drugs.

[0243] The compounds of the present invention achieve at least one of the following technical effects:

[0244] (1) It has high inhibitory activity against target cells.

[0245] (2) Excellent physicochemical properties (e.g. solubility, physical and / or chemical stability).

[0246] (3) Excellent pharmacokinetic properties (e.g., good stability in plasma, appropriate half-life and duration of action).

[0247] (4) Excellent safety (lower toxicity and / or fewer side effects to non-target normal cells or tissues, wider therapeutic window), etc.

[0248] Example

[0249] In order to more clearly illustrate the purpose and technical scheme of the present invention, the present invention is further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The specific experimental methods not mentioned in the following examples are all carried out according to conventional experimental methods.

[0250] Instruments, Materials and Reagents

[0251] Unless otherwise specified, the instruments and reagents used in the examples are commercially available and can be used directly without further purification.

[0252] LCMS: SHIMADZ LCMS2020, Column: Waters SunFireTM 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 TM C18 10μm OBD 19*250mm; mobile phase A: H2O (containing 0.1% formic acid); mobile phase B: CH3CN.

[0253] NMR: Bruker Avance III 400M

[0254] OVCAR3 cells were obtained from ATCC CAT#HTB-161.

[0255] Synthesis scheme

[0256] The compound of formula (I) or its pharmaceutically acceptable salt can be synthesized by different methods, some exemplary methods are provided below and in the Examples. Other synthetic methods can be easily proposed by those skilled in the art based on the information disclosed in the present invention.

[0257] In the reactions described below, it may be necessary to protect the active groups to prevent them from participating in other undesirable reactions: such groups as hydroxyl, amino, imino, sulfhydryl or carboxyl groups, which are contained in the final product. Commonly used protecting groups can be found in TW Greene and PGM Wuts in "Protective Groups in Organic Chemistry" John Wiley and Sons, 1991.

[0258] The synthetic schemes of all compounds of the present invention are illustrated by the following schemes and examples. The raw materials used are commercially available or can be prepared according to existing process methods or the methods exemplified herein.

[0259] As shown in Synthesis Scheme 1, the compound of formula (I) can be prepared and synthesized from compound M1 and compound M2 known in the literature or understood by those skilled in the art by various methods. For example, compound M1 and compound M2 are subjected to cyclization reaction to obtain the compound of formula (I). 1 ,y 2 are reactive groups for cyclization reaction, such as a 1,3-dipole group and an alkynyl group, wherein the 1,3-dipole group is, for example, an azido group.

[0260]

[0261] 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, for example, CuSO4 and a reducing agent (such as sodium ascorbate) can be used, or CuBr or CuOAc can be used. In one embodiment, the cyclization reaction is carried out in a tert-butyl alcohol-water mixed solvent, and optionally carried out under heating conditions.

[0262] Another synthetic route of the compound of formula (I) is shown in Synthesis Scheme 2. Compound M1 and compound M3 are used as starting materials to obtain compound M4 through cyclization reaction. 1 is a leaving group, for example, selected from halogen, OTf, especially halogen. 2 The reagent undergoes nucleophilic substitution or coupling reaction to obtain the compound of formula (I). The coupling reaction is, for example, Ullmann reaction or Buchwald reaction.

[0263]

[0264] 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 use an amino acid catalyst or a ligand (such as an amine), and is optionally carried out in the presence of a base, and is optionally carried out under heating conditions.

[0265] The intermediate compound can be prepared using a known method, for example, using the corresponding amine compound to react with an azidating agent in the presence of a diazotating agent to prepare a compound with an azidating agent (compound M1 or compound M2), wherein the diazotating agent is such as tert-butyl nitrite, etc., and the azidating agent is such as TMSN3, etc. For another example, using the corresponding compound with a leaving group to react with an alkynylating agent to prepare a compound with an alkynylating agent, wherein the leaving group is such as a halogen, and the alkynylating agent is such as trimethylsilylacetylene, etc.

[0266] In some cases, the order in which the above reaction schemes are carried out can be changed to promote the reaction or to avoid unwanted reaction products. The following examples are provided so that the present invention can be more fully understood. These examples are illustrative only and should not be construed as limiting the present invention in any way.

[0267] Example 1 2-Hydroxy-N-(4-(1-(3-(piperidin-1-yl)phenyl)-1H-1,2,3-triazol-4-yl)-3-(6- Azaspiro[2.5]octan-6-yl)phenyl)ethane-1-sulfonamide (Compound 001)

[0268]

[0269] 1.1 Synthesis of intermediate 1-2

[0270]

[0271] Dissolve 1-fluoro-3-nitrobenzene (500 mg) in DMSO (10 mL), add piperidine (1.15 g) and potassium carbonate (933 mg), and stir at 100 ° C for 16 hours. Cool to room temperature, pour the reaction solution into water (30 mL), extract with ethyl acetate (10 mL x 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is purified and separated by silica gel column (petroleum ether: ethyl acetate = 100: 1) to obtain intermediate 1-2 (730 mg). LCMS: MS m / z (ESI): 207.1 [M+H] + .

[0272] 1.2 Synthesis of intermediates 1-3

[0273]

[0274] Dissolve intermediate 1-2 (2.2 g) in ethanol (200 mL), add dry palladium carbon (200 mg), replace with hydrogen three times, and react at room temperature for 16 h under a hydrogen atmosphere. The reaction solution is filtered through celite, and the filtrate is concentrated under reduced pressure to obtain intermediate 1-3 (1.8 g). LCMS: MS m / z (ESI): 177.1 [M+H] + .

[0275] 1.3 Synthesis of intermediates 1-4

[0276]

[0277] Dissolve the intermediate 1-3 (1g) in acetonitrile (10mL), add tert-butyl nitrite (1.76g) at 0℃ under nitrogen protection, and react at room temperature for 2h. Add trimethylsilyl azide (1.57g) at 0℃, heat to 40℃ and stir to react for 16h. Cool to room temperature, pour the reaction solution into water (20mL), extract with ethyl acetate (10mLx3), combine the organic phases, dry over anhydrous sodium sulfate and filter, concentrate the filtrate under reduced pressure, and purify and separate the residue by silica gel column (petroleum ether: ethyl acetate = 50:1) to obtain intermediate 1-4 (220mg). LCMS:MS m / z(ESI):203.1[M+H] + .

[0278] 1.4 Synthesis of intermediates 1-5

[0279]

[0280] 4-Bromo-2-fluoro-1-nitrobenzene (1 g) was dissolved in NMP (20 mL), and 6-azaspiro[2.5]octane hydrochloride (876 mg) and DIEA (3.52 g) were added in sequence. The mixture was heated to 100°C and stirred for 16 h. The mixture was cooled to room temperature, diluted with water (40 mL), extracted with ethyl acetate (20 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified and separated by a silica gel column (petroleum ether: ethyl acetate = 100: 1) to obtain intermediate 1-5 (1.4 g). LCMS: MS m / z (ESI): 311.0 [M+H] + .

[0281] 1.5 Synthesis of intermediate 1-6

[0282]

[0283] Dissolve the intermediate 1-5 (1.4 g) in tetrahydrofuran (40 mL), add ethanol (40 mL) and water (20 mL), then add reduced iron powder (1.1 g) and ammonium chloride (1.05 g), and stir at 60 ° C for 2 h. Cool to room temperature, filter the reaction solution, pour the filtrate into water (150 mL), extract with ethyl acetate (40 mL x 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain intermediate 1-6 (1.2 g). LCMS: MS m / z (ESI): 281.1 [M+H] + .

[0284] 1.6 Synthesis of intermediates 1-7

[0285]

[0286] Add intermediate 1-6 (650 mg) and p-toluenesulfonic acid (1.32 g) to a mixed solution of acetonitrile (75 mL) and water (15 mL), add an aqueous solution (5 mL) of sodium nitrite (319 mg) dropwise at 0°C, and stir at 25°C for 2 h after the addition is complete. Dissolve potassium iodide (959 mg) in water (5 mL), add to the reaction solution, and stir at 25°C for 16 h. Dilute with water (150 mL), extract with ethyl acetate (40 mL x 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is separated and purified by silica gel column (petroleum ether: ethyl acetate = 50:1) to obtain intermediate 1-7 (480 mg). LCMS: MS m / z (ESI): 391.9 [M+H] + .

[0287] 1.7 Synthesis of intermediates 1-8

[0288]

[0289] Intermediate 1-7 (500 mg), trimethylsilyl acetylene (138 mg), cuprous iodide (24 mg), dichlorobis(triphenylphosphine)palladium (90 mg) and triethylamine (258 mg) were dissolved in dichloromethane (25 mL) in sequence, replaced with nitrogen three times, and stirred at 30°C for 16 h. The reaction solution was directly concentrated under reduced pressure, and the residue was purified and separated by silica gel column (petroleum ether: ethyl acetate = 100: 1) to obtain intermediate 1-8 (50 mg). LCMS: MS m / z (ESI): 362.0 [M+H] + .

[0290] 1.8 Synthesis of intermediates 1-9

[0291]

[0292] Dissolve intermediate 1-8 (600 mg) in tetrahydrofuran (5 mL), add tetrabutylammonium fluoride tetrahydrofuran solution (1M, 2 mL), and stir at room temperature for 30 min. Dilute with water (20 mL), extract with ethyl acetate (5 mL x 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain intermediate 1-9 (360 mg). LCMS: MS m / z (ESI): 290.0 [M+H] + .

[0293] 1.9 Synthesis of intermediate 1-10

[0294]

[0295] Intermediate 1-9 (220 mg) and intermediate 1-4 (153 mg) were dissolved in a mixed solution of tert-butyl alcohol (10 mL) and water (3 mL), and copper sulfate monohydrate (13 mg) and sodium ascorbate (15 mg) were added in sequence, and the temperature was raised to 50°C for reaction for 16 h. The reaction solution was diluted with water (30 mL), extracted with ethyl acetate (10 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified and separated by silica gel column (petroleum ether: ethyl acetate = 20: 1) to obtain intermediate 1-10 (240 mg). LCMS: MS m / z (ESI): 492.1 [M+H] + .

[0296] 1.10 Synthesis of Compound 001

[0297]

[0298] 2-Hydroxyethane-1-sulfonamide (250 mg), (1R,2R)-N 1 ,N 2-Dimethylcyclohexane-1,2-diamine (578 mg), cuprous iodide (387 mg), and potassium phosphate (1.08 g) were dissolved in DMF (5 mL) in sequence, replaced with nitrogen three times, and stirred at 50° C. for 30 min. Intermediate 1-10 (100 mg) was added and stirred at 100° C. for 16 h. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in DMF (2 mL) and purified by preparative HPLC (mobile phase A: H2O containing 0.1% formic acid, mobile phase B: CH3CN, A / B = 90%-5% gradient) to give the pure target product 2-hydroxy-N-(4-(1-(3-(piperidin-1-yl)phenyl)-1H-1,2,3-triazol-4-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)ethane-1-sulfonamide (Compound 001) (35 mg).

[0299] 1 H NMR (400MHz, DMSO) δ9.87 (s, 1H), 9.05 (s, 1H), 7.88 (d, J = 8.4Hz, 1H), 7.42 (t, J = 8.1Hz ,1H),7.34(t,J=2.2Hz,1H),7.22(dd,J=7.7,1.9Hz,1H),7.13(d,J=2.2Hz,1H),7.07(d d,J=8.4,2.5Hz,1H),7.01(dd,J=8.4,2.1Hz,1H),4.95(s,1H),3.76(t,J=6.7Hz,2H), 3.33–3.25(m,6H),2.83(t,J=5.3Hz,4H),1.69–1.54(m,6H),1.48(s,4H),0.32(s,4H).

[0300] LCMS:MS m / z(ESI):537.2[M+H] + .

[0301] Example 2 N-(4-(4-(2-(4,4-difluoropiperidin-1-yl)thiazol-4-yl)-1H-1,2,3-triazol-1-yl)- 3-(6-Azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (Compound 002)

[0302]

[0303] 2.1 Synthesis of intermediate 2-2

[0304]

[0305] 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 stirred at 100°C for 16 hours. The reaction solution was poured into ice water (20 mL), extracted with ethyl acetate (3×20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (EA / PE: 0-5%) to obtain intermediate 2-2 (1.2 g). LCMS: MS m / z (ESI): 358.9 [M+H] + .

[0306] 2.2 Synthesis of intermediate 2-3

[0307]

[0308] At room temperature, the intermediate 2-2 (1.4 g) was dissolved in a mixed solution of ethanol / tetrahydrofuran / water (40 mL / 40 mL / 20 mL), and reduced iron powder (1.1 g) and ammonium chloride (1.05 g) were added. The mixture was stirred at 60°C for 2 hours. After filtration, the filtrate was diluted with water (100 mL), extracted with ethyl acetate (3×100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the intermediate 2-3 (crude product, 1.2 g), which was used directly in the subsequent reaction. LCMS: MS m / z (ESI): 329.0 [M+H] + .

[0309] 2.3 Synthesis of intermediate 2-4

[0310]

[0311] Intermediate 2-3 (0.1 g) was dissolved in acetonitrile (2 mL), tert-butyl nitrite (47 mg) and trimethylsilyl azido (53 mg) were added dropwise at 0°C, and the reaction was stirred at room temperature for one hour. Water (20 mL) was added to the reaction solution to quench, and it 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 (EAin PE: 0-2%) to obtain intermediate 2-4 (67 mg). LCMS: MS m / z (ESI): 355.2 [M+H] + .

[0312] 2.4 Synthesis of intermediate 2-5

[0313]

[0314] 2,4-Dibromothiazole (1.00 g) and 4,4-difluoropiperidine hydrochloride (530 mg) were dissolved in N-methylpyrrolidone (10.0 mL) at room temperature, and N,N-diisopropylethylamine (3.18 g) was added. Under nitrogen protection, the mixture was sealed and stirred at 100°C for 12 hours. Water (50.0 mL) was added to the reaction solution for dilution, and the mixture was extracted with ethyl acetate (3x50.0 mL). The organic phase was washed with saturated sodium chloride aqueous solution (3x50.0 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (EA in PE: 0-10%) to obtain intermediate 2-5 (1.10 g). LCMS: MS m / z (ESI): 283.0 [M+H] + .

[0315] 2.5 Synthesis of intermediate 2-6

[0316]

[0317] At room temperature, the intermediate 2-5 (1 g) was dissolved in a mixed solution of tetrahydrofuran (30 mL) and diisopropylamine (10 mL), and bistriphenylphosphine palladium dichloride (300 mg), triphenylphosphine (743 mg) and cuprous iodide (270 mg) were added thereto. After stirring for 10 min, trimethylsilyl acetylene (1.05 g) was added, and the mixture was stirred at 70 ° C for 4 hours under nitrogen protection. Water (50.0 mL) was added to the reaction solution for dilution, and the mixture was extracted with ethyl acetate (3x100.0 mL). The organic phase was washed with a saturated sodium chloride aqueous solution (3x100.0 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (EAin PE: 0-10%) to obtain the intermediate 2-6 (830 mg). LCMS: MS m / z (ESI): 301.1 [M+H] + .

[0318] 2.6 Synthesis of intermediate 2-7

[0319]

[0320] At room temperature, the intermediate 2-6 (730 mg) was dissolved in methanol (20 ml), and a saturated potassium carbonate solution (10 mL) was added dropwise. The reaction mixture was stirred at room temperature for 10 min. The reaction solution was concentrated under reduced pressure, diluted with water (50.0 mL), extracted with ethyl acetate (3*100.0 mL), and the organic phase was washed with a saturated sodium chloride aqueous solution (3x100.0 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the intermediate 2-7 (520 mg). LCMS: MS m / z (ESI): 229.3 [M+H] + .

[0321] 2.7 Synthesis of Intermediate 2-8

[0322]

[0323] At room temperature, intermediate 2-7 (200 mg), intermediate 2-4 (340 mg), anhydrous copper sulfate (20 mg), sodium L-ascorbate (180 mg) were dissolved in a mixed solution of water (10 mL) and tert-butyl alcohol (10 mL), and stirred at 60 ° C for 2 h under nitrogen protection. Water (50.0 mL) was added to the reaction solution for dilution, extracted with ethyl acetate (3x100.0 mL), and the organic phase was washed with saturated sodium chloride aqueous solution (3x100.0 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain intermediate 2-8 (480 mg). LCMS: MS m / z (ESI): 583.4 [M+H] + .

[0324] 2.8 Synthesis of Compound 002

[0325]

[0326] 2-Hydroxyethane-1-sulfonamide (400 mg) was dissolved in N,N-dimethylformamide (10.00 mL) at room temperature, and sarcosine (300.0 mg), cuprous iodide (200.0 mg) and potassium phosphate (2 g) were added. The mixture was heated and stirred at 50 °C under nitrogen protection for 5 minutes, and then intermediate 2-8 (500 mg) was added. The temperature was raised to 100 °C under nitrogen protection and the mixture was reacted for 2 h. The reaction mixture was cooled to room temperature, saturated aqueous sodium chloride solution (10.0 mL) was added to dilute the mixture, and the mixture was extracted with ethyl acetate (3×10.0 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (EAin PE: 0-80%) to give the target product N-(4-(4-(2-(4,4-difluoropiperidin-1-yl)thiazol-4-yl)-1H-1,2,3-triazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (Compound 002) (100 mg).

[0327] 1H NMR (400MHz, DMSO) δ10.03(s,1H),8.66(s,1H),7.50(d,J=8.6Hz,1H),7.29(s,1H),7.12(s,1H),7.02(d,J=8.6Hz,1H),4.98(s,1H),3.82–3 .76(m,2H),3.68–3.64(m,4H),3.38–3.32(m,2H),2.68(s,4H),2.19–2.07(m,4H),1.28(s,4H),0.25(s,4H).LCMS:MSm / z(ESI):580.1[M+H] + .

[0328] Example 3 N-(4-(4-(2-(4,4-difluoropiperidin-1-yl)thiazol-4-yl)-1H-1,2,3-triazol-1-yl)- 3-(6-Azaspiro[2.5]octan-6-yl)phenyl)-2-fluoroethane-1-sulfonamide (Compound 003)

[0329]

[0330] 3.1 Synthesis of intermediate 3-2

[0331]

[0332] Sarcosine (500 mg), cuprous iodide (530.0 mg) and potassium phosphate (3.0 g) were added to a solution of 2-hydroxyethane-1-sulfonamide (1.05 g) in N, N-dimethylformamide (30.00 mL) at room temperature. After heating and stirring at 50 ° C for 5 minutes under nitrogen protection, intermediate 2-2 (1.0 g) was added. After heating and stirring at 100 ° C for 3 hours under nitrogen protection. Saturated sodium chloride aqueous solution (10.0 mL) was added to the reaction solution for dilution and extracted with ethyl acetate (3x10.0 mL). The organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether: 0-50%) to obtain intermediate 3-2 (800 mg). LCMS: MS m / z (ESI): 356.2 [M+H] +

[0333] 3.2 Synthesis of intermediate 3-3

[0334]

[0335] Dissolve the intermediate 3-2 (500 mg) in anhydrous dichloromethane (20 mL), cool to 0 ° C, and add DAST (700 mg) to the reaction solution. Slowly heat to room temperature and stir to react for 8 hours. The reaction solution is concentrated under reduced pressure, and the crude product is separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether: 0-30%) to obtain intermediate 3-3 (150 mg). LCMS: MS m / z (ESI): 358.0 [M+H] +

[0336] 3.3 Synthesis of intermediate 3-4

[0337]

[0338] Reduced iron powder (160 mg) and ammonium chloride (160 mg) were added to a mixed solution of ethanol (10 ml), tetrahydrofuran (10 ml) and water (5 ml) of intermediate 3-3 (100 mg) 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), extracted with ethyl acetate (3×100 mL), the organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether: 0-20%) to obtain intermediate 3-4 (81 mg). LCMS: MS m / z (ESI): 328.4 [M+H] + .

[0339] 3.4 Synthesis of intermediate 3-5

[0340]

[0341] Dissolve intermediate 3-4 (100 mg) in acetonitrile (5 mL), cool to 0 ° C, and add tert-butyl nitrite (47 mg) and trimethylsilyl azido (53 mg) dropwise to the reaction solution under nitrogen protection. Warm to room temperature and stir to react for 1 hour. Add water (20 mL) to the reaction solution, extract with ethyl acetate (2×20 mL), combine the organic phases, dry over anhydrous sodium sulfate, and filter. The filtrate is concentrated under reduced pressure, and the crude product is separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether: 0-10%) to obtain intermediate 3-5 (80 mg). LCMS: MSm / z (ESI): 354.4 [M+H] + .

[0342] 3.5 Synthesis of Compound 003

[0343]

[0344] Intermediate 2-7 (32 mg), intermediate 3-5 (50 mg), anhydrous copper sulfate (3 mg), sodium L-ascorbate (28 mg) were dissolved in a mixed solution of water (5 mL) and tert-butyl alcohol (5 mL) at room temperature, and stirred at 60° C. for 2 hours under nitrogen protection. The reaction solution was diluted with water (50.0 mL), extracted with ethyl acetate (3×100.0 mL), the organic phases were combined, washed with saturated aqueous sodium chloride solution (3×100.0 mL), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by preparative HPLC (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-(2-(4,4-difluoropiperidin-1-yl)thiazol-4-yl)-1H-1,2,3-triazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-fluoroethane-1-sulfonamide (Compound 003) (18.16 mg).

[0345] 1 H NMR (400MHz, DMSO) δ8.64(s,1H),7.45(d,J=8.8Hz,1H),7.28(s,1H),7.06(s,1H),6.96(d,J=8.8Hz,1H),4.77( dt,J=47.2,5.2Hz,2H),3.66–3.57(m,6H),2.66(t,J=5.2Hz,4H),2.15–2.09(m,4H),1.27(s,4H),0.25(s,4H).

[0346] 19 F NMR(377MHz,DMSO)δ-95.74,17.27.

[0347] LCMS:MS m / z(ESI):582.2[M+H] + .

[0348] Example 4 Synthesis of Compounds 004, 005, and 027

[0349] Referring to the synthesis method of Example 2, the 2-hydroxyethane-1-sulfonamide in step 2.8 was replaced with the corresponding sulfonamide to obtain the following compound:

[0350]

[0351] Example 5 N-(4-(4-(2-(4,4-difluoropiperidin-1-yl)oxazol-5-yl)-1H-1,2,3-triazol-1-yl)- 3-(6-Azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (Compound 006)

[0352]

[0353] 5.1 Synthesis of intermediate 6-2

[0354]

[0355] Sodium bicarbonate (16.0 g) was added to a mixed solution of water (180 mL) and dichloromethane (50 mL) of 4,4-difluoropiperidine hydrochloride (10.0 g) at room temperature. The reaction mixture was cooled to 0°C. A solution of bromonitrile (8.40 g) in dichloromethane (5 mL) was slowly added dropwise. The reaction mixture was naturally warmed to room temperature and stirred for 16 hours. The reaction solution was extracted with dichloromethane (3×10 mL), the organic phases were combined, washed with saturated sodium bicarbonate (10 mL) and saturated sodium chloride aqueous solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 6-2 (8.07 g). LCMS: MS m / z (ESI): 147.01 [M+H] + .

[0356] 5.2 Synthesis of intermediate 6-3

[0357]

[0358] At room temperature, the intermediate 6-2 (2.0 g) was dissolved in 1,2-dichloroethane (40 mL), and p-toluenesulfonic acid (7.07 g) was added to the reaction solution. After stirring at room temperature for 30 minutes, ethanolaldehyde diethyl acetal (2.90 g) was added dropwise. Stirring was continued at room temperature for 30 minutes. After the reaction was completed, the reaction solution was washed with saturated sodium bicarbonate (10 mL) and saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate and filtered. The residue after the filtrate was concentrated under reduced pressure was dissolved in 1,2-dichloroethane (20 mL) and reacted at 120°C under microwave for 30 minutes. After the reaction solution was cooled, it was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether: 0-25%) to obtain intermediate 6-3 (385 mg). LCMS: MS m / z (ESI): 189.3 [M+H] + .

[0359] 5.3 Synthesis of intermediate 6-4

[0360]

[0361] The intermediate 6-3 (710 mg) was dissolved in dry THF (10.0 mL), cooled to -78 ° C, and n-BuLi (2.5 M, 1.66 mL) in n-hexane was added dropwise to the reaction solution under argon protection. After stirring at -78 ° C for 30 minutes, a solution of iodine (1.15 g) in THF (4.00 mL) was added dropwise to the reaction solution. Stir the reaction at -78 ° C for 3 hours. Ethyl acetate (30.0 mL) was added to the reaction solution for dilution, washed with saturated sodium bisulfite aqueous solution (2×30.0 mL) and saturated sodium chloride aqueous solution (30.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether: 0-5%) to obtain intermediate 6-4 (636 mg).

[0362] 1 H NMR (400MHz, CDCl3) δ6.82 (s, 1H), 3.66 (t, J = 6.0Hz, 4H), 2.10–2.00 (m, 4H). 19 FNMR (377MHz,CDCl3)δ-97.91.

[0363] 5.4 Synthesis of intermediate 6-5

[0364]

[0365] At room temperature, the intermediate 6-4 (286 mg) was dissolved in acetonitrile (15 mL), triethylamine (644 mg) was added, and bistriphenylphosphine palladium dichloride (16 mg) and cuprous iodide (3.5 mg) were added to the reaction solution. The air was replaced by nitrogen three times. After stirring at room temperature for 10 minutes, trimethylsilyl acetylene (107 mg) was added. The reaction was stirred at room temperature for 3 hours under nitrogen protection. The reaction solution was diluted with water (50.0 mL), extracted with ethyl acetate (3×100.0 mL), the organic phases were combined, washed with saturated sodium chloride aqueous solution (3×100.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether: 0-30%) to obtain intermediate 6-5 (120 mg). LCMS: MS m / z (ESI): 285.3 [M+H] + .

[0366] 5.5 Synthesis of intermediate 6-6

[0367]

[0368] Saturated aqueous potassium carbonate solution (10 mL) was added dropwise to a solution of intermediate 6-5 (120 mg) in methanol (15 mL) at room temperature. The reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residual solution was diluted with water (50.0 mL), extracted with ethyl acetate (3×100.0 mL), the organic phases were combined, washed with saturated aqueous sodium chloride solution (3×100.0 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain intermediate 6-6 (80 mg). LCMS: MS m / z (ESI): 213.4 [M+H] + .

[0369] 5.6 Synthesis of intermediate 6-7

[0370]

[0371] At room temperature, intermediate 6-6 (80 mg), intermediate 2-4 (150 mg), anhydrous copper sulfate (6 mg), sodium L-ascorbate (75 mg) were dissolved in a mixed solution of water (10 mL) and tert-butanol (10 mL). The mixture was stirred at 60 ° C for 2 hours under nitrogen protection. The reaction solution was diluted with water (50.0 mL), extracted with ethyl acetate (3×100.0 mL), the organic phases were combined, washed with saturated sodium chloride aqueous solution (3×100.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 6-7 (120 mg). LCMS: MS m / z (ESI): 567.2 [M+H] + .

[0372] 5.7 Synthesis of Compound 006

[0373]

[0374] Sarcosine (19 mg), cuprous iodide (20 mg) and potassium phosphate (113 mg) were added to a solution of 2-hydroxyethane-1-sulfonamide (40 mg) in N,N-dimethylformamide (5.00 mL) at room temperature. The mixture was heated and stirred at 50°C under nitrogen protection for 5 minutes, and then intermediate 6-7 (60 mg) was added. The mixture was heated and stirred at 100°C under nitrogen protection for 3 hours. The reaction solution was diluted with saturated aqueous sodium chloride solution (10.0 mL), 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 crude product was purified by preparative HPLC (mobile phase A: H2O containing 0.1% formic acid, mobile phase B: CH3CN, A / B=80%-5% gradient) to obtain the target product N-(4-(4-(2-(4,4-difluoropiperidin-1-yl)oxazol-5-yl)-1H-1,2,3-triazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (Compound 006) (15.01 mg).

[0375] 1 H NMR (400MHz, DMSO) δ10.05(s,1H),8.74(s,1H),7.48(d,J=8.6Hz,1H),7.27(s,1H),7.12(d,J=2.3Hz,1H),7.02(dd,J=8.6,2.3Hz,1H ),3.78(t,J=6.4Hz,2H),3.67–3.64(m,4H),3.36–3.33(m,2H),2.67–2.65(m,4H),2.16–2.08(m,4H),1.28–1.26(m,4H),0.26(s,4H).

[0376] LCMS:MS m / z(ESI):564.5[M+H] + .

[0377] Example 6 Synthesis of Compounds 008 and 009

[0378] Referring to the synthesis method of Example 5, the 2-hydroxyethane-1-sulfonamide in step 5.7 was replaced with other corresponding sulfonamides to obtain the following compound:

[0379]

[0380] Example 7 Synthesis of Compounds 010, 042, and 043

[0381] Referring to the synthesis method of Example 2, the 4,4-difluoropiperidine hydrochloride in step 2.4 was replaced with the corresponding nitrogen heterocycle to obtain the following compound:

[0382]

[0383] Example 8 N-(4-(4-(3-(4,4-difluoropiperidin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)-3-(6- [2.5] octan-6-yl)phenyl]-2-hydroxyethane-1-sulfonamide (Compound 022)

[0384]

[0385] 8.1 Synthesis of Intermediate 22-2

[0386]

[0387] Triethylamine (15.0 mL) was added to a solution of 1-bromo-3-iodobenzene (1.0 g) in tetrahydrofuran (30 mL) at room temperature, and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (130 mg) and cuprous iodide (20 mg) were added to the reaction solution. The air was replaced with nitrogen three times. After stirring at room temperature for 10 minutes, trimethylsilyl acetylene (380 mg, 3.87 mmol) was added. The reaction was stirred at room temperature for 3 hours under nitrogen protection. The reaction solution was diluted with water (50.0 mL), extracted with ethyl acetate (3×100.0 mL), the organic phases were combined, washed with saturated sodium chloride aqueous solution (3×100.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether: 0-1%) to obtain intermediate 22-2 (890 mg).

[0388] 8.2 Synthesis of Intermediate 22-3

[0389]

[0390] Pd2(dba)3(72.5mg) and DavePhos(32mg) were added to a solution of intermediate 22-2(400mg) and 4,4-difluoropiperidine(211mg) in THF(15.0mL) at room temperature. The air was replaced by nitrogen three times. A solution of LiHMDS(1M, 4mL) in THF was slowly added. The reaction was stirred at 70°C for 2 hours under nitrogen protection. The reaction solution was diluted with water(50.0mL), extracted with ethyl acetate(3×50.0mL), the organic phases were combined, washed with saturated aqueous sodium chloride solution(3×50.0mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography(ethyl acetate / petroleum ether: 0-3%) to obtain intermediate 22-3(400mg). LCMS:MS m / z(ESI):294.2[M+H] + .

[0391] 8.3 Synthesis of Intermediate 22-4

[0392]

[0393] Saturated potassium carbonate aqueous solution (10 mL) was added dropwise to a solution of intermediate 22-3 (350 mg) in methanol (15 mL) at room temperature, and the reaction was stirred at room temperature for 10 minutes. The reaction solution was concentrated under reduced pressure, and water (50.0 mL) was added to the residue for dilution, and extracted with ethyl acetate (3×100.0 mL). The organic phase was washed with saturated sodium chloride aqueous solution (3×100.0 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain intermediate 22-4 (250 mg). LCMS: MS m / z (ESI): 222.4 [M+H] + .

[0394] 8.4 Synthesis of Intermediate 22-5

[0395]

[0396] At room temperature, intermediate 22-4 (160 mg), intermediate 2-4 (282 mg), anhydrous copper sulfate (12 mg), sodium L-ascorbate (144 mg) were dissolved in a mixed solution of water (15 mL) and tert-butanol (15 mL). The mixture was stirred at 60 ° C for 2 hours under nitrogen protection. The reaction solution was diluted with water (50.0 mL) and extracted with ethyl acetate (3×100.0 mL). The organic phases were combined and washed with saturated sodium chloride aqueous solution (3×100.0 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain intermediate 22-5 (372 mg). LCMS: MS m / z (ESI): 576.5 [M+H] + .

[0397] 8.5 Synthesis of Compound 022

[0398]

[0399] Sarcosine (32 mg), cuprous iodide (75 mg) and potassium phosphate (140 mg) were added to a solution of 2-hydroxyethane-1-sulfonamide (50 mg) in N,N-dimethylformamide (5.00 mL) at room temperature. The mixture was heated and stirred at 50°C under nitrogen protection for 5 minutes, and then intermediate 22-5 (75 mg) was added. The mixture was heated to 100°C and stirred for 3 hours. The reaction solution was diluted with saturated aqueous sodium chloride solution (10.0 mL), 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 crude product was purified by preparative HPLC (mobile phase A: H2O containing 0.1% formic acid, mobile phase B: CH3CN, A / B=80%-5% gradient) to obtain the target product N-(4-(4-(3-(4,4-difluoropiperidin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl]-2-hydroxyethane-1-sulfonamide (Compound 022) (31.43 mg).

[0400] 1 H NMR (400MHz, DMSO) δ9.01(s,1H),7.55(d,J=2.2Hz,1H),7.47(d,J=8.5Hz,1H),7.41–7.29(m,2H),7.11(d,J=2.3Hz,1H),7.05–6.97(m,2H ),3.78(t,J=6.6Hz,2H),3.43(t,J=5.8Hz,4H),3.33(t,J=6.6Hz,2H),2.67(t,J=5.3Hz,4H),2.14–2.01(m,4H),1.26(s,4H),0.23(s,4H).

[0401] 19 F NMR (377 MHz, DMSO) δ-95.13.

[0402] LCMS:MS m / z(ESI):573.4[M+H] + .

[0403] Example 9 N-(4-(4-(2-(4,4-difluoropiperidin-1-yl)pyrimidin-4-yl)-1H-1,2,3-triazol-1-yl)- 3-(6-Azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (Compound 023)

[0404]

[0405] 9.1 Synthesis of Intermediate 23-2

[0406]

[0407] 2,4-Dichloropyrimidine (1.00 g), Pd(PPh3)2Cl2 (23.6 mg), triphenylphosphine (17.6 mg) and cuprous iodide (12.8 mg) were dissolved in THF (5 ml) at room temperature, and the air was replaced by nitrogen three times. Triethylamine (7.50 ml) and trimethylsilyl acetylene (725 mg) were added, and the nitrogen was replaced three times. The reaction mixture was heated under reflux under nitrogen protection for 4.5 hours. After cooling to room temperature, the reaction solution was filtered, the filter cake was washed with ethyl acetate (3×50 mL), the filtrate was combined, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether: 0-10%) to obtain intermediate 23-2 (714 mg). LCMS: MS m / z (ESI): 211.2 [M+H] + .

[0408] 9.2 Synthesis of Intermediate 23-3

[0409]

[0410] At room temperature, the intermediate 23-2 (590 mg) was dissolved in NMP (8.0 mL), and 4,4-difluoropiperidine hydrochloride (441 mg) and N,N-diisopropylethylamine (2.17 g) were added. The reaction was stirred at 80 ° C for 2 hours. After cooling to room temperature, the reaction solution was diluted with water (5 mL) and 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, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether: 0-10%) to obtain intermediate 23-3 (440 mg). LCMS: MS m / z (ESI): 296.3 [M+H] + .

[0411] 9.3 Synthesis of Intermediate 23-4

[0412]

[0413] Potassium carbonate (1.03 g) was added to a mixed solution of methanol (5 mL) and water (3 mL) of intermediate 23-3 (440 mg) at room temperature. The reaction was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure to remove methanol, and the residual liquid was extracted with ethyl acetate (3×5 mL). The organic phases were combined, washed with saturated sodium chloride aqueous solution (3×5 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain intermediate 23-4 (225 mg), and the crude product was directly used in the next reaction. LCMS: MS m / z (ESI): 224.3 [M+H] + .

[0414] 9.4 Synthesis of Intermediate 23-5

[0415]

[0416] To a mixed solution of tert-butanol (6 mL) and water (6 mL) of intermediate 23-4 (100 mg) was added intermediate 2-4 (175 mg), copper sulfate (10.1 mg), and sodium L-ascorbate (93.2 mg) at room temperature. The reaction mixture was stirred at 60°C for 3 hours under nitrogen protection. The mixture was cooled to room temperature, concentrated under reduced pressure to remove the solvent tert-butanol, and the residual liquid was extracted with ethyl acetate (3×5 mL). The organic phases were combined, washed with saturated sodium chloride aqueous solution (3×5 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether: 0-20%) to obtain intermediate 23-5 (178 mg). LCMS: MS m / z (ESI): 578.4 [M+H] + .

[0417] 9.5 Synthesis of Compound 023

[0418]

[0419] Sarcosine (12.4 mg), cuprous iodide (53.0 mg) and potassium phosphate (148 mg) were added to a solution of 2-hydroxyethane-1-sulfonamide (69.3 mg) in N,N-dimethylformamide (2.00 mL) at room temperature. The mixture was stirred and heated at 50°C for 5 minutes under nitrogen protection, and then intermediate 23-5 (80 mg) was added. The mixture was heated at 100°C for 2 hours under nitrogen protection. The mixture was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (2×10 mL). The organic phase was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the crude product was separated and purified by silica gel column chromatography (methanol / dichloromethane: 0-10%) to give N-(4-(4-(2-(4,4-difluoropiperidin-1-yl)pyrimidin-4-yl)-1H-1,2,3-triazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (Compound 023) (16 mg).

[0420] 1H NMR (400MHz, DMSO) δ10.06 (s, 1H), 9.28 (s, 1H), 8.53 (d, J = 5.0Hz, 1H), 7.58 ( d,J=8.6Hz,1H),7.30(d,J=5.0Hz,1H),7.14(d,J=2.3Hz,1H),7.04(dd,J=8.6 ,2.3Hz,1H),4.99(s,1H),4.02–3.97(m,4H),3.78(t,J=6.5Hz,2H),3.37–3.3 2(m,2H),2.67(t,J=5.4Hz,4H),2.04–1.99(m,4H),1.29(s,4H),0.25(s,4H).

[0421] LCMS:MS m / z(ESI):575.6[M+H] + .

[0422] Example 10 N-(4-(4-(6-(4,4-difluoropiperidin-1-yl)-5-methoxypyridin-2-yl)-1H-1,2,3-trifluoropiperidin-1-yl)-5-methoxypyridin-2-yl)-1H-1,2,3-trifluoropiperidin-1-yl oxazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (Compound 024)

[0423]

[0424] 10.1 Synthesis of Intermediate 24-2

[0425]

[0426] Potassium carbonate (1.08 g) was added to a solution of 2-chloro-6-iodopyridin-3-ol (1.00 g) in N,N-dimethylformamide (88.0 mL) at room temperature. The reaction was stirred at room temperature for 5 minutes under nitrogen protection. Methyl iodide (2.78 g) was added and the reaction was stirred at 100°C for 2 hours. After cooling to room temperature, water (30.0 mL) was added to the reaction solution for dilution and extraction with ethyl acetate (100 mL×3). The organic phase was collected, washed with saturated sodium chloride aqueous solution (100 mL), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate=20:1-10:1) to obtain intermediate 24-2 (1.04 g). LCMS: MSm / z(ESI):269.9[M+H] + .

[0427] 10.2 Synthesis of Intermediate 24-3

[0428]

[0429] Potassium carbonate (1.28 g) and 4,4-difluoropiperidine hydrochloride (878 mg) were added to a solution of intermediate 24-2 (500 mg) in dimethyl sulfoxide (6.00 mL) at room temperature. The reaction was stirred at 120 ° C overnight under sealed conditions. Cooled to room temperature, water (30.0 mL) was added to the reaction solution to dilute it, and extracted with ethyl acetate (60 mL×2). The organic phase was collected, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 40:1-30:1) to obtain intermediate 24-3 (200 mg). LCMS: MS m / z (ESI): 355.0 [M+H] + .

[0430] 10.3 Synthesis of Intermediate 24-4

[0431]

[0432] At room temperature, the intermediate 24-3 (200 mg), triphenylphosphine (119 mg), cuprous iodide (43.0 mg), PdCl2(PPh3)2 (39.7 mg), and diisopropylethylamine (2.00 mL) were added to tetrahydrofuran (6.00 mL) in sequence. Stir at room temperature for 10 minutes under nitrogen protection. Trimethylsilyl acetylene (166 mg) was added to the reaction solution, and the temperature was raised to 70°C and stirred for 4 hours. Cooled to room temperature, water (20 mL) was added to the reaction solution for dilution, and extracted with ethyl acetate (40.0 mL×2). The organic phase was collected, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50:1-30:1) to obtain intermediate 24-4 (160 mg). LCMS: MS m / z (ESI): 325.2 [M+H] + .

[0433] 10.4 Synthesis of Compound 024

[0434] Referring to the synthesis method of Example 9, the intermediate 23-3 in step 9.3 was replaced by the intermediate 24-4 to finally obtain the target product N-(4-(4-(6-(4,4-difluoropiperidin-1-yl)-5-methoxypyridin-2-yl)-1H-1,2,3-triazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (Compound 024).

[0435] 1H NMR (400MHz, DMSO) δ9.99(br,1H),8.94(s,1H),7.59-7.56(m,2H),7.41(d,J=8.4Hz,1H),7.12(d,J=2.3Hz,1H),7.03(dd,J=8.4,2.3Hz,1H),4.95( br,1H),3.87(s,3H),3.78(t,J=6.4Hz,2H),3.64-3.61(m,4H),3.34-3.3 1(m,2H),2.69-2.67(m,4H),2.13-2.03(m,4H),1.34(s,4H),0.24(s,4H).

[0436] 19 F NMR (377 MHz, DMSO) δ-94.16.

[0437] LCMS:MS m / z(ESI):604.4[M+H] + .

[0438] Example 11 N-(4-(3-(2-(4,4-difluoropiperidin-1-yl)thiazol-4-yl)-1,2,4-oxadiazol-5-yl)- 3-(6-Azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (Compound 031)

[0439]

[0440] 11.1 Synthesis of Intermediate 31-2

[0441]

[0442] Zinc powder (37 mg), zinc cyanide (448 mg), bis(diphenylphosphinoferrocene) (212 mg) and tris(dibenzylideneacetone)dipalladium (176 mg) were added to a solution of intermediate 2-5 (1.80 g) in N,N-dimethylacetamide (20.0 mL) at room temperature. Microwave reaction was carried out at 110°C for 40 minutes under argon protection. Water (20.0 mL) was added to the reaction solution, and ethyl acetate (3×20.0 mL) was used for extraction. The organic phases were combined, washed with saturated sodium chloride aqueous solution (2×20.0 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 300:1 to 80:1) to obtain intermediate 31-2 (970 mg). LCMS: MS m / z (ESI): 230.2 [M+H] + .

[0443] 11.2 Synthesis of Intermediate 31-3

[0444]

[0445] Intermediate 31-2 (870 mg) was dissolved in a mixed solution of ethanol (10.0 mL) and water (1.00 mL) at room temperature. Hydroxylamine hydrochloride (527 mg) and sodium hydroxide (455 mg) were added to the reaction solution in sequence. The reaction was stirred at 80°C for 12 hours. Water (20.0 mL) was added to the reaction solution and extracted with ethyl acetate (3×20.0 mL). The organic phases were combined, washed with saturated sodium chloride aqueous solution (2×20.0 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain intermediate 31-3 (800 mg). LCMS: MS m / z (ESI): 263.2 [M+H] + .

[0446] 11.3 Synthesis of Intermediate 31-4

[0447]

[0448] At room temperature, intermediate 31-3 (299 mg), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (274 mg), 1-hydroxybenzotriazole (193 mg) and N,N-diisopropylethylamine (246 mg) were added to a solution of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (340 mg) in N,N-dimethylformamide (15.0 mL). The reaction was stirred overnight at room temperature. Water (20.0 mL) was added to the reaction solution for dilution, and the mixture was extracted with ethyl acetate (3×20.0 mL). The organic phases were combined, washed with saturated sodium chloride aqueous solution (4×20.0 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1). The crude product was purified by preparative thin layer chromatography (petroleum ether: ethyl acetate = 2:1) to obtain intermediate 31-4 (200 mg). LCMS:MS m / z(ESI):602.2[M+H] + .

[0449] 11.4 Synthesis of Intermediate 31-5

[0450]

[0451] 1,8-diazabicyclo[5.4.0]undec-7-ene (76 mg) was added to a solution of intermediate 31-4 (200 mg) in N,N-dimethylformamide (2.00 mL) at room temperature, and the reaction was stirred overnight at room temperature. Water (20.0 mL) was added to the reaction solution for dilution, and extracted with ethyl acetate (3×20.0 mL). The organic phases were combined, washed with saturated sodium chloride aqueous solution (4×20.0 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by thin layer preparative chromatography (petroleum ether: ethyl acetate = 10:1) to obtain intermediate 31-5 (180 mg). LCMS: MS m / z (ESI): 584.1 [M+H] + .

[0452] 11.5 Synthesis of Compound 031

[0453]

[0454] At room temperature, the intermediate 31-5 (180 mg) was dissolved in dry N,N-dimethylformamide (5.00 mL), and 2-hydroxyethane-1-sulfonamide (116 mg), sarcosine (41 mg), cuprous iodide (59 mg) and potassium phosphate (329 mg) were added in sequence. After the air was replaced by argon gas three times, the mixture was heated to 100 ° C and stirred for 2 hours. Water (10.0 mL) was added to the reaction solution to dilute it, and it was extracted with ethyl acetate (3×10.0 mL). The organic phases were combined and washed with a mixed solution of saturated ammonium chloride aqueous solution: ammonia water = 10:1 (2×10.0 mL), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by thin layer preparative chromatography (dichloromethane: methanol = 10:1) to give the target product N-(4-(3-(2-(4,4-difluoropiperidin-1-yl)thiazol-4-yl)-1,2,4-oxadiazol-5-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (Compound 031) (87.32 mg).

[0455] 1 H NMR (400MHz, DMSO) δ10.25(s,1H),7.92(d,J=8.6Hz,1H),7.69(s,1H),7.08(d,J=2.2Hz,1H),6.96(dd,J=8.6,2.2Hz,1H),4.96(s,1H),3 .76(t,J=6.5Hz,2H),3.67(t,J=5.9Hz,4H),3.37(t,J=6.5Hz,2H),2.95(t,J=5.2Hz,4H),2.21–2.08(m,4H),1.51(brs,4H),0.34(s,4H). 19F NMR (377 MHz, DMSO) δ-95.87.

[0456] LCMS:MS m / z(ESI):581.3[M+H] + .

[0457] Example 12 N-(4-(5-(2-(4,4-difluoropiperidin-1-yl)thiazol-4-yl)-1,3,4-oxadiazol-2-yl)- 3-(6-Azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (Compound 032)

[0458]

[0459] 12.1 Synthesis of Intermediate 32-2

[0460]

[0461] Methyl 2-bromothiazole-4-carboxylate (1.00 g) was dissolved in a dry dioxane solution (20.0 mL) at room temperature. Under argon protection, 4,4-difluoropiperidine hydrochloride (1.07 g), tris(dibenzylideneacetone)dipalladium (413 mg), Xantphos (521 mg), and cesium carbonate (2.93 g) were added and stirred at 100°C for 16 hours. Water (50.0 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3x50.0 mL). The organic phase was washed with a saturated sodium chloride aqueous solution (3x50.0 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether: 0-10%) to obtain intermediate 32-2 (672 mg). LCMS: MS m / z (ESI): 263.1 [M+H] + .

[0462] 12.2 Synthesis of Intermediate 32-3

[0463]

[0464] 80% hydrazine hydrate (460 mg) was slowly added dropwise to a solution of intermediate 32-2 (500 mg) in ethanol (10 mL) at room temperature, and the mixture was refluxed for 3 hours under nitrogen protection. The reaction solution was cooled to room temperature and crushed ice was added. The filter cake was filtered and washed with 0°C ethanol and dried in vacuo to obtain intermediate 32-3 (370 mg). LCMS: MS m / z (ESI): 263.2 [M+H] + .

[0465] 12.3 Synthesis of Intermediate 32-4

[0466]

[0467] At room temperature, the intermediate 32-3 (200 mg) was dissolved in phosphorus oxychloride (5 mL), and 4-iodo-2-(6-azaspiro[2.5]octane-6-yl)benzoic acid (408 mg) was added to the reaction solution. After stirring the reaction at room temperature overnight, the temperature was raised to 50°C and the reaction was stirred for 24 hours. The reaction solution was cooled to room temperature, slowly dripped into water (50 mL), the pH was adjusted to 8 with saturated sodium bicarbonate aqueous solution, and extracted with dichloromethane (50 mL×3). The organic phases were combined, washed with saturated sodium chloride aqueous solution (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate: petroleum ether=1:10~1:4) to obtain intermediate 32-4 (300 mg). LCMS:MS m / z(ESI):584.1[M+H] + .

[0468] 12.4 Synthesis of Compound 032

[0469]

[0470] At room temperature, the intermediate 32-4 (100 mg) was dissolved in dry DMF (3 mL), and 2-hydroxyethane-1-sulfonamide (64 mg), sarcosine (15 mg), cuprous iodide (32.3 mg), and potassium phosphate (180 mg) were added in sequence. The air was replaced with nitrogen four times, and the reaction was stirred at 100°C for 2.5 hours. After cooling to room temperature, water (30 mL) was added to the reaction solution for dilution, and the mixture was extracted with ethyl acetate (3×30 mL). The organic phases were combined, washed with saturated aqueous sodium chloride solution (30 mL), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC (mobile phase A: H2O containing 0.1% formic acid, mobile phase B: CH3CN, A / B = 70%-5% gradient) to give N-(4-(5-(2-(4,4-difluoropiperidin-1-yl)thiazol-4-yl)-1,3,4-oxadiazol-2-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (Compound 032) (37 mg).

[0471] 1 H NMR (400MHz, DMSO) δ7.85(d,J=8.5Hz,1H),7.79(s,1H),7.06(d,J=2.2Hz,1H),6.95(dd,J=8.5,2.2Hz,1H),3.76(t,J=6 .5Hz,2H),3.69(t,J=5.5Hz,4H),3.37–3.35(m,2H),2.91(t,J=5.2Hz,4H),2.20–2.07(m,4H),1.53(s,4H),0.31(s,4H).

[0472] 19 F NMR (377 MHz, DMSO) δ-95.90.

[0473] LCMS:MS m / z(ESI):581.3[M+H] + .

[0474] Example 13 N-(4-(1-(2-(4,4-difluoropiperidin-1-yl)thiazol-4-yl)-1H-1,2,3-triazole-4-yl 1-(6-azaspiro)[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (Compound 037)

[0475]

[0476] 13.1 Synthesis of Intermediate 37-2:

[0477]

[0478] Sodium azide (1.15 g), sodium L-ascorbate (180 mg), iodide (175 mg) and DMEDA (185 mg) were added to a mixed solution of intermediate 2-5 (500 mg) in ethanol (17.5 mL) and water (7.5 mL) at room temperature, and the mixture was stirred at 70°C for 30 min under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (EA / PE: 0-10%) to obtain intermediate 37-2 (100 mg). LCMS: MS m / z (ESI): 246.3 [M+H] + .

[0479] 13.2 Synthesis of Compound 037:

[0480] The remaining steps refer to Example 1, replacing intermediate 1-4 with intermediate 37-2 to finally obtain the target product N-(4-(1-(2-(4,4-difluoropiperidin-1-yl)thiazol-4-yl)-1H-1,2,3-triazol-4-yl)-3-(6-azaspiro)[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (Compound 037).

[0481] 1 H NMR (400MHz, DMSO) δ9.86(s,1H),9.07(s,1H),8.00(d,J=8.4Hz,1H),7.30(s,1H),7.15(d,J=2.2Hz,1H),7.04(dd,J=8.4,2.2Hz,1H),4.94(s ,1H),3.76(t,J=6.7Hz,2H),3.69(t,J=5.8Hz,4H),3.29(t,J=6.7Hz,2H),2.82(t,J=5.3Hz,4H),2.23–2.08(m,4H),1.52(s,4H),0.34(s,4H).19 F NMR (377MHz, DMSO) δppm-95.82.

[0482] LCMS:MS m / z(ESI):580.0[M+H] + .

[0483] Example 14 N-(4-(4-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-1H-1,2,3-trifluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-1H-1,2,3-trifluoropiperidin-1-yl oxazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (Compound 039)

[0484]

[0485] Referring to the synthetic method of Example 9, the 2,4-dichloropyrimidine in step 9.1 was replaced with 2,4-dichloro-6-methylpyrimidine to obtain the target product N-(4-(4-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-1H-1,2,3-triazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (Compound 039).

[0486] 1 H NMR (400MHz, DMSO) δ10.05(s,1H),9.22(s,1H),7.58(d,J=8.5Hz,1H),7.22(s,1H),7.14(d,J=2.3Hz,1H),7.04(dd,J=8.5,2.3Hz,1H),4.97(s, 1H),3.99(t,J=5.9Hz,4H),3.81–3.76(m,2H),3.38–3.32(m,2H),2.71– 2.64(m,4H),2.41(s,3H),2.07–1.95(m,4H),1.29(s,4H),0.25(s,4H).

[0487] 19 F NMR (377 MHz, DMSO) δ-94.76.

[0488] LCMS:MS m / z(ESI):589.5[M+H] + .

[0489] Example 15 N-(4-(1-(2-(4,4-difluoropiperidin-1-yl)pyrimidin-4-yl)-1H-1,2,3-triazole-4-yl 1-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (Compound 040)

[0490]

[0491] 15.1 Synthesis of Intermediate 40-2

[0492]

[0493] Sodium azide (2.0 g) was added to a DMF (30 mL) solution of 4-chloro-2-(methylthio)pyrimidine (1.60 g) at room temperature. The reaction was stirred at room temperature for 3 days. Water (50 mL) was added to the reaction solution and extracted with ethyl acetate (2×100 mL). The organic phases were combined, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether: 0-20%) to obtain intermediate 40-2 (1.3 g). LCMS: MS m / z (ESI): 168.1 [M+H] + .

[0494] 15.2 Synthesis of Intermediate 40-3

[0495]

[0496] To a solution of intermediate 40-2 (500 mg) in ethyl acetate (10 mL) was added a solution of potassium peroxymonosulfonate (5.5 g) in water (10 mL) at room temperature, and the mixture was stirred at room temperature for 3 hours. The reaction solution was extracted with ethyl acetate (3×20 mL), the organic phases were combined, dried over anhydrous sodium sulfate, and filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether: 0-20%) to obtain intermediate 40-3 (440 mg). LCMS: MS m / z (ESI): 200.3 [M+H] + .

[0497] 15.3 Synthesis of Intermediate 40-4

[0498]

[0499] Under nitrogen protection, diisopropylethylamine (1.4 g) and 4,4-difluoropiperidine hydrochloride (1.70 g) were added to a solution of intermediate 40-3 (440 mg) in acetonitrile (20 mL), and the mixture was stirred at 80°C for 2 hours. 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 then filtered. The filtrate was concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether: 0-25%) to obtain intermediate 40-4 (140 mg). LCMS: MS m / z (ESI): 241.3 [M+H] + .

[0500] 15.4 Synthesis of Compound 040

[0501] Referring to the synthesis method of Example 1, the intermediate 1-4 in step 1.9 was replaced by intermediate 40-4 to finally obtain the target product N-(4-(1-(2-(4,4-difluoropiperidin-1-yl)pyrimidin-4-yl)-1H-1,2,3-triazol-4-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (Compound 040).

[0502] 1 H NMR (400MHz, DMSO) δ9.48 (s, 1H), 8.67 (d, J = 5.2Hz, 1H), 8.08 (d, J = 8.4Hz, 1H), 7.38 (d, J = 5.2Hz, 1H), 7.16 (d, J = 2.2Hz, 1H), 7.05 (dd, J = 8.4, 2.2Hz,1H),4.03–4.01(m,4H),3.75(t,J=6.8Hz,2H),3.30–3.25(m,2H),2.85(t,J=5.2Hz,4H),2.12–2.05(m,4H),1.55(s,4H),0.37(s,4H).

[0503] LCMS:MS m / z(ESI):575.3[M+H] + .

[0504] Example 16 4-(4-(2-(4,4-difluoropiperidin-1-yl)thiazol-4-yl)-1H-1,2,3-triazol-1-yl)-N- (2-Hydroxyethyl)-3-(6-azaspiro[2.5]octan-6-yl)benzenesulfonamide (Compound 041)

[0505]

[0506] 16.1 Synthesis of Compound 041

[0507]

[0508] To a solution of intermediate 2-8 (50 mg) in isopropanol (2.00 mL) was added 1,4-diazabicyclo[2.2.2]octane-1,4-disulfinic acid (12.4 mg), palladium acetate (6 mg), n-butyldi(1-adamantyl)phosphine (12.3 mg) and triethylamine (26 mg) at room temperature. Stir the mixture in a sealed tube at 85°C for 3 hours under nitrogen protection. The reaction mixture was cooled to room temperature, and then ethanolamine (11 mg) and 10% sodium hypochlorite aqueous solution (120 mg) were added, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3×20 mL). The organic phases were combined, washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by preparative HPLC (mobile phase A: H2O containing 0.1% formic acid, mobile phase B: CH3CN, A / B = 50%-5% gradient) to obtain 4-(4-(2-(4,4-difluoropiperidin-1-yl)thiazol-4-yl)-1H-1,2,3-triazol-1-yl)-N-(2-hydroxyethyl)-3-(6-azaspiro[2.5]octane-6-yl)benzenesulfonamide (Compound 041) (4 mg).

[0509] 1 H NMR (400MHz, DMSO) δ8.87(s,1H),7.82–7.76(m,2H),7.66(d,J=2.0Hz,1H),7.59(dd,J=8.2,2.0Hz,1H),7.33(s,1H),4.73(t,J=5.5Hz,1H ),3.66(t,J=5.9Hz,4H),3.41(q,J=6.0Hz,2H),2.87(t,J=6.0Hz,2H),2.74(t,J=5.5Hz,4H),2.19–2.07(m,4H),1.33(s,4H),0.27(s,4H). 19 F NMR (377 MHz, DMSO) δ-95.72.

[0510] LCMS:MS m / z(ESI):578.4[MH] - .

[0511] Example 17 Synthesis of Compounds 044, 045, and 046

[0512] Referring to the synthesis method of Example 9, the 2-hydroxyethane-1-sulfonamide in step 9.5 was replaced with other corresponding sulfonamides to obtain the following compound:

[0513]

[0514] Example 18 N-(4-(4-(2-(4,4-difluoropiperidin-1-yl)pyrimidin-4-yl)-1H-1,2,3-triazol-1-yl)- 3-(6-Azaspiro[2.5]octan-6-yl)phenyl)-2-fluoroethane-1-sulfonamide (Compound 047)

[0515]

[0516] Referring to the synthesis method of Example 3, the intermediate 2-7 in step 3.5 was replaced by the intermediate 23-4 to obtain the target compound N-(4-(4-(2-(4,4-difluoropiperidin-1-yl)pyrimidin-4-yl)-1H-1,2,3-triazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-fluoroethane-1-sulfonamide (Compound 047).

[0517] 1 H NMR (400MHz, DMSO) δ10.30 (s, 1H), 9.27 (s, 1H), 8.53 (d, J = 5.0Hz, 1H), 7.58 (d ,J=8.5Hz,1H),7.29(d,J=5.0Hz,1H),7.13(d,J=2.3Hz,1H),7.03(dd,J=8.5,2 .3Hz,1H),4.79(dt,J=47.0,5.1Hz,2H),4.03–3.95(m,4H),3.68(dt,J=25.3,5 .1Hz,2H),2.68(t,J=5.3Hz,4H),2.07–1.95(m,4H),1.29(s,4H),0.25(s,4H).

[0518] LCMS:MS m / z(ESI):577.2[M+H] + .

[0519] Example 19 N-(4-(4-(5-chloro-2-(4,4-difluoropiperidin-1-yl)thiazol-4-yl)-1H-1,2,3-triazole- 1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (Compound 051)

[0520]

[0521] 19.1 Synthesis of Intermediate 51-2:

[0522]

[0523] Methyl 2-bromothiazole-4-carboxylate (1.00 g) was dissolved in a dry dioxane solution (20.0 mL) at room temperature. Under argon protection, 4,4-difluoropiperidine hydrochloride (1.07 g), tris(dibenzylideneacetone)dipalladium (413 mg), Xantphos (521 mg), and cesium carbonate (2.93 g) were added and stirred at 100°C for 16 hours. Water (50.0 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3x50.0 mL). The organic phase was washed with a saturated sodium chloride aqueous solution (3x50.0 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (EA / PE: 0-10%) to obtain intermediate 51-2 (672 mg). LCMS: MS m / z (ESI): 263.1 [M+H] + .

[0524] 19.2 Synthesis of Intermediate 51-3:

[0525]

[0526] N-chlorosuccinimide (560 mg) was added to a solution of intermediate 51-2 (1.0 g, 3.81 mmol) in acetonitrile (20 mL) at room temperature, and the mixture was stirred at 80°C overnight. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE:EA=10:1) to obtain intermediate 51-3 (970 mg). LCMS:MS m / z(ESI):297.0[M+H] + .

[0527] 19.3 Synthesis of Intermediate 51-4:

[0528]

[0529] To a solution of intermediate 51-3 (970 mg) in tetrahydrofuran (10 mL) was added a solution of lithium borohydride (2 M, 8.2 mL) in tetrahydrofuran at 0°C. The reaction was naturally heated to 70°C and stirred for 6 hours. After the reaction was completed, methanol was added to quench. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (EA:PE=1:5) to obtain intermediate 51-4 (820 mg).

[0530] LCMS:MS m / z(ESI):269.0[M+H] + .

[0531] 19.4 Synthesis of Intermediate 51-5:

[0532]

[0533] The reaction system was cooled to -78°C, and dimethyl sulfoxide (348 mg) was added dropwise to a solution of oxalyl chloride (283 mg) in dichloromethane (8 mL) under nitrogen protection, and stirred at -78°C for 30 minutes. A solution of intermediate 51-4 (400 mg) in dichloromethane (4 ml) was added dropwise, and the reaction was stirred at -78°C for 1 hour. A solution of triethylamine (600 mg) in dichloromethane (2 mL) was added at -78°C to quench the reaction and stirred for 30 minutes. The reaction mixture was naturally warmed to room temperature and a saturated ammonium chloride solution (40 mL) was added to the reaction solution, which was extracted with dichloromethane (3×40 mL). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA:PE=1:10) to obtain intermediate 51-5 (160 mg). LCMS:MS m / z(ESI):267.0[M+H] + .

[0534] 19.5 Synthesis of Intermediate 51-6:

[0535]

[0536] At 0°C, under nitrogen protection, dimethyl (1-diazo-2-oxopropyl)phosphonate (784 mg) was slowly added dropwise to a solution of intermediate 51-5 (543 mg) in methanol (10 mL), and then potassium carbonate (846 mg) was added and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure at low temperature, the residue was diluted with water, and extracted with dichloromethane (3×20 mL). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA:PE=1:10) to obtain intermediate 51-6 (250 mg). LCMS:MS m / z(ESI):263.1[M+H] + .

[0537] 19.6 Synthesis of Compound 051:

[0538] The remaining steps refer to Example 2, replacing intermediate 2-7 with intermediate 51-6 to obtain the target product N-(4-(4-(5-chloro-2-(4,4-difluoropiperidin-1-yl)thiazol-4-yl)-1H-1,2,3-triazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (Compound 051).

[0539] 1H NMR (400MHz, DMSO) δppm: 8.87 (s, 1H), 7.53 (d, J = 8.4Hz, 1H), 7.12 (d, J = 2.0Hz, 1H), 7.02 (dd, J = 8.4, 2.0Hz, 1H), 3.78 ( t,J=6.8Hz,2H),3.64–3.60(m,4H),3.34–3.31(m,2H),2.68–2.65(m,4H),2.16–2.07(m,4H),1.29(s,4H),0.25(s,4H).

[0540] LCMS:MS m / z(ESI):614.5[M+H] + .

[0541] Example 20 Synthesis of Compound 053 and Compound 054

[0542] With reference to Example 10, the intermediate 24-2 in step 10.2 was replaced by 2-bromo-6-fluoropyridine and 4-bromo-2-fluoropyridine, respectively, to finally obtain compound 053 and compound 054.

[0543]

[0544] Example 21 N-(4-(1-(2-(4,4-difluoropiperidin-1-yl)-5-methylthiazol-4-yl)-1H-1,2,3-triazol-1 oxazol-4-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (Compound 068)

[0545]

[0546] 21.1 Synthesis of Intermediate 68-2:

[0547]

[0548] To a solution of 2,4-dibromo-5-methylthiazole (1.00 g) in N-methylpyrrolidone (5.00 mL) was added DIEA (2.52 g) and 4,4-difluoropiperidine hydrochloride (1.84 g) at room temperature. The mixture was stirred in a sealed tube at 100°C overnight. Water (50.0 mL) was added to the reaction solution, and the mixture was 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 residue was purified by silica gel column chromatography (PE:EA=30:1-20:1) to obtain intermediate 68-2 (1.03 g). LCMS:MS m / z(ESI):297.0[M+H] + .

[0549] 21.2 Synthesis of Compound 068:

[0550] The remaining steps refer to Example 13, replacing the intermediate 2-5 in the first step with intermediate 68-2 to obtain the target product N-(4-(1-(2-(4,4-difluoropiperidin-1-yl)-5-methylthiazol-4-yl)-1H-1,2,3-triazol-4-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (Compound 068).

[0551] 1 H NMR (400MHz, DMSO) δ9.01(s,1H),7.99(d,J=8.4Hz,1H),7.13(d,J=2.2Hz,1H),7.03(dd,J=8.4,2.2Hz,1H),3.75(t,J=6.7Hz,2H ),3.61(t,J=5.9Hz,4H),3.28(t,J=6.7Hz,2H),2.81(t,J=5.3Hz,4H),2.49(s,3H),2.20–2.05(m,4H),1.52(s,4H),0.33(s,4H). 19 F NMR(377MHz,DMSO)δppm-95.65.LCMS:MS m / z(ESI):594.2[M+H] + .

[0552] Example 22 N-(6-(1-(2-(4,4-difluoropiperidin-1-yl)thiazol-4-yl)-1H-1,2,3-triazol-4-yl)- 5-(6-Azaspiro[2.5]octan-6-yl)pyridin-3-yl)-2-hydroxyethane-1-sulfonamide (Compound 069)

[0553]

[0554] 22.1 Synthesis of Intermediate 69-2:

[0555]

[0556] 2,5-Dibromo-3-fluoropyridine (800 mg), 6-aza-spiro[2.5]octane hydrochloride (605 mg) and DIEA (2.0 g) were dissolved in DMSO (15.0 mL) at room temperature and stirred at 100°C for 16 hours. Water (20.0 mL) was added to the reaction solution, and it was extracted with ethyl acetate (3×20.0 mL). The organic phases were combined and washed with saturated sodium chloride aqueous solution (3×20.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA in PE: 0-20%) to obtain intermediate 69-2 (220 mg). LCMS: MS m / z (ESI): 346.9 [M+H] + .

[0557] 22.2 Synthesis of Intermediate 69-3:

[0558]

[0559] Triethylamine (80 mg), bistriphenylphosphine palladium dichloride (30.0 mg) and cuprous iodide (10.0 mg) were added to a solution of intermediate 69-2 (100 mg) in tetrahydrofuran (5.00 mL) at room temperature. The mixture was replaced with nitrogen three times, and trimethylsilyl acetylene (32 mg) was added after stirring at room temperature for 10 minutes. The mixture was stirred at room temperature for 3 hours under nitrogen protection. The reaction solution was diluted with water (10.0 mL) and extracted with ethyl acetate (3×10.0 mL). The organic phases were combined and washed with saturated aqueous sodium chloride solution (3×10.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EAin PE: 0-15%) to obtain intermediate 69-3 (60 mg). LCMS: MS m / z (ESI): 363.0 [M+H] + .

[0560] 22.3 Synthesis of Intermediate 69-4:

[0561]

[0562] Saturated potassium carbonate solution (10.0 mL) was added dropwise to a solution of intermediate 69-3 (100.0 mg) in methanol (10 ml) at room temperature, and the reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to remove the solvent methanol. The residual solution was diluted with water (10.0 mL) and extracted with ethyl acetate (3×20.0 mL). The organic phases were combined and washed with saturated sodium chloride aqueous solution (3×20.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 69-4 (75 mg). LCMS: MS m / z (ESI): 291.0 [M+H] + .

[0563] 22.4 Synthesis of Compound 069:

[0564] The remaining steps were carried out with reference to Example 1 and Example 13 to obtain the target product N-(6-(1-(2-(4,4-difluoropiperidin-1-yl)thiazol-4-yl)-1H-1,2,3-triazol-4-yl)-5-(6-azaspiro[2.5]octan-6-yl)pyridin-3-yl)-2-hydroxyethane-1-sulfonamide (Compound 069).

[0565] 1H NMR (400MHz, DMSO) δ9.01(s,1H),8.16(d,J=2.2Hz,1H),7.44(d,J=2.3Hz,1H),7.32(s,1H),3.77(t,J=6.4Hz,2H ),3.69(t,J=5.9Hz,4H),3.32–3.28(m,2H),2.87(t,J=5.3Hz,4H),2.21–2.08(m,4H),1.50(s,4H),0.33(s,4H). 19 F NMR(376MHz,DMSO)δ-95.86.LCMS:MS m / z(ESI):581.2[M+H] + .

[0566] Example 23 N-(4-(4-(5-bromo-2-(4,4-difluoropiperidin-1-yl)thiazol-4-yl)-1H-1,2,3-triazole- 1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (Compound 070)

[0567]

[0568] Referring to Example 19, the N-chlorosuccinimide and solvent acetonitrile in step 19.2 were replaced with N-bromosuccinimide and solvent carbon tetrachloride to finally obtain the target compound N-(4-(4-(5-bromo-2-(4,4-difluoropiperidin-1-yl)thiazol-4-yl)-1H-1,2,3-triazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (Compound 070).

[0569] 1 H NMR(400MHz,DMSO)δppm 8.90(s,1H),7.52(d,J=8.4Hz,1H),7.12(d,J=2.0Hz,1H),7.02(dd,J=8.4,2.0Hz,1H),3.78(t,J=6.4Hz,2H), 3.63(t,J=5.2Hz,4H),3.37–3.31(m,2H),2.67(t,J=4.8Hz,4H),2.17–2.08(m,4H),1.31(s,4H),0.26(s,4H). 19 FNMR(377MHz,DMSO)δppm:-95.69.LCMS:MS m / z(ESI):658.1[M+H] + .

[0570] Example 24 N-(4-(4-(2'H-spiro[cyclohexane-1,3'-furo[3,2-b]pyridine]-5'-yl)-1H-1,2, 3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (Compound 071)

[0571]

[0572] 24.1 Synthesis of Intermediate 71-2:

[0573]

[0574] -78 ℃, under argon protection, slowly add diisobutylaluminum hydride solution (1M, 78mL) to a solution of 1-cyclohexene-1-carboxylic acid methyl ester (5.00g) in ultra-dry dichloromethane (100.0mL). After the addition, react at -78 ℃ for 2 hours. Add methanol (70.0mL) and saturated sodium potassium tartrate aqueous solution (70mL) to quench the reaction. Return to room temperature and stir overnight. Filter, rinse the filter cake with dichloromethane, separate the filtrate, extract the aqueous phase with ethyl acetate (3×50.0mL), combine the organic phases, wash with saturated sodium chloride aqueous solution (3×50.0mL) and saturated sodium potassium tartrate aqueous solution (3×50.0mL), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the crude product by silica gel column chromatography (EA in PE: 0~20%) to obtain intermediate 71-2 (3.2g).

[0575] 24.2 Synthesis of Intermediate 71-3:

[0576]

[0577] To a solution of intermediate 71-2 (1.0 g) in ultra-dry tetrahydrofuran (10 mL) was added 6-bromo-2-iodopyridin-3-ol (1.3 g) and triphenylphosphine (2.33 g). The mixture was cooled to 0°C under argon protection, and diisopropyl azodicarboxylate (1.8 g) was added dropwise, and the mixture was reacted at room temperature for 16 hours. Water (10.0 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3×10.0 mL). The organic phases were combined and washed with saturated aqueous sodium chloride solution (3×20.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA in PE: 0-10%) to obtain intermediate 71-3 (1.50 g). LCMS: MS m / z (ESI): 394.0 [M+H] + .

[0578] 24.3 Synthesis of Intermediate 71-4:

[0579]

[0580] Tributyltin hydride (1.10 g) and azobisisobutyronitrile (208.4 mg) were added to a toluene (10 mL) solution of the intermediate 71-3 (1.0 g) at room temperature, and the mixture was heated to 80°C under argon protection and stirred for 1 hour. Water (10.0 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3×10.0 mL). The organic phases were combined and washed with a saturated aqueous sodium chloride solution (3×20.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA in PE: 0-10%) to obtain the intermediate 71-4 (300 mg). 1 H NMR (400MHz, CDCl3) δ7.09 (d, J = 8.4Hz, 1H), 6.83 (d, J = 8.4Hz, 1H), 4.40 (s, 2 H),1.86–1.71(m,4H),1.60(d,J=12.0Hz,2H),1.24(dd,J=13.4,10.5Hz,4H).

[0581] 24.4 Synthesis of Compound 071:

[0582] The remaining steps refer to Example 2, replacing intermediate 2-5 in step 2.5 with intermediate 71-4 to obtain the target product N-(4-(4-(2'H-spiro[cyclohexane-1,3'-furo[3,2-b]pyridine]-5'-yl)-1H-1,2,3-triazol-1-yl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-hydroxyethane-1-sulfonamide (Compound 071).

[0583] 1 H NMR (400MHz, DMSO) δ8.98(s,1H),7.79(d,J=8.4Hz,1H),7.60(d,J=8.4Hz,1H),7.29(d,J=8.4Hz,1H),7.13(d,J=2.0Hz,1H),7.03(dd,J=8.4,2.0Hz,1H ),4.48(s,2H),3.79(t,J=6.8Hz,2H),3.36–3.33(m,2H),2.70(t,J=5.2Hz, 4H),1.95–1.75(m,4H),1.67–1.63(m,3H),1.58–1.36(m,7H),0.26(s,4H).

[0584] LCMS:MS m / z(ESI):565.1[M+H] + .

[0585] Compounds 007, 011-021, 025-026, 028-030, 033-052, 055-059 listed in Table 1 were prepared in substantially the same manner as in Examples 1 and 2, using commercially available starting materials or materials prepared according to literature methods. Table 1 gives the names and structures of the compounds.

[0586] Table 1

[0587]

[0588]

[0589]

[0590]

[0591]

[0592] Effect Example 1 Kif18A enzyme activity inhibition experiment

[0593] The inhibition of Kif18A ATPase activity was measured by ADP-Glo ​​assay. The recombinant human Kif18A protein fragment (M1-V374, N-terminal His tag) was obtained by 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 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 compound to be tested was diluted 3-fold into 10 concentrations, 0.25 μL of the 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 start the enzymatic reaction, and the reaction was carried out at room temperature for 15 minutes. 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). XLfit 5.5.0 software was used to establish a nonlinear regression equation, fit the concentration-response curve, and calculate the IC50 The experimental results are shown in Table 2.

[0594] Table 2 Results of enzymatic activity test of compound Kif18A

[0595] Compound <![CDATA[IC 50 (nM)]]> Compound <![CDATA[IC 50 (nM)]]> Compound <![CDATA[IC 50 (nM)]]> 001 98.9 024 85.0 045 85.3 002 16.5 027 151 046 72.6 003 70.8 032 35.3 047 49.7 004 54.6 037 14.9 051 21.5 005 66.2 039 70.7 053 11.1 006 40.7 040 34.3 054 14.2 008 68.5 041 24.9 068 45.3 009 121 042 71.9 069 44.0 010 241 043 174 070 56.8 022 43.82 044 38.2 071 36.4 023 33.0 - - - -

[0596] Effect Example 2 Cell Proliferation Experiment

[0597] OVCAR3 cells (from ATCC) were seeded in 96-well plates at the optimal concentration for a 4-day cell growth assay. The next day, the test compound or DMSO was diluted three times from the starting 10 μM and then added to the cells for co-incubation. After the compound and cells were incubated at 37 ° C for 4 days, ADP-Glo ​​reagent was added to each well and incubated at room temperature for 30 minutes. The luminescence intensity of the sample was then measured using an ELISA reader (from BMG). XLfit 5.5.0 software was used to establish a nonlinear regression equation, fit the concentration-response curve, and calculate the IC 50 The experimental results are shown in Table 3.

[0598] Table 3 Results of the OVCAR3 cell inhibitory activity test of compound

[0599] Compound <![CDATA[IC 50 (nM)]]> Compound <![CDATA[IC 50 (nM)]]> Compound <![CDATA[IC 50 (nM)]]> 002 38.65 009 178.19 037 44.26 003 159.13 022 47.07 039 19.79 004 44.03 023 14.09 040 21.19 005 52.62 024 21.3 041 21.00 006 164.79 027 83.18 044 12.81 008 155.05 032 99.79 071 57.5

Claims

1. Compounds of formula (I): or a pharmaceutically acceptable salt thereof, in, Ring A is selected from C 6-14 Aromatic rings and 5-14 membered heteroaromatic rings; Ring B is selected from a 5-membered heteroaromatic ring; Q is selected from wherein M is selected from N, CH and C; U and V are each independently selected from O, S, L is selected from a chemical bond, -O-, -S-, -NR 7 -、C 1-2 Alkylene and C 2-4 Alkyne; each Respectively represent the connection site; X 1 , X 2 and X 3 Each independently selected from N and C(R 8 ); R 1 Selected from C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclyl, aryl, -C 1-4 Alkylene-aryl, heteroaryl, -C 1-4 Alkylene-heteroaryl, -NR A R B 、-OR A 、-SR A 、-C(=O)R A 、-C(=NR E )R A 、-C(=N-OR B )R A 、-C(=O)OR A 、-OC(=O)R A 、-C(=O)NR A R B 、-NR F C(=O)R A 、-C(=NR E )NR A R B 、-NR F C(=NR E )R A 、-OC(=O)NR A R B 、-NR F C(=O)OR A 、-NR F C(=O)NR A R B 、-NR F C(=S)NR A R B 、-NR F C(=NR E )NR A R B 、-S(=O) r R A 、-S(=O)(=NR E )R A 、-N=S(=O)R A R B 、-S(=O)2OR A 、-OS(=O)2R A 、-NR F S(=O) r R A 、-NR F S(=O)(=NR E )R A 、-S(=O) r NR A R B 、-S(=O)(=NR E )NR A R B 、-NR F S(=O)2NR A R B and-NR F S(=O)(=NR E )NR A R B , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R X1 Substituents are substituted; R 2 selected from -(CR C2 R D2 ) t -S(=O) r R A2 、-(CR C2 R D2 ) t -S(=O)(=NR E2 )R B2 、-(CR C2 R D2 ) t - N=S(=O)R A2 R B2 、-(CR C2 R D2 ) t -S(=O)2OR A2 、-(CR C2 R D2 ) t -OS(=O)2R A2 、-(CR C2 R D2 ) t -NR A2 S(=O) r R B2 、-(CR C2 R D2 ) t -NR A2 S(=O)(=NR E2 )R B2 、-(CR C2 R D2 ) t -S(=O) r NR A2 R B2 、-(CR C2 R D2 ) t -S(=O)(=NR E2 )NR A2 R B2 、-(CR C2 R D2 ) t -NR A2 S(=O)2NR A2 R B2 and -NR A2 S(=O)(=NR E2 )NR A2 R B2 ; Each R 3 Independently selected from halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclyl, aryl, -C 1-4 Alkylene-aryl, heteroaryl, -C 1-4 Alkylene-heteroaryl, CN, NO2, -NR A3 R B3 、-OR A3 、-SR A3 、-C(=O)R A3 、-C(=O)OR A3 、-OC(=O)R A3 、-C(=O)NR A3 R B3 、-NR A3 C(=O)R B3 、-NR A3 C(=NR E3 )R B3 、-OC(=O)NR A3 R B3 、-NR A3 C(=O)OR B3 、-NR A3 C(=O)NR A3 R B3 、-NR A3 C(=S)NR A3 R B3 、-NR A3 C(=NR E3 )NR A3 R B3 、-S(=O) r R A3 、-S(=O)(=NR E3 )R B3 、-N=S(=O)R A3 R B3 、-S(=O)2OR A3 、-OS(=O)2R A3 、-NR A3 S(=O) r R B3 、-NR A3 S(=O)(=NR E3 )R B3 、-S(=O) r NR A3 R B3 、-S(=O)(=NR E3 )NR A3 R B3 、-NR A3 S(=O)2NR A3 R B3 and-NR A3 S(=O)(=NR E3 )NR A3 R B3 , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R X3 Substituents are substituted; or R 1 With adjacent R 3 Together with the atoms to which they are attached, they form C 5-12 A hydrocarbon ring or a 5-12 membered heterocyclic ring containing 1, 2 or 3 heteroatoms, wherein the hydrocarbon ring and the heterocyclic ring are monocyclic or bicyclic, wherein the heteroatoms contained in the heterocyclic ring are independently selected from oxygen, sulfur, nitrogen and phosphorus; the ring is unsubstituted or substituted by at least one independently selected from R X3 Substituents are substituted; Each R 4 Independently selected from halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclyl, aryl, -C 1-4 Alkylene-aryl, heteroaryl, -C 1-4 Alkylene-heteroaryl, CN, NO2, -NR A4 R B4 、-OR A4 、-SR A4 、-C(=O)R A4 、-C(=O)OR A4 、-OC(=O)R A4 、-C(=O)NR A4 R B4 、-NR A4 C(=O)R B4 、-NR A4 C(=NR E4 )R B4 、-OC(=O)NR A4 R B4 、-NR A4 C(=O)OR B4 、-NR A4 C(=O)NR A4 R B4 、-NR A4 C(=S)NR A4 R B4 、-NR A4 C(=NR E4 )NR A4 R B4 、-S(=O) r R A4 、-S(=O)(=NR E4 )R B4 、-N=S(=O)R A4 R B4 、-S(=O)2OR A4 、-OS(=O)2R A4 、-NR A4 S(=O) r R B4 、-NR A4 S(=O)(=NR E4 )R B4 、-S(=O) r NR A4 R B4 、-S(=O)(=NR E4 )NR A4 R B4 、-NR A4 S(=O)2NR A4 R B4 and-NR A4 S(=O)(=NR E4 )NR A4 R B4 , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R X4 Substituents are substituted; Each R 5 Independently selected from halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclic group, CN, NO2, -NR A5 R B5 、-OR A5 、-SR A5 、-C(=O)R A5 、-C(=O)OR A5 、-OC(=O)R A5 、-C(=O)NR A5 R B5 、-NR A5 C(=O)R B5 、-NR A5 C(=NR E5 )R B5 、-OC(=O)NR A5 R B5 、-NR A5 C(=O)OR B5 、-NR A5 C(=O)NR A5 R B5 、-NR A5 C(=S)NR A5 R B5 、-NR A5 C(=NR E5 )NR A5 R B5 、-S(=O) r R A5 、-S(=O)(=NR E5 )R B5 、-N=S(=O)R A5 R B5 、-S(=O)2OR A5 、-OS(=O)2R A5 、-NR A5 S(=O) r R B5 、-NR A5 S(=O)(=NR E5 )R B5 、-S(=O) r NR A5 R B5 、-S(=O)(=NR E5 )NR A5 R B5 、-NR A5 S(=O)2NR A5 R B5 and-NR A5 S(=O)(=NR E5 )NR A5 R B5 , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl and heterocyclyl is unsubstituted or substituted with at least one independently selected from R X5 Substituents are substituted; R 5a and R 5b are each independently selected from hydrogen and R 5 ; or R 5a and R 5b Together with the carbon atoms to which they are attached, they form a saturated or unsaturated 3-7 membered ring containing 0, 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, which ring is unsubstituted or substituted with 1, 2 or 3 R X5 Substituent substitution; R 6a and R 6b are independently selected from hydrogen, halogen, C 1-10 Alkyl and C 3-10 Cycloalkyl, wherein alkyl and cycloalkyl are unsubstituted or substituted with at least one independently selected from R X6 Substituents are substituted; or R 6a and R 6b Together with the carbon atoms to which they are attached, they form a saturated or unsaturated 3-7 membered ring containing 0, 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, which ring is unsubstituted or substituted with 1, 2 or 3 R X6 Substituent substitution; R 7 Selected from hydrogen and C 1-10 Alkyl, wherein the alkyl group is unsubstituted or substituted with at least one independently selected from R X7 Substituents are substituted; Each R 8 independently selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclyl, aryl, -C 1-4 Alkylene-aryl, heteroaryl, -C 1-4 Alkylene-heteroaryl, CN, NO2, -NR A8 R B8 、-OR A8 、-SR A8 、-C(=O)R A8 、-C(=O)OR A8 、-OC(=O)R A8 、-C(=O)NR A8 R B8 、-NR A8 C(=O)R B8 、-NR A8 C(=NR E8 )R B8 、-OC(=O)NR A8 R B8 、-NR A8 C(=O)OR B8 、-NR A8 C(=O)NR A8 R B8 、-NR A8 C(=S)NR A8 R B8 、-NR A8 C(=NR E8 )NR A8 R B8 、-S(=O) r R A8 、-S(=O)(=NR E8 )R B8 、-N=S(=O)R A8 R B8 、-S(=O)2OR A8 、-OS(=O)2R A8 、-NR A8 S(=O) r R B8 、-NR A8 S(=O)(=NR E8 )R B8 、-S(=O) r NR A8 R B8 、-S(=O)(=NR E8 )NR A8 R B8 、-NR A8 S(=O)2NR A8 R B8 and-NR A8 S(=O)(=NR E8 )NR A8 R B8 , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R X8 Substituents are substituted; Each R F , R A , R B , R A2 , R A3 , R A4 , R A5 , R A8 , R B2 , R B3 , R B4 , R B5 and R B8 independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclyl, aryl, -C 1-4 Alkylene-aryl, heteroaryl and -C 1-4 Alkylene-heteroaryl, wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R X Substituents are substituted; or "R A and R B ” or "R A2 and R B2 ” or "R A3 and R B3 ” or "R A4 and R B4 ” or "R A5 and R B5 ” or "R A8 and R B8 "together with the atoms or atoms to which they are attached, they form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, which ring is unsubstituted or substituted with 1, 2 or 3 atoms selected from R X Substituents are substituted; Each R C2 and R D2 independently selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclyl, aryl, -C 1-4 Alkylene-aryl, heteroaryl and -C 1-4 Alkylene-heteroaryl, wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R X Substituents are substituted; Or each "R C2 and R D2 "Together with the single or multiple carbon atoms to which they are attached, they form a 3-12 membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, which ring is unsubstituted or substituted with 1, 2 or 3 independently selected from R X Substituents are substituted; Each R E , R E2 , R E3 , R E4 , R E5 and R E8 independently selected from hydrogen, C 1-10 Alkyl, CN, NO2, -S(=O) r R a1 、-C(=O)R a1 、-C(=O)OR a1 、-C(=O)NR a1 R b1 and -S(=O) r NR a1 R b1 , wherein the alkyl group is unsubstituted or substituted with at least one independently selected from R X Substituents are substituted; Each R X , R X1 , R X3 , R X4 , R X5 , R X6 , R X7 and R X8 Independently selected from halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclyl, aryl, -C 1-4 Alkylene-aryl, heteroaryl, -C 1-4 Alkylene-heteroaryl, CN, NO2, -(CR c1 R d1 ) u NR a1 R b1 、-(CR c1 R d1 ) u OR b1 、-(CR c1 R d1 ) u C(=O)R a1 、-(CR c1 R d1 ) 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)2OR b1 、-(CR c1 R d1 ) u OS(=O)2R 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)2NR 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, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R Y Substituents are substituted; Each R a1 and R b1 independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclyl, aryl, -C 1-4 Alkylene-aryl, heteroaryl and -C 1-4 Alkylene-heteroaryl, wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R Y Substituents are substituted; or R a1 and R b1 Together with the atoms to which they are attached, they form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, which ring is unsubstituted or substituted with 1, 2 or 3 atoms selected from R Y Substituents are substituted; Each R c1 and R d1 independently selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclyl, aryl, -C 1-4 Alkylene-aryl, heteroaryl and -C 1-4 Alkylene-heteroaryl, wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one independently selected from R Y Substituents are substituted; Or each R c1 and R d1 Together with the single or multiple carbon atoms to which they are attached, they form a 3-12 membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, which ring is unsubstituted or substituted with 1, 2 or 3 heteroatoms independently selected from R Y Substituents are substituted; Each R e1 independently selected from hydrogen, C 1-10 Alkyl, CN, NO2, -S(=O) r R a1 、-C(=O)R a1 、-C(=O)OR a1 、-C(=O)NR a1 R b1 and -S(=O) r NR a1 R b1 , wherein the alkyl group is unsubstituted or substituted with at least one independently selected from R Y Substituents are substituted; Each R Y Independently selected from halogen, NO2, -CN, C 1-10 Alkyl, -OH, -O(C 1-10 Alkyl), -O(C 3-10 Cycloalkyl), -O(C 1-4 Alkylene-C 3-10 Cycloalkyl), -O(heterocyclyl), -O(C 1-4 Alkylene-heterocyclyl), -SH, -S(C 1-10 Alkyl), -S(C 3-10 Cycloalkyl), -S(C 1-4 Alkylene-C 3-10 Cycloalkyl), -S(heterocyclyl), -S(C 1-4 Alkylene-heterocyclyl), -NH2, -NH(C 1-10 Alkyl), -N(C 1-10 Alkyl)2, -NH(C 3-10 Cycloalkyl), -NH(C 1-4 Alkylene-C 3-10 Cycloalkyl), -NH(heterocyclyl) and -NH(C 1-4 alkylene-heterocyclyl); g is selected from 0, 1, 2, 3 and 4; 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.

2. The compound of claim 1, wherein R 1 Selected from C 3-10 Cycloalkyl, -C 1-4 Alkylene-C 3-10 Cycloalkyl, heterocyclic, -C 1-4 Alkylene-heterocyclyl, wherein each alkylene, cycloalkyl and heterocyclyl is unsubstituted or substituted with at least one independently selected from R X1 Substituents are substituted; Preferably, R 1 Selected from cyclohexyl, Among them, cyclohexyl Optionally, at least one independently selected from R X1 substituted by a substituent.

3. The compound of claim 1 or 2, wherein R 2 Selected from -NH-S(=O)2-C 1-3 Alkyl, -NH-S(=O)2-C 1-3 Alkylene-OH, -NH-S(=O)2-C 1-3 Alkylene-F and -NH-S(=O)2-C 3-6 Cycloalkyl; Preferably, R 2 Selected from 4. The compound of any one of claims 1 to 3, wherein Each R 3 Independently selected from halogen, CN, NO2, C 1-10 Alkyl, -OR A3 、-C(=O)R A3 、-C(=O)NR A3 R B3 and-NR A3 C(=O)R B3 , wherein each alkyl group is unsubstituted or substituted with at least one independently selected from R X3 Substituents are substituted; Preferably, each R 3 independently selected from F, Cl, Br, methyl, methoxy, acetyl and 5. The compound of any one of claims 1 to 4, wherein R 1 With adjacent R 3 Together with the atoms to which they are attached, they form a C5 monocyclic hydrocarbon ring or a C 10-12 A bicyclic hydrocarbon ring or a 5-membered monocyclic heterocyclic ring or a 10-12-membered bicyclic heterocyclic ring containing 1, 2 or 3 heteroatoms, wherein the heteroatoms contained in the heterocyclic ring are independently selected from oxygen, sulfur and nitrogen; the ring is unsubstituted or substituted by at least one independently selected from R X3 Substituents are substituted; Preferably, R 1 With adjacent R 3 Together with the atoms to which they are attached they form 2-oxaspiro[4.5]decane-3-ene.

6. The compound of any one of claims 1 to 5, wherein Each R 4 Independently selected from halogen, C 1-10 alkyl, CN and NO2, wherein each alkyl is unsubstituted or substituted with at least one independently selected from R X4 Substituents are substituted; Preferably, each R 4 are independently selected from halogen.

7. The compound of any one of claims 1 to 6, wherein Each R 5 Independently selected from halogen, C 1-10 Alkyl, C 3-10 Cycloalkyl, CN and NO2, wherein each alkyl and cycloalkyl is unsubstituted or substituted with at least one independently selected from R X5 Substituents are substituted; Preferably, each R 5 Methyl or F.

8. The compound of any one of claims 1 to 7, wherein Q has the following structure: in, p1 is an integer selected from 0 to 13; Preferably, M is N; or Q has the structure of the following formula (iii): in, p1 is an integer selected from 0 to 13; Preferably, L is -O-.

9. The compound of claim 8, wherein R 5a and R 5b are independently selected from hydrogen, halogen and C 3-10 Cycloalkyl, wherein each cycloalkyl is unsubstituted or substituted with at least one independently selected from R X5 Preferably, R 5a and R 5b is hydrogen, or R 5a and R 5b is F; or R 5a and R 5b Together with the carbon atoms to which they are attached, they form a saturated or unsaturated 3-7 membered hydrocarbon ring which is unsubstituted or consists of 1, 2 or 3 R X5 Substituent substitution.

10. The compound of any one of claims 1 to 7, wherein Q has the following structure: in, p2 is an integer selected from 0 to 11; Preferably, M is N; or Q has the structure of formula (iv): in, p2 is an integer selected from 0 to 11; Preferably, L is -O-.

11. The compound of claim 10, wherein R 6a and R 6b are independently selected from hydrogen, halogen and C 1-10 Alkyl, wherein the alkyl group is unsubstituted or substituted with at least one independently selected from R X6 Preferably, R 6a and R 6b F, or R 6a and R 6b is methyl; or R 6a and R 6b Together with the carbon atoms to which they are attached, they form a saturated or unsaturated 3-7 membered hydrocarbon ring which is unsubstituted or consists of 1, 2 or 3 R X6 Substituent substitution.

12. The compound of any one of claims 1 to 11, wherein Q is selected from:

13. The compound of any one of claims 1 to 12, wherein X 1 , X 2 and X 3 Each independently selected from C(R 8 ); or, X 2 It is N, X 1 and X 3 Each independently selected from C(R 8 ); in, R 8 H is preferred.

14. The compound of any one of claims 1 to 13, wherein Ring A is selected from The structure is independently selected from R 3 substituted by a substituent; wherein Represents ring A and R 1 The site of attachment, "" indicates another site where ring A is attached to the rest of the molecule.

15. The compound of any one of claims 1 to 14, wherein Ring B is selected from The structure is independently selected from R 4 substituted by a substituent; wherein " indicates the site where ring B is attached to ring A, and "" indicates another site where ring B is attached to the rest of the molecule.

16. A compound selected from:

17. A pharmaceutical composition comprising a preventively or therapeutically effective amount of a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

18. Use of a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 17, in the preparation of a medicament for treating a disease, disorder or condition selected from a cell proliferation disorder.

19. Use of a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 17 in the preparation of a medicament for treating a disease, disorder or condition, wherein The disease, disorder or condition is cancer; Preferably, the cancer is selected from: (a) a solid tumor or a blood-derived tumor selected from the following cancers: bladder cancer, endometrial cancer, squamous cell lung cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, small cell lung cancer, esophageal cancer, gallbladder cancer, brain cancer, head and neck cancer, ovarian cancer, pancreatic cancer, gastric cancer, cervical cancer, thyroid cancer, prostate cancer and skin cancer; (b) a hematopoietic tumor of the lymphoid system selected from the following: leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma (c) a hematopoietic neoplasm of the myeloid lineage selected from the group consisting of acute and chronic myeloid leukemias, myelodysplastic syndromes and promyelocytic leukemias; (d) a tumor of mesenchymal origin selected from the group consisting of fibrosarcoma and rhabdomyosarcoma; (e) a tumor of the central and peripheral nervous system selected from the group consisting of astrocytoma, neuroblastoma, glioma and schwannoma; or (f) a melanoma, a seminoma, a teratoma, an osteosarcoma, a xeroderma pigmentosum, a keratoacanthoma, a follicular thyroid carcinoma or a Kaposi's sarcoma; More preferably, the cancer is selected from melanoma, colon cancer, lung cancer, pancreatic cancer, prostate cancer, bladder cancer, head cancer, neck cancer, breast cancer, cervical cancer, ovarian cancer and leukemia.

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