Nitrogen-containing heterocyclic derivative PARP1 inhibitor as well as preparation method and medical application thereof

Abstract

The invention provides a compound containing a nitrogen heterocyclic derivative PARP1 inhibitor or a pharmaceutically acceptable salt, a stereoisomer, a solvate, a polymorphic substance, an isotope derivative or a prodrug of the compound, a preparation method of the compound, and medical application of the compound in prevention or treatment of diseases or symptoms related to PARP1 expression increase. The present invention provides methods of treating cancers such as prostate cancer, pancreatic cancer, breast cancer, ovarian cancer, and the like. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a compound as a PARP1 inhibitor with a novel structure or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, isotope derivative or prodrug thereof, as well as a preparation method and medical use thereof. Background Art

[0002] PARP is located in the cell nucleus and is a key enzyme in the repair of cellular DNA damage. It includes at least 17 protein subtypes. PARP can be activated by damaged DNA fragments and catalyzes the attachment of polyadenosine ribose (ADP-ribose) to various target proteins. This leads to the catalytic activity of the target protein and the regulation of protein-protein interactions. PARP is involved in a variety of biological processes, including DNA repair, gene transcription, cell cycle progression (including proliferation and differentiation), cell death, chromatin function, genome (such as chromosome) stability and telomere length. Among its many subtypes, PARP1 is very important for the stability of the genome of normal cells. In tumor treatment, PARP1 repairs tumor cell DNA damaged by radiotherapy and chemotherapy, which antagonizes the tumor-killing effect of radiotherapy and chemotherapy. Therefore, PARP1 inhibitors can be developed as sensitizers for tumor radiotherapy and chemotherapy.

[0003] PARP inhibitors have achieved great success in precision medicine in the field of tumors, especially for tumors with BRCA mutations or defects. Currently, many PARP inhibitors have been successfully developed, such as Olaparib, Rucaparib and Niraparib, but adverse reactions limit the scope and ability of their use. This may be related to the lack of selectivity of the PARP family in the PARP inhibitors on the market. These side effects include intestinal toxicity caused by end-anchor polymerase inhibition, blood toxicity caused by PARP2 inhibition, and blood system toxicity such as anemia. Therefore, there is an urgent need to develop a highly selective PARP1 inhibitor with a new skeleton to reduce the related toxic side effects of non-selective PARP inhibitors, which is clinically safe and effective. Summary of the invention

[0004] The object of the present invention is to provide a PARP1 inhibitory compound, a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, isotope derivative or prodrug thereof, and a preparation method and medical use thereof.

[0005] In a first aspect, the present invention provides a compound represented by Formula I, Formula II, Formula III or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, isotopic derivative or prodrug thereof:

[0006]

[0007] Specifically, the first technical solution of the first aspect of the present invention relates to a compound represented by formula I or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, isotope derivative or prodrug thereof:

[0008]

[0009] Wherein:

[0010] X1 is selected from N and C;

[0011] X2 is selected from N, C, S and O;

[0012] f is 0 or 1;

[0013] n is the number of R5 and is 0, 1, 2, 3 or 4;

[0014] m is the number of R6 and is 0, 1, 2, 3 or 4;

[0015] Ring A is selected from C 3-10 cycloalkyl, heterocyclic group and heteroaryl, wherein C 3-10 cycloalkyl, heterocyclic group and heteroaryl are each unsubstituted or substituted by at least one substituent, and the substituents are independently selected from R5;

[0016] Ring B is selected from heterocyclic group, aryl and heteroaryl, wherein the heterocyclic group, aryl and heteroaryl are each unsubstituted or substituted by at least one substituent, and the substituents are independently selected from R6;

[0017] Z is selected from a bond, -(CR z1 R z2 )u-, -(CR z1 R z2 )uO(CR z1 R z2 )t-, -(CR z1 R z2 )uNR z3 (CR z1 R z2 )t-, and -(CR z1 R z2 )uS(CR z1 R z2 )t-, preferably Z is selected from a bond;

[0018] R1 is selected from hydrogen, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 1-4 alkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclic group, heterocyclic group-C 1-4Alkyl, Aryl, Aryl-C 1-4 Alkyl, Heteroaryl, Heteroaryl-C 1-4 Base, CN, NO2, -NR 1a R 1b 、-OR 1a 、-OR 1a 、-C(O)R 1a 、-C(=NR 1c )R 1a AND-C(=N-OR 1b )R 1a R 1b , -NR 1a C(O)R 1b ,-C(=NR 1c )NR 1a R 1b 、-NR 1a R 1b , -NR 1a CR 1b , -N)R 1a R 1b , -S(O)2OR 1a , -OS(O)2R 1a , -NR 1a S(O,-P(O)R 1a R 1b AND-P(O)(OR 1a )(OR 1b ), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R 1d ;

[0019] R2 is selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 1-4 Alkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, Heteroaryl, Heteroaryl-C 1-4 Base, CN, NO2, -NR 2a R 2b 、-OR 2a 、-OR 2a 、-C(O)R 2a 、-C(=NR 2c )R 2a AND-C(=N-OR 2b )R2a R 2b , -NR 2a C(O)R 2b ,-C(=NR 2c )NR 2a R 2b 、-NR 2a R 2b , -NR 2a CR 2b , -N)R 2a R 2b , -S(O)2OR 2a , -OS(O)2R 2a , -NR 2a S(O,-P(O)R 2a R 2b AND-P(O)(OR 2a )(OR 2b ), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R 2d ;

[0020] Or, R1 and R2 together with the atoms to which they are attached form a 3-7 membered cycloalkyl, heterocyclyl, aryl and heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl group are each unsubstituted or substituted with at least one substituent independently selected from R7;

[0021] R3 is selected from hydrogen, halogen, C 1-10 Alkyl, carbonyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, CN, NO2, -NR 3a R 3b 、-OR 3a and -C(O)R 3a , wherein alkyl, alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl are each unsubstituted or substituted with at least one substituent independently selected from R 3c ;

[0022] R4 is selected from hydrogen, halogen, C 1-10 Alkyl, carbonyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4Alkyl, CN, NO2, -NR 4a R 4b 、-OR 4a and -C(O)R 4a , wherein alkyl, alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl are each unsubstituted or substituted with at least one substituent independently selected from R 4c ;

[0023] R5 is selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 1-4 Alkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, Heteroaryl, Heteroaryl-C 1-4 Base, CN, NO2, -NR 5a R 5b 、-OR 5a 、-C(O)R 5a 、-C(=NR 5c )R 5a 、-C(=N-OR 5b )R 5a 、-C(O)OR 5a 、-OC(O)R 5a 、-C(O)NR 5a R 5b 、-NR 5a C(O)R 5b 、-C(=NR 5c )NR 5a R 5b 、-NR 5a C(=NR 5c )R 5b 、-OC(O)NR 5a R 5b 、-NR 5a C(O)OR 5b 、-NR 5a C(O)NR 5a R 5b 、-NR 5a C(S)NR 5a R 5b 、-NR 5a C(=NR 5c )NR 5a R 5b 、-S(O)rR 5a 、-S(O)(=NR5c )R 5b 、-N=S(O)R 5a R 5b 、-S(O)2OR 5a 、-OS(O)2R 5a 、-NR 5a S(O)r 5b 、-NR 5a S(O)(=NR 5c )R 5b 、-S(O)rNR 5a R 5b 、-S(O)(=NR 5c )NR 5a R 5b 、-NR 5a S(O)2NR 5a R 5b 、-NR 5a S(O)(=NR 5c )NR 5a R 5b 、-P(O)R 5a R 5b AND-P(O)(OR 5a )(OR 5b ), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R 5d ;

[0024] R6 is selected from hydrogen, halogen, -CN, C 1-10 Alkyl, halogenated C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 1-4 Alkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, Heteroaryl, Heteroaryl-C 1-4 Base, NO2, SF5, -NR 6a R 6b 、-OR 6a 、-C(O)R 6a 、-C(=NR 6c )R 6a 、-C(=N-OR 6b )R 6a 、-C(O)OR 6a 、-OC(O)R 6a 、-C(O)NR6a R 6b 、-NR 6a C(O)R 6b 、-C(=NR 6c )NR 6a R 6b 、-NR 6a C(=NR 6c )R 6b 、-OC(O)NR 6a R 6b 、-NR 6a C(O)OR 6b 、-NR 6a C(O)NR 6a R 6b 、-NR 6a C(S)NR 6a R 6b 、-NR 6a C(=NR 6c )NR 6a R 6b 、-S(O)rR 6a 、-S(O)(=NR 6c )R 6b 、-N=S(O)R 6a R 6b 、-S(O)2OR 6a 、-OS(O)2R 6a 、-NR 6a S(O)r 6b 、-NR 6a S(O)(=NR 6c )R 6b 、-S(O)rNR 6a R 6b 、-S(O)(=NR 6c )NR 6a R 6b 、-NR 6a S(O)2NR 6a R 6b 、-NR 6a S(O)(=NR 6c )NR 6a R 6b 、-P(O)R 6a R 6b AND-P(O)(OR 6a )(OR 6b ), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R 6d ;

[0025] R z1 and R z2 are each independently selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R P ;

[0026] or R z1 and R z2 Together with the atoms to which they are attached, they form a group comprising 0, 1 or 2 atoms independently selected from oxygen, sulfur and nitrogen and optionally 1, 2 or 3 R p A 3-12 membered ring of a heteroatom substituted by a group;

[0027] R z3 are each independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R P ;

[0028] R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , R 6b are independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, aryl, aryl C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R P ;

[0029] or R 1a and R 1b , R 2a and R 2b , R 3a and R 3b , R 4a and R 4b , R 5a and R 5b , R 6a and R 6b Together with the atoms to which they are attached, they form a group comprising 0, 1 or 2 atoms independently selected from oxygen, sulfur and nitrogen and optionally 1, 2 or 3 R p A 3-12 membered ring of a heteroatom substituted by a group;

[0030] R 1c , R 2c , R 5c , R 6c are each independently selected from hydrogen, C 1-10 Alkyl, CN, NO2, -OR w 、-SR w 、-S(O)rR w 、-C(O)R w 、-C(O)OR w 、-C(O)OR w ;-C(O)NR w R x and -S(O)rNR w R x ;

[0031] R 1d , R 3c , R 4c R 2d , R 5d , R 6d , R7 are each independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, aryl, aryl C1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 Alkyl, halogen, CN, NO2, -(CR y R z ) t NR w R x 、-(CR y R z ) t OR x 、-(CR y R z ) t C(O)R w 、-(CR y R z ) t C(=NR t )R w 、-(CR y R z ) t C(=N-OR x )R w 、-(CR y R z ) t C(O)OR x 、-(CR y R z ) t OC(O)R x 、-(CR y R z ) t C(O)NR w R x 、-(CR y R z ) t NR w C(O)R x 、-(CR y R z ) t C(=NR t )NR w R x 、-(CR y R z ) t NR w C(=NR t )R x 、-(CR y R z ) t OC(O)NR w R x 、-(CR y R z )t NR w C(O)OR x 、-(CR y R z ) t NR w C(O)NR w R x 、-(CR y R z ) t NR w C(S)NR w R x 、-(CR y Rz) t NR w C(=NR t )NR w R x 、-(CR y R z ) t S(O)rR x 、-(CR y R z ) t S(O)(=NR t )R x 、-(CR y R z ) t N=S(O)R w R x 、-(CR y R z ) t S(O)2OR x 、-(CR y R z ) t OS(O)2R x 、-(CR y R z ) t NR w S(O)rR x 、-(CR y R z ) t NR w S(O)(=NR t )R x 、-(CR y R z ) t S(O)rNR w R x 、-(CR y R z ) t S(O)(=NRt )NR w R x 、-(CR y R z ) t NR w S(O)2NR w R x 、-(CR y R z ) t NR w S(O)(=NR t )NR w R x 、-(CR y R z ) t P(O)R w R x and-(CR y R z ) t P(O)(OR w )(OR x ), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R q ;

[0032] R P , R q , R w , R x , R y , R z , R t Each independently selected from hydrogen, halogen, CN, NO2, C 1-10 Alkyl, C 3-10 Cycloalkyl, C 3-10 -cycloalkyl-C 1-4 Alkyl, C 1-10 Alkoxy, C 3-10 Cycloalkoxy, -C(O)C 1-4 Alkyl, -C(O)C 3-10 Cycloalkyl, -C(O)OC 1-4 Alkyl, -C(O)OC 3-10 Cycloalkyl, -C(O)N(C 1-4 Alkyl)2,-C(O)N(C 3-10 Cycloalkyl)2,-S(O)2C 1-4 Alkyl, -S(O)2C 3-10 Cycloalkyl, -S(O)2N(C 1-4 Alkyl)2 and -S(O)2N(C 3-10 Cycloalkyl)2;

[0033] u is selected from 0, 1, 2, 3 and 4;

[0034] t is selected from 0, 1, 2, 3 and 4.

[0035] Unless otherwise specified, the above-mentioned heterocycloalkane, heterocycloalkyl, heteroaryl, and heteroaromatic ring contain 1, 2, 3, 4, or 5 heteroatoms selected from nitrogen, oxygen, and sulfur; in certain embodiments, the heterocycloalkane, heterocycloalkyl, heteroaryl, and heteroaromatic ring contain 1, 2, 3, or 4 heteroatoms selected from nitrogen, oxygen, and sulfur; the heterocycloalkane, heterocycloalkyl, heteroaryl, and heteroaromatic ring contain 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, and sulfur; the heterocycloalkane, heterocycloalkyl, heteroaryl, and heteroaromatic ring contain 1 or 2 heteroatoms selected from nitrogen, oxygen, and sulfur.

[0036] Specifically, the second technical solution of the first aspect of the present invention relates to a compound of formula II or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, isotopic derivative or prodrug thereof:

[0037]

[0038]

[0039] in:

[0040] X1 is selected from N and C;

[0041] X2 is selected from N, C, S and O;

[0042] n is the number of R5 and is 0, 1, 2, 3 or 4;

[0043] m is the number of R6 and is 0, 1, 2, 3 or 4;

[0044] g is the number of R7 and is 0, 1, 2, 3 or 4;

[0045] Ring A is selected from C 3-10 Cycloalkyl, heterocyclyl and heteroaryl, wherein C 3-10 Cycloalkyl, heterocyclyl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R5;

[0046] Ring B is selected from heterocyclyl, aryl and heteroaryl, wherein heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R6;

[0047] Z is selected from a bond, -(CR z1 R z2 )u-、-(CR z1 R z2 )uO(CR z1 R z2)t-, -(CR z1 R z2 )uNR z3 (CR z1 R z2 )t-, and -(CR z1 R z2 )uS(CR z1 R z2 )t-, preferably Z is selected from a bond;

[0048] R1 is selected from hydrogen, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 1-4 alkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclic group, heterocyclic group-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl, heteroaryl-C 1-4 group, CN, NO2, -NR 1a R 1b , -OR 1a , -OR 1a , -C(O)R 1a , -C(=NR 1c )R 1a and -C(=N-OR 1b )R 1a R 1b , -NR 1a C(O)R 1b , -C(=NR 1c )NR 1a R 1b , -NR 1a R 1b , -NR 1a CR 1b , -N)R 1a R 1b , -S(O)2OR 1a , -OS(O)2R 1a , -NR 1a , -NR 1a R 1b and -P(O)(OR 1a )(OR 1b ), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl and heteroaryl are each unsubstituted or substituted by at least one substituent, and the substituents are independently selected from R 1d ;

[0049] R2 is selected from hydrogen, halogen, C1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 1-4 Alkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, Heteroaryl, Heteroaryl-C 1-4 Base, CN, NO2, -NR 2a R 2b 、-OR 2a 、-OR 2a 、-C(O)R 2a 、-C(=NR 2c )R 2a AND-C(=N-OR 2b )R 2a R 2b , -NR 2a C(O)R 2b ,-C(=NR 2c )NR 2a R 2b 、-NR 2a R 2b , -NR 2a CR 2b , -N)R 2a R 2b , -S(O)2OR 2a , -OS(O)2R 2a , -NR 2a S(O,-P(O)R 2a R 2b AND-P(O)(OR 2a )(OR 2b ), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R 2d ;

[0050] Or, R1 and R2 together with the atoms to which they are attached form a 3-7 membered cycloalkyl, heterocyclyl, aryl and heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl group are each unsubstituted or substituted with at least one substituent independently selected from R7;

[0051] R3 is selected from hydrogen, halogen, C 1-10 Alkyl, carbonyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, CN, NO2, -NR 3a R 3b 、-OR 3a and -C(O)R 3a , wherein alkyl, alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl are each unsubstituted or substituted with at least one substituent independently selected from R 3c ;

[0052] R4 is selected from hydrogen, halogen, C 1-10 Alkyl, carbonyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, CN, NO2, -NR 4a R 4b 、-OR 4a and -C(O)R 4a , wherein alkyl, alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl are each unsubstituted or substituted with at least one substituent independently selected from R 4c ;

[0053] R5 is selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 1-4 Alkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, Heteroaryl, Heteroaryl-C 1-4 Base, CN, NO2, -NR 5a R 5b 、-OR 5a 、-C(O)R 5a 、-C(=NR 5c )R 5a 、-C(=N-OR 5b )R 5a 、-C(O)OR 5a 、-OC(O)R 5a 、-C(O)NR 5a R 5b 、-NR 5a C(O)R 5b 、-C(=NR 5c )NR5a R 5b 、-NR 5a C(=NR 5c )R 5b 、-OC(O)NR 5a R 5b 、-NR 5a C(O)OR 5b 、-NR 5a C(O)NR 5a R 5b 、-NR 5a C(S)NR 5a R 5b 、-NR 5a C(=NR 5c )NR 5a R 5b 、-S(O)rR 5a 、-S(O)(=NR 5c )R 5b 、-N=S(O)R 5a R 5b 、-S(O)2OR 5a 、-OS(O)2R 5a 、-NR 5a S(O)r 5b 、-NR 5a S(O)(=NR 5c )R 5b 、-S(O)rNR 5a R 5b 、-S(O)(=NR 5c )NR 5a R 5b 、-NR 5a S(O)2NR 5a R 5b 、-NR 5a S(O)(=NR 5c )NR 5a R 5b 、-P(O)R 5a R 5b AND-P(O)(OR 5a )(OR 5b ), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R 5d ;

[0054] R6 is selected from hydrogen, halogen, -CN, C 1-10 Alkyl, halogenated C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C3-10 Cycloalkyl, C 1-4 Alkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, Heteroaryl, Heteroaryl-C 1-4 Base, NO2, SF5, -NR 6a R 6b 、-OR 6a 、-C(O)R 6a 、-C(=NR 6c )R 6a 、-C(=N-OR 6b )R 6a 、-C(O)OR 6a 、-OC(O)R 6a 、-C(O)NR 6a R 6b 、-NR 6a C(O)R 6b 、-C(=NR 6c )NR 6a R 6b 、-NR 6a C(=NR 6c )R 6b 、-OC(O)NR 6a R 6b 、-NR 6a C(O)OR 6b 、-NR 6a C(O)NR 6a R 6b 、-NR 6a C(S)NR 6a R 6b 、-NR 6a C(=NR 6c )NR 6a R 6b 、-S(O)rR 6a 、-S(O)(=NR 6c )R 6b 、-N=S(O)R 6a R 6b 、-S(O)2OR 6a 、-OS(O)2R 6a 、-NR 6a S(O)r 6b 、-NR 6a S(O)(=NR 6c )R 6b 、-S(O)rNR 6a R 6b、-S(O)(=NR 6c )NR 6a R 6b 、-NR 6a S(O)2NR 6a R 6b 、-NR 6a S(O)(=NR 6c )NR 6a R 6b 、-P(O)R 6a R 6b AND-P(O)(OR 6a )(OR 6b ), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R 6d ;

[0055] R z1 and R z2 are each independently selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R P ;

[0056] or R z1 and R z2 Together with the atoms to which they are attached, they form a group comprising 0, 1 or 2 atoms independently selected from oxygen, sulfur and nitrogen and optionally 1, 2 or 3 R p A 3-12 membered ring of a heteroatom substituted by a group;

[0057] R z3 are each independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R P ;

[0058] R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , R 6b are independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, aryl, aryl C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R P ;

[0059] or R 1a and R 1b , R 2a and R 2b , R 3a and R 3b , R 4a and R 4b , R 5a and R 5b , R 6a and R 6b Together with the atoms to which they are attached, they form a group comprising 0, 1 or 2 atoms independently selected from oxygen, sulfur and nitrogen and optionally 1, 2 or 3 R p A 3-12 membered ring of a heteroatom substituted by a group;

[0060] R 1c , R 2c , R 5c , R 6c are each independently selected from hydrogen, C 1-10 Alkyl, CN, NO2, -OR w 、-SR w 、-S(O)rR w 、-C(O)R w、-C(O)OR w 、-C(O)OR w ;-C(O)NR w R x and -S(O)rNR w R x ;

[0061] R 1d , R 3c , R 4c R 2d , R 5d , R 6d , R7 are each independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, aryl, aryl C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 Alkyl, halogen, CN, NO2, -(CR y R z ) t NR w R x 、-(CR y R z ) t OR x 、-(CR y R z ) t C(O)R w 、-(CR y R z ) t C(=NR t )R w 、-(CR y R z ) t C(=N-OR x )R w 、-(CR y R z ) t C(O)OR x 、-(CR y R z ) t OC(O)R x 、-(CR y R z ) t C(O)NR w R x 、-(CRy R z ) t NR w C(O)R x 、-(CR y R z ) t C(=NR t )NR w R x 、-(CR y R z ) t NR w C(=NR t )R x 、-(CR y R z ) t OC(O)NR w R x 、-(CR y R z ) t NR w C(O)OR x 、-(CR y R z ) t NR w C(O)NR w R x 、-(CR y R z ) t NR w C(S)NR w R x 、-(CR y Rz) t NR w C(=NR t )NR w R x 、-(CR y R z ) t S(O)rR x 、-(CR y R z ) t S(O)(=NR t )R x 、-(CR y R z ) t N=S(O)R w R x 、-(CR y R z ) t S(O)2OR x、-(CR y R z ) t OS(O)2R x 、-(CR y R z ) t NR w S(O)r x 、-(CR y R z ) t NR w S(O)(=NR t )R x 、-(CR y R z ) t S(O)r w R x 、-(CR y R z ) t S(O)(=NR t )NR w R x 、-(CR y R z ) t NR w S(O)2NR w R x 、-(CR y R z ) t NR w S(O)(=NR t )NR w R x 、-(CR y R z ) t P(O)R w R x and-(CR y R z ) t P(O)(OR w )(OR x ), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R q ;

[0062] R P , R q , R w , R x , R y , R z , R tEach independently selected from hydrogen, halogen, CN, NO2, C 1-10 Alkyl, C 3-10 Cycloalkyl, C 3-10 -cycloalkyl-C 1-4 Alkyl, C 1-10 Alkoxy, C 3-10 Cycloalkoxy, -C(O)C 1-4 Alkyl, -C(O)C 3-10 Cycloalkyl, -C(O)OC 1-4 Alkyl, -C(O)OC 3-10 Cycloalkyl, -C(O)N(C 1-4 Alkyl)2,-C(O)N(C 3-10 Cycloalkyl)2,-S(O)2C 1-4 Alkyl, -S(O)2C 3-10 Cycloalkyl, -S(O)2N(C 1-4 alkyl)2 and -S(O)2N(C 3-10 Cycloalkyl)2;

[0063] u is selected from 0, 1, 2, 3 and 4;

[0064] t is selected from 0, 1, 2, 3 and 4.

[0065] Specifically, the third technical solution of the first aspect of the present invention relates to a compound of formula III or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, isotopic derivative or prodrug thereof:

[0066]

[0067] in:

[0068] X1 is selected from N and C;

[0069] X2 is selected from N, C, S and O;

[0070] n is the number of R5 and is 0, 1, 2, 3 or 4;

[0071] m is the number of R6 and is 0, 1, 2, 3 or 4;

[0072] Ring A is selected from C 3-10 Cycloalkyl, heterocyclyl and heteroaryl, wherein C 3-10 Cycloalkyl, heterocyclyl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R5;

[0073] Ring B is selected from heterocyclyl, aryl and heteroaryl, wherein heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R6;

[0074] Z is selected from a bond, -(CR z1 R z2 )u-, -(CR z1 R z2 )uO(CR z1 R z2 )t-, -(CR z1 R z2 )uNR z3 (CR z1 R z2 )t-, and -(CR z1 R z2 )uS(CR z1 R z2 )t-, preferably Z is selected from a bond;

[0075] R1 is selected from hydrogen, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 1-4 alkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclic group, heterocyclic group-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl, heteroaryl-C 1-4 group, CN, NO2, -NR 1a R 1b , -OR 1a , -OR 1a , -C(O)R 1a , -C(=NR 1c )R 1a and -C(=N-OR 1b )R 1a R 1b , -NR 1a C(O)R 1b , -C(=NR 1c )NR 1a R 1b , -NR 1a R 1b , -NR 1a CR 1b , -N)R 1a R 1b , -S(O)2OR 1a , -OS(O)2R 1a , -NR 1a S(O, -P(O)R 1a R 1b and -P(O)(OR 1a )(OR 1b), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R 1d ;

[0076] R2 is selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 1-4 Alkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, Heteroaryl, Heteroaryl-C 1-4 Base, CN, NO2, -NR 2a R 2b 、-OR 2a 、-OR 2a 、-C(O)R 2a 、-C(=NR 2c )R 2a AND-C(=N-OR 2b )R 2a R 2b , -NR 2a C(O)R 2b ,-C(=NR 2c )NR 2a R 2b 、-NR 2a R 2b , -NR 2a CR 2b , -N)R 2a R 2b , -S(O)2OR 2a , -OS(O)2R 2a , -NR 2a S(O,-P(O)R 2a R 2b AND-P(O)(OR 2a )(OR 2b ), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R 2d ;

[0077] Or, R1 and R2 together with the atoms to which they are attached form a 3-7 membered cycloalkyl, heterocyclyl, aryl and heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl group are each unsubstituted or substituted with at least one substituent independently selected from R7;

[0078] R3 is selected from hydrogen, halogen, C 1-10 Alkyl, carbonyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, CN, NO2, -NR 3a R 3b 、-OR 3a and -C(O)R 3a , wherein alkyl, alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl are each unsubstituted or substituted with at least one substituent independently selected from R 3c ;

[0079] R4 is selected from hydrogen, halogen, C 1-10 Alkyl, carbonyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, CN, NO2, -NR 4a R 4b 、-OR 4a and -C(O)R 4a , wherein alkyl, alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl are each unsubstituted or substituted with at least one substituent independently selected from R 4c ;

[0080] R5 is selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 1-4 Alkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, Heteroaryl, Heteroaryl-C 1-4 Base, CN, NO2, -NR 5a R 5b 、-OR 5a 、-C(O)R 5a 、-C(=NR 5c )R 5a 、-C(=N-OR 5b )R 5a 、-C(O)OR 5a 、-OC(O)R 5a、-C(O)NR 5a R 5b 、-NR 5a C(O)R 5b 、-C(=NR 5c )NR 5a R 5b 、-NR 5a C(=NR 5c )R 5b 、-OC(O)NR 5a R 5b 、-NR 5a C(O)OR 5b 、-NR 5a C(O)NR 5a R 5b 、-NR 5a C(S)NR 5a R 5b 、-NR 5a C(=NR 5c )NR 5a R 5b 、-S(O)rR 5a 、-S(O)(=NR 5c )R 5b 、-N=S(O)R 5a R 5b 、-S(O)2OR 5a 、-OS(O)2R 5a 、-NR 5a S(O)r 5b 、-NR 5a S(O)(=NR 5c )R 5b 、-S(O)rNR 5a R 5b 、-S(O)(=NR 5c )NR 5a R 5b 、-NR 5a S(O)2NR 5a R 5b 、-NR 5a S(O)(=NR 5c )NR 5a R 5b 、-P(O)R 5a R 5b AND-P(O)(OR 5a )(OR 5b ), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R 5d ;

[0081] R6 is selected from hydrogen, halogen, -CN, C 1-10 Alkyl, halogenated C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 1-4 Alkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, Heteroaryl, Heteroaryl-C 1-4 Radical, NO2, -NR 6a R 6b 、-OR 6a 、-C(O)R 6a 、-C(=NR 6c )R 6a 、-C(=N-OR 6b )R 6a 、-C(O)OR 6a 、-OC(O)R 6a 、-C(O)NR 6a R 6b 、-NR 6a C(O)R 6b 、-C(=NR 6c )NR 6a R 6b 、-NR 6a C(=NR 6c )R 6b 、-OC(O)NR 6a R 6b 、-NR 6a C(O)OR 6b 、-NR 6a C(O)NR 6a R 6b 、-NR 6a C(S)NR 6a R 6b 、-NR 6a C(=NR 6c )NR 6a R 6b 、-S(O)rR 6a 、-S(O)(=NR 6c )R 6b 、-N=S(O)R 6a R 6b 、-S(O)2OR 6a 、-OS(O)2R 6a 、-NR 6a S(O)r 6b、-NR 6a S(O)(=NR 6c )R 6b 、-S(O)rNR 6a R 6b 、-S(O)(=NR 6c )NR 6a R 6b 、-NR 6a S(O)2NR 6a R 6b 、-NR 6a S(O)(=NR 6c )NR 6a R 6b 、-P(O)R 6a R 6b AND-P(O)(OR 6a )(OR 6b ), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R 6d ;

[0082] R z1 and R z2 are each independently selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R P ;

[0083] or R z1 and R z2 Together with the atoms to which they are attached, they form a group comprising 0, 1 or 2 atoms independently selected from oxygen, sulfur and nitrogen and optionally 1, 2 or 3 R p A 3-12 membered ring of a heteroatom substituted by a group;

[0084] R z3 are each independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4Alkyl, Aryl, Aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R P ;

[0085] R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , R 6b are independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, aryl, aryl C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R P ;

[0086] or R 1a and R 1b , R 2a and R 2b , R 3a and R 3b , R 4a and R 4b , R 5a and R 5b , R 6a and R 6b Together with the atoms to which they are attached, they form a group comprising 0, 1 or 2 atoms independently selected from oxygen, sulfur and nitrogen and optionally 1, 2 or 3 R p A 3-12 membered ring of a heteroatom substituted by a group;

[0087] R 1c , R 2c , R 5c , R 6c are each independently selected from hydrogen, C 1-10 Alkyl, CN, NO2, -OR w 、-SRw 、-S(O)rR w 、-C(O)R w 、-C(O)OR w 、-C(O)OR w ;-C(O)NR w R x and -S(O)rNR w R x ;

[0088] R 1d , R 3c , R 4c R 2d , R 5d , R 6d , R7 are each independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, aryl, aryl C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 Alkyl, halogen, CN, NO2, -(CR y R z ) t NR w R x 、-(CR y R z ) t OR x 、-(CR y R z ) t C(O)R w 、-(CR y R z ) t C(=NR t )R w 、-(CR y R z ) t C(=N-OR x )R w 、-(CR y R z ) t C(O)OR x 、-(CR y R z ) t OC(O)R x 、-(CR y R z )t C(O)NR w R x 、-(CR y R z ) t NR w C(O)R x 、-(CR y R z ) t C(=NR t )NR w R x 、-(CR y R z ) t NR w C(=NR t )R x 、-(CR y R z ) t OC(O)NR w R x 、-(CR y R z ) t NR w C(O)OR x 、-(CR y R z ) t NR w C(O)NR w R x 、-(CR y R z ) t NR w C(S)NR w R x 、-(CR y Rz) t NR w C(=NR t )NR w R x 、-(CR y R z ) t S(O)rR x 、-(CR y R z ) t S(O)(=NR t )R x 、-(CR y R z ) t N=S(O)R w R x 、-(CR yR z ) t S(O)2OR x 、-(CR y R z ) t OS(O)2R x 、-(CR y R z ) t NR w S(O)r x 、-(CR y R z ) t NR w S(O)(=NR t )R x 、-(CR y R z ) t S(O)r w R x 、-(CR y R z ) t S(O)(=NR t )NR w R x 、-(CR y R z ) t NR w S(O)2NR w R x 、-(CR y R z ) t NR w S(O)(=NR t )NR w R x 、-(CR y R z ) t P(O)R w R x and-(CR y R z ) t P(O)(OR w )(OR x ), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R q ;

[0089] R P , R q , R w , R x , Ry , R z , R t Each independently selected from hydrogen, halogen, CN, NO2, C 1-10 Alkyl, C 3-10 Cycloalkyl, C 3-10 -cycloalkyl-C 1-4 Alkyl, C 1-10 Alkoxy, C 3-10 Cycloalkoxy, -C(O)C 1-4 Alkyl, -C(O)C 3-10 Cycloalkyl, -C(O)OC 1-4 Alkyl, -C(O)OC 3-10 Cycloalkyl, -C(O)N(C 1-4 Alkyl)2,-C(O)N(C 3-10 Cycloalkyl)2,-S(O)2C 1-4 Alkyl, -S(O)2C 3-10 Cycloalkyl, -S(O)2N(C 1-4 alkyl)2 and -S(O)2N(C 3-10 Cycloalkyl)2;

[0090] u is selected from 0, 1, 2, 3 and 4;

[0091] t is selected from 0, 1, 2, 3 and 4.

[0092] In a preferred embodiment, ring A is selected from a heterocyclic group.

[0093] In another preferred embodiment, ring A is preferably selected from:

[0094]

[0095] In a preferred embodiment, R5 is independently selected from hydrogen, C 1-4 Alkyl and cycloalkyl.

[0096] In a preferred embodiment, Selected from

[0097]

[0098] In a preferred embodiment, ring B is selected from aryl and heteroaryl.

[0099] In another preferred embodiment, Ring B is selected from:

[0100]

[0101] In a preferred embodiment, wherein R6 is selected from hydrogen, halogen, -CN, C 1-4 Alkyl, halogenated C 1-10 Alkyl, C2-10 Alkynyl, C 3-10 Cycloalkyl, heteroaryl, heteroaryl-C 1-4 Base, -NR 6a R 6b 、-OR 6a 、-C(O)NR 6a R 6b and cycloalkyl, R 6a or R 6b are independently selected from hydrogen, methyl, halomethyl, ethyl, cyclopropyl, or R 6a and R 6b Together with the N atom to which they are attached, they form a 4-6 membered ring.

[0102] In a preferred embodiment, wherein the independent Selected from

[0103]

[0104] Specifically, in a preferred embodiment, the compound of formula II or its pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, isotopic derivative or prodrug:

[0105]

[0106] in:

[0107] X1 is selected from N;

[0108] X2 is selected from S;

[0109] n is the number of R5 and is 0, 1, 2, 3 or 4;

[0110] m is the number of R6 and is 0, 1, 2, 3 or 4;

[0111] Ring A is selected from a heterocyclic group, preferably a 5-7-membered heterocyclic group, more preferably a 6-membered heterocyclic group containing 1 or 2 N;

[0112] Ring B is selected from aryl and heteroaryl, preferably ring B is selected from benzene ring or pyridine;

[0113] Z is selected from a bond;

[0114] R1 and R2 together with the atoms to which they are attached form a 5-membered heteroaryl group, more preferably a 5-membered heteroaryl group containing 1 or 2 N atoms, wherein the heteroaryl group is unsubstituted;

[0115] R3 is selected from hydrogen, C 1-4 Alkyl and carbonyl groups;

[0116] R4 is selected from hydrogen and C 1-4 alkyl;

[0117] R5 is selected from hydrogen, C 1-4 Alkyl and cycloalkyl; preferably R5 is selected from methyl, ethyl and cyclopropyl;

[0118] R6 is selected from hydrogen, halogen, -CN, C 1-4 Alkyl, halogenated C 1-10 Alkyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, heteroaryl, heteroaryl-C 1-4 Base, -NR 6a R 6b 、-OR 6a 、-C(O)NR 6a R 6b and cycloalkyl, R 6a or R 6b are independently selected from hydrogen, methyl, ethyl, cyclopropyl, or R 6a and R 6b Together with the N atom to which they are attached, they form a 4-6 membered ring.

[0119] Specifically, in another preferred embodiment, the compound of formula II or its pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, isotopic derivative or prodrug:

[0120]

[0121] in:

[0122] X1 is selected from N;

[0123] X2 is selected from S;

[0124] n is the number of R5 and is 0, 1, 2, 3 or 4;

[0125] m is the number of R6 and is 0, 1, 2, 3 or 4;

[0126] g is the number of R7 and is 0, 1, 2, 3 or 4;

[0127] Ring A is selected from a heterocyclic group, preferably a 5-7-membered heterocyclic group, more preferably a 6-membered heterocyclic group containing 1 or 2 N;

[0128] Ring B is selected from aryl and heteroaryl, preferably ring B is selected from benzene ring or pyridine;

[0129] Z is selected from a bond;

[0130] R1 and R2 together with the atoms to which they are attached form a 5-membered heteroaryl group, more preferably a 5-membered heteroaryl group containing 1 or 2 N atoms, wherein the heteroaryl group is unsubstituted;

[0131] R3 is selected from hydrogen, C 1-4Alkyl and carbonyl groups;

[0132] R4 is selected from hydrogen and C 1-4 alkyl;

[0133] R5 is selected from hydrogen, C 1-4 Alkyl and cycloalkyl; preferably R5 is selected from methyl, ethyl and cyclopropyl;

[0134] R6 is selected from hydrogen, F, Cl, Br, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, difluoroethyl, trifluoroethyl, isopropyl, cyclopropyl, methoxy, ethoxy, -CN, ethynyl, -NHCH, -C(O)NHCH3, -C(O)N(CH3)2,

[0135]

[0136] Specifically, in a preferred embodiment, the compound of formula III or its pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, isotopic derivative or prodrug:

[0137]

[0138] in:

[0139] X1 is selected from N and C;

[0140] X2 is selected from S;

[0141] n is the number of R5 and is 0, 1, 2, 3 or 4;

[0142] m is the number of R6 and is 0, 1, 2, 3 or 4;

[0143] Ring A is selected from a heterocyclic group, preferably a 5-7-membered heterocyclic group, more preferably a 6-membered heterocyclic group containing 1 or 2 N;

[0144] Ring B is selected from aryl and heteroaryl, preferably ring B is selected from benzene ring or pyridine;

[0145] Z is selected from a bond;

[0146] R1 is selected from hydrogen and C 1-4 alkyl;

[0147] When X1 is selected from C, R2 is selected from hydrogen;

[0148] R3 is selected from hydrogen, C 1-4 Alkyl and carbonyl groups;

[0149] R4 is selected from hydrogen and C 1-4 alkyl;

[0150] R5 is selected from hydrogen, C 1-4Alkyl and cycloalkyl; preferably R5 is selected from methyl, ethyl and cyclopropyl;

[0151] R6 is selected from hydrogen, halogen, -CN, C 1-4 Alkyl, halogenated C 1-10 Alkyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, heteroaryl, heteroaryl-C 1-4 Base, -NR 6a R 6b 、-OR 6a 、-C(O)NR 6a R 6b and cycloalkyl, R 6a or R 6b are independently selected from hydrogen, methyl, ethyl, cyclopropyl, or R 6a and R 6b Together with the N atom to which they are attached, they form a 4-6 membered ring.

[0152] Specifically, in another preferred embodiment, the compound of formula III or its pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, isotopic derivative or prodrug:

[0153]

[0154] in:

[0155] X1 is selected from N and C;

[0156] X2 is selected from S;

[0157] n is the number of R5 and is 0, 1, 2, 3 or 4;

[0158] m is the number of R6 and is 0, 1, 2, 3 or 4;

[0159] Ring A is selected from a heterocyclic group, preferably a 5-7-membered heterocyclic group, more preferably a 6-membered heterocyclic group containing 1 or 2 N;

[0160] Ring B is selected from aryl and heteroaryl, preferably ring B is selected from benzene ring or pyridine;

[0161] Z is selected from a bond;

[0162] R1 is selected from hydrogen and C 1-4 alkyl;

[0163] When X1 is selected from C, R2 is selected from hydrogen;

[0164] R3 is selected from hydrogen, C 1-4 Alkyl and carbonyl groups;

[0165] R4 is selected from hydrogen and C 1-4 alkyl;

[0166] R5 is selected from hydrogen, C 1-4 Alkyl and cycloalkyl; preferably R5 is selected from methyl, ethyl and cyclopropyl;

[0167] R6 is selected from hydrogen, F, Cl, Br, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, difluoroethyl, trifluoroethyl, isopropyl, cyclopropyl, methoxy, ethoxy, -CN, ethynyl, -NHCH, -C(O)NHCH3, -C(O)N(CH3)2,

[0168]

[0169] In a preferred embodiment, the compound or its pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, isotopic derivative or prodrug comprises:

[0170]

[0171]

[0172] In a preferred embodiment, the compound or its pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, isotopic derivative or prodrug comprises:

[0173]

[0174]

[0175]

[0176]

[0177] In the second aspect of the present invention, a pharmaceutically acceptable salt of a compound of formula I, formula II, or formula III is provided, wherein the pharmaceutically acceptable salt is prepared by adding a pharmaceutically acceptable acid to a compound of formula I, II, or III, preferably the acid is an inorganic acid or an organic acid, wherein the inorganic acid is selected from HCl, H3PO4, H2SO4, HNO3, HBr, and HI, and the organic acid is selected from formic acid, acetic acid, CF3COOH, propionic acid, butyric acid, oxalic acid, adipic acid, malic acid, tartaric acid, semi-tartaric acid, amino acids, methanesulfonic acid, benzenesulfonic acid, p-TsOH, naphthalenesulfonic acid, fumaric acid, maleic acid, succinic acid, cholic acid, deoxycholic acid, citric acid, mucic acid, hippuric acid, and gentisic acid.

[0178] In the third aspect of the present invention, a pharmaceutical composition is provided, which contains a pharmaceutically acceptable excipient or carrier, and a compound represented by the above-mentioned Formula I, Formula II, Formula III or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, isotope derivative or prodrug thereof as an active ingredient.

[0179] In the fourth aspect of the present invention, there is provided a use of the compounds represented by the above-mentioned formula I, formula II, formula III or their pharmaceutically acceptable salts, stereoisomers, solvates, polymorphs, isotope derivatives or prodrugs, or the pharmaceutical composition as described in the third aspect in the preparation of drugs for treating diseases related to PARP1.

[0180] In the fifth aspect of the present invention, a method for preventing or treating a disease or condition associated with increased PARP1 expression is provided, comprising administering. In the fourth aspect of the present invention, a compound of the above-mentioned formula I, formula II, formula III or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, isotope derivative or prodrug thereof, or a pharmaceutical composition as described above is provided.

[0181] In a preferred embodiment, the disease or disorder is a hyperplasia associated with a defective DNA repair pathway.

[0182] In a preferred embodiment, the disease or condition is hyperplasia associated with BRCA1 and / or BRCA2 mutations.

[0183] In a preferred embodiment, the disease or disorder is hyperplasia related.

[0184] In a preferred embodiment, the disease or condition is prostate cancer, pancreatic cancer, pheochromocytoma, paraganglioma, squamous cell lung cancer, glioblastoma, glioma, breast cancer, breast cancer with BRCA1 / 2 mutation, oral squamous cell carcinoma, non-small cell lung cancer, small cell lung cancer, neuroendocrine cancer, lung adenocarcinoma, ovarian cancer, ovarian cancer with BRCA1 / 2 mutation, endometrial cancer, nasopharyngeal cancer, colorectal cancer, rectal cancer, acute myeloid leukemia, gastric cancer, fallopian tube cancer, primary peritoneal cancer, non-Hodgkin's lymphoma, brain cancer, acute lymphocytic leukemia, acute myeloid leukemia, acute megakaryocytic leukemia, acute monocytic leukemia, atypical chronic myeloid leukemia, Hodgkin's lymphoma, mesothelioma, NK / T cell lymphoma, cervical cancer, head and neck squamous cell carcinoma, oropharyngeal cancer, liver cancer, soft tissue sarcoma, bone cancer, biliary tract cancer, bladder cancer or neurodegenerative disease.

[0185] Before detailed description, it should be understood that the following detailed description is only exemplary in nature and is not intended to limit the present invention or its application and use. Therefore, for ease of explanation, although the present disclosure is described and recorded as shown in some illustrative embodiments, it should be understood that the present disclosure can be implemented in various other types of embodiments and equivalents and in various other systems and environments. In addition, it is not subject to any theoretical constraints proposed in the aforementioned background technology or the following detailed description.

[0186] Terms and Definitions

[0187] The compounds are generally described herein using standard nomenclature. For compounds with asymmetric centers, it is understood that (unless otherwise specified) all optical stereoisomers and mixtures thereof are included. In addition, compounds with carbon-carbon double bonds can exist in Z-type and E-type, and unless otherwise specified, all isomeric forms of the compounds are included in the present invention. When compounds exist in various tautomeric forms, the compounds listed are not limited to any one specific tautomeric stereoisomer, but are intended to include all tautomeric forms.

[0188] As used herein, "substituent" and "substituted" refer to a molecular moiety that is covalently bonded to an atom within the subject molecule. For example, a ring substituent can be part of a group such as a halogen, alkyl, haloalkyl, or other group that is covalently bonded to an atom (preferably a carbon or nitrogen atom) that is a ring member. Substituents of aromatic groups are typically covalently bonded to a ring carbon atom.

[0189] When using the compounds of Formula I, Formula II, and Formula III, the term "pharmaceutically acceptable" is intended to mean a compound form that is safe for administration to a subject. For example, the free base, salt form, solvate, hydrate, prodrug or derivative form of the compound of Formula I is pharmaceutically acceptable and has been approved by an administrative agency or regulatory agency, such as the U.S. Food and Drug Administration (FDA), for use in mammals by oral ingestion or any other route of administration.

[0190] The compounds of formula I, formula II, and formula III include pharmaceutically acceptable salt forms of free base compounds. The term "pharmaceutically acceptable salt" includes salts commonly used to form alkali metal salts and addition salts of free acids or free bases, which have been approved by regulatory agencies. Salts are formed by ion association, charge-charge interaction, covalent bonding, complexation, coordination, etc. The nature of the salt is not important as long as it is pharmaceutically acceptable.

[0191] In some embodiments, the compounds of Formula I, Formula II, and Formula III are used to treat subjects by administering the compounds as pharmaceutical compositions. To this end, in one embodiment, the compounds are combined with one or more pharmaceutically acceptable excipients (including carriers, diluents, or adjuvants) to form a suitable composition, which is described in more detail herein.

[0192] The term "excipient" as used herein means any pharmaceutically acceptable additive, carrier, adjuvant or other suitable ingredient other than the active pharmaceutical ingredient (API), which is typically included for formulation and / or administration purposes. "Diluent" and "adjuvant" are defined below.

[0193] As used herein, the terms "treat," "treating," "treatment," and "treatment" refer to treatment, including but not limited to curative treatment, prophylactic treatment, and preventive treatment. Prophylactic treatment generally constitutes preventing the onset of a disorder or delaying the onset of a preclinically evident disorder stage in an individual.

[0194] The term "halogen" as used herein refers to F, Cl, Br, I or isotopes thereof.

[0195] The term "halogenated" as used herein means substituted by one or more halogens selected from F, Cl, Br, I or their isotopes. The upper limit of the number of halogen substituents is equal to the sum of the number of hydrogens that can be substituted by the substituted group. Unless otherwise specified, the number of halogen substituents is any integer between 1 and the upper limit. When the number of halogen substituents is greater than 1, they can be substituted by the same or different halogens. It usually includes 1-5 halogen substitutions, 1-3 halogen substitutions, 1-2 halogen substitutions, and 1 halogen substitution.

[0196] The term "stereoisomer" used herein refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, tautomers, enantiomers and conformational isomers.

[0197] The phrase "effective amount" is intended to quantify the amount of each agent that will achieve the goal of improving the severity of the disorder and the frequency of treatment by each agent itself, while avoiding the adverse side effects typically associated with alternative therapies. In one embodiment, the effective amount is administered in a single dosage form or in multiple dosage forms.

[0198] Deuterium (D or 2 Deuterium (H) is a non-radioactive, stable isotope of hydrogen, and its natural abundance is about 0.015%. If the deuterium content of a compound is above the natural abundance level of 0.015%, the compound should be considered unnatural.

[0199] In the compounds of the invention, it is understood that when a particular position is designated as deuterium, the abundance of deuterium is significantly greater than the natural abundance of deuterium of 0.015%. Positions designated as deuterium generally have a minimum isotopic enrichment factor of at least 3000 per atom designated as deuterium in the compound. The concentration of naturally abundant stable hydrogen is small and insignificant compared to the degree of stable isotope substitution in the compounds of the invention.

[0200] In some embodiments, the abundance of the compounds of Formula I, Formula II, and Formula III for each designated deuterium atom is at least greater than 0.015% of the natural abundance of deuterium. In certain embodiments, the deuterium enrichment in the compounds of Formula I, Formula II, and Formula III is at least about 1%.

[0201] In other embodiments, the compounds of the invention have an isotopic enrichment factor of at least 3500, at least 4000, at least 4500, at least 5000, or at least 5500, at least 6000, at least 6333.3, at least 6466.7, or at least 6633.3 per designated deuterium atom.

[0202] As used herein, the term "isotopic enrichment factor" refers to the ratio of isotopic abundance to the natural abundance of a particular isotope.

[0203] Regardless of the route of administration selected, the compound of the present invention (which may be used in a suitable hydrated form) and / or the pharmaceutical composition of the present invention are formulated into a pharmaceutically acceptable dosage form or by other methods known to those skilled in the art.

[0204] Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied to obtain an effective amount of the active ingredient to achieve the desired therapeutic response for a particular patient, composition, and mode of administration without being toxic to the patient.

[0205] The selected dosage level will depend upon a variety of factors, including the activity of the specific compound of the invention employed, the route of administration, the time of administration, the excretion rate of the specific compound employed, the duration of the treatment, other drugs, compounds and / or materials used in combination with the specific PARP1 inhibitor employed, the age, sex, weight, condition, general health and previous medical history of the patient being treated, and other factors known in the medical art.

[0206] A doctor or veterinarian with ordinary skills in the art can easily determine and prescribe the effective amount of the desired pharmaceutical composition. For example, a doctor or veterinarian can start the dosage of the compound of the present invention used in the pharmaceutical composition at a level lower than that required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved.

[0207] Usually, the suitable daily dose of the compounds of the present invention is the amount of the compound of the lowest dose that effectively produces the therapeutic effect. This effective dose usually depends on the above factors. Usually, the intravenous, intraventricular and subcutaneous dose range of the compounds of the present invention for patients is about 0.0001 to about 1500 mg per kilogram of body weight per day, including but not limited to 1-1500 mg, 1-1400 mg, 1-1300 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 1-500 mg, 1-400 mg, 1-300 mg, 1-250 mg, 1-200 mg, 1-150 mg, 1-125 mg, 1-100 mg, 1-80 mg, 1-60 mg, 1-50 mg, 1-40 mg, 1-25 mg, 1-20mg, 5-1500mg, 5-1000mg, 5-900mg, 5-800mg, 5-700mg, 5-600mg, 5-500mg, 5-400mg, 5-300mg, 5-250mg, 5-200mg, 5-150mg, 5-125mg, 5-10 0mg, 5-90mg, 5-70mg, 5-80mg, 5-60mg, 5-50mg, 5-40mg, 5-30mg, 5-25mg, 5-20mg, 10-1500mg, 10-1000mg, 10-900mg, 10-800mg, 10-700mg, 10-6 00mg, 10-500mg, 10-450mg, 10-400mg, 10-300mg, 10-250mg, 10-200mg, 10-150mg, 10-125mg, 10-100mg, 10-90mg, 10-80mg, 10-70mg, 10-60mg , 10-50mg, 10-40mg, 10-30mg, 10-20mg; 20-1500mg, 20-1000mg, 20-900mg, 20-800mg, 20-700mg, 20-600mg, 20-500mg, 20-400mg, 20-350mg, 20 -300mg, 20-250mg, 20-200mg, 20-150mg, 20-125mg, 20-100mg, 20-90mg, 20-80mg, 20-70mg, 20-60mg, 20-50mg, 20-40mg, 20-30mg; 50-1500mg, 50-1000mg, 50-900mg, 50-800mg, 50-700mg, 50-600mg, 50-500mg, 50-400mg, 50-300mg, 50-250mg, 50-200mg, 50-150mg, 50-125mg, 50-100mg;100-1500mg, 100-1000mg, 100-900mg, 100-800mg, 100-700mg, 100-600mg, 100-500mg, 100-400mg, 100-300mg, 100-250mg, 100-200mg. ;

[0208] The route of administration has a significant effect on the dosage. Higher doses may be used with local delivery routes.

[0209] If desired, the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses, administered separately at appropriate intervals throughout the day, optionally, in unit dosage form. Those skilled in the art will readily appreciate that dosage levels may vary depending on the specific compound, the severity of the symptoms, and the sensitivity of the subject to side effects. The dosage of a given compound disclosed herein can be readily determined by a variety of methods by those skilled in the art.

[0210] The carbon-hydrogen bonds of all compounds contain a naturally occurring distribution of hydrogen isotopes, i.e. 1 H or protium (about 99.9844%), 2 H or deuterium (about 0.0156%) and 3 H or tritium (per 10 18 Protium atoms, tritium atoms range between about 0.5 and 67). The increased level of deuterium incorporation produces a detectable kinetic isotope effect (KIE) that can affect the pharmacokinetic, pharmacological and / or toxicological parameters of such anti-tumor agents relative to compounds with naturally occurring levels of deuterium. Some aspects of the invention disclosed herein describe novel methods for designing and synthesizing novel analogs of these PARP1 inhibitors by chemical modification and derivatization of carbon-hydrogen bonds of these PARP1 inhibitors and / or chemical precursors used to synthesize the PARP1 inhibitors. In some embodiments, appropriate modification of certain carbon-hydrogen bonds to carbon-deuterium bonds produces novel PARP1 inhibitors that have unexpected and non-obvious improvements in pharmacological, pharmacokinetic and toxicological properties compared to non-isotopically enriched anti-tumor agents. The present invention relies on the precise and successful application of chemical kinetics in drug design. The level of deuterium incorporation in the compounds of the present invention is significantly higher than the naturally occurring level and is sufficient to produce at least one substantial improvement described herein.

[0211] Various deuteration modes are used to a) reduce or eliminate unwanted metabolites, b) increase the half-life of the parent drug, and / or c) reduce the production of harmful metabolites in specific tissues and produce more effective drugs and safer drugs for compounding, whether compounding is intended or not. Deuteration methods have a strong potential to slow metabolism through various oxidative mechanisms.

[0212] The deuterated analogs of the present invention uniquely maintain the beneficial aspects of non-isotopically enriched drugs while significantly increasing the maximum tolerated dose, reducing toxicity, and increasing the half-life (T 1 / 2 ), reducing the maximum plasma concentration (C max ), lower effective doses, thereby reducing non-mechanism-related toxicities, and / or reducing the potential for drug-drug interactions. These drugs also have great potential to reduce cost of goods (COG) due to the availability of inexpensive deuterated agents combined with the previously mentioned potential for lower therapeutic doses.

[0213] Pharmaceutical compositions / preparations

[0214] One embodiment provides a pharmaceutical composition comprising a compound of Formula I, Formula II, Formula III, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof, and at least one pharmaceutically acceptable excipient.

[0215] In some embodiments, the present invention provides a method for inhibiting PARP1. The method comprises administering a therapeutically effective amount of at least one compound of Formula I, Formula II, or Formula III to a mammalian subject. The method includes treating or preventing stroke, prostate cancer, pancreatic cancer, pheochromocytoma, paraganglioma, squamous cell lung cancer, glioblastoma, glioma, breast cancer, breast cancer with BRCA1 / 2 mutation, oral squamous cell carcinoma, non-small cell lung cancer, small cell lung cancer, neuroendocrine cancer, lung adenocarcinoma, ovarian cancer, ovarian cancer with BRCA1 / 2 mutation, endometrial cancer, nasopharyngeal cancer, colorectal cancer, rectal cancer, acute myeloid leukemia, gastric cancer, fallopian tube cancer, primary peritoneal cancer, non-Hodgkin lymphoma, brain cancer, acute lymphocytic leukemia, acute myeloid leukemia, acute megakaryocytic leukemia, acute monocytic leukemia, atypical chronic myeloid leukemia, Hodgkin lymphoma, mesothelioma, NK / T cell lymphoma, cervical cancer, head and neck squamous cell carcinoma, oropharyngeal cancer, liver cancer, soft tissue sarcoma, bone cancer, biliary tract cancer, bladder cancer or neurodegenerative disease.

[0216] In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that aid in processing the active compound into a pharmaceutically usable preparation. The appropriate formulation depends on the route of administration selected. An overview of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed., Easton, Pa.: Mack Publishing Company (1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania (1975); Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY (1980); and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed., Lippincott Williams & Wilkins (1999), the disclosures of which are incorporated herein by reference.

[0217] The pharmaceutical composition used herein refers to a mixture of a compound of formula I, formula II, and formula III with other chemical components (i.e., pharmaceutically acceptable inactive ingredients), such as carriers, excipients, adhesives, fillers, suspending agents, flavoring agents, sweeteners, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers, humectants, plasticizers, stabilizers, penetration enhancers, wetting agents, defoamers, antioxidants, preservatives, or one or more combinations thereof. The pharmaceutical composition helps to administer the compound to an organism. When implementing the methods or uses provided herein, a therapeutically effective amount of the compound described herein is administered in the form of a pharmaceutical composition to a mammal suffering from a disease, disorder, or condition to be treated. In some embodiments, the mammal is a human. The therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the efficacy of the compound used, and other factors. The compound can be used alone or in combination with one or more therapeutic agents as a component of the mixture.

[0218] The pharmaceutical preparations described herein are administered to the subject by an appropriate route of administration, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, oral, topical, rectal or transdermal routes of administration. The pharmaceutical preparations described herein include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, delayed release formulations, extended release formulations, pulsed release formulations, multi-particulate formulations, and mixed immediate and controlled release formulations.

[0219] All preparations for oral administration are in a dosage suitable for this administration. Examples of such dosage units are tablets or capsules. In some embodiments, they contain about 1 to 2000 mg, advantageously about 1 to 500 mg, usually about 5 to 150 mg of active ingredient. For people or other mammals, suitable daily doses vary widely according to the patient's condition and other factors, but can again be determined using conventional methods and practice.

[0220] Conventional formulation techniques include, for example, one or more methods in combination: (1) dry blending, (2) direct compression, (3) grinding, (4) dry or non-aqueous granulation, (5) wet granulation, or (6) fusion. Other methods include, for example, spray drying, pan coating, melt granulation, granulation, fluidized bed spray drying or coating (e.g., wurster coating), tangential coating, top spraying, tableting, extrusion, etc.

[0221] Suitable carriers for the solid dosage forms described herein include, but are not limited to, gum arabic, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerol, magnesium silicate, sodium caseinate, soy lecithin, sodium chloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyl lactylate, carrageenan, monoglycerides, diglycerides, pregelatinized starch, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate stearate, sucrose, microcrystalline cellulose, lactose, mannitol, and the like.

[0222] Suitable fillers for the solid dosage forms described herein include, but are not limited to, lactose, calcium carbonate, calcium phosphate, calcium dibasic phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrates, dextran, starch, pregelatinized starch, hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate stearate (HPMCAS), sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.

[0223] Suitable disintegrants for use in the solid dosage forms described herein include, but are not limited to, natural starches, such as corn starch or potato starch, pregelatinized starch, or sodium starch glycolate; celluloses, such as methylcrystalline cellulose, methylcellulose, microcrystalline cellulose, croscarmellose; or cross-linked celluloses, such as cross-linked sodium carboxymethyl cellulose, cross-linked carboxymethyl cellulose, or cross-linked carboxycellulose; cross-linked starches, such as sodium starch glycolate; cross-linked polymers, such as cross-linked povidone, cross-linked polyvinyl pyrrolidone; alginates, such as alginic acid or a salt of alginic acid such as sodium alginate; gums, such as agar, guar, locust bean, karaya, pectin, or tragacanth; sodium starch glycolate, bentonite, sodium lauryl sulfate, sodium lauryl sulfate in combined starches, and the like.

[0224] Binders impart cohesion to solid oral dosage form formulations: for powder-filled capsule formulations, they help form plugs that can be filled into soft- or hard-shell capsules, and for tablet formulations, they ensure that the tablet remains intact after compression and help ensure blend homogeneity prior to the compression or filling steps. Materials suitable for use as binders in the solid dosage forms described herein include, but are not limited to, carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate stearate, hydroxyethylcellulose, hydroxypropylcellulose, ethylcellulose and microcrystalline cellulose, microcrystalline dextrose, amylose, magnesium aluminum silicate, polysaccharide acids, bentonite, gelatin, polyvinylpyrrolidone / vinyl acetate copolymer, cross-linked polyvinylpyrrolidone, povidone, starch, pregelatinized starch, tragacanth, dextrin, sugars (e.g., sucrose, glucose, dextrose, molasses, mannitol, sorbitol, xylitol, lactose), natural or synthetic gums (e.g., gum arabic, tragacanth, gum ghatti, mucilage of isapol peel), starch, polyvinylpyrrolidone, larch arabogalactan, polyethylene glycol, wax, sodium alginate, and the like.

[0225] Typically, binder levels of 20-70% are used in powder-filled gelatin capsule formulations. Binder levels in tablet formulations vary, whether they are direct compression, wet granulation, roller compaction, or using other excipients (such as fillers that can themselves act as moderate binders). Binder levels of up to 70% in tablet formulations are common.

[0226] Suitable lubricants or glidants for use in the solid dosage forms described herein include, but are not limited to, stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, alkali metal and alkaline earth metal salts (e.g., aluminum salts, calcium salts, magnesium salts, zinc salts), stearic acid, sodium stearate, magnesium stearate, zinc stearate, waxes, Boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, polyethylene glycol, or methoxypolyethylene glycol such as Carbowax TM, PEG 4000, PEG 5000, PEG 6000, propylene glycol, sodium oleate, glyceryl behenate, glyceryl palmitostearate, glyceryl benzoate, magnesium lauryl sulfate or sodium lauryl sulfate, etc.

[0227] Suitable diluents for use in the solid dosage forms described herein include, but are not limited to, sugars (including lactose, sucrose and dextrose), polysaccharides (including dextran and maltodextrin), polyols (including mannitol, xylitol and sorbitol), cyclodextrins, and the like.

[0228] Suitable wetting agents for use in the solid dosage forms described herein include, for example, oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, quaternary ammonium compounds (e.g., Polyquat ), sodium oleate, sodium lauryl sulfate, magnesium stearate, docusate sodium, triacetin, vitamin E TPGS, etc.

[0229] Suitable surfactants for use in the solid dosage forms described herein include, for example, sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, e.g. (BASF) etc.

[0230] Suitable suspending agents for the solid dosage forms described herein include, but are not limited to, polyvinylpyrrolidone, such as polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, polyethylene glycol, such as polyethylene glycol can have a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 7000 to about 5400, vinylpyrrolidone / vinyl acetate copolymer (S630), sodium carboxymethylcellulose, methylcellulose, cellulose, hydroxypropyl methylcellulose, polysorbate-80, hydroxyethylcellulose, sodium alginate, gums such as tragacanth and gum arabic, guar gum, xanthan gums including xanthan gum, sugars, celluloses such as sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, polysorbate-80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone, and the like.

[0231] Synthesis of compounds

[0232] The examples and preparations provided below illustrate and exemplify the compounds described herein and methods of making these compounds. Generally, the compounds described herein can be prepared by methods known in the general chemical art.

[0233] The compounds of the present invention can be prepared from commercially available materials using various synthetic routes (including those described below). The raw materials of the present invention are known, commercially available, or can be synthesized similarly to or according to methods known in the art. Many raw materials can be prepared according to known methods, particularly using the methods described in the examples. When synthesizing raw materials, in some cases, the functional group is protected with a suitable protecting group when necessary. The functional group can be removed according to methods known in the art.

[0234] The protection of functional groups by protecting groups, the protecting groups themselves and reactions for their removal (generally referred to as "deprotection") are described, for example, in standard reference texts, such as JFW McOmie, Protective Groups in OrganiChemistry, Plenum Press, London and New York (1973), in TW Greene, Protective Groups in OrganiC Synthesis, Wiley, New York (1981), in The Peptides, Volume 3, E. Gross and J. Meienhofer editors, Academic Press, London and New York (1981), in Methoden der Organischen Chemie (Methods of OrganiChemistry), Houben Weyl, 4 th edition,Volume 15 / 1,Georg Thieme Verlag,Stuttgart(1974),in H.-D.Jakubke and H.Jescheit, Peptide, Proteine ​​(Amino Acids, Peptides, Proteins), Verlag Chemie, Weinheim, Deerfield Beach, and Basel (1982), and in Jochen Lehmann, Chemie der Kohlenhydrate: Monosaccharide und Derivate (Chemistry of Carbohydrates: Monosaccharides and Derivatives), Georg Thieme Verlag, Stuttgart (1974).

[0235] All synthetic methods described herein can be carried out under known reaction conditions, advantageously under those described herein, in the absence or presence (usually) of a solvent or diluent. The solvent should be inert and should be able to dissolve the starting materials and other reagents used. The solvent should be able to partially or completely dissolve the reactants in the absence or presence of a catalyst, a condensing agent or a neutralizing agent, such as an ion exchanger, typically a cation exchanger, such as H + The ability of a solvent to permit and / or influence the progress or rate of a reaction generally depends on the type and nature of the solvent, the reaction conditions including temperature, pressure, atmospheric conditions such as under an inert atmosphere of argon or nitrogen, concentrations, and the reactants themselves.

[0236] Suitable solvents for conducting the reaction of synthesizing the compounds of the present invention include, but are not limited to, water; esters, including lower alkyl-lower alkanoic acid esters, such as ethyl acetate; ethers, including aliphatic ethers, such as Et2O and ethylene glycol dimethyl ether or cyclic ethers, such as THF; liquid aromatic hydrocarbons, including benzene, toluene and xylene; alcohols, including MeOH, EtOH, 1-propanol, i-PrOH, n-butanol and tert-butanol; nitriles, including CH3CN; halogenated hydrocarbons, including CH2Cl2, CHCl3 and CCl4; amides, including DMF; sulfoxides, including DMSO; bases, including heterocyclic nitrogen bases, such as pyridine; carboxylic acids, including lower alkanecarboxylic acids, such as AcOH; inorganic acids, including HCl, HBr, HF, H2SO4, etc.; carboxylic acid anhydrides, including lower alkanoic acid anhydrides, such as acetic anhydride; cyclic, straight-chain or branched hydrocarbons, including cyclohexane, hexane, pentane, isopentane, etc., and mixtures of these solvents, such as pure organic solvent combinations or aqueous solvent combinations, such as aqueous solutions. These solvents and solvent mixtures may also be used to "work up" the reaction and to work up the reaction and / or isolate the reaction products, for example in chromatography.

[0237] The present invention also includes "intermediate" compounds, including structures prepared by the synthetic methods described, whether or not isolated, prior to obtaining the final desired compound. Structures obtained by performing steps on transient starting materials, structures isolated at any stage by the methods described, and structures formed from starting materials under the reaction conditions described are all "intermediates" encompassed by the present invention. In addition, structures generated by using starting materials in the form of active derivatives or salts, or structures generated by compounds obtainable by the methods according to the present invention, as well as structures obtained by in situ processing of the compounds of the present invention are also within the scope of the present invention.

[0238] When the compounds of formula I, formula II, and formula III are synthesized according to the desired procedure, the steps in some embodiments are carried out in an order suitable for preparing the compound, including the procedures described herein or alternative orders of the steps; in one embodiment, when necessary, before or after other protection / deprotection steps. In certain embodiments, the procedure should further use appropriate reaction conditions, including inert solvents, additional reagents, such as bases (e.g., LDA, DIEA, pyridine, K2CO3, etc.), catalysts, and the above-mentioned salt forms. The intermediates in some embodiments are separated or carried in situ with or without purification. Purification methods are known in the art, including, for example, crystallization, chromatography (liquid phase and gas phase, etc.), extraction, distillation, grinding, reverse phase HPLC, etc. Reaction conditions such as temperature, duration, pressure, and atmosphere (inert gas, ambient temperature) are known in the art and can be appropriately adjusted according to the reaction.Synthetic chemistry transformations and protecting group methods (protection and deprotection) that can be used to synthesize the inhibitor compounds described herein are known in the art and include, for example, those described in the following articles: R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); A. Katritzky and A. Pozharski, Handbook of HeterocycliChemistry, 2nd edition (2001); M. Bodanszky, A. Bodanszky, The Practice of Peptide Synthesis, Springer-Verlag, Berlin Heidelberg (1984); J. Seyden-Penne, Reductions by the Alumino-and Borohydrides in OrganiCSynthesis, 2nd edition, Wiley-VCH (1997); and L. Paquette, editor, Encyclopedia of Reagents for OrganiCSynthesis, John Wiley and Sons (1995).

[0239] In the reaction, in certain embodiments, reactive functional groups must be protected, for example hydroxyl, amino, thiol or carboxyl, which are necessary in the final product to prevent them from undesirably participating in the reaction. Protective groups are used to block some or all of the reactive moieties and prevent these groups from participating in chemical reactions until the protective group is removed. In one embodiment, each protective group can be removed in different ways. Under completely different reaction conditions, the protective group of cracking meets the requirements of different removals. In some embodiments, the protective group is removed by acid, base and / or hydrogenolysis. DETAILED DESCRIPTION

[0240] The present disclosure is further explained below with reference to examples. The description of specific exemplary embodiments of the present disclosure is for illustration and example. The present disclosure is further explained below with reference to examples. The description of specific exemplary embodiments of the present disclosure is for illustration and example, and many changes and variations can be made. The purpose of selecting and describing the exemplary embodiments is to explain the specific principles of the present disclosure and its practical application, so that those skilled in the art can realize and utilize various different exemplary embodiments of the present disclosure and various different selections and changes.

[0241] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0242] Unless otherwise specified, the materials and reagents used in the following examples can be obtained from commercial sources.

[0243] Example 1: Synthesis of Compound A1

[0244] Step 1, A1-int-1 is synthesized as follows :

[0245]

[0246] (1) Synthesis of Compound A1-int-1-C

[0247] A1-int-1-A (1.98 g, 10.0 mmol) and A1-int-1-B (1.5 g, 12.0 mmol) were dissolved in 20 mL of anhydrous DMF, and cesium carbonate (6.5 g, 20.0 mmol) was added thereto. After reacting at 60°C for 2 h, TLC showed that the reaction was complete. After cooling to room temperature, water (60 mL) was added thereto. The aqueous phase was extracted with ethyl acetate (50 mL*3). After the organic phases were combined and washed with saturated brine (20 mL*3), the organic phases were dried and spin-dried. The crude product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain compound A1-int-1-C (1.8 g, yield 59%).

[0248] (2) Synthesis of Compound A1-int-1-D

[0249] A1-int-1-C (1.8 g, 5.92 mmol) and ammonium chloride (1.57 g, 29.6 mmol) were dissolved in methanol / water (18 / 8 mL), and iron powder (1.66 g, 29.6 mmol) was added thereto. After reacting at 80°C for 2 h, TLC showed that the reaction was complete. After hot filtration, the filter cake was rinsed with 50 mL of ethyl acetate. The organic phases were combined and washed with saturated brine (10 mL*3), dried and spin-dried. The crude product was separated and purified by column chromatography (dichloromethane: methanol = 100: 1) to obtain compound A1-int-1-D (1.0 g, yield 70%).

[0250] (3) Synthesis of Compound A1-int-1

[0251] A1-int-1-D (850 mg, 3.51 mmol) was dissolved in 15 mL of anhydrous tetrahydrofuran, and lithium aluminum hydride (7 mL, 1 M, 7 mmol) was added thereto under ice bath. After reacting at room temperature for 2 h, TLC showed that the reaction was complete. After the reaction solution was quenched with water (25 mL), the aqueous phase was extracted with ethyl acetate (30 mL*3), combined, dried and spin-dried. The crude product was separated and purified by column chromatography (dichloromethane: methanol = 30:1) to obtain compound A1-int-1 (370 mg, yield 49%).

[0252] Step 2, A1-int-2 is synthesized as follows :

[0253]

[0254] (1) Synthesis of Compound A1-int-2-C

[0255] A1-int-2-A (1.1 g, 5.17 mmol), A1-int-2-B (1.12 g, 5.63 mmol) and cesium carbonate (2.50 g, 7.67 mmol) were dissolved in 20 mL of dioxane, and Pd2(dba)3 (469 mg, 0.51 mmol) and BINAP (637 mg, 1.02 mmol) were added thereto. After reacting overnight at 90 ° C under nitrogen protection, TLC showed that the reaction was complete. The reaction solution was filtered, and the filtrate was diluted with water (30 mL) and extracted with ethyl acetate (20 mL*3). The organic phases were combined and washed with saturated brine (10 mL*3), and the organic phases were dried and spin-dried. The crude product was separated and purified by column chromatography (dichloromethane: methanol = 20:1) to obtain compound A1-int-2-C (1.2 g, yield 69%).

[0256] (2) Synthesis of Compound A1-int-2

[0257] A1-int-2-C (1.2 g, 3.58 mmol) was dissolved in 8 mL of methanol, and methylamine alcohol solution (30%, 8 mL) was added thereto. After reacting at room temperature overnight, TLC showed that the reaction was complete. After the solvent was dried, the crude product was separated and purified by column chromatography (dichloromethane: methanol = 20:1) to obtain compound A1-int-2 (950 mg, yield 79%).

[0258] Step 3, General Route A :

[0259]

[0260] (1) Synthesis of Compound A1-int-2-D

[0261] A1-int-2 (100 mg, 0.30 mmol) was dissolved in 4 mL of ethyl acetate, and HCl / ethyl acetate (4 mL, 2 M) was added thereto. After reacting at room temperature for 2 h, TLC showed that the reaction was complete. The reaction solution was spin-dried to obtain compound A1-int-2-D (100 mg, crude product), which was directly used in the next step.

[0262] (2) Synthesis of Compound A1-int-1-E

[0263] A1-int-1 (43 mg, 0.20 mmol) was dissolved in 2 mL HBr / acetic acid and reacted at 80°C for 1 h. TLC showed that the reaction was complete. The reaction solution was spin-dried to obtain compound A1-int-1-E (70 mg, crude product) which was directly used in the next step.

[0264] (3) Synthesis of Compound A1

[0265] A1-int-1-E (70 mg, crude product, 0.20 mmol) and A1-int-2-D (100 mg, crude product, 0.30 mmol) were dissolved in 2 mL of acetonitrile, and DIPEA (65 mg, 0.50 mmol) was added thereto. After reacting at 80°C for 5 h, TLC showed that the reaction was complete. After cooling to room temperature, water (20 mL) was added thereto. The aqueous phase was extracted with ethyl acetate (20 mL*3). After the organic phases were combined and washed with saturated brine (20 mL*3), the organic phases were dried and spin-dried. The crude product was separated and purified by column chromatography (dichloromethane: methanol = 20:1) to obtain compound A1 (46 mg, yield 53%).

[0266] 1 H NMR (400MHz, DMSO) δ11.26(s,1H),8.40–8.31(m,1H),8.20(d,J=2.7Hz,1H),8.17–8.13(m,1H),8.00(d,J=8.4Hz,1H), 7.83(d,J=8.4Hz,1H),7.38-7.28(m,2H),7.17(dd,J=8.4,1.3Hz,1H),7.02(dd,J=3.8,1.3Hz,1H),6.67(dd,J=3.7,2. 9Hz,1H),4.27–4.16(m,1H),3.66-3.57(m,2H),3.47(d,J=13.6Hz,1H),3.11–3.03(m,1H),2.97-2.87(m,1H),2.78(d, J=4.8Hz,3H),2.73-2.67(m,1H),2.29(dd,J=11.1,3.2Hz,1H),2.22-2.13(m,1H),1.12(d,J=6.6Hz,3H).ESI-MS(M+H)+ :431.3.

[0267] Example 2: Synthesis of Compound A2

[0268] Step 1, A2-int-2 is synthesized as follows:

[0269]

[0270] A2-int-2-A (500 mg, 4.09 mmol) and A1-int-2-B (818 mg, 4.09 mmol) were dissolved in 20 mL of acetonitrile, and potassium carbonate (620 mg, 4.49 mmol) was added thereto. After reacting at 80°C for 5 h, TLC showed that the reaction was complete. After cooling to room temperature, water (50 mL) was added thereto. The aqueous phase was extracted with ethyl acetate (30 mL*3). After the organic phases were combined and washed with saturated brine (20 mL*3), the organic phases were dried and spin-dried. The crude product was separated and purified by column chromatography (dichloromethane: methanol = 20:1) to obtain compound A2-int-2 (750 mg, yield 61%).

[0271] Step 2, synthesis of compound A2:

[0272]

[0273] Compound A2 was prepared by the method of Reference Example 1.

[0274] 1 H NMR (400MHz, DMSO) δ11.25(s,1H),8.48(d,J=2.2Hz,1H),8.15(dd,J=2.7,1.4Hz,1H),8.00(d,J=8.4Hz,1H),7.83(dd,J=9 .1,2.4Hz,1H),7.33(s,1H),7.17(dd,J=8.4,1.3Hz,1H),7.02(dd,J=3.8,1.3Hz,1H),6.87(d,J=9.1Hz,1H),6.67(dd,J=3 .7,2.9Hz,1H),4.65-4.52(m,1H),4.27-4.15(m,1H),3.61(d,J=13.6Hz,1H),3.46(d,J=13.6Hz,1H),3.13(td,J=12.8,3. 2Hz,1H),2.96-2.89(m,1H),2.76-2.69(m,1H),2.21-2.13(m,1H),2.12-2.02(m,1H),1.22(d,J=6.6Hz,3H).ESI-MS(M+H) + :399.3.

[0275] Example 3: Synthesis of Compound A3

[0276] Step 1, A3-int-2 synthesis: Refer to WO2021013735A1, page 20, Intermediate 22

[0277]

[0278] Step 2, synthesis of compound A3:

[0279]

[0280] Compound A3 was prepared by the method of Reference Example 1.

[0281] 1 H NMR (400MHz, DMSO) δ11.50 (s, 1H), 8.44 (q, J = 4.6Hz, 1H), 8.25–8.19 (m, 1H), 8.14(d,J=8.4Hz,1H),7.88(d,J=7.9Hz,1H),7.67(dd,J=10.5,8.2Hz,1H),7 .51–7.39(m,2H),7.07(dd,J=3.8,1.2Hz,1H),6.78–6.69(m,1H),4.43(s,2H ),3.78-3.58(m,2H),3.33-3.13(m,6H),2.77(d,J=4.8Hz,3H).ESI-MS(M+H) + :435.3.

[0282] Example 4: Synthesis of Compound A4

[0283] Step 1, A4-int-2 synthesis: Refer to Intermediate 116 on page 76 of WO2021260092A1;

[0284]

[0285] Step 2, synthesis of compound A4:

[0286]

[0287] Compound A4 was prepared by the method of Reference Example 1.

[0288] 1H NMR (400MHz, DMSO) δ11.22 (s, 1H), 8.41 (q, J = 4.5Hz, 1H), 8.16 (s, 1H), 8.01 (d ,J=8.4Hz,1H),7.79(d,J=8.3Hz,1H),7.48(d,J=8.3Hz,1H),7.30(s,1H),7.18 (d,J=8.3Hz,1H),7.06–6.98(m,1H),6.72–6.63(m,1H),3.61(s,2H),3.03-2. 89(m,4H),2.80(d,J=4.9Hz,3H),2.68-2.53(m,4H),2.49(s,3H).ESI-MS(M+H) + :431.2.

[0289] Example 5: Synthesis of Compound A5

[0290] Step 1, A5-int-2 synthesis: Refer to Intermediate 113 on page 75 of WO2021260092A1;

[0291] Step 2, synthesis of compound A5:

[0292]

[0293] Compound A5 was prepared by the method of Reference Example 1.

[0294] 1 H NMR (400MHz, DMSO) δ11.20 (s, 1H), 8.41 (q, J = 4.6Hz, 1H), 8.16 (s, 1H), 8.00 (d, J = 8. 4Hz,1H),7.93(d,J=8.2Hz,1H),7.66(d,J=8.2Hz,1H),7.29(d,J=1.3Hz,1H),7.17( dd,J=8.4,1.4Hz,1H),7.02(dd,J=3.8,1.4Hz,1H),6.67(dd,J=3.8,2.8Hz,1H),3.5 9(s,2H),3.16-3.06(m,4H),2.79(d,J=4.8Hz,3H),2.62-2.54(m,4H).ESI-MS(M+H) + :451.2.

[0295] Example 6: Synthesis of Compound A6

[0296] Step 1, A6-int-2 synthesis: Refer to Intermediate 37 on page 27 of WO2021013735A1;

[0297]

[0298] Step 2, synthesis of compound A6:

[0299]

[0300] 1 H NMR (400MHz, DMSO) δ11.22(s,1H),8.41(q,J=4.8Hz,1H),8.23–8.12(m,2H),8.03-7.98(m,2H),7.30(s,1H),7.18(d,J=6.7Hz,1H),7 .02(dd,J=3.8,1.3Hz,1H),6.71–6.64(m,1H),3.59(s,2H),3.10-2.96(m,4H),2.82(d,J=4.8Hz,3H),2.65-2.52(m,4H).ESI-MS(M+H) + :485.2.

[0301] Example 7: Synthesis of Compound A7

[0302] Step 1, A7-int-2 is synthesized as follows: Refer to Intermediate 35 on page 24 of WO2021013735A1;

[0303]

[0304] Step 2, synthesis of compound A7:

[0305]

[0306] 1 H NMR (400MHz, DMSO) δ11.23(s,1H),8.44(q,J=4.6Hz,1H),8.12(s,1H),7.96(d,J=8.4 Hz,1H),7.77(d,J=8.2Hz,1H),7.48(d,J=8.3Hz,1H),7.27(d,J=9.5Hz,1H),7.16(d,J =8.3Hz,1H),7.03(d,J=3.7Hz,1H),6.68(dd,J=10.5,7.5Hz,1H),3.72(s,2H),2.95-2 .84(m,4H),2.83–2.73(m,5H),2.63-2.54(m,4H),1.27(t,J=7.4Hz,3H).ESI-MS(M+H) + :445.4.

[0307] Example 8: Synthesis of Compound A8

[0308] Step 1, A8-int-2 is synthesized as follows:

[0309]

[0310] A8-int-2-A (200 mg, 0.50 mmol, synthesis reference WO2021013735A1, page 24 Intermediate 33), cyclopropylboronic acid (65 mg, 0.75 mmol) and cesium carbonate (325 mg, 1.0 mmol) were dissolved in dioxane / water (6 mL / 3 mL), and Pd(dppf)Cl2 (55 mg, 0.075 mmol) was added thereto. After reacting overnight at 90 ° C under nitrogen protection, TLC showed that the reaction was complete. The reaction solution was filtered, and the filtrate was diluted with water (20 mL) and extracted with ethyl acetate (20 mL*3). After the organic phases were combined and washed with saturated brine (10 mL*3), the organic phases were dried and spin-dried. The crude product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound A8-int-2 (110 mg, yield 61%).

[0311] Step 2, synthesis of compound A8:

[0312]

[0313] 1 H NMR (400MHz, DMSO) δ11.24(s,1H),8.27(q,J=4.8Hz,1H),8.16(s,1H),8.01(d,J=7.3Hz ,1H),7.72(d,J=8.3Hz,1H),7.43(d,J=8.2Hz,1H),7.31(s,1H),7.19(s,1H),7.02(d,J= 2.9Hz,1H),6.74–6.63(m,1H),3.59(s,2H),3.15-2.96(m,4H),2.78(d,J=4.8Hz,3H),2 .70-2.55(m,4H),2.38–2.28(m,1H),1.30-1.20(m,2H),1.02-0.93(m,2H).ESI-MS(M+H) + :457.3.

[0314] Example 9: Synthesis of Compound A9

[0315] Step 1, A9-int-2 was synthesized as follows : Reference A1-int-2

[0316]

[0317] Step 2, synthesis of compound A9:

[0318]

[0319] 1 H NMR(400MHz,DMSO)δ11.20(s,1H),8.30(q,J=4.6Hz,1H),8.20–8.12(m,1H),8.00(d,J =8.4Hz,1H),7.54(d,J=7.9Hz,1H),7.29(d,J=1.2Hz,1H),7.24(d,J=8.0Hz,1H),7.16 (dd,J=8.4,1.4Hz,1H),7.01(dd,J=3.8,1.3Hz,1H),6.71–6.63(m,1H),3.99(s,3H),3 .56(s,2H),3.14-3.10(m,4H),2.81(d,J=4.8Hz,3H),2.60-2.52(m,4H).ESI-MS(M+H) + :447.2.

[0320] Example 10: Synthesis of Compound A10

[0321] Step 1, A10-int-2 was synthesized as follows:

[0322]

[0323] A3-int-2 (356 mg, 1.0 mmol) was dissolved in methylamine alcohol solution (30%, 15 mL). After microwave reaction at 90°C for 8 h, TLC showed that the reaction was complete. After the solvent was dried, the crude product was separated and purified by column chromatography (dichloromethane: methanol = 20:1) to obtain compound A10-int-2 (105 mg, yield 30%).

[0324] Step 2, synthesis of compound A10:

[0325]

[0326] 1H NMR (400MHz, DMSO) δ11.23 (s, 1H), 8.27 (d, J = 5.0Hz, 1H), 8.17 (s, 1H), 8.0 2(d,J=8.4Hz,1H),7.30(s,1H),7.25–7.14(m,3H),7.02(d,J=2.8Hz,1H),6 .72–6.60(m,1H),5.89(q,J=4.7Hz,1H),3.59(s,2H),2.93(d,J=4.8Hz,3H) ,2.90-2.81(m,4H),2.80(d,J=4.9Hz,3H),2.68-2.57(m,4H).ESI-MS(M+H) + :446.2.

[0327] Example 11: Synthesis of Compound A11

[0328] Step 1, A11-int-2 is synthesized as follows:

[0329]

[0330] (1) Synthesis of Compound A11-int-2-A

[0331] A8-int-2-A (500 mg, 1.25 mmol, synthesis reference WO2021013735A1, page 24 Intermediate 33), trimethylethynylsilane (148 mg, 1.51 mmol) and cuprous iodide (48 mg, 0.25 mmol) were dissolved in triethylamine / DMF (3 mL / 3 mL), and Pd(PPh3)2Cl2 (89 mg, 0.13 mmol) was added thereto. After reacting at 50 ° C for 3 h under nitrogen protection, TLC showed that the reaction was complete. The reaction solution was filtered, and the filtrate was diluted with water (20 mL) and extracted with ethyl acetate (20 mL*3). After the organic phases were combined and washed with saturated brine (10 mL*3), the organic phases were dried and dried. The crude product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound A11-int-2-A (150 mg, yield 29%).

[0332] (2) Synthesis of Compound A11-int-2

[0333] A11-int-2-A (150 mg, 0.36 mmol) was dissolved in 6 mL of tetrahydrofuran, and tetrabutylammonium fluoride (0.7 mL, 1 M, 0.7 mmol) was added thereto. After reacting at room temperature overnight, TLC showed that the reaction was complete. The reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (20 mL*3). The organic phases were combined and dried and spin-dried. The crude product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound A11-int-2 (100 mg, yield 81%).

[0334] Step 2, synthesis of compound A11:

[0335]

[0336] 1 H NMR (400MHz, DMSO) δ11.22 (s, 1H), 8.38 (q, J = 4.5Hz, 1H), 8.16 (s, 1H), 8.00 (d, J=8.4Hz,1H),7.92(d,J=8.6Hz,1H),7.53(d,J=8.6Hz,1H),7.29(s,1H),7.17( d,J=8.4Hz,1H),7.02(d,J=3.8Hz,1H),6.70–6.62(m,1H),4.66(s,1H),3.58(s ,2H),3.30-3.20(m,4H),2.78(d,J=4.8Hz,3H),2.63-2.54(m,4H).ESI-MS(M+H) + :441.2.

[0337] Example 12: Synthesis of Compound A12

[0338] Step 1, A12-int-2 synthesis: Reference A1-int-2;

[0339]

[0340] Step 2, synthesis of compound A12:

[0341]

[0342] 1H NMR (400MHz, DMSO) δ11.20(s,1H),8.32(q,J=4.5Hz,1H),8.15(s,1H),8.00(d,J=8.4Hz,1H),7.64–7.53(m,2H),7.29(s,1H),7.16(d,J= 8.3Hz,1H),7.09–6.99(m,2H),6.71–6.63(m,1H),3.56(s,2H),3.16-3.06(m,4H),2.75(d,J=4.4Hz,3H),2.60-2.52(m,4H).ESI-MS(M+H) + :434.3.

[0343] Example 13: Synthesis of Compound A13

[0344] Step 1, A13-int-2 synthesis: Reference A1-int-2;

[0345]

[0346] Step 2, synthesis of compound A13:

[0347]

[0348] 1 H NMR (400MHz, DMSO) δ11.21(s,1H),8.15(d,J=5.3Hz,1H),8.10(s,1H),8.00(d,J=8.4Hz,1H),7.40-7.32(m,1H),7.29(s,1H),7.16(d,J=8.3Hz,1H), 7.02(d,J=3.7Hz,1H),6.90-6.85(m,1H),6.71–6.64(m,1H),3.56(s,2H), 3.20-3.09(m,4H),2.75(d,J=4.5Hz,3H),2.61-2.55(m,4H).ESI-MS(M+H) + :452.3.

[0349] Example 14: Synthesis of Compound A14

[0350] Step 1, A14-int-2 synthesis: Reference A1-int-2;

[0351]

[0352] Step 2, synthesis of compound A14:

[0353]

[0354] 1 H NMR (400MHz, DMSO) δ11.18(s,1H),8.37(q,J=4.6Hz,1H),8.25(d,J=2.7Hz,1H),8.14(s,1H),7.98(d,J=8.4Hz ,1H),7.81(d,J=8.8Hz,1H),7.38(dd,J=8.9,2.8Hz,1H),7.31(s,1H),7.17(d,J=8.4Hz,1H),7.02(dd,J=3.8, 1.2Hz,1H),6.71–6.63(m,1H),4.08-3.99(m,1H),3.74-3.65(m,1H),3.64-3.56(m,1H),3.27-3.20(m,1H),3. 00-2.90(m,1H),2.83–2.69(m,5H),2.62-2.53(m,1H),2.29-2.20(m,1H),1.18(d,J=6.1Hz,3H).ESI-MS(M+H) + :431.2.

[0355] Example 15: Synthesis of Compound A15

[0356] Step 1, A15-int-2 synthesis: Reference A1-int-2;

[0357]

[0358] Step 2, synthesis of compound A15:

[0359]

[0360] 1 H NMR (400MHz, DMSO) δ11.18(s,1H),8.41(q,J=4.5Hz,1H),8.15(s,1H),8.00(d,J=8.4Hz,1H),7.79(d, J=8.2Hz,1H),7.47(d,J=8.3Hz,1H),7.32(s,1H),7.18(d,J=8.3Hz,1H),7.02(d,J=3.7Hz,1H),6.71– 6.64(m,1H),4.03(d,J=13.7Hz,1H),3.29–3.27(m,1H),3.07(d,J=9.9Hz,1H),3.04-2.95(m,1H),2.8 5-2.72(m,5H),2.70–2.59(m,2H),2.49(s,3H),2.39–2.31(m,1H),1.19(d,J=6.0Hz,3H).ESI-MS(M+H)+ :445.5.

[0361] Example 16: Synthesis of Compound A16

[0362] Step 1, A16-int-2 synthesis: Reference A1-int-2;

[0363]

[0364] Step 2, synthesis of compound A16:

[0365]

[0366] 1 H NMR (400MHz, DMSO) δ11.16(s,1H),8.43(q,J=4.9Hz,1H),8.14(s,1H),7.97(d,J=8.4Hz, 1H),7.83(d,J=8.3Hz,1H),7.56(d,J=8.3Hz,1H),7.26(s,1H),7.15(d,J=8.3Hz,1H),7. 01(d,J=3.8Hz,1H),6.71–6.63(m,1H),3.90(s,2H),3.04-2.95(m,2H),2.93-2.82(m,4H ),2.80(d,J=4.8Hz,3H),2.50(s,3H),0.76-0.70(m,2H),0.66-0.59(m,2H).ESI-MS(M+H) + :457.2.

[0367] Example 17: Synthesis of Compound A17

[0368] Step 1, A17-int-2 synthesis:

[0369]

[0370] (1) Synthesis of Compound A17-int-2-B

[0371] A15-int-2-A (200 mg, 0.87 mmol), A17-int-2-A (325 mg, 1.0 mmol) and potassium carbonate (138 mg, 0.1 mmol) were dissolved in dioxane / water (16 mL / 4 mL), and tetrakistriphenylphosphine palladium (100 mg, 0.086 mmol) was added thereto. Nitrogen was replaced three times, and after reacting at 80°C for 3 hours, TLC showed that the reaction was complete. The reaction solution was filtered, and the filtrate was diluted with ethyl acetate (60 mL). The organic phase was washed with saturated brine (20 mL*3) and the solution was dried by spin drying to obtain compound A17-int-2-B (500 mg, crude product) which was directly used in the next step reaction.

[0372] (2) Synthesis of Compound A17-int-2-C

[0373] A17-int-2-B (500 mg, crude product, 0.87 mmol), methylamine hydrochloride (75 mg, 1.1 mmol) and triethylamine (370 mg, 3.6 mmol) were dissolved in 18 mL of dichloromethane, and HATU (510 mg, 1.4 mmol) was added thereto. After reacting at room temperature for 2 h, TLC showed that the reaction was complete. After the reaction solution was diluted with dichloromethane (60 mL), the organic phase was washed with saturated brine (20 mL*3) and the solution was dried by rotary evaporation. The crude product was separated and purified by column chromatography (dichloromethane: methanol = 20:1) to obtain compound A17-int-2-C (250 mg, yield 82%).

[0374] (3) Synthesis of Compound A17-int-2

[0375] A17-int-2-C (180 mg, 0.5 mmol) was dissolved in 10 mL of methanol, and Pd / C (30 mg, 5%) was added thereto. After the reaction was allowed to react overnight at room temperature under a hydrogen atmosphere, TLC showed that the reaction was complete. The reaction solution was filtered, the filter cake was rinsed with methanol, and the filtrate was dried to obtain compound A17-int-2 (180 mg, yield 100%).

[0376] Step 2, synthesis of compound A17:

[0377]

[0378] 1H NMR (400MHz, DMSO) δ11.28(s,1H),8.54(q,J=4.7Hz,1H),8.17(d,J=1.1Hz,1H),8.04( d,J=8.3Hz,1H),7.82(d,J=8.0Hz,1H),7.76(d,J=7.9Hz,1H),7.32(s,1H),7.21(d,J=8 .2Hz,1H),7.03(dd,J=3.8,1.2Hz,1H),6.73–6.65(m,1H),3.78(s,2H),3.17-2.99(m,2 H),2.91-2.76(m,4H),2.58(s,3H),2.44-2.31(m,2H),1.84–1.64(m,4H).ESI-MS(M+H) + :430.3.

[0379] Example 18: Synthesis of Compound A18

[0380] Step 1, A18-int-2 synthesis:

[0381]

[0382] Step 2, synthesis of compound A18:

[0383]

[0384] 1 H NMR (400MHz, DMSO) δ11.21(s,1H),8.56(q,J=4.6Hz,1H),8.14(d,J=8.1Hz,1H),8.00(d,J=8.4H z,1H),7.79(d,J=8.4Hz,1H),7.64(d,J=7.6Hz,1H),7.33(d,J=1.1Hz,1H),7.18(dd,J=8.4,1.3 Hz,1H),7.02(dd,J=3.8,1.3Hz,1H),6.70–6.63(m,1H),5.70(s,1H),3.64(s,2H),3.14-3.05(m ,2H),2.82(d,J=4.9Hz,3H),2.67(t,J=5.4Hz,2H),2.52(s,3H),2.40-2.30(m,2H).ESI-MS(M+H) + :428.3.

[0385] Example 19: Synthesis of Compound A19

[0386] Step 1, A19-int-2 synthesis: Reference A1-int-2;

[0387]

[0388] Step 2, synthesis of compound A19:

[0389]

[0390] 1 H NMR (400MHz, DMSO) δ11.21(s,1H),8.41(q,J=4.6Hz,1H),8.21–8.10(m,1H),7.99(d,J=8.4 Hz,1H),7.78(d,J=8.3Hz,1H),7.49(d,J=8.3Hz,1H),7.42(s,1H),7.22(d,J=8.3Hz,1H),7. 01(dd,J=3.8,1.1Hz,1H),6.70–6.61(m,1H),3.59(s,2H),3.28-3.16(m,2H),2.99-2.88(m, 4H),2.80(d,J=4.9Hz,3H),2.53(s,3H),2.07–1.95(m,2H),1.97-1.87(m,2H).ESI-MS(M+H) + :457.4.

[0391] Example 20: Synthesis of Compound A20

[0392] Step 1, A20-int-2 synthesis: Reference A1-int-2;

[0393]

[0394] Step 2, synthesis of compound A20:

[0395]

[0396] 1 H NMR (400MHz, DMSO) δ11.16(s,1H),8.38(q,J=4.9Hz,1H),8.14(s,1H),7.96(d,J =8.4Hz,1H),7.79(d,J=8.4Hz,1H),7.61(d,J=8.5Hz,1H),7.34(s,1H),7.19(d,J =8.4Hz,1H),7.00(d,J=3.8Hz,1H),6.70–6.60(m,1H),3.75–3.60(m,6H),3.28- 3.16(m,2H),2.81(d,J=4.8Hz,3H),2.64(s,3H),2.54-2.45(m,2H).ESI-MS(M+H) +:443.3.

[0397] Example 21: Synthesis of Compound A21

[0398] Step 1, A21-int-2 synthesis: Reference A1-int-2;

[0399]

[0400] Step 2, synthesis of compound A21:

[0401]

[0402] 1 H NMR (400MHz, DMSO) δ11.14(s,1H),8.30(q,J=4.7Hz,1H),8.10(s,1H),7.85(d,J=8 .4Hz,1H),7.68(d,J=8.3Hz,1H),7.15(s,1H),7.00-6.97(m,2H),6.84(d,J=8.4Hz, 1H),6.70–6.63(m,1H),4.45(d,J=5.5Hz,2H),3.49(s,2H),2.93(d,J=11.0Hz,2H), 2.84-2.77(m,5H),2.63-2.55(m,1H),2.34(s,3H),2.04-1.98(m,1H).ESI-MS(M+H) + :443.2.

[0403] Example 22: Synthesis of Compound A22

[0404] Step 1, A22-int-2 synthesis:

[0405]

[0406] (1) Synthesis of Compound A22-int-2-B

[0407] A22-int-2-A (2.0 g, 10.2 mmol), 1-tert-butyloxycarbonylpiperazine (2.1 g, 11.2 mmol) and cesium carbonate (8.31 g, 25.5 mmol) were dissolved in 30 mL of dioxane, and Pd2(dba)3 (1.87 g, 2.04 mmol) and Xphos (1.95 g, 4.08 mmol) were added thereto. After reacting overnight at 90 ° C under nitrogen protection, TLC showed that the reaction was complete. The reaction solution was filtered, and the filtrate was diluted with water (30 mL) and extracted with ethyl acetate (20 mL*3). The organic phases were combined and washed with saturated brine (10 mL*3), and the organic phases were dried and spin-dried. The crude product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain compound A22-int-2-B (2.2 g, yield 71%).

[0408] (2) Synthesis of Compound A22-int-2

[0409] A22-int-2-B (1.0 g, 3.3 mmol) was dissolved in 10 mL of anhydrous methanol, and sodium methoxide methanol solution (6.2 mL, 30%) was added thereto. After reacting at room temperature for 1 h, formic hydrazide (594 mg, 9.9 mmol) was added thereto. After the reaction solution was heated to 70 ° C and reacted for 3 days, TLC showed that the reaction was complete. The reaction solution was spin-dried, and the crude product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain compound A22-int-2 (160 mg, yield 14%).

[0410] Step 2, synthesis of compound A22:

[0411]

[0412] 1 H NMR(400MHz,DMSO)δ8.36(br s,1H),8.21–8.08(m,2H),8.00(d,J=8.4Hz,1H),7.85(d,J=8.3Hz,1H),7.51(d,J=8.4Hz,1H),7.31(s,1H),7.18(d,J=8.3Hz,1H ),7.02(dd,J=3.8,1.3Hz,1H),6.72–6.61(m,1H),3.59(s,2H),3.02-2.86(m,4H),2.67-2.54(m,4H),2.52(s,3H).ESI-MS(M+H) + :441.1.

[0413] Example 23: Synthesis of Compound A23

[0414] Step 1, A23-int-2 synthesis:

[0415]

[0416] (1) Synthesis of Compound A23-int-2-B

[0417] A23-int-2-B (520 mg, 1.55 mmol, refer to Intermediate 15 on page 20 of WO2021260092A1) was dissolved in tetrahydrofuran / water (5 mL / 5 mL), and lithium hydroxide (195 mg, 4.65 mmol) was added thereto. After reacting at room temperature for 1 h, TLC showed that the reaction was complete. Water (20 mL) was added to the reaction solution to quench the reaction. The aqueous phase was adjusted to pH 3-4 with 1M dilute hydrochloric acid. The precipitated solid was filtered. The filter cake was rinsed with water and dried to obtain compound A23-int-2-B (480 mg, yield 96%).

[0418] (2) Synthesis of Compound A23-int-2

[0419] A23-int-2-B (90 mg, 0.28 mmol), dimethylamine hydrochloride (27 mg, 0.34 mmol) and N,N-diisopropylethylamine (180 mg, 1.40 mmol) were dissolved in 8 mL of dichloromethane, and HATU (58 mg, 0.42 mmol) was added thereto. After reacting at room temperature for 1 h, TLC showed that the reaction was complete. After the reaction solution was diluted with dichloromethane (60 mL), the organic phase was washed with saturated brine (20 mL*3) and the solution was dried by spin drying. The crude product was separated and purified by column chromatography (dichloromethane: methanol = 20:1) to obtain compound A23-int-2 (87 mg, yield 89%).

[0420] Step 2, synthesis of compound A23:

[0421]

[0422] 1 H NMR (400MHz, DMSO) δ11.21 (s, 1H), 8.17-8.16 (m, 1H), 8.01 (d, J = 8.4Hz, 1H), 7 .46(d,J=8.3Hz,1H),7.36(d,J=8.2Hz,1H),7.31(d,J=1.3Hz,1H),7.18(dd,J =8.4,1.4Hz,1H),7.02(dd,J=3.8,1.3Hz,1H),6.70–6.64(m,1H),3.59(s,2H) ,2.98(s,6H),2.96-2.93(m,4H),2.65-2.54(m,4H),2.45(s,3H).ESI-MS(M+H) + :445.4.

[0423] Example 24: Synthesis of Compound A24

[0424] Step 1, A24-int-2 synthesis: Reference A23-int-2;

[0425]

[0426] Step 2, synthesis of compound A24:

[0427]

[0428] 1 H NMR (400MHz, DMSO) δ11.21(s,1H),8.16(s,1H),8.00(d,J=8.4Hz,1H),7.53(d,J=8.3 Hz,1H),7.44(d,J=8.3Hz,1H),7.30(s,1H),7.17(d,J=8.4Hz,1H),7.01(dd,J=3.8,1. 3Hz,1H),6.72–6.62(m,1H),3.65(t,J=6.6Hz,2H),3.58(s,2H),3.46(t,J=6.6Hz,2H ),2.97-2.88(m,4H),2.63-2.53(m,4H),2.44(s,3H),1.87-1.76(m,4H).ESI-MS(M+H) + :471.5.

[0429] Example 25: Synthesis of Compound A25

[0430] Step 1, A25-int-2 synthesis: Reference A23-int-2;

[0431]

[0432] Step 2, synthesis of compound A25:

[0433]

[0434] 1H NMR (400MHz, DMSO) δ11.21(s,1H),8.31(d,J=4.7Hz,1H),8.20–8.14(m,1H),8.00(d,J =8.4Hz,1H),7.79(d,J=8.3Hz,1H),7.48(d,J=8.3Hz,1H),7.30(s,1H),7.17(d,J=8.4 Hz,1H),7.01(dd,J=3.8,1.3Hz,1H),6.71–6.64(m,1H),3.59(s,2H),3.01-2.91(m,4H ),2.89–2.79(m,1H),2.63-2.53(m,4H),2.48(s,3H),0.73–0.59(m,4H).ESI-MS(M+H) + :457.3.

[0435] Example 26: Synthesis of Compound A26

[0436] Step 1, A26-int-1 synthesis:

[0437]

[0438] Step 2, synthesis of compound A26:

[0439] A26 was prepared using A26-int-1 and A14-int-2.

[0440]

[0441] 1 H NMR (400MHz, DMSO) δ11.30(s,1H),8.37(d,J=4.8Hz,1H),8.26(d,J=2.7Hz,1H),8.16(s,1H),8.11(dd,J =2.6,1.5Hz,1H),7.82(d,J=8.8Hz,1H),7.66(d,J=1.5Hz,1H),7.39(dd,J=8.8,2.8Hz,1H),7.09(dd,J=3 .7,1.4Hz,1H),6.75–6.69(m,1H),4.08(d,J=13.9Hz,2H),3.76-3.67(m,1H),3.63–3.56(m,1H),3.01-2 .92(m,1H),2.84–2.72(m,5H),2.68-2.56(m,1H),2.34-2.23(m,1H),1.20(d,J=6.1Hz,3H).ESI-MS(M+H) + :432.3.

[0442] Example 27: Synthesis of Compound A27

[0443] Synthesis of Compound A27 : A27 was prepared using A26-int-1 and A1-int-2;

[0444]

[0445] 1 H NMR (400MHz, DMSO) δ11.38(s,1H),8.35(q,J=4.6Hz,1H),8.20(d,J=2.7Hz,1H),8.16(d,J=1.6Hz,1H),8.11(dd ,J=2.7,1.6Hz,1H),7.82(d,J=8.8Hz,1H),7.69(d,J=1.6Hz,1H),7.33(dd,J=8.9,2.8Hz,1H),7.09(dd,J=3.8, 1.5Hz,1H),6.76–6.69(m,1H),4.26–4.16(m,1H),3.70-3.51(m,3H),3.13-3.03(m,1H),2.98-2.89(m,1H),2.7 8(d,J=4.8Hz,3H),2.76-2.70(m,1H),2.38-2.29(m,1H),2.27-2.16(m,1H),1.12(d,J=6.5Hz,3H).ESI-MS(M+H) + :432.3.

[0446] Example 28: Synthesis of Compound A28

[0447] Step 1, A28-int-1 was synthesized as follows:

[0448]

[0449] (1) Synthesis of Compound A28-int-1-C

[0450] A28-int-1-A (3.38 g, 20.0 mmol) and A28-int-1-B (2.24 g, 20.0 mmol) were dissolved in 50 mL of dichloromethane, and triethylamine (5.05 g, 50.0 mmol) and HATU (9.12 g, 24.0 mmol) were added thereto. After reacting at room temperature overnight, TLC showed that the reaction was complete. Water (30 mL) was added thereto to quench the reaction. The aqueous phase was extracted with dichloromethane (30 mL*3). After the organic phases were combined and washed with saturated brine (20 mL*3), the organic phases were dried and spin-dried. The crude product was separated and purified by column chromatography (dichloromethane: methanol = 25:1) to obtain compound A28-int-1-C (1.72 g, yield 33%).

[0451] (2) Synthesis of Compound A28-int-1-D

[0452] A28-int-1-C (1.7 g, 6.46 mmol) and cesium carbonate (4.2 g, 12.9 mmol) were dissolved in 20 mL DMF. After reacting at 120 °C for 8 h, TLC showed that the reaction was complete. Water (50 mL) was added to quench the reaction. The aqueous phase was extracted with ethyl acetate (30 mL*3). The organic phases were combined and washed with saturated brine (20 mL*3), and then the organic phases were dried and spin-dried. The obtained compound A28-int-1-D (2.42 g, crude product) was directly used for the next step reaction.

[0453] (3) Synthesis of Compound A28-int-1

[0454] A28-int-1-D (2.42 g, 6.46 mmol) was dissolved in 15 mL of anhydrous tetrahydrofuran, and lithium aluminum hydride (7.2 mL, 1 M, 7.2 mmol) was added thereto under ice bath. After reacting at room temperature for 2 h, TLC showed that the reaction was complete. After the reaction solution was quenched with water (25 mL), the aqueous phase was extracted with ethyl acetate (30 mL*3), combined, dried and spin-dried. The crude product was separated and purified by column chromatography (dichloromethane: methanol = 30:1) to obtain compound A28-int-1 (550 mg, yield 39%).

[0455] Step 2, synthesis of compound A28:

[0456] A28 was prepared using A28-int-1 and A1-int-2.

[0457]

[0458] 1 H NMR (400MHz, DMSO) δ11.90 (s, 1H), 8.35 (q, J = 4.6Hz, 1H), 8.20 (d, J = 2.8Hz, 1H), 8.11 (d, J = 8. 3Hz,1H),8.06(d,J=2.1Hz,1H),7.82(d,J=8.8Hz,1H),7.45(s,1H),7.34-7.29(m,2H),7.14( d,J=2.1Hz,1H),4.29–4.17(m,1H),3.69-3.49(m,3H),3.14-3.02(m,1H),2.98-2.89(m,1H), 2.82-2.69(m,4H),2.36-2.28(m,1H),2.26-2.15(m,1H),1.15(d,J=6.4Hz,3H).ESI-MS(M+H) +:432.3.

[0459] Example 29: Synthesis of Compound A29

[0460] Synthesis of Compound A29 : A28-int-1 and A14-int-2 were used to prepare A29;

[0461]

[0462] 1 H NMR (400MHz, DMSO) δ11.82(s,1H),8.36(q,J=4.6Hz,1H),8.26(d,J=2.8Hz,1H),8.10(d,J=8.3Hz,1H),8 .06(d,J=2.1Hz,1H),7.82(d,J=8.8Hz,1H),7.43–7.36(m,2H),7.30(dd,J=8.4,1.4Hz,1H),7.14(d,J=2 .1Hz,1H),4.09(d,J=13.8Hz,1H),3.75-3.66(m,1H),3.64-3.55(m,1H),3.27(d,J=13.8Hz,1H),3.01-2 .92(m,1H),2.83–2.72(m,5H),2.65–2.55(m,1H),2.31–2.22(m,1H),1.19(d,J=6.1Hz,3H).ESI-MS(M+H) + :432.3.

[0463] Example 30: Synthesis of Compound A30

[0464] Synthesis of compound A30 : A28-int-1 and A15-int-2 were used to prepare A30;

[0465]

[0466] 1H NMR (400MHz, DMSO) δ11.83(s,1H),8.43(q,J=4.7Hz,1H),8.11(d,J=8.3Hz,1H),8.06(d,J=2.1Hz,1H ),7.79(d,J=8.3Hz,1H),7.47(d,J=8.3Hz,1H),7.43(s,1H),7.32(dd,J=8.4,1.4Hz,1H),7.14(d,J=2 .1Hz,1H),4.07(d,J=13.7Hz,1H),3.37(d,J=11.2Hz,1H),3.11-3.04(m,1H),3.03-2.96(m,1H),2.84 –2.74(m,5H),2.73–2.61(m,2H),2.50(s,3H),2.42-2.31(m,1H),1.20(d,J=5.9Hz,3H).ESI-MS(M+H) + :446.3.

[0467] Example 31: Synthesis of Compound A31

[0468] Step 1, A31-int-1 was synthesized as follows :

[0469]

[0470] (1) Synthesis of Compound A31-int-1-B

[0471] A31-int-1-A (2.0 g, 9.05 mmol) and A1-int-1-B (1.13 g, 9.05 mmol) were dissolved in 20 mL of acetonitrile, and potassium carbonate (3.75 g, 27.1 mmol) was added thereto. After reacting at 70°C for 2 h, TLC showed that the reaction was complete. After cooling to room temperature, the reaction solution was filtered, and the filter cake was rinsed with ethyl acetate. The filtrates were combined and dried by spin drying. The crude product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain compound A31-int-1-B (900 mg, yield 32%).

[0472] (2) Synthesis of Compound A31-int-1-C

[0473] A31-int-1-B (900 mg, 2.90 mmol) was dissolved in 15 mL of methanol, and Pd / C (300 mg, 5%) was added thereto. After reacting at room temperature for 2 h under a hydrogen atmosphere, TLC showed that the reaction was complete. The reaction solution was filtered, the filter cake was rinsed with methanol, and the filtrate was dried to obtain compound A31-int-1-C (480 mg, yield 59%).

[0474] (3) Synthesis of Compound A31-int-1-D

[0475] A31-int-1-C (480 mg, 1.71 mmol) was dissolved in glacial acetic acid / water (5 mL / 0.5 mL). After reacting at 70°C for 4 h, TLC showed that the reaction was complete. After cooling to room temperature, the reaction solution was filtered, and the filter cake was rinsed with water and dried to obtain compound A31-int-1-D (300 mg, yield 70%).

[0476] (4) Synthesis of Compound A31-int-1

[0477] A31-int-1-D (300 mg, 1.21 mmol) was dissolved in 10 mL of anhydrous tetrahydrofuran, and lithium aluminum hydride (58 mg, 2.42 mmol) was added thereto under ice bath. After reacting at room temperature for 2 h, TLC showed that the reaction was complete. After the reaction solution was quenched with water (25 mL), the aqueous phase was extracted with ethyl acetate (30 mL*3), combined, dried and spin-dried. The crude product was separated and purified by column chromatography (dichloromethane: methanol = 30:1) to obtain compound A31-int-1 (200 mg, yield 74%).

[0478] Step 2, General Route B :

[0479]

[0480] (1) Synthesis of Compound A31-int-1-E

[0481] A31-int-1 (220 mg, 1.0 mmol) was dissolved in 2 mL of dichloromethane, and 2 mL of thionyl chloride was added thereto. After reacting at room temperature for 2 h, TLC showed that the reaction was complete. The reaction solution was spin-dried to dryness. The obtained compound A31-int-1-E (320 mg, crude product) was directly used for the next step reaction.

[0482] (2) Synthesis of Compound A31

[0483] A31-int-1-E (80 mg, crude product, 0.25 mmol) and A31-int-2 (50 mg, 0.25 mmol) were dissolved in 5 mL of acetonitrile, and DIPEA (60 mg, 0.46 mmol) was added thereto. After reacting at 80°C for 2 h, TLC showed that the reaction was complete. After cooling to room temperature, water (20 mL) was added thereto. The aqueous phase was extracted with ethyl acetate (20 mL*3). The organic phases were combined and washed with saturated brine (20 mL*3), and then the organic phases were dried and spin-dried. The crude product was separated and purified by column chromatography (dichloromethane: methanol = 20:1) to obtain compound A31 (5 mg, yield 6%).

[0484] 1H NMR (400MHz, DMSO) δ11.36(s,1H),7.61(dd,J=2.5,1.4Hz,1H),7.22(d,J=9.0Hz,2H),7.00(dd,J=4.0,1.3Hz,1H),6.94(d ,J=9.1Hz,2H),6.83(s,1H),6.62(dd,J=3.9,2.7Hz,1H),3.77(s,2H),3.19–3.09(m,4H),2.67–2.56(m,4H).ESI-MS(M+H) + :399.2.

[0485] Example 32: Synthesis of Compound A32

[0486] Synthesis of compound A32 : A32 was prepared using A31-int-1 and A13-int-2;

[0487]

[0488] 1 H NMR (400MHz, DMSO) δ11.37(s,1H),8.10(s,1H),7.65–7.57(m,1H),7.40-7.32(m,1H),7.03–6.98(m,1H),6.93-6.85(m,1H ),6.83(s,1H),6.65–6.57(m,1H),3.79(s,2H),3.20-3.11(m,4H),2.75(d,J=4.5Hz,3H),2.70-2.59(m,4H).ESI-MS(M+H) + :458.2.

[0489] Example 33: Synthesis of Compound A33

[0490] Step 1, A33-int-2 synthesis: Reference A2-int-2;

[0491]

[0492] Step 2, synthesis of compound A33:

[0493]

[0494] 1H NMR (400MHz, DMSO) δ11.34(s,1H),8.42(d,J=2.9Hz,1H),7.74(d,J=8.9Hz,1H),7.61(dd,J=2.6,1.4Hz,1H),7.36(dd,J=8.9,3.0Hz,1H) ,7.00(dd,J=4.0,1.4Hz,1H),6.83(s,1H),6.62(dd,J=3.9,2.6Hz,1H),3.78(s,2H),3.48–3.39(m,4H),2.66–2.54(m,4H).ESI-MS(M+H) + :391.3.

[0495] Example 34: Synthesis of Compound A34

[0496] Step 1, A34-int-2 synthesis: Reference A1-int-2;

[0497]

[0498] Step 2, synthesis of compound A34:

[0499]

[0500] 1 H NMR (400MHz, DMSO) δ11.36 (s, 1H), 8.38 (q, J = 4.6Hz, 1H), 8.27 (d, J = 2.8Hz, 1H) ,7.83(d,J=8.8Hz,1H),7.61(dd,J=2.5,1.4Hz,1H),7.39(dd,J=8.8,2.9Hz,1H) ,7.00(dd,J=4.0,1.4Hz,1H),6.83(s,1H),6.62(dd,J=3.9,2.7Hz,1H),3.78(s ,2H),3.37-3.33(m,4H),2.78(d,J=4.8Hz,3H),2.67–2.59(m,4H).ESI-MS(M+H) + :423.2.

[0501] Example 35: Synthesis of Compound A35

[0502] Synthesis of compound A35 : A35 was prepared using A31-int-1 and A4-int-2;

[0503]

[0504] 1H NMR (400MHz, DMSO) δ11.37(s,1H),8.41(q,J=4.8Hz,1H),7.79(d,J=8.3Hz,1H),7.62(dd,J=2.5,1.4Hz,1H),7.49(d,J=8.3Hz,1H),7.00(dd,J=4.0,1. 3Hz,1H),6.84(s,1H),6.62(dd,J=3.9,2.7Hz,1H),3.81(s,2H),3.00-2.90 (m,4H),2.80(d,J=4.9Hz,3H),2.72-2.62(m,4H),2.49(s,3H).ESI-MS(M+H) + :437.3.

[0505] Example 36: Synthesis of Compound A36

[0506] Synthesis of Compound A36 : A31-int-1 and A3-int-2 were used to prepare A36;

[0507]

[0508] 1 H NMR (400MHz, DMSO) δ8.39(q,J=4.5Hz,1H),7.84(d,J=7.9Hz,1H),7.63–7.54(m,2H),7.00(dd,J=4.0,1.3Hz,1H),6.83(s ,1H),6.62(dd,J=3.9,2.7Hz,1H),3.79(s,2H),3.22-3.12(m,4H),2.76(d,J=4.8Hz,3H),2.70-2.59(m,4H).ESI-MS(M+H) + :441.2.

[0509] Example 37: Synthesis of Compound A37

[0510] Synthesis of compound A37 : A37 was prepared using A31-int-1 and A5-int-2;

[0511]

[0512] 1H NMR (400MHz, DMSO) δ11.38(s,1H),8.42(q,J=4.4Hz,1H),7.94(d,J=8.2Hz,1H),7.68(d,J=8.2Hz,1H),7.61(dd,J=2.4,1.4Hz,1H),7.00(dd,J=3 .9,1.3Hz,1H),6.84(s,1H),6.62(dd,J=3.9,2.7Hz,1H),3.81(s,2H),3.19-3.07(m,4H),2.79(d,J=4.8Hz,3H),2.73-2.61(m,4H).ESI-MS(M+H) + :457.2.

[0513] Example 38: Synthesis of Compound A38

[0514] Synthesis of Compound A38 : A38 was prepared using A31-int-1 and A6-int-2;

[0515]

[0516] 1 H NMR (400MHz, DMSO) δ11.37(s,1H),8.41(q,J=4.8Hz,1H),8.19(d,J=8.5Hz,1H),8.05(d,J=8.6Hz,1H),7.61(dd,J=2.5,1.4Hz,1H),7.00(dd,J=4 .0,1.3Hz,1H),6.84(s,1H),6.62(dd,J=3.9,2.7Hz,1H),3.80(s,2H),3.09-2.99(m,4H),2.82(d,J=4.8Hz,3H),2.70-2.58(m,4H).ESI-MS(M+H) + :491.2.

[0517] Example 39: Synthesis of Compound A39

[0518] Synthesis of Compound A39 : A39 was prepared using A31-int-1 and A7-int-2;

[0519]

[0520] 1H NMR (400MHz, DMSO) δ11.37(s,1H),8.40(q,J=4.7Hz,1H),7.79(d,J=8.2Hz,1H),7.62(d,J=1.3Hz,1H),7.52(d,J=8.3Hz,1H),7.04–6.96(m,1 H),6.83(s,1H),6.63-6.60(m,1H),3.81(s,2H),3.00-2.88(m,4H),2.85-2.75(m,5H),2.73-2.59(m,4H),1.30(t,J=7.2Hz,3H).ESI-MS(M+H) + :451.3.

[0521] Example 40: Synthesis of Compound A40

[0522] Synthesis of Compound A40 : A40 was prepared using A31-int-1 and A8-int-2;

[0523]

[0524] 1 H NMR (400MHz, DMSO) δ11.39(s,1H),8.27(q,J=4.6Hz,1H),7.70(d,J=8.2Hz,1H),7.61( dd,J=2.4,1.4Hz,1H),7.44(d,J=8.3Hz,1H),7.01(dd,J=4.0,1.3Hz,1H),6.84(s,1H), 6.62(dd,J=3.9,2.7Hz,1H),3.81(s,2H),3.12-2.96(m,4H),2.78(d,J=4.8Hz,3H),2. 74-2.64(m,4H),2.39–2.28(m,1H),1.18-1.00(m,2H),1.02–0.93(m,2H).ESI-MS(M+H) + :463.2.

[0525] Example 41: Synthesis of Compound A41

[0526] Synthesis of Compound A41 : A41 was prepared using A31-int-1 and A9-int-2;

[0527]

[0528] 1H NMR (400MHz, DMSO) δ11.36(s,1H),8.30(q,J=4.5Hz,1H),7.61(s,1H),7.55(d,J=7.9Hz,1H),7.26(d,J=7.9Hz,1H),7.00(d,J=3.9Hz,1 H),6.82(s,1H),6.66–6.56(m,1H),3.99(s,3H),3.78(s,2H),3.17-3.05(m,4H),2.81(d,J=4.8Hz,3H),2.67-2.57(m,4H).ESI-MS(M+H) + :453.2.

[0529] Example 42: Synthesis of Compound A42

[0530] Synthesis of Compound A42 : A42 was prepared using A31-int-1 and A10-int-2;

[0531]

[0532] 1 H NMR (400MHz, DMSO) δ11.38 (s, 1H), 8.26 (q, J = 4.7Hz, 1H), 7.62 (dd, J = 2.4, 1. 4Hz,1H),7.23-7.18(m,2H),7.00(dd,J=3.9,1.2Hz,1H),6.83(s,1H),6.62(d d,J=3.8,2.7Hz,1H),5.90(q,J=4.9Hz,1H),3.80(s,2H),2.92(d,J=4.8Hz,3 H),2.90-2.82(m,4H),2.80(d,J=4.9Hz,3H),2.75-2.61(m,4H).ESI-MS(M+H) + :452.2.

[0533] Example 43: Synthesis of Compound A43

[0534] Synthesis of Compound A43 : A43 was prepared using A31-int-1 and A11-int-2;

[0535]

[0536] 1H NMR (400MHz, DMSO) δ11.38(s,1H),8.38(q,J=4.5Hz,1H),7.92(d,J=8.6Hz,1H),7.61(s,1H),7.53(d,J=8.6Hz,1H),7.04–6.96(m,1H) ,6.83(s,1H),6.65–6.58(m,1H),4.65(s,1H),3.80(s,2H),3.33-3.21(m,4H),2.79(d,J=4.8Hz,3H),2.71-2.61(m,4H).ESI-MS(M+H) + :447.2.

[0537] Example 44: Synthesis of Compound A44

[0538] Synthesis of Compound A44 : A44 was prepared using A31-int-1 and A14-int-2;

[0539]

[0540] 1 H NMR (400MHz, DMSO) δ11.36(s,1H),8.37(q,J=4.6Hz,1H),8.26(d,J=2.7Hz,1H),7.82(d,J=8.8Hz,1H ),7.61(dd,J=2.4,1.4Hz,1H),7.39(dd,J=8.9,2.8Hz,1H),6.99(dd,J=3.9,1.2Hz,1H),6.82(s,1H), 6.61(dd,J=3.8,2.7Hz,1H),4.11(d,J=14.9Hz,1H),3.71–3.58(m,3H),3.06-2.96(m,1H),2.95–2.87 (m,1H),2.81–2.73(m,4H),2.72-2.63(m,1H),2.45-2.35(m,1H),1.17(d,J=6.1Hz,3H).ESI-MS(M+H) + :437.2.

[0541] Example 45: Synthesis of Compound A45

[0542] Synthesis of Compound A45 : A45 was prepared using A31-int-1 and A15-int-2;

[0543]

[0544] 1H NMR (400MHz, DMSO) δ8.41(q,J=4.7Hz,1H),7.79(d,J=8.2Hz,1H),7.62(dd,J=2.5,1.4Hz,1H),7.4 8(d,J=8.3Hz,1H),7.00(dd,J=4.0,1.3Hz,1H),6.83(s,1H),6.61(dd,J=3.9,2.7Hz,1H),4.10(d,J =14.9Hz,1H),3.70(d,J=14.9Hz,1H),3.04(t,J=11.3Hz,2H),2.91(dd,J=7.9,3.5Hz,1H),2.87–2 .71(m,5H),2.69-2.59(m,1H),2.55-2.51(m,1H),2.49(s,3H),1.18(d,J=6.2Hz,3H).ESI-MS(M+H) + :451.2.

[0545] Example 46: Synthesis of Compound A46

[0546] Step 1, A46-int-2 synthesis: Reference A15-int-2;

[0547]

[0548] Step 2, synthesis of compound A46:

[0549]

[0550] 1 H NMR (400MHz, DMSO) δ11.36(s,1H),8.45(q,J=4.9Hz,1H),7.82(d,J=8.2Hz,1H),7.69–7. 58(m,2H),7.00(dd,J=4.0,1.4Hz,1H),6.83(s,1H),6.62(dd,J=3.9,2.6Hz,1H),3.84–3 .72(m,2H),3.13-3.02(m,1H),2.89-2.78(m,4H),22.76-2.61(m,2H),2.58-2.53(m,1H) ,2.30-2.19(m,1H),2.49(s,3H),2.04–1.92(m,1H),0.81(d,J=6.1Hz,3H).ESI-MS(M+H) + :451.3.

[0551] Example 47: Synthesis of Compound A47

[0552] Synthesis of Compound A47: A47 was prepared using A31-int-1 and A16-int-2;

[0553]

[0554] 1 H NMR (400MHz, DMSO) δ11.32(s,1H),8.43(q,J=4.7Hz,1H),7.82(d,J=8.2Hz,1H),7.61(s,1H),7.54(d,J=8.3Hz,1H),6.98(d,J=3.0Hz,1H),6.81 (s,1H),6.63–6.52(m,1H),4.12(s,2H),3.09-2.94(m,4H),2.88-2.76( m,5H),2.50(s,3H),0.76-0.70(m,2H),0.66-0.59(m,2H).ESI-MS(M+H) + :463.3.

[0555] Example 48: Synthesis of Compound A48

[0556] Synthesis of Compound A48 : A48 was prepared using A31-int-1 and A17-int-2;

[0557]

[0558] 1 H NMR (400MHz, DMSO) δ11.37 (s, 1H), 8.54 (q, J = 4.6Hz, 1H), 7.83-7.78 (m, 2H), 7 .62(dd,J=2.5,1.4Hz,1H),7.01(dd,J=4.0,1.3Hz,1H),6.82(s,1H),6.63(dd, J=3.9,2.7Hz,1H),3.77(s,2H),3.10-3.01(m,2H),2.82(d,J=4.9Hz,3H),2.80 –2.72(m,1H),2.58(s,3H),2.27-2.17(m,2H),1.80-1.58(m,4H).ESI-MS(M+H) + :436.3.

[0559] Example 49: Synthesis of Compound A49

[0560] Synthesis of Compound A49 : A49 was prepared using A31-int-1 and A19-int-2;

[0561]

[0562] 1 H NMR (400MHz, DMSO) δ11.34(s,1H),8.42(q,J=4.5Hz,1H),7.79(d,J=8.3Hz,1H),7.64(d,J=1.3Hz,1H),7.50(d,J=8.3Hz,1H),7.03–6.95(m,1H),6.8 1(s,1H),6.63–6.57(m,1H),3.78(s,2H),3.28-3.16(m,2H),3.04–2.86(m ,4H),2.80(d,J=4.8Hz,3H),2.54(s,3H),2.06–1.87(m,4H).ESI-MS(M+H) + :463.3.

[0563] Example 50: Synthesis of Compound A50

[0564] Synthesis of compound A50 : A50 was prepared using A31-int-1 and A20-int-2;

[0565]

[0566] 1 H NMR (400MHz, DMSO) δ11.34(s,1H),8.39(q,J=4.7Hz,1H),7.79(d,J=8.4Hz,1H),7.62-7.60(m,2H),6.99(d,J=3.8Hz,1H),6.84(s, 1H),6.66–6.54(m,1H),4.04-3.61(m,6H),3.28-3.16(m,2H),2.81(d,J=4.8Hz,3H),2.62(s,3H),2.54-2.45(m,2H).ESI-MS(M+H) + :449.2.

[0567] Example 51: Synthesis of Compound A51

[0568] Synthesis of compound A51 : A51 was prepared using A31-int-1 and A21-int-2;

[0569]

[0570] 1H NMR (400MHz, DMSO) δ11.29(s,1H),8.35(q,J=4.9Hz,1H),7.72(d,J=8.3Hz,1H ),7.25(s,1H),7.05(d,J=8.4Hz,1H),6.97(d,J=3.9Hz,1H),6.67(s,1H),6.62 –6.54(m,1H),4.45(d,J=5.5Hz,2H),3.73(s,2H),3.15(d,J=10.7Hz,2H),2.88 -2.78(m,5H),2.68-2.61(m,1H),2.36(s,3H),1.82-1.72(m,1H).ESI-MS(M+H) + :449.4.

[0571] Example 52: Synthesis of Compound A52

[0572] Synthesis of Compound A52 : A52 was prepared using A31-int-1 and A22-int-2;

[0573]

[0574] 1 H NMR(400MHz,DMSO)δ11.38(s,1H),8.00(br s,1H),7.86(d,J=8.3Hz,1H),7.63(dd,J=2.5,1.4Hz,1H),7.54(d,J=7.6Hz,1H),7.01(dd,J=4.0,1.3Hz,1H),6.85 (s,1H),6.63(dd,J=3.9,2.7Hz,1H),3.82(s,2H),3.05-2.89(m,4H),2.77-2.61(m,4H),2.53(s,3H).ESI-MS(M+H) + :447.2.

[0575] Example 53: Synthesis of Compound A53

[0576] Step 1, A53-int-2 synthesis:

[0577]

[0578] (1) Synthesis of Compound A53-int-2

[0579] A23-int-2-B (321 mg, 1.0 mmol) was dissolved in 15 mL of dichloromethane, and A53-int-2-A (451 mg, 1.5 mmol) was added thereto. After reacting at room temperature overnight, TLC showed that the reaction was complete. The reaction solution was spin-dried. The crude product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound A52-int-2 (220 mg, yield 64%).

[0580] Step 2, synthesis of compound A53:

[0581]

[0582] 1 H NMR (400MHz, DMSO) δ11.37(s,1H),9.31(s,1H),7.97(d,J=8.3Hz,1H),7.62(dd,J=2.5,1.4Hz,1H),7.57(d,J=8.4Hz,1H),7.00(dd,J=4 .0,1.3Hz,1H),6.84(s,1H),6.62(dd,J=3.9,2.7Hz,1H),3.82(s,2H),3.07-2.96(m,4H),2.75-2.62(m,4H),2.52(s,3H).ESI-MS(M+H) + :448.0.

[0583] Example 54: Synthesis of Compound A54

[0584] Step 1, A54-int-2 synthesis:

[0585]

[0586] (1) Synthesis of Compound A54-int-2-B

[0587] A54-int-2-A (1.0 g, 5.21 mmol) and 1-tert-butyloxycarbonylpiperazine (1.06 g, 5.70 mmol) were dissolved in 20 mL of acetonitrile, and DIPEA (810 mg, 6.28 mmol) was added thereto. After reacting at 80°C overnight, TLC showed that the reaction was complete. The reaction solution was spin-dried. The crude product was separated and purified by column chromatography (dichloromethane: methanol = 20:1) to obtain compound A54-int-2-B (750 mg, yield 42%).

[0588] (2) Synthesis of Compound A54-int-2

[0589] A54-int-2-B (400 mg, 1.20 mmol), methylamine hydrochloride (95 mg, 1.40 mmol) and triethylamine (470 mg, 4.7 mmol) were dissolved in 30 mL of dichloromethane, and HATU (650 mg, 1.8 mmol) was added thereto. After reacting at room temperature for 2 h, TLC showed that the reaction was complete. After the reaction solution was diluted with dichloromethane (60 mL), the organic phase was washed with saturated brine (20 mL*3) and the solution was dried by spin drying. The crude product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound A54-int-2 (300 mg, yield 72%).

[0590] Step 2, synthesis of compound A54:

[0591]

[0592] 1 H NMR (400MHz, DMSO) δ11.36(s,1H),8.61(d,J=2.0Hz,1H),8.46(q,J=4.5Hz,1H),8.12(d,J=2.0Hz,1H),7.62(dd,J=2.5,1.4Hz,1H),7.00(dd,J=4 .0,1.3Hz,1H),6.83(s,1H),6.62(dd,J=3.9,2.7Hz,1H),3.79(s,2H),3.45-3.40(m,4H),2.77(d,J=4.5Hz,3H),2.69-2.59(m,4H).ESI-MS(M+H) + :457.2.

[0593] Example 55: Synthesis of Compound A55

[0594] Synthesis of Compound A55 : A55 was prepared using A31-int-1 and A23-int-2;

[0595]

[0596] 1 H NMR (400MHz, DMSO) δ11.37(s,1H),7.62(s,1H),7.46(d,J=8.3Hz,1H),7.35(d,J=8.2Hz,1H),7.00(d,J=3.9Hz,1H ),6.84(s,1H),6.65–6.59(m,1H),3.80(s,2H),3.00-2.89(m,10H),2.72-2.60(m,4H),2.44(s,3H).ESI-MS(M+H) + :451.2.

[0597] Example 56: Synthesis of Compound A56

[0598] Synthesis of Compound A56 : Using A31-int-1 and A24-int-2, A56 was prepared;

[0599]

[0600] 1 H NMR (400MHz, DMSO) δ11.37(s,1H),7.62(dd,J=2.5,1.4Hz,1H),7.54(d,J=8.3Hz ,1H),7.46(d,J=8.4Hz,1H),7.00(dd,J=4.0,1.3Hz,1H),6.84(s,1H),6.62(dd, J=3.9,2.7Hz,1H),3.81(s,2H),3.65(t,J=6.5Hz,2H),3.47(t,J=6.7Hz,2H),3. 02-2.90(m,4H),2.73-2.61(m,4H),2.44(s,3H),1.87-1.78(m,4H).ESI-MS(M+H) + :477.3.

[0601] Example 57: Synthesis of Compound A57

[0602] Step 1, A57-int-2 synthesis:

[0603]

[0604] (1) Synthesis of Compound A57-int-2-B

[0605] A57-int-2-A (1.0 g, 4.6 mmol) was dissolved in 15 mL of methanol, and 0.5 mL of thionyl chloride was added thereto under ice bath. After reacting at 60°C for 4 h, TLC showed that the reaction was complete. The reaction solution was cooled to room temperature, and saturated sodium bicarbonate solution was added thereto to adjust the pH to 8. The aqueous phase was extracted with dichloromethane (80 mL*3), and the organic phases were combined and dried to give compound A57-int-2-B (930 mg, yield 88%).

[0606] (2) Synthesis of Compound A57-int-2-C

[0607] A57-int-2-B (730 mg, 3.2 mmol), 1-tert-butyloxycarbonylpiperazine (710 mg, 3.8 mmol) and cesium carbonate (2.1 g, 6.4 mmol) were dissolved in 20 mL of dioxane, and Pd2(dba)3 (440 mg, 0.48 mmol) and BINAP (580 mg, 0.96 mmol) were added thereto. After reacting overnight at 90 ° C under nitrogen protection, TLC showed that the reaction was complete. The reaction solution was filtered, and the filtrate was diluted with water (30 mL) and extracted with ethyl acetate (20 mL*3). The organic phases were combined and washed with saturated brine (10 mL*3), and the organic phases were dried and spin-dried. The crude product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound A57-int-2-C (790 mg, yield 74%).

[0608] (3) Synthesis of Compound A57-int-2

[0609] A57-int-2-C (230 mg, 0.68 mmol) was dissolved in 8 mL of methanol, and methylamine alcohol solution (30%, 8 mL) was added thereto. After reacting at room temperature overnight, TLC showed that the reaction was complete. After the solvent was dried, the crude product was separated and purified by column chromatography (dichloromethane: methanol = 20:1) to obtain compound A57-int-2 (220 mg, yield 96%).

[0610] Step 2, synthesis of compound A57:

[0611]

[0612] 1 H NMR (400MHz, DMSO) δ11.35(s,1H),8.52(q,J=4.8Hz,1H),8.21(s,1H),7.80(s,1H),7.61(dd,J=2.6,1.4Hz,1H),7.00(dd,J=4.0,1.4Hz,1H), 6.84(s,1H),6.62(dd,J=3.9,2.6Hz,1H),3.81(s,2H),3.09-2.99(m,4H),2.79(d,J=4.9Hz,3H),2.71-2.59(m,4H),2.31(s,3H).ESI-MS(M+H) + :437.2.

[0613] Example 58: Synthesis of Compound A58

[0614] Step 1, A58-int-2 synthesis: Reference A1-int-2;

[0615]

[0616] Step 2, synthesis of compound A58:

[0617]

[0618] 1 H NMR (400MHz, DMSO) δ11.37(s,1H),8.22(q,J=4.5Hz,1H),7.70–7.56(m,3H),7.03(d,J=8.2Hz,1H),7.00(d,J=3.9Hz,1H),6.83 (s,1H),6.66–6.58(m,1H),3.79(s,2H),2.96-2.87(m,4H),2.74(d,J=4.4Hz,3H),2.69-2.58(m,4H),2.26(s,3H).ESI-MS(M+H) + :436.2.

[0619] Example 59: Synthesis of Compound A59

[0620] Step 1, A59-int-1 synthesis:

[0621]

[0622] (1) Synthesis of Compound A59-int-1-A

[0623] A31-int-1-A (2.0 g, 9.0 mmol) and DL-alanine methyl ester hydrochloride (1.4 g, 9.0 mmol) were dissolved in 20 mL DMF, and potassium carbonate (3.1 g, 22.8 mmol) was added thereto. After reacting at room temperature overnight, TLC showed that the reaction was complete. Water (60 mL) was added thereto. The aqueous phase was extracted with ethyl acetate (50 mL*3). After the organic phases were combined and washed with saturated brine (20 mL*3), the organic phase was dried and spin-dried. The crude product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain compound A59-int-1-A (2.0 g, yield 77%).

[0624] (2) Synthesis of Compound A59-int-1-B

[0625] A59-int-1-A (1.8 g, 5.92 mmol) was dissolved in acetic acid / water (30 / 3 mL), and iron powder (2.6 g, 46.3 mmol) was added thereto. After reacting at 70°C for 2 h, TLC showed that the reaction was complete. After hot filtration, the filter cake was rinsed with 100 mL of dichloromethane. The organic phases were combined and washed with saturated brine (20 mL*3), dried and spin-dried. The crude product was separated and purified by column chromatography (dichloromethane: methanol = 50:1) to obtain compound A59-int-1-B (1.0 g, yield 75%).

[0626] (3) Synthesis of Compound A59-int-1-C

[0627] A59-int-1-B (1.0 g, 4.42 mmol) was added to 100 mL of tetrahydrofuran, and manganese dioxide (8.0 g, 88 mmol) was added thereto. After reacting at room temperature for 2 h, TLC showed that the reaction was complete. After the reaction solution was filtered, the filter cake was rinsed with 100 mL of dichloromethane. The organic phases were combined and then spin-dried. The obtained compound A59-int-1-C (1.0 g, crude product) was directly used for the next step reaction.

[0628] (4) Synthesis of Compound A59-int-1

[0629] A59-int-1-C (1.0 g, 4.42 mmol) was dissolved in 50 mL of anhydrous tetrahydrofuran, and lithium aluminum hydride (304 mg, 8.0 mmol) was added thereto under ice bath. After 3 h of reaction at room temperature, TLC showed that the reaction was complete. After the reaction solution was quenched with water (25 mL), the aqueous phase was extracted with ethyl acetate (30 mL*3), combined, dried and spin-dried. The crude product was separated and purified by column chromatography (dichloromethane: methanol = 20:1) to obtain compound A59-int-1 (430 mg, yield 50%).

[0630] Step 2, synthesis of compound A59: A59-int-1 and A59-int-2 (synthesis reference WO2021013735A1 page 22 intermediate 24) were used to prepare A59

[0631]

[0632] 1H NMR (600MHz, CDCl3) δ8.14(d,J=2.8Hz,1H),8.04(d,J=8.7Hz,1H),7.78(q,J=5.0Hz,1H),7.20(dd,J=8.8,2.9Hz,1H ),6.94(s,1H),3.80(s,2H),3.39–3.31(m,4H),3.00(d,J=5.1Hz,3H),2.75–2.65(m,4H),2.55(s,3H).ESI-MS(M+H) + :399.2.

[0633] Example 60: Synthesis of Compound A60

[0634] Synthesis of compound A60: A60 was prepared using A59-int-1 and A22-int-2-B.

[0635]

[0636] 1 H NMR (400MHz, DMSO) δ7.78(d,J=8.3Hz,1H),7.48(d,J=8.3Hz,1H),6.90(s,1H),3.84( s,2H),3.04–2.97(m,4H),2.70-2.60(m,4H),2.45(s,3H),2.33(s,3H).ESI-MS(M+H) + :381.2.

[0637] Example 61: Synthesis of Compound A61

[0638] Synthesis of compound A61: A61 was prepared using A59-int-1 and A4-int-2.

[0639]

[0640] 1 H NMR (400MHz, DMSO) δ8.41(q,J=4.6Hz,1H),7.79(d,J=8.3Hz,1H),7.49(d,J=8.3Hz,1H),6.90(s,1H),3.84( s,2H),3.00-2.84(m,4H),2.80(d,J=4.9Hz,3H),2.71-2.58(m,4H),2.48(s,3H),2.33(s,3H).ESI-MS(M+H) + :413.3.

[0641] Example 62: Synthesis of Compound A62

[0642] Synthesis of compound A62: A62 was prepared using A59-int-1 and A3-int-2.

[0643]

[0644] 1 H NMR (400MHz, DMSO) δ8.40(q,J=4.8Hz,1H),7.85(d,J=8.0Hz,1H),7.58(dd,J=10.4,8.3Hz,1H),6.92(s, 1H),3.84(s,2H),3.23-3.13(m,4H),2.77(d,J=4.7Hz,3H),2.69-2.56(m,4H),2.34(s,3H).ESI-MS(M+H) + :417.2.

[0645] Example 63: Synthesis of Compound A63

[0646] Synthesis of compound A63: A63 was prepared using A59-int-1 and A5-int-2.

[0647]

[0648] 1 H NMR (400MHz, DMSO) δ8.41(q,J=4.8Hz,1H),7.92(d,J=8.4Hz,1H),7.66(d,J=8.4Hz,1H),6.91(s,1H) ,3.83(s,2H),3.18-3.05(m,4H),2.78(d,J=4.7Hz,3H),2.70-2.57(m,4H),2.33(s,3H).ESI-MS(M+H) + :433.2.

[0649] Example 64: Synthesis of Compound A64

[0650] Synthesis of compound A64: A64 was prepared using A59-int-1 and A14-int-2.

[0651]

[0652] 1H NMR (400 MHz, DMSO) δ 12.50 (br s,1H),8.41(q,J=4.7Hz,1H),7.79(d,J=8.2Hz,1H),7.48(d,J=8.3Hz,1H), 6.90(s,1H),4.14(d,J=15.1Hz,1H),3.73(d,J=15.1Hz,1H),3.09-2.97(m,2 H),2.92–2.82(m,2H),2.80(d,J=4.9Hz,3H),2.77-2.71(m,1H),2.67–2.60 (m,1H),2.50-2.43(m,4H),2.33(s,3H),1.17(d,J=6.2Hz,3H).ESI-MS(M+H) + :413.2.

[0653] Example 65: Synthesis of Compound A65

[0654] Synthesis of compound A65: A65 was prepared using A59-int-1 and A15-int-2.

[0655]

[0656] 1 H NMR (400 MHz, DMSO) δ 12.50 (br s,1H),8.41(q,J=4.7Hz,1H),7.79(d,J=8.2Hz,1H),7.48(d,J=8.3Hz,1H), 6.90(s,1H),4.14(d,J=15.1Hz,1H),3.73(d,J=15.1Hz,1H),3.09-2.97(m,2 H),2.92–2.82(m,2H),2.80(d,J=4.9Hz,3H),2.77-2.71(m,1H),2.67–2.60 (m,1H),2.50-2.43(m,4H),2.33(s,3H),1.17(d,J=6.2Hz,3H).ESI-MS(M+H) + :427.2.

[0657] Example 66: Synthesis of Compound A66

[0658] Synthesis of compound A66: A66 was prepared using A59-int-1 and A46-int-2.

[0659]

[0660] 1H NMR (400MHz, DMSO) δ8.45(q,J=4.7Hz,1H),7.80(d,J=8.4Hz,1H),7.64(d,J=8.4Hz,1H),6.90(s,1H),3.85-3.70(m,2H),3.14-3.03(m,1H),2.85-2. 74(m,4H),2.75-2.61(m,2H),2.59-2.53(m,2H),2.49(s,3H),2.33(s,3H) ,2.28–2.17(m,1H),2.05-1.95(m,1H),0.82(d,J=6.0Hz,3H).ESI-MS(M+H) + :427.3.

[0661] Example 67: Synthesis of Compound A67

[0662] Synthesis of compound A67: A67 was prepared using A59-int-1 and A22-int-2.

[0663]

[0664] 1 H NMR(400MHz,DMSO)δ8.02(br s,1H),7.83(d,J=8.4Hz,1H),7.53(d,J=8.4Hz,1H),6.91(s,1H),3.84(s,2H) ,3.01-2.89(m,4H),2.71-2.58(m,4H),2.51(s,3H),2.33(s,3H).ESI-MS(M+H) + :423.3.

[0665] Example 68: Synthesis of Compound A68

[0666] Step 1, A68-int-2 synthesis: refer to A53-int-2

[0667]

[0668] Step 2, Compound Synthesis of A68:

[0669]

[0670] 1H NMR (400MHz, DMSO) δ12.57(s,1H),9.26(s,1H),8.46(d,J=2.8Hz,1H),7.97(d,J=8.9Hz,1H),7.46(dd,J=8 .9,2.9Hz,1H),6.91(s,1H),3.83(s,2H),3.47-3.40(m,4H),2.70-2.57(m,4H),2.34(s,3H).ESI-MS(M+H) + :410.2.

[0671] Example 69: Synthesis of Compound A69

[0672] Step 1, synthesis of A69-int-2:

[0673]

[0674] (1) Synthesis of Compound A69-int-2-A

[0675] A1-int-2-A (750 mg, 3.5 mmol) was dissolved in 5 mL of ammonia methanol (5 mL, 7 M, 35 mmol). After reacting at room temperature overnight, TLC showed that the reaction was complete. The reaction solution was spin-dried to obtain compound A69-int-2-A (700 mg, yield 99%).

[0676] (2) Synthesis of Compound A69-int-2-B

[0677] A69-int-2-A (2.0 g, 10.2 mmol) was dissolved in 3 mL DMF-DMA. After reacting at room temperature overnight, TLC showed that the reaction was complete. The reaction solution was spin-dried to obtain compound A69-int-2-B (750 mg, yield 84%).

[0678] (3) Synthesis of Compound A69-int-2-C

[0679] A69-int-2-B (250 mg, 1.0 mmol) and methylhydrazine sulfate (576 mg, 4.0 mmol) were dissolved in 5 mL of glacial acetic acid. After reacting at 90°C overnight, TLC showed that the reaction was complete. After cooling to room temperature, water (20 mL) was added thereto. The aqueous phase was extracted with ethyl acetate (20 mL*3). After the organic phases were combined and washed with saturated brine (20 mL*3), the organic phase was dried and spin-dried. The crude product was separated and purified by column chromatography (dichloromethane: methanol = 20:1) to obtain compound A69-int-2-C (100 mg, yield 42%).

[0680] (4) Synthesis of Compound A69-int-2

[0681] A69-int-2-C (100 mg, 0.42 mmol), 1-tert-butyloxycarbonylpiperazine (93 mg, 0.5 mmol) and cesium carbonate (273 mg, 0.84 mmol) were dissolved in 10 mL of dioxane, and Pd2(dba)3 (31 mg, 0.034 mmol) and Xphos (30 mg, 0.063 mmol) were added thereto. After reacting at 90 ° C for 4 h under nitrogen protection, TLC showed that the reaction was complete. The reaction solution was filtered, and the filtrate was diluted with water (30 mL) and extracted with ethyl acetate (20 mL*3). After the organic phases were combined and washed with saturated brine (10 mL*3), the organic phases were dried and spin-dried. The crude product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound A69-int-2 (65 mg, yield 45%).

[0682] Step 2, synthesis of compound A69:

[0683]

[0684] 1 H NMR (400MHz, DMSO) δ12.52(s,1H),8.41(d,J=2.9Hz,1H),7.95-7.92(m,2H),7.47(dd,J=8.9,2.9Hz,1H) ,6.91(s,1H),4.21(s,3H),3.82(s,2H),3.47-3.40(m,4H),2.69–2.57(m,4H),2.34(s,3H).ESI-MS(M+H) + :423.2.

[0685] Example 70: Synthesis of Compound A70

[0686] Synthesis of compound A70: A70 was prepared using A59-int-1 and A23-int-2.

[0687]

[0688] 1 H NMR (400MHz, DMSO) δ7.47(d,J=8.3Hz,1H),7.35(d,J=8.2Hz,1H),6.91(s,1H),3.83(s,2H) ,2.97(s,6H),2.96-2.89(m,4H),2.70-2.59(m,4H),2.43(s,3H),2.33(s,3H).ESI-MS(M+H) + :427.4.

[0689] Example 71: Synthesis of Compound A71

[0690] Synthesis of compound A71: A71 was prepared using A59-int-1 and A25-int-2.

[0691]

[0692] 1 H NMR (400MHz, DMSO) δ8.31(d,J=4.7Hz,1H),7.78(d,J=8.3Hz,1H),7.49(d,J=8.3Hz,1H),6.92(s,1H),3.83(s,2H),2.99-2.9 0(m,4H),2.89–2.78(m,1H),2.69-2.58(m,4H),2.47(s,3H),2.33(s,3H),0.73-0.66(m,2H),0.66–0.60(m,2H).ESI-MS(M+H) + :439.2.

[0693] Example 72: Synthesis of Compound A72

[0694] Synthesis of compound A72: A72 was prepared using A59-int-1 and A58-int-2.

[0695]

[0696] 1 H NMR (400MHz, DMSO) δ8.22(q,J=4.5Hz,1H),7.63-7.60(m,2H),7.04(d,J=8.2Hz,1H),6.90(s,1H),3.82(s ,2H),2.96-2.86(m,4H),2.74(d,J=4.5Hz,3H),2.69-2.57(m,4H),2.33(s,3H),2.25(s,3H).ESI-MS(M+H) + :412.3.

[0697] Example 73: Synthesis of Compound A73

[0698] Step 1, synthesis of A73-int-1: Reference A59-int-1;

[0699]

[0700] Step 2, synthesis of compound A73: A73 was prepared using A73-int-1 and A4-int-2.

[0701]

[0702] 1 H NMR (400MHz, DMSO) δ8.41(q,J=4.6Hz,1H),7.79(d,J=8.2Hz,1H),7.49(d,J=8.3Hz,1H),6.90(s,1H),3.84(s,2H),3.00-2. 89(m,4H),2.80(d,J=4.9Hz,3H),2.73(q,J=7.4Hz,2H),2.68-2.57(m,4H),2.48(s,3H),1.17(t,J=7.4Hz,3H).ESI-MS(M+H) + :427.2.

[0703] Example 74: Synthesis of Compound A74

[0704] Synthesis of compound A74: A74 was prepared using A73-int-1 and A3-int-2.

[0705]

[0706] 1 H NMR (400MHz, DMSO) δ8.38(q,J=4.8Hz,1H),7.84(d,J=8.0Hz,1H),7.58(dd,J=10.6,8.2Hz,1H),6.90(s,1H) ,3.83(s,2H),3.22-3.14(m,4H),2.79–2.69(m,5H),2.67-2.58(m,4H),1.17(t,J=7.4Hz,3H).ESI-MS(M+H) + :431.2.

[0707] Example 75: Synthesis of Compound A75

[0708] Synthesis of compound A75: A75 was prepared using A73-int-1 and A5-int-2.

[0709]

[0710] 1H NMR (400MHz, DMSO) δ8.42(q,J=4.9Hz,1H),7.93(d,J=8.2Hz,1H),7.68(d,J=8.3Hz,1H),6.91(s,1H),3.84(s,2H),3. 18-3.07(m,4H),2.79(d,J=4.8Hz,3H),2.73(q,J=7.4Hz,2H),2.69-2.59(m,4H),1.17(t,J=7.4Hz,3H).ESI-MS(M+H) + :447.2

[0711] Example 76: Synthesis of Compound A76

[0712] Synthesis of compound A76: A76 was prepared using A73-int-1 and A54-int-2.

[0713]

[0714] 1 H NMR (400MHz, DMSO) δ8.61(d,J=2.0Hz,1H),8.50–8.41(m,1H),8.11(d,J=2.0Hz,1H),6.89(s,1H),3.82(s,2H),3.4 8-3.40(m,4H),2.77(d,J=4.5Hz,3H),2.72(q,J=7.5Hz,2H),2.65–2.57(m,4H),1.17(t,J=7.4Hz,3H).ESI-MS(M+H) + :447.2.

[0715] Example 77: Synthesis of Compound A77

[0716]

[0717] Step 1, synthesis of A77-int-1:

[0718] A73-int-1-C (100 mg, 0.42 mmol) was dissolved in methanol / water (10 mL / 5 mL), and lithium hydroxide (50 mg, 1.30 mmol) was added thereto. After reacting at 60°C for 1 h, TLC showed that the reaction was complete. Water (20 mL) was added to the reaction solution to quench the reaction. The pH of the aqueous phase was adjusted to 3-4 with 1M dilute hydrochloric acid. The precipitated solid was filtered. The filter cake was rinsed with water and dried to obtain compound A77-int-1 (70 mg, yield 75%).

[0719] Step 2, synthesis of compound A77:

[0720] A77-int-1 (70 mg, 0.28 mmol), A4-int-2-deBoc (85 mg, 0.37 mmol) and triethylamine (130 mg, 1.3 mmol) were dissolved in 20 mL of dichloromethane, and HATU (170 mg, 0.47 mmol) was added thereto. After reacting at room temperature overnight, TLC showed that the reaction was complete. After the reaction solution was diluted with dichloromethane (60 mL), the organic phase was washed with saturated brine (20 mL*3) and the solution was dried by spin drying. The crude product was separated and purified by column chromatography (dichloromethane: methanol = 20:1) to obtain compound A77 (50 mg, yield 36%).

[0721] 1 H NMR (400MHz, DMSO) δ8.45(q,J=4.6Hz,1H),7.81(d,J=8.2Hz,1H),7.51(d,J=8.3Hz,1H),7.23(s,1H),3. 89-3.78(m,4H),3.05-2.94(m,4H),2.85–2.73(m,5H),2.54(s,3H),1.19(t,J=7.4Hz,3H).ESI-MS(M+H) + :441.2.

[0722] Example 78: Synthesis of Compound A78

[0723] Step 1, synthesis of A78-int-1:

[0724]

[0725] (1) Synthesis of Compound A78-int-1-B

[0726] A78-int-1-A (1.9 g, 10.0 mmol) and zinc cyanide (1.17 g, 10.0 mmol) were dissolved in 20 mL DMF, and Pd2(dba)3 (458 mg, 0.50 mmol) and DPPF (416 mg, 0.75 mmol) were added thereto. After reacting at 100 °C for 3 h under nitrogen protection, TLC showed that the reaction was complete. The reaction solution was filtered, and the filtrate was diluted with water (60 mL) and extracted with ethyl acetate (60 mL*3). The organic phases were combined and washed with saturated brine (20 mL*3), and the organic phases were dried and spin-dried. The crude product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound A78-int-1-B (950 mg, yield 70%).

[0727] (2) Synthesis of Compound A78-int-1-C

[0728] A78-int-1-B (950 mg, 7.0 mmol) was dissolved in 10 mL of concentrated hydrochloric acid. After reacting at 100°C for 2 h, TLC showed that the reaction was complete. The reaction solution was spin-dried to obtain compound A78-int-1-C (1.2 g, crude product) which was directly used in the next step.

[0729] (3) Synthesis of Compound A78-int-1-D

[0730] A78-int-1-C (1.2 g, 7.0 mmol, crude product), hydroxylamine hydrochloride (686 mg, 7.0 mmol) and DIPEA (2.71 g, 21 mmol) were dissolved in 20 mL DMF, and HATU (3.99 g, 10.5 mmol) was added thereto. After reacting at room temperature for 2 h, TLC showed that the reaction was complete. The reaction solution was diluted with water (60 mL) and extracted with ethyl acetate (60 mL*3). The organic phases were combined and washed with saturated brine (20 mL*3), and then dried and spin-dried. The crude product was separated and purified by column chromatography (dichloromethane: methanol = 20:1) to obtain compound A78-int-1-D (650 mg, yield 47%).

[0731] (4) Synthesis of Compound A78-int-1-E

[0732] A78-int-1-D (650 mg, 3.28 mmol) was dissolved in 20 mL of toluene. Diisobutylaluminum hydride (4 mL, 1 M, 4.0 mmol) was added dropwise at -60 °C. After reacting at -60 °C for 2 h, TLC showed that the reaction was complete. Protective ammonium chloride solution was added to quench the reaction. The aqueous phase was extracted with ethyl acetate (20 mL*3). The organic phases were combined and washed with saturated brine (20 mL*3), and the organic phase was dried and spin-dried to obtain compound A78-int-1-E (456 mg, yield 100%).

[0733] (5) Synthesis of Compound A78-int-1-F

[0734] A78-int-1-E (456 mg, 3.28 mmol) and methyl thioglycolate (522 mg, 4.92 mmol) were dissolved in 20 mL DMF, and triethylamine (994 mg, 9.84 mmol) was added thereto. After reacting at 100 °C for 3 h, TLC showed that the reaction was complete. The reaction solution was cooled to room temperature and diluted with water (60 mL), and then extracted with ethyl acetate (60 mL*3). The organic phases were combined and washed with saturated brine (20 mL*3), and the organic phases were dried and spin-dried. The crude product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound A78-int-1-F (350 mg, yield 51%).

[0735] (6) Synthesis of compound A78-int-1-G

[0736] A78-int-1-F (350 mg, 1.70 mmol) was dissolved in 20 mL of dichloromethane. Meta-chloroperbenzoic acid (585 mg, 3.4 mmol) was added thereto under ice bath. After 5 h of reaction at room temperature, TLC showed that the reaction was complete. After the reaction solution was diluted with dichloromethane (60 mL), the aqueous phase was washed with saturated sodium bicarbonate solution (20 mL*3) and saturated brine (20 mL*3) in turn. The organic phase was dried and spin-dried to obtain compound A78-int-1-G (400 mg, crude product) which was directly used in the next step reaction.

[0737] ⑺Synthesis of compound A78-int-1-H

[0738] A78-int-1-G (350 mg, 1.70 mmol) was dissolved in 10 mL of acetic anhydride. After reacting at 140 ° C overnight, TLC showed that the reaction was complete. After the reaction solution was cooled to room temperature and quenched with water (60 mL), the aqueous phase was extracted with ethyl acetate (60 mL * 3). After the organic phases were combined and washed with saturated brine (20 mL * 3), the organic phase was dried and spin-dried. The crude product was separated and purified by column chromatography (dichloromethane: methanol = 20: 1) to obtain compound A78-int-1-H (260 mg, yield 69%).

[0739] ⑻Synthesis of Compound A78-int-1

[0740] A78-int-1-H (260 mg, 1.17 mmol) was dissolved in 20 mL of anhydrous tetrahydrofuran, and lithium aluminum hydride (1.5 mL, 1 M, 1.5 mmol) was added thereto under ice bath. After 3 h of reaction at room temperature, TLC showed that the reaction was complete. After the reaction solution was quenched with water (25 mL), the aqueous phase was extracted with ethyl acetate (30 mL*3), combined, dried and spin-dried. The crude product was separated and purified by column chromatography (dichloromethane: methanol = 20:1) to obtain compound A78-int-1 (190 mg, yield 83%).

[0741] Step 2, synthesis of compound A78: A78 was prepared using A78-int-1 and A4-int-2;

[0742]

[0743] 1H NMR (400MHz, DMSO) δ12.03(s,1H),8.41(q,J=4.6Hz,1H),7.83–7.75(m,2H),7.49(d,J=8.3Hz,1H),6.88(s,1H), 3.81(s,2H),3.09-2.90(m,4H),2.80(d,J=4.9Hz,3H),2.71-2.57(m,4H),2.48(s,3H),2.03(s,3H).ESI-MS(M+H) + :412.2.

[0744] Example 79: Synthesis of Compound A79

[0745] Synthesis of compound A79: A79 was prepared using A78-int-1 and A5-int-2.

[0746]

[0747] 1 H NMR (400MHz, DMSO) δ12.03(s,1H),8.42(q,J=4.6Hz,1H),7.93(d,J=8.2Hz,1H),7.79(s,1H),7.67(d,J=8.2Hz,1H) ,6.88(s,1H),3.82(s,2H),3.17-3.06(m,4H),2.79(d,J=4.8Hz,3H),2.70-2.57(m,4H),2.03(s,3H).ESI-MS(M+H) + :432.2.

[0748] Biological Assessment

[0749] Experimental instruments: centrifuge (Eppendorf 5810R); microplate reader (BioTek Synergy H1 or PerkinElmer Envision); pipette (Eppendorf or Rainin).

[0750] Experimental reagents: PARP1 Chemiluminescent Assay Kit was purchased from BPS bioscience with the catalog number 80569; 20×PBST was purchased from Thermo with the catalog number 28352; PBS was purchased from Gibco with the catalog number 10010023.

[0751] Experimental method: The chemiluminescence method was used to detect the inhibitory activity of the compound on the PARP1 enzyme. This experiment was carried out in a 384-well plate. First, histones were coated in the 384-well plate: 5×histone solution was diluted 5 times with PBS and added to the 384-well ELISA plate, 25μL per well, and incubated overnight at 4 degrees Celsius. The coated ELISA plate was washed with 1×PBST buffer and then blocked with blocking solution (blocking buffer 3 in the kit) for 30 to 120 minutes, 100μL per well, and washed 3 to 6 times with 1×PBST buffer. A mixture of PARP reaction biotin-labeled substrate, activated DNA, 10×PARP buffer and water was added, 12.5μL per well. Compound solutions of different concentrations were prepared using the experimental buffer (10% DMSO aqueous solution containing 1.25mM DTT), with the final concentration of 100nM as the starting point, 3-fold dilution, 8 concentrations, and added to the 384-well plate reaction wells, 2.5μL per well, 2.5μL of 10% DMSO aqueous solution containing 1.25mM DTT was added to the positive control group and the blank well, 2.5μL per well, and then 10μL of PARP1 enzyme solution prepared with 1×PARP buffer was added to start the reaction, centrifuged at 1000rpm for 1 minute, and reacted at room temperature for 60 minutes. After the reaction, the reaction solution was poured out, washed with 1×PBST buffer, and Streptavidin HRP solution diluted 50 times with Blocking buffer 3 was added, 25μL per well, and incubated at room temperature for 30 minutes. After the reaction solution was poured out, it was washed 3 to 6 times with 1×PBST buffer. The luminescent reaction solution mixed with ECL substrate A and ELISA ECL substrate B 1:1 was added to react, 50μL per well. Perform chemiluminescence readings immediately using a BioTek Synergy H1 or Envision instrument.

[0752] Experimental data processing method: Read the samples with BioTek Synergy H1 or Envision instrument, record the chemiluminescence readings, calculate the inhibition rate, and use Graphpad Prism software to perform nonlinear regression curve fitting on the concentration and inhibition rate to obtain the IC50 value.

[0753] Table 1 Inhibitory activity of the compounds in the examples on PARP1 enzyme

[0754]

[0755] AZD5305 (CAS#: 2589531-76-8) was purchased from an external source. As shown in Table 1, compared with AZD5305, most of the compounds represented by Formula I, Formula II, and Formula III of the present invention showed excellent biological activity in the PARP1 enzyme activity inhibition experiment.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, isotopic derivative or prodrug thereof: in: X1 is selected from N and C; X2 is selected from N, C, S and O; f is 0 or 1; n is the number of R5 and is 0, 1, 2, 3 or 4; m is the number of R6 and is 0, 1, 2, 3 or 4; Ring A is selected from C 3-10 Cycloalkyl, heterocyclyl and heteroaryl, wherein C 3-10 Cycloalkyl, heterocyclyl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R5; Ring B is selected from heterocyclyl, aryl and heteroaryl, wherein heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R6; Z is selected from a bond, -(CR z1 R z2 )u-, -(CR z1 R z2 )uO(CR z1 R z2 )t-, -(CR z1 R z2 )uNR z3 (CR z1 R z2 )t-, and -(CR z1 R z2 )uS(CR z1 R z2 )t-, preferably Z is selected from a bond; R1 is selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 1-4 Alkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, Heteroaryl, Heteroaryl-C 1-4 Base, CN, NO2, -NR 1a R 1b 、-OR 1a 、-OR 1a 、-C(O)R 1a 、-C(=NR 1c )R 1a AND-C(=N-OR 1b )R 1a R 1b , -NR 1a C(O)R 1b ,-C(=NR 1c )NR 1a R 1b 、-NR 1a R 1b , -NR 1a CR 1b , -N)R 1a R 1b , -S(O)2OR 1a , -OS(O)2R 1a , -NR 1a S(O,-P(O)R 1a R 1b AND-P(O)(OR 1a )(OR 1b ), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R 1d ; R2 is selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 1-4 Alkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, Heteroaryl, Heteroaryl-C 1-4 Base, CN, NO2, -NR 2a R 2b 、-OR 2a 、-OR 2a 、-C(O)R 2a 、-C(=NR 2c )R 2a AND-C(=N-OR 2b )R 2a R 2b , -NR 2a C(O)R 2b ,-C(=NR 2c )NR 2a R 2b 、-NR 2a R 2b , -NR 2a CR 2b , -N)R 2a R 2b , -S(O)2OR 2a , -OS(O)2R 2a , -NR 2a S(O,-P(O)R 2a R 2b AND-P(O)(OR 2a )(OR 2b ), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R 2d ; Or, R1 and R2 together with the atoms to which they are attached form a 3-7 membered cycloalkyl, heterocyclyl, aryl and heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl group are each unsubstituted or substituted with at least one substituent independently selected from R7; R3 is selected from hydrogen, halogen, C 1-10 Alkyl, carbonyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, CN, NO2, -NR 3a R 3b 、-OR 3a and -C(O)R 3a , wherein alkyl, alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl are each unsubstituted or substituted with at least one substituent independently selected from R 3c ; R4 is selected from hydrogen, halogen, C 1-10 Alkyl, carbonyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, CN, NO2, -NR 4a R 4b 、-OR 4a and -C(O)R 4a , wherein alkyl, alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl are each unsubstituted or substituted with at least one substituent independently selected from R 4c ; R5 is selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 1-4 Alkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, Heteroaryl, Heteroaryl-C 1-4 Base, CN, NO2, -NR 5a R 5b 、-OR 5a 、-C(O)R 5a 、-C(=NR 5c )R 5a 、-C(=N-OR 5b )R 5a 、-C(O)OR 5a 、-OC(O)R 5a 、-C(O)NR 5a R 5b 、-NR 5a C(O)R 5b 、-C(=NR 5c )NR 5a R 5b 、-NR 5a C(=NR 5c )R 5b 、-OC(O)NR 5a R 5b 、-NR 5a C(O)OR 5b 、-NR 5a C(O)NR 5a R 5b 、-NR 5a C(S)NR 5a R 5b 、-NR 5a C(=NR 5c )NR 5a R 5b 、-S(O)rR 5a 、-S(O)(=NR 5c )R 5b 、-N=S(O)R 5a R 5b 、-S(O)2OR 5a 、-OS(O)2R 5a 、-NR 5a S(O)r 5b 、-NR 5a S(O)(=NR 5c )R 5b 、-S(O)rNR 5a R 5b 、-S(O)(=NR 5c )NR 5a R 5b 、-NR 5a S(O)2NR 5a R 5b 、-NR 5a S(O)(=NR 5c )NR 5a R 5b 、-P(O)R 5a R 5b AND-P(O)(OR 5a )(OR 5b ), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R 5d ; R6 is selected from hydrogen, halogen, -CN, C 1-10 Alkyl, halogenated C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 1-4 Alkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, Heteroaryl, Heteroaryl-C 1-4 Base, NO2, SF5, -NR 6a R 6b 、-OR 6a 、-C(O)R 6a 、-C(=NR 6c )R 6a 、-C(=N-OR 6b )R 6a 、-C(O)OR 6a 、-OC(O)R 6a 、-C(O)NR 6a R 6b 、-NR 6a C(O)R 6b 、-C(=NR 6c )NR 6a R 6b 、-NR 6a C(=NR 6c )R 6b 、-OC(O)NR 6a R 6b 、-NR 6a C(O)OR 6b 、-NR 6a C(O)NR 6a R 6b 、-NR 6a C(S)NR 6a R 6b 、-NR 6a C(=NR 6c )NR 6a R 6b 、-S(O)rR 6a 、-S(O)(=NR 6c )R 6b 、-N=S(O)R 6a R 6b 、-S(O)2OR 6a 、-OS(O)2R 6a 、-NR 6a S(O)r 6b 、-NR 6a S(O)(=NR 6c )R 6b 、-S(O)rNR 6a R 6b 、-S(O)(=NR 6c )NR 6a R 6b 、-NR 6a S(O)2NR 6a R 6b 、-NR 6a S(O)(=NR 6c )NR 6a R 6b 、-P(O)R 6a R 6b AND-P(O)(OR 6a )(OR 6b ), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R 6d ; R z1 and R z2 are each independently selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R P ; or R z1 and R z2 Together with the atoms to which they are attached, they form a group comprising 0, 1 or 2 atoms independently selected from oxygen, sulfur and nitrogen and optionally 1, 2 or 3 R p A 3-12 membered ring of a heteroatom substituted by a group; R z3 are each independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R P ; R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , R 6b are independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, aryl, aryl C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R P ; or R 1a and R 1b , R 2a and R 2b , R 3a and R 3b , R 4a and R 4b , R 5a and R 5b , R 6a and R 6b Together with the atoms to which they are attached, they form a group comprising 0, 1 or 2 atoms independently selected from oxygen, sulfur and nitrogen and optionally 1, 2 or 3 R p A 3-12 membered ring of a heteroatom substituted by a group; R 1c , R 2c , R 5c , R 6c are each independently selected from hydrogen, C 1-10 Alkyl, CN, NO2, -OR w 、-SR w 、-S(O)rR w 、-C(O)R w 、-C(O)OR w 、-C(O)OR w ;-C(O)NR w R x and -S(O)rNR w R x ; R 1d , R 3c , R 4c R 2d , R 5d , R 6d , R7 are each independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, aryl, aryl C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 Alkyl, halogen, CN, NO2, -(CR y R z ) t NR w R x 、-(CR y R z ) t OR x 、-(CR y R z ) t C(O)R w 、-(CR y R z ) t C(=NR t )R w 、-(CR y R z ) t C(=N-OR x )R w 、-(CR y R z ) t C(O)OR x 、-(CR y R z ) t OC(O)R x 、-(CR y R z ) t C(O)NR w R x 、-(CR y R z ) t NR w C(O)R x 、-(CR y R z ) t C(=NR t )NR w R x 、-(CR y R z ) t NR w C(=NR t )R x 、-(CR y R z ) t OC(O)NR w R x 、-(CR y R z ) t NR w C(O)OR x 、-(CR y R z ) t NR w C(O)NR w R x 、-(CR y R z ) t NR w C(S)NR w R x 、-(CR y Rz) t NR w C(=NR t )NR w R x 、-(CR y R z ) t S(O)rR x 、-(CR y R z ) t S(O)(=NR t )R x 、-(CR y R z ) t N=S(O)R w R x 、-(CR y R z ) t S(O)2OR x 、-(CR y R z ) t OS(O)2R x 、-(CR y R z ) t NR w S(O)rR x 、-(CR y R z ) t NR w S(O)(=NR t )R x 、-(CR y R z ) t S(O)r w R x 、-(CR y R z ) t S(O)(=NR t )NR w R x 、-(CR y R z ) t NR w S(O)2NR w R x 、-(CR y R z ) t NR w S(O)(=NR t )NR w R x 、-(CR y R z ) t P(O)R w R x and-(CR y R z ) t P(O)(OR w )(OR x ), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R q ; R P , R q , R w , R x , R y , R z , R t Each independently selected from hydrogen, halogen, CN, NO2, C 1-10 Alkyl, C 3-10 Cycloalkyl, C 3-10 -cycloalkyl-C 1-4 Alkyl, C 1-10 Alkoxy, C 3-10 Cycloalkoxy, -C(O)C 1-4 Alkyl, -C(O)C 3-10 Cycloalkyl, -C(O)OC 1-4 Alkyl, -C(O)OC 3-10 Cycloalkyl, -C(O)N(C 1-4 Alkyl)2,-C(O)N(C 3-10 Cycloalkyl)2,-S(O)2C 1-4 Alkyl, -S(O)2C 3-10 Cycloalkyl, -S(O)2N(C 1-4 Alkyl)2 and -S(O)2N(C 3-10 Cycloalkyl)2; u is selected from 0, 1, 2, 3 and 4; t is selected from 0, 1, 2, 3 and 4.

2. The compound of formula I according to claim 1 or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, isotopic derivative or prodrug thereof, having formula II: wherein X1, X2, Ring A, Ring B, Z, R1, R2, R7, R3, R4, R5, R6, n and m are as defined in claim 1.

3. A compound of formula I according to claim 1 or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, isotopic derivative or prodrug thereof, having a compound of formula III: wherein X1, X2, Ring A, Ring B, Z, R1, R2, R3, R4, R5, R6, n and m are as defined in claim 1.

4. The compound according to any one of claims 1 to 3, wherein ring A is selected from a heterocyclic group; Preferably, Ring A is selected from:

5. The compound according to any one of claims 1 to 4, wherein R5 is independently selected from hydrogen, C 1-4 Alkyl and cycloalkyl.

6. The compound according to claims 1 to 5, wherein Selected from 7. The compound according to any one of claims 1 to 6, wherein ring B is selected from aryl and heteroaryl; Preferably, Ring B is selected from:

8. The compound according to any one of claims 1 to 7, wherein R6 is selected from hydrogen, halogen, -CN, C 1-4 Alkyl, halogenated C 1-10 Alkyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, heteroaryl, heteroaryl-C 1-4 Base, -NR 6a R 6b 、-OR 6a 、-C(O)NR 6a R 6b and cycloalkyl, R 6a or R 6b are independently selected from hydrogen, methyl, halomethyl, ethyl, cyclopropyl, or R 6a and R 6b Together with the N atom to which they are attached, they form a 4-6 membered ring.

9. The compound according to any one of claims 1 to 8, wherein Independently selected 10. A compound according to any one of claims 1 to 2, 4 to 9 or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, isotopic derivative or prodrug thereof, having formula II: in: X1 is selected from N; X2 is selected from S; n is the number of R5 and is 0, 1, 2, 3 or 4; m is the number of R6 and is 0, 1, 2, 3 or 4; g is the number of R7 and is 0, 1, 2, 3 or 4; Ring A is selected from a heterocyclic group, preferably a 5-7-membered heterocyclic group, more preferably a 6-membered heterocyclic group containing 1 or 2 N; Ring B is selected from aryl and heteroaryl, preferably ring B is selected from benzene ring or pyridine; Z is selected from a bond; R1 and R2 together with the atoms to which they are attached form a 5-membered heteroaryl group, more preferably a 5-membered heteroaryl group containing 1 or 2 N atoms, wherein the heteroaryl group is unsubstituted; R3 is selected from hydrogen, C 1-4 Alkyl and carbonyl groups; R4 is selected from hydrogen and C 1-4 alkyl; R5 is selected from hydrogen, C 1-4 Alkyl and cycloalkyl; preferably R5 is selected from methyl, ethyl and cyclopropyl; R6 is selected from hydrogen, halogen, -CN, C 1-4 Alkyl, halogenated C 1-10 Alkyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, heteroaryl, heteroaryl-C 1-4 Base, -NR 6a R 6b 、-OR 6a 、-C(O)NR 6a R 6b and cycloalkyl, R 6a or R 6b are independently selected from hydrogen, methyl, ethyl, halomethyl, cyclopropyl, or R 6a and R 6b Together with the N atom to which they are attached, they form a 4-6 membered ring; preferably R6 is selected from hydrogen, F, Cl, Br, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, difluoroethyl, trifluoroethyl, isopropyl, cyclopropyl, methoxy, trifluoromethoxy, ethoxy, -CN, ethynyl, -NHCH, -C(O)NHCH3, -C(O)N(CH3)2, 11. A compound according to claim 1, 3 to 9 or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, isotopic derivative or prodrug thereof, having formula III: in: X1 is selected from N and C; X2 is selected from S; n is the number of R5 and is 0, 1, 2, 3 or 4; m is the number of R6 and is 0, 1, 2, 3 or 4; Ring A is selected from a heterocyclic group, preferably a 5-7-membered heterocyclic group, more preferably a 6-membered heterocyclic group containing 1 or 2 N; Ring B is selected from aryl and heteroaryl, preferably ring B is selected from benzene ring or pyridine; Z is selected from a bond; R1 is selected from hydrogen and C 1-4 alkyl; When X1 is selected from C, R2 is selected from hydrogen; R3 is selected from hydrogen, C 1-4 Alkyl and carbonyl groups; R4 is selected from hydrogen and C 1-4 alkyl; R5 is selected from hydrogen, C 1-4 Alkyl and cycloalkyl; preferably R5 is selected from methyl, ethyl and cyclopropyl; R6 is selected from hydrogen, halogen, -CN, C 1-4 Alkyl, halogenated C 1-10 Alkyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, heteroaryl, heteroaryl-C 1-4 Base, -NR 6a R 6b 、-OR 6a 、-C(O)NR 6a R 6b and cycloalkyl, R 6a or R 6b are independently selected from hydrogen, methyl, ethyl, halomethyl, cyclopropyl, or R 6a and R 6b Together with the N atom to which they are attached, they form a 4-6 membered ring; preferably R6 is selected from hydrogen, F, Cl, Br, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, difluoroethyl, trifluoroethyl, isopropyl, cyclopropyl, methoxy, trifluoromethoxy, ethoxy, -CN, ethynyl, -NHCH, -C(O)NHCH3, -C(O)N(CH3)2, 12. The compound according to claim 1, wherein the compound is selected from:

13. The compound according to claim 1, wherein the compound is selected from:

14. A pharmaceutically acceptable salt as claimed in any one of claims 1 to 13, wherein the pharmaceutically acceptable salt is prepared by adding a pharmaceutically acceptable acid to a compound of formula I, II or III, preferably the acid is an inorganic acid or an organic acid, wherein the inorganic acid is selected from HCl, H3PO4, H2SO4, HNO3, HBr and HI, and the organic acid is selected from formic acid, acetic acid, CF3COOH, propionic acid, butyric acid, oxalic acid, adipic acid, malic acid, tartaric acid, hemitartaric acid, amino acids, methanesulfonic acid, benzenesulfonic acid, p-TsOH, naphthalenesulfonic acid, fumaric acid, maleic acid, succinic acid, cholic acid, deoxycholic acid, citric acid, mucic acid, hippuric acid and gentisic acid.

15. A pharmaceutical composition comprising a pharmaceutically acceptable excipient or carrier and a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, isotopic derivative or prodrug thereof as an active ingredient.

16. Use of the compound according to any one of claims 1 to 13 or its stereoisomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the pharmaceutical composition according to claim 15 in the preparation of a drug for treating diseases related to PARP1.

17. A method for preventing or treating a disease or condition associated with increased PARP1 expression, comprising administering a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, isotopic derivative or prodrug thereof, or a pharmaceutical composition according to claim 15.

18. The method according to claim 17, wherein The disease or condition is a hyperplasia associated with a defective DNA repair pathway; and / or, the disease or condition is hyperplasia associated with BRCA1 and / or BRCA2 mutations; and / or, the disease or condition is hyperplasia related; And / or, the disease or condition is prostate cancer, pancreatic cancer, pheochromocytoma, paraganglioma, squamous cell lung cancer, glioblastoma, glioma, breast cancer, breast cancer with BRCA1 / 2 mutation, oral squamous cell carcinoma, non-small cell lung cancer, small cell lung cancer, neuroendocrine cancer, lung adenocarcinoma, ovarian cancer, ovarian cancer with BRCA1 / 2 mutation, endometrial cancer, nasopharyngeal cancer, colorectal cancer, rectal cancer, acute myeloid leukemia, gastric cancer, fallopian tube cancer, primary peritoneal cancer, non-Hodgkin lymphoma, brain cancer, acute lymphocytic leukemia, acute myeloid leukemia, acute megakaryocytic leukemia, acute monocytic leukemia, atypical chronic myeloid leukemia, Hodgkin lymphoma, mesothelioma, NK / T cell lymphoma, cervical cancer, head and neck squamous cell carcinoma, oropharyngeal cancer, liver cancer, soft tissue sarcoma, bone cancer, biliary tract cancer, bladder cancer or neurodegenerative disease.

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