KRAS-PROTAC chimeric compound as well as preparation method and application thereof

Abstract

The invention relates to a compound shown in a formula (I) or pharmaceutically acceptable salt and stereoisomer thereof, and application thereof in treating diseases such as tumors, immunity or inflammation. The invention also relates to a pharmaceutical preparation, a pharmaceutical composition and application of the compound.

Description

KRAS-PROTAC chimeric compounds and preparation methods and uses thereof Technical Field

[0001] The present invention belongs to the field of medicine, and specifically relates to PROTAC chimeric compounds and their use in preparing drugs for treating or preventing diseases such as tumors. Background Art

[0002] Protein degradation targeting chimeras (PROTAC) technology stems from the discovery of ubiquitin (Ub)-regulated protein degradation. Eukaryotic cells constantly strive to maintain appropriate protein levels, producing and degrading thousands of proteins at any given moment. A key factor in maintaining protein homeostasis is a small protein molecule called ubiquitin. When ubiquitin is linked to proteins, it transports them to the proteasome for degradation.

[0003] Targeted protein degradation is an emerging area of ​​drug development. These drugs attempt to engineer small molecules into novel therapeutics. While traditional small molecules block protein function, targeted protein degraders degrade these proteins by delivering them to the proteasome.

[0004] Drs. Craig Crews and Raymond Deshaies designed a series of bifunctional chimeric molecules based on peptide compounds to induce the degradation of methionyl aminopeptidase 2 (MetAP-2). They formally proposed the PROTAC concept and applied for related patent WO2002020740A3. However, because these large and bulky peptide-based linker compounds had difficulty entering cells, the first generation of PROTACs failed.

[0005] In 2008, Crews' team designed the second-generation PROTACs based on the E3 ubiquitin protein ligase MDM2 to degrade the androgen receptor (AR).

[0006] In 2015, Crews' team designed a new generation of PROTACs based on the novel E3 ubiquitin ligase VHL and CRBN ligand.

[0007] The KRAS (Kirsten Rat Sarcoma Viral Oncogene Homolog) gene is one of the most commonly mutated oncogenes, with nearly 30% of cancer patients having KRAS gene mutations. KRAS G12D is the most common KRAS mutation, present in approximately 34% of pancreatic cancers, 10-12% of colorectal cancers, 4% of lung adenocarcinomas, 11% of bile duct cancers, 5% of endometrial cancers, and several other cancers. G12D It is clearly a well-established cancer target; however, effective targeting of other KRAS mutants requires overcoming a number of challenges.

[0008] Drug development targeting KRAS mutants is an important approach to intervene in or treat these cancers. For a long time, KRAS has been labeled "undruggable" and "untargetable" due to its extremely high affinity for guanosine triphosphate (GTP) and the difficulty of targeting due to its smooth surface.

[0009] One of the biggest advantages of PROTACs technology is its ability to transform targets from "undruggable" to "druggable." Most traditional small molecule drugs or monoclonal antibodies need to bind to the active sites of enzymes or receptors to work, however, PROTACs can grab the target protein through any corner or crevice.

[0010] Therefore, small molecule therapeutics that can selectively bind to Kras G12D and inhibit its function would be very useful. The KRAS-PROTAC chimeric compounds of the present invention are attractive drugs for cancers with this mutation.

[0011] Summary of the Invention

[0012] One object of the present invention is to provide protein degradation-targeted chimeric compounds having good KRAS G12D inhibitory / degradation activity and capable of inducing KRAS degradation, as well as pharmaceutically acceptable salts and stereoisomers thereof, and their use in treating tumor, immune or inflammatory diseases.

[0013] The present invention provides a compound of formula (I): [BL] n -KRAS ligand (I),

[0014] or a pharmaceutically acceptable salt or stereoisomer thereof,

[0015] wherein the KRAS ligand is, for example, a KRAS inhibitor, further a KRAS G12D inhibitor,

[0016] B is a degradation tag, such as an E3 ligase ligand,

[0017] L is a linker between B and the KRAS ligand,

[0018] n is the number of the degradation tags connected to the KRAS ligand, selected from 1, 2 or 3.

[0019] The attachment site, number of attachments, and choice of attachment site on the KRAS inhibitor will affect the activity of the compound.

[0020] KRAS ligands

[0021] In some embodiments, the KRAS ligand according to the present invention is a compound represented by the following formula (KI):

[0022] or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,

[0023] in:

[0024] X1 is N or C;

[0025] X2 and X3 are independently N or CR 100 ;

[0026] R 100 are independently hydrogen, deuterium, halogen, hydroxyl, amino, -CN, -C 1-8 Alkyl, -OC 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -CONR 100a R 100b , cycloalkyl, heterocyclic, aryl or heteroaryl, the -C 1-8 Alkyl, -OC 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are each optionally substituted with one or more deuterium, halogen, cyano, hydroxyl, -C 1-8 Alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl substitution;

[0027] R 100a 、R 100b are each independently hydrogen, deuterium, halogen, cyano, hydroxyl or -C 1-8 alkyl;

[0028] m is an integer from 0 to 3;

[0029] L1, L2 and L3 are independently a single bond, -C 1-8 Alkylene-, -O-, -S-, -NR 1a -、 -R 1b C=CR1c -、-C(R 1a R 1b )-, -C(=O)-, -S(=O)-, -S(=O)2-, -PR 1a -、-P(=O)R 1a , -C(=O)O-, -OC(=O)-, -C(=O)NR 1a -、-NR 1a C(=O)-, S(=O)O-, -OS(=O)-, -OS(=O)2-, -S(=O)NR 1a -、-NR 1a S(=O)-、-S(=O)2NR 1a -、-NR 1a S(=O)2-, -OC(=O)O-, -OC(=O)NR 1a -、-NR 1a C(=O)O-, or -NR 1a C(=O)NR 1b -;

[0030] n is an integer from 1 to 10;

[0031] R 1 Selected from hydrogen, halogen, amino, hydroxy, -C 1-8 Alkyl, -SC 1-8 Alkyl, -OC 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR 1a 、-SO2R 1a 、-COR 1a 、-CO2R 1a 、-CONR 1a R 1b 、-CH2C(=O)NR 1a R 1b 、-C 2-8 Alkynyl (NR 1a )2、-C(=NR 1a )NR 1b R 1c 、-NR 1a R 1b 、-NR 1a COR 1b 、-NR 1a CONR 1b R 1c 、-NR 1a CO2R 1b 、-NR 1a SONR1b R 1c 、-NR 1a SO2NR 1b R 1c , or -NR 1a SO2R 1b , the -C 1-8 Alkyl, -SC 1-8 Alkyl, -OC 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are each optionally substituted by hydrogen, deuterium, halogen, cyano, hydroxyl, -C 1-8 Alkoxy, -NR 1d R 1e , cycloalkyl, heterocyclyl, aryl, or heteroaryl substituted;

[0032] Each R 1a 、R 1b , and R 1c are independently hydrogen, deuterium, halogen, cyano, amino, hydroxyl, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups are each optionally substituted with at least one substituent R 1d Replace; or

[0033] (R 1a and R 1b )、(R 1b and R 1c ), or (R 1c and R 1a ) together with the atom or atoms to which they are attached form a 3- to 9-membered ring comprising 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, said ring optionally substituted with at least one substituent R 1e replace;

[0034] where R 1d and R 1e are independently hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR 1f 、-SO2R 1f 、-COR 1f、-CO2R 1f 、-CONR 1f R 1g 、-C(=NR 1f )NR 1g R 1h 、-NR 1f R 1g 、-NR 1f COR 1g 、-NR 1f CONR 1g R 1h 、-NR 1f CO2R 1g 、-NR 1f SONR 1g R 1h 、-NR 1f SO2NR 1g R 1h , or -NR 1f SO2R 1g , the-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one selected from halogen, -C 1-8 Alkyl, -OR 1i 、-NR 1i R 1j , cycloalkyl, heterocyclyl, aryl, or heteroaryl substituents;

[0035] R 1f 、R 1g 、R 1h 、R 1i and R 1j are independently hydrogen, -C 1-8 Alkyl, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

[0036] R 2 is aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted by one or more R 2a replace;

[0037] Each R 2a are independently hydrogen, halogen, amino, hydroxy, -C 1-8 Alkyl, -SC 1-8 Alkyl, -OC 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR 2b 、-SO2R 2b 、-COR 2b 、-CO2R 2b 、-CONR 2b R 2c 、-CH2C(=O)NR 2b R 2c 、-C(=NR 2b )NR 2c R 2d 、-NR 2b R 2c 、-NR 2b COR 2c 、-NR 2b CONR 2c R 2d 、-NR 2b CO2R 2c 、-NR 2b SONR 2c R 2d 、-NR 2b SO2NR 2c R 2d , or -NR 2b SO2R 2c , the -C 1-8 Alkyl, -SC 1-8 Alkyl, -OC 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are each optionally substituted with deuterium, halogen, cyano, hydroxyl, -NR 2e R 2f , amino, -C 1-8 Alkyl, -C 1-8 Alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl substitution;

[0038] Each R 2b 、R 2c 、R 2d 、R 2e 、R 2f are independently hydrogen, deuterium, halogen or C 1-8 alkyl;

[0039] R 3 and R 4 are independently hydrogen, halogen, hydroxy, amino, -C 1-8 Alkyl, -OC 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR 4a 、-SO2R 4a 、-SO2NR 4a R 4b 、-COR 4a 、-CO2R 4a 、-CONR 4a R 4b 、-C(=NR 4a )NR 4b R 4c 、-NR 4a R 4b 、-NR 4a COR 4b 、-NR 4a CONR 4b R 4c 、-NR 4a CO2R 4b 、-NR 4a SONR 4b R 4c 、-NR 4a SO2NR 4b R 4c , or -NR 4a SO2R 4b , the-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups are each optionally substituted with at least one substituent R 4d replace;

[0040] R 4a 、R 4b , and R 4c are independently hydrogen, hydroxyl, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups are each optionally substituted with at least one substituent R 4e Replace; or

[0041] (R 4a and R 4b )、(R 4b and R 4c ), or (R 4c and R 4a) together with the atom or atoms to which they are attached form a 3 to 12 membered ring comprising 0, 1, 2 or 3 further heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, said ring optionally substituted with at least one substituent R 4e Replace; or

[0042] R 4d and R 4e are independently hydrogen, deuterium, halogen, hydroxyl, amino, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR 4f 、-SO2R 4f 、-SO2NR 4f R 4g 、-COR 4f 、-CO2R 4f 、-CONR 4f R 4g 、-C(=NR 4f )NR 4g R 4h 、-NR 4f R 4g 、-NR 4f COR 4g 、-NR 4f CONR 4g R 4h 、-NR 4f CO2R 4f 、-NR 4f SONR 4f R 4g 、-NR 4f SO2NR 4g R 4h , or -NR 4f SO2R 4g , the-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one selected from halogen, -C 1-8 Alkyl, -OR 4i 、-NR 4i R 4j , cycloalkyl, heterocyclyl, aryl, or heteroaryl substituents;

[0043] R 4f 、R 4g 、R 4h 、R 4i , and R4j are independently hydrogen, -C 1-8 Alkyl, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

[0044] R 5 、R 6 、R 7 、R 8 are independently hydrogen, deuterium, halogen, hydroxyl, amino, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR 5a 、-SO2R 5a 、-SO2NR 5a R 5b 、-COR 5a 、-CO2R 5a 、-CONR 5a R 5b 、-C(=NR 5a )NR 5b R 5c 、-NR 5a R 5b 、-NR 5a COR 5b 、-NR 5a CONR 5b R 5c 、-NR 5a CO2R 5b 、-NR 5a SONR 5b R 5c 、-NR 5a SO2NR 5b R 5c , or -NR 5a SO2R 5b , the-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups are each optionally substituted with at least one substituent R 5d replace;

[0045] R 5a 、R 5b , and R 5c are independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups are each optionally substituted with at least one substituent R 5e replace;

[0046] R 5d and R 5e are independently hydrogen, hydroxy, amino, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR 5f 、-SO2R 5f 、-SO2NR 5f R 5g 、-COR 5f 、-CO2R 5f 、-CONR 5f R 5g 、-C(=NR 5f )NR 5g R 5h 、-NR 5f R 5g 、-NR 5f COR 5g 、-NR 5f CONR 5g R 5h 、-NR 5f CO2R 5f 、-NR 5f SONR 5f R 5g 、-NR 5f SO2NR 5g R 5h , or -NR 5f SO2R 5g , the-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one selected from halogen, hydroxy, amino, cyano, -C 1-8 Alkyl, -C 1-8 Alkyl-OH, -OR 5i 、-NR 5i R 5j , cycloalkyl, heterocyclyl, aryl, or heteroaryl substituents;

[0047] R 5f 、R5g 、R 5h 、R 5i , and R 5j are independently hydrogen, -C 1-8 Alkyl, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

[0048] p is independently an integer from 1 to 5;

[0049] q is independently an integer from 1 to 5;

[0050] Z is selected from hydrogen, amino, hydroxy, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR 9 、-SR 9 、-SO2R 9 、-COR 9 、-CO2R 9 、-CONR 9 R 10 、-C(=NR 9 )NR 10 R 11 、 -NR 9 R 10 、-NR 9 COR 10 、-NR 9 CONR 10 R 11 、-NR 9 CO2R 10 、-NR 9 SONR 10 R 11 、-NR 9 SO2NR 10 R 11 , or -NR 9 SO2R 10 , the-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with hydrogen, deuterium, oxo, halogen, cyano, hydroxyl, amino, -C 1-8 Alkyl, -OR 9a 、-NR 9a R 9b 、-NR 9aCOR 9b 、-C 1-8 Alkoxy, -C 1-8 Alkyl-OR 9a , cycloalkyl, heterocyclyl, aryl, or heteroaryl substituted;

[0051] R 9 、R 10 , and R 11 are independently hydrogen, -C 1-8 Alkyl, -OC 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, the -C 1-8 Alkyl, -OC 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups are each optionally substituted with at least one substituent R 9a Replace; or

[0052] (R 9 and R 10 )、(R 10 and R 11 ), or (R 11 and R 9 ) together with the atom or atoms to which they are attached form a 3 to 12 membered ring comprising 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, said ring optionally substituted with at least one substituent R 9b replace;

[0053] or

[0054] When q is 1, (R 8 and Z) together with the atom or atoms to which they are attached form a 3 to 12 membered ring comprising 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, said ring optionally substituted with at least one substituent R 9b replace;

[0055] where R 9a and R 9b are each independently hydrogen, deuterium, halogen, hydroxyl, amino, carbonyl, carbonyl-C 1-8 Alkyl, -C 1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR 9c 、-SO2R9c 、-C 1-8 Alkyl-OR 9c 、-COR 9c 、-CO2R 9c 、-CONR 9c R 9d 、-C(=NR 9c )NR 9d R 9e 、-NR 9c R 9d 、-NR 9c COR 9d 、-NR 9c CONR 9d R 9e 、-NR 9c CO2R 9d 、-NR 9c SONR 9d R 9e 、-NR 9c SO2NR 9d R 9e , or -NR 9c SO2R 9d , the-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one selected from halogen, -C 1-8 Alkyl, -OR 9f 、-NR 9f R 9g , cycloalkyl, heterocyclyl, aryl, or heteroaryl substituents;

[0056] R 9c 、R 9d 、R 9e 、R 9f and R 9g are independently hydrogen, -C 1-8 Alkyl, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0057] Furthermore, R 3 and R 4 At least one of them is F, Cl, -NO2 or -CN. In some embodiments, R 3 and R 4 One of them is hydrogen, and the other is F or Cl, more preferably F.

[0058] In some embodiments, the KRAS ligand according to the present invention is a compound represented by the following formula (KII):

[0059] or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,

[0060] Among them, X1, X2, X3, R 100 ,m,L1,n,R 1 , L3, R 2 , L2, R 3 、R 4 、R 5 、R 6 、R 7 、R 8 , p, q are as defined above for the formula (KI).

[0061] Furthermore, R 3 and R 4 At least one of them is F, Cl, -NO2 or -CN. In some embodiments, R 3 and R 4 One of them is hydrogen, and the other is F or Cl, more preferably F.

[0062] In some embodiments of the present invention, X1 is N, and the other variables are as defined herein.

[0063] In some embodiments of the present invention, X1 is C, and the other variables are as defined herein.

[0064] In some embodiments of the present invention, X2 and X3 are N, and the other variables are as defined herein.

[0065] In some embodiments of the present invention, R 100 Select hydrogen, halogen (fluorine, chlorine, bromine), cyano, -OC 1-8 Alkyl (such as: ), C3-8 cycloalkyl (such as ), and other variables are as defined in the present invention.

[0066] In some embodiments of the present invention, R 100 are independently halogen, hydroxy, amino, -CN, or cycloalkyl, preferably halogen or cycloalkyl, more preferably F, Cl and cyclopropyl.

[0067] In some embodiments of the present invention, R 3 and R 4 are independently hydrogen, halogen, cyano, -OC 1-8 Alkyl, C 1-8 Alkyl, cycloalkyl, the -C 1-8 Alkyl, -OC 1-8Alkyl, cycloalkyl, each optionally deuterated, halogen, cyano, hydroxy, amino, -OC 1-8 Alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl substituted, provided that R 3 or R 4 At least one is F, Cl, -NO2 or -CN; the other variables are as defined in the present invention.

[0068] Furthermore, R 3 and R 4 independently selected from halogen, hydrogen, C 1-6 Alkyl, cyano, -NO2, provided that R 3 or R 4 At least one is F, Cl, -NO2 or -CN.

[0069] Furthermore, R 3 and R 4 are independently selected from -F, hydrogen, methyl, -CN, Cl, -NO2, provided that R 3 or R 4 At least one is F, Cl, -NO2 or -CN.

[0070] Furthermore, R 3 and R 4 are independently selected from -F, hydrogen, methyl, -CN, Cl, -NO2, provided that R 3 or R 4 At least one is F or -CN. In some embodiments, R 3 and R 4 One of them is hydrogen, and the other is F or Cl, more preferably F.

[0071] In some embodiments of the present invention, L1, L2 and L3 are independently a single bond, -C 1-6 Alkylene-, -O-, -S-, -NR 1a -、 -R 1b C=CR 1c -、-C(R 1a R 1b )-, -C(=O)-, -S(=O)-, -S(=O)2-, -PR 1a -、-P(=O)R 1a , -C(=O)O-, -OC(=O)-, -C(=O)NR 1a -、-NR 1a C(=O)-, S(=O)O-, -OS(=O)-, -OS(=O)2-, -S(=O)NR 1a -、-NR 1a S(=O)-、-S(=O)2NR 1a-、-NR 1a S(=O)2-, -OC(=O)O-, -OC(=O)NR 1a -、-NR 1a C(=O)O-、-NR 1a C(=O)NR 1b -;as well as

[0072] n is an integer from 1 to 10.

[0073] In some embodiments of the present invention, L3 is selected from a single bond, and the other variables are as defined herein.

[0074] In some embodiments of the present invention, L2 is selected from a single bond, -NH-, -CH2-, -O-, -S-, and other variables are as defined in the present invention.

[0075] In some embodiments of the present invention, L2 is selected from -O-, -NH-, -CH2-, and the other variables are as defined herein.

[0076] In some embodiments of the present invention, L2 is selected from -O-, and the other variables are as defined herein.

[0077] In some embodiments of the present invention, L1 is selected from a single bond, -NH-, -O-, -S-, -NHC(=O)-, -CH2-, -(CH2)2-, n=1 or 2, and other variables are as defined in the present invention.

[0078] In some embodiments of the present invention, -(L1) n - is selected from a single bond, -NH-, -O-, -S-, -OCH2-、-S-CH2-、 -NHC(=O)-, -CH2-, -(CH2)2-, and other variables are as defined in the present invention.

[0079] In some embodiments of the present invention, R 1 Selected from hydrogen, halogen, amino, hydroxy, -C 1-8 Alkyl, -SC 1-8 Alkyl, -OC 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR 1a 、-SO2R 1a 、-COR 1a 、-CO2R 1a 、-CONR 1a R 1b 、-CH2C(=O)NR 1a R1b 、-C 2-8 Alkynyl (NR 1a )2、-C(=NR 1a )NR 1b R 1c 、-NR 1a R 1b 、-NR 1a COR 1b 、-NR 1a CONR 1b R 1c 、-NR 1a CO2R 1b 、-NR 1a SONR 1b R 1c 、-NR 1a SO2NR 1b R 1c , or -NR 1a SO2R 1b , the -C 1-8 Alkyl, -SC 1-8 Alkyl, -OC 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are each optionally substituted with deuterium, halogen, cyano, hydroxyl, -C 1-8 Alkoxy, -NR 1d R 1e , cycloalkyl, heterocyclyl, aryl, or heteroaryl substituted;

[0080] R 1a 、R 1b , and R 1c are independently hydrogen, deuterium, halogen, cyano, amino, hydroxyl, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups are each optionally substituted with at least one substituent R 1d Replace; or

[0081] (R 1a and R 1b )、(R 1b and R 1c ), or (R 1c and R 1a) together with the atom or atoms to which they are attached form a 3- to 9-membered ring comprising 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, said ring optionally substituted with at least one substituent R 1e replace;

[0082] where R 1d and R 1e are independently hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR 1f 、-SO2R 1f 、-COR 1f 、-CO2R 1f 、-CONR 1f R 1g 、-C(=NR 1f )NR 1g R 1h 、-NR 1f R 1g 、-NR 1f COR 1g 、-NR 1f CONR 1g R 1h 、-NR 1f CO2R 1g 、-NR 1f SONR 1g R 1h 、-NR 1f SO2NR 1g R 1h , or -NR 1f SO2R 1g , the-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one selected from halogen, -C 1-8 Alkyl, -OR 1i 、-NR 1i R 1j , cycloalkyl, heterocyclyl, aryl, or heteroaryl substituents;

[0083] R 1f 、R 1g 、R 1h 、R 1i and R 1j are independently hydrogen, -C 1-8 Alkyl, C 1-8 Alkoxy-C1-8 Alkyl-, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

[0084] In some embodiments of the present invention, R 1 Selected from C 3-10 Cycloalkyl, C 3-10 Heterocyclic group, C 6-10 Aryl, C 6-10 Heteroaryl, the cycloalkyl, heterocyclic, aryl, heteroaryl are each optionally substituted by deuterium, halogen, cyano, hydroxyl, -C 1-8 Alkoxy, -NR 1d R 1e , cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0085] In some embodiments of the present invention, R 1 Selected from C 3-10 Heterocyclic group, preferably C containing N 3-10 Heterocyclic group, preferably In some embodiments of the present invention, the N-containing C 3-10 Heterocyclic groups are Preferred

[0086] In some embodiments of the present invention, R 1 Selected from C 4-10 Heterocyclic or C 4-10 Heteroaryl, wherein the heterocyclic group or heteroaryl group contains 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, preferably wherein M is N, CH; Cy3 is a 4-10 membered heterocyclic or heteroaryl group, wherein the heterocyclic or heteroaryl group contains 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, and the heterocyclic or heteroaryl group is optionally substituted by hydrogen, deuterium, halogen, cyano, hydroxyl, -C 1-8 Alkoxy, -NR 1d R 1e , cycloalkyl, heterocyclyl, aryl, or heteroaryl. In some preferred embodiments, R 1 yes In some preferred embodiments, R 1 yes Preferred

[0087] In some embodiments of the present invention, R 1 Selected from C 3-10 Cycloalkyl (such as C4 cycloalkyl), wherein each of the cycloalkyl groups is optionally substituted by -NR 1d R1e Substituted, preferably

[0088] In some embodiments of the present invention, R 1 Selected from-NR 1a R 1b , preferably

[0089] In some embodiments of the present invention, R 1 Selected from Other variables are as defined in the present invention.

[0090] In some embodiments of the present invention, -(L1) n -R 1 Selected from -R 1 , that is, L1 is a single bond, and the R 1 Selected from C 4-10 Heterocyclic or C 4-10 Heteroaryl, wherein the heterocyclic group or heteroaryl group contains 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, preferably wherein M is N, CH; Cy3 is a 4-10 membered heterocyclic or heteroaryl group, wherein the heterocyclic or heteroaryl group contains 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, and the heterocyclic or heteroaryl group is optionally substituted by hydrogen, deuterium, halogen, cyano, hydroxyl, -C 1-8 Alkoxy, -NR 1d R 1e , cycloalkyl, heterocyclyl, aryl, or heteroaryl. In some preferred embodiments, -(L1) n -R 1 yes In some preferred embodiments, -(L1) n -R 1 yes Preferred

[0091] In some embodiments of the present invention, -(L1) n Selected from -NH-, -O-, -S-, -OCH2-、-S-CH2-、 -NHC(=O)-, -CH2-, -(CH2)2-; and / or

[0092] R 1 Selected from R 1 Selected from-NR 1a R 1b 、C 3-10 Cycloalkyl, each of which is optionally substituted by -NR1d R 1e Substituted, preferably

[0093] Furthermore, -(L1) n -R 1 Selected from

[0094] In some embodiments of the present invention, -(L1) n -R 1 Selected from Other variables are as defined herein. Alternatively or additionally, in some embodiments, -(L1) n -R 1 yes

[0095] In some embodiments of the present invention, R 2 is aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted by one or more R 2a replace;

[0096] Each R 2a are independently hydrogen, halogen, amino, hydroxy, -C 1-8 Alkyl, -SC 1-8 Alkyl, -OC 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR 2b 、-SO2R 2b 、-COR 2b 、-CO2R 2b 、-CONR 2b R 2c 、-CH2C(=O)NR 2b R 2c 、-C(=NR 2b )NR 2c R 2d 、-NR 2b R 2c 、-NR 2b COR 2c 、-NR 2b CONR 2c R 2d 、-NR 2b CO2R 2c 、-NR 2b SONR 2c R 2d 、-NR 2b SO2NR2c R 2d , or -NR 2b SO2R 2c , the -C 1-8 Alkyl, -SC 1-8 Alkyl, -OC 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are each optionally substituted with deuterium, halogen, cyano, hydroxyl, -NR 2e R 2f , amino, -C 1-8 Alkyl, -C 1-8 Alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl substitution;

[0097] Each R 2b 、R 2c 、R 2d 、R 2e 、R 2f are independently hydrogen, deuterium, halogen or C 1-8 alkyl.

[0098] In some embodiments of the present invention, R 2 C 6-12 Aryl or C 6-12 Heteroaryl, the aryl or the heteroaryl is optionally substituted by one or more R 2a replace.

[0099] In some embodiments of the present invention, R 2 C 6-12 Aryl, which is replaced by one or more R 2a Substitute, the C 6-12 Aryl is selected from benzene ring Naphthalene ring

[0100] In some embodiments of the present invention, R 2 C 6-12 Heteroaryl, which is replaced by one or more R 2a Substitute, the C 6-12 Heteroaryl is selected from

[0101] The above R 2a Selected from halogen, hydroxyl, C 1-8 Alkyl, -C 2-8 Alkynyl, amino, cyano, -C substituted by halogen 1-8 Alkyl; preferably selected from -F, -Cl, methyl, hydroxy, ethynyl, ethyl, amino, cyano, -CF3.

[0102] In some embodiments of the present invention, R2 Selected from Other variables are as defined in the present invention.

[0103] In some embodiments of the present invention, R 2 for

[0104] In some embodiments of the present invention, R 5 、R 6 、R 7 、R 8 are independently hydrogen, deuterium, halogen, hydroxyl, amino, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR 5a 、-SO2R 5a 、-SO2NR 5a R 5b 、-COR 5a 、-CO2R 5a 、-CONR 5a R 5b 、-C(=NR 5a )NR 5b R 5c 、-NR 5a R 5b 、-NR 5a COR 5b 、-NR 5a CONR 5b R 5c 、-NR 5a CO2R 5b 、-NR 5a SONR 5b R 5c 、-NR 5a SO2NR 5b R 5c , or -NR 5a SO2R 5b , the-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups are each optionally substituted with at least one substituent R 5d replace;

[0105] R 5a 、R 5b , and R 5c are independently hydrogen, -C 1-8 Alkyl, -C2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups are each optionally substituted with at least one substituent R 5e replace;

[0106] R 5d and R 5e are independently hydrogen, hydroxy, amino, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR 5f 、-SO2R 5f 、-SO2NR 5f R 5g 、-COR 5f 、-CO2R 5f 、-CONR 5f R 5g 、-C(=NR 5f )NR 5g R 5h 、-NR 5f R 5g 、-NR 5f COR 5g 、-NR 5f CONR 5g R 5h 、-NR 5f CO2R 5f 、-NR 5f SONR 5f R 5g 、-NR 5f SO2NR 5g R 5h , or -NR 5f SO2R 5g , the-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one selected from halogen, hydroxy, amino, cyano, -C 1-8 Alkyl, -C 1-8 Alkyl-OH, -OR 5i 、-NR 5i R 5j , cycloalkyl, heterocyclyl, aryl, or heteroaryl substituents;

[0107] R 5f 、R 5g 、R 5h 、R 5i , and R 5j are independently hydrogen, -C 1-8 Alkyl, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0108] In some embodiments of the present invention, R 5 、R 6 、R 7 、R 8 are independently hydrogen, deuterium or C 1-8 alkyl.

[0109] In some embodiments of the present invention, R 5 is selected from hydrogen, and the other variables are as defined in the present invention.

[0110] In some embodiments of the present invention, R 6 is selected from hydrogen, and the other variables are as defined in the present invention.

[0111] In some embodiments of the present invention, R 7 is selected from hydrogen, and the other variables are as defined in the present invention.

[0112] In some embodiments of the present invention, R 8 is selected from hydrogen, and the other variables are as defined in the present invention.

[0113] In some embodiments of the present invention, p is independently selected from 1 and 2, and other variables are as defined herein.

[0114] In some embodiments of the present invention, q is independently selected from 1 and 2, and other variables are as defined herein.

[0115] In some embodiments of the present invention, Z is selected from hydrogen, amino, hydroxy, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR 9 、-SR 9 、-SO2R 9 、-COR 9 、-CO2R 9 、-CONR 9 R 10 、-C(=NR 9 )NR 10 R 11、-NR 9 R 10 、-NR 9 COR 10 、-NR 9 CONR 10 R 11 、-NR 9 CO2R 10 、-NR 9 SONR 10 R 11 、-NR 9 SO2NR 10 R 11 , or -NR 9 SO2R 10 , the-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with hydrogen, deuterium, oxo, halogen, cyano, hydroxyl, amino, -C 1-8 Alkyl, -OR 9a 、-NR 9a R 9b 、-NR 9a COR 9b 、-C 1-8 Alkoxy, -C 1-8 Alkyl-OR 9a , cycloalkyl, heterocyclyl, aryl, or heteroaryl substituted;

[0116] R 9 、R 10 , and R 11 are independently hydrogen, -C 1-8 Alkyl, -OC 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, the -C 1-8 Alkyl, -OC 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups are each optionally substituted with at least one substituent R 9a Replace; or

[0117] (R 9 and R 10 )、(R 10 and R 11 ), or (R 11 and R 9) together with the atom or atoms to which they are attached form a 3 to 12 membered ring comprising 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, said ring optionally substituted with at least one substituent R 9b replace;

[0118] or

[0119] When q is 1, (R 8 and Z) together with the atom or atoms to which they are attached form a 3 to 12 membered ring comprising 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, said ring optionally substituted with at least one substituent R 9b replace;

[0120] where R 9a and R 9b are each independently hydrogen, deuterium, halogen, hydroxyl, amino, carbonyl, carbonyl-C 1-8 Alkyl, -C 1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR 9c 、-SO2R 9c 、-C 1-8 Alkyl-OR 9c 、-COR 9c 、-CO2R 9c 、-CONR 9c R 9d 、-C(=NR 9c )NR 9d R 9e 、-NR 9c R 9d 、-NR 9c COR 9d 、-NR 9c CONR 9d R 9e 、-NR 9c CO2R 9d 、-NR 9c SONR 9d R 9e 、-NR 9c SO2NR 9d R 9e , or -NR 9c SO2R 9d , the-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one selected from halogen, -C 1-8 Alkyl, -OR 9f 、-NR 9f R 9g , cycloalkyl, heterocyclyl, aryl, or heteroaryl substituents;

[0121] R 9c 、R 9d 、R 9e 、R 9f and R 9g are independently hydrogen, -C 1-8 Alkyl, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0122] In some embodiments of the present invention, when q is 1, (R 8 and Z) together with the atom or atoms to which they are attached form a 3 to 12 membered ring comprising 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, said ring optionally substituted with at least one substituent R 9b replace;

[0123] Furthermore, R 8 and Z form C 3-9 Heterocyclic group, said heterocyclic group is optionally substituted by at least one R 9b Replacement, R 9b is selected from hydrogen, methyl, and ethyl;

[0124] Furthermore, R8 and Z form C 3-9 Heterocyclic groups are It is optionally substituted with methyl, further

[0125] In some embodiments of the present invention, Z is selected from hydrogen, amino, hydroxyl, -OR 9 、-SR 9 、-NR 9 R 10 、-NR 9 COR 10 , cycloalkyl, heterocyclic group, aryl, heteroaryl, wherein the cycloalkyl, heterocyclic group, aryl, heteroaryl are each optionally substituted by hydrogen, deuterium, oxo, halogen, cyano, hydroxyl, amino, -C 1-8 Alkyl, -OR 9a 、-NR 9a R 9b 、-NR9a COR 9b 、-C 1-8 Alkoxy, -C 1-8 Alkyl-OR 9a , cycloalkyl, heterocyclyl, aryl, or heteroaryl substituted;

[0126] R 9 、R 10 are independently (in accordance with valence bond theory) hydrogen, C 1-8 Alkyl, -OC 1-8 Alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, the C 1-8 Alkyl, -OC 1-8 Alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with hydrogen, deuterium, halogen, cyano, hydroxyl, amino, -C 1-8 Alkoxy, -OR 9c , cycloalkyl, heterocyclyl, aryl, or heteroaryl; or

[0127] R 9 With R 10 Together with the one or more atoms to which they are attached, they form a 3- to 12-membered ring comprising 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, the ring being optionally substituted with hydrogen, deuterium, halogen, cyano, hydroxy, oxo, amino, carbonyl, carbonyl-C 1-8 Alkyl, -C 1-8 Alkyl, -OR 9c 、-C 1-8 Alkyl-OR 9c , cycloalkyl, heterocyclyl, aryl, or heteroaryl substituted;

[0128] R 9a 、R 9b 、R 9c are each independently hydrogen, deuterium or -C 1-8 alkyl.

[0129] In some embodiments of the present invention, Z is selected from -OR 9 、-SR 9 、-NR 9 R 10 、-NR 9 COR 10 ,

[0130] R 9 、R 10 are independently (in accordance with valence bond theory) hydrogen, C 1-8 Alkyl, -OC 1-8 Alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, the C 1-8 Alkyl, -OC1-8 Alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with hydrogen, deuterium, halogen, cyano, hydroxyl, amino, -C 1-8 Alkoxy, -OR 9c , cycloalkyl, heterocyclyl, aryl, or heteroaryl; or

[0131] R 9 With R 10 Together with the one or more atoms to which they are attached, they form a 3- to 12-membered ring comprising 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, the ring being optionally substituted with hydrogen, deuterium, halogen, cyano, hydroxy, oxo, amino, carbonyl, carbonyl-C 1-8 Alkyl, -C 1-8 Alkyl, -OR 9c 、-C 1-8 Alkyl-OR 9c , cycloalkyl, heterocyclyl, aryl, or heteroaryl substituted;

[0132] R 9c are each independently hydrogen, deuterium or -C 1-8 alkyl.

[0133] In some embodiments of the present invention, Z is selected from -NR 9 COR 10 , where R 9 、R 10 are independently hydrogen, methyl, or ethyl.

[0134] In some aspects of the present invention, Z is preferably selected from -NR 9 R 10 , where R 9 、R 10 are independently hydrogen, methyl, ethyl, ethyl substituted with -OCH3; or wherein R 9 and R 10 It forms a 3- to 12-membered heterocyclic group.

[0135] In some embodiments of the present invention, Z is selected from -NR 9 R 10 , where R 9 、R 10 are independently hydrogen, methyl, ethyl, ethyl substituted with -OCH3; further selected from

[0136] In some embodiments of the present invention, Z is selected from -NR 9 R 10 , where R 9 and R 10 A 3- to 12-membered heterocyclic group, wherein the heterocyclic group is selected from Further, the heterocyclic group is optionally substituted by oxo, halogen, methyl, -OCH3, -CH2-OH, heterocyclic group, and can be selected from

[0137] In some embodiments of the present invention, Z is selected from -OR 9 , where R 9 Selected from hydrogen, methyl, ethyl substituted by hydroxyl, C3 cycloalkyl; further selected from

[0138] In some embodiments of the present invention, Z is selected from Other variables are as defined in the present invention.

[0139] In some embodiments of the present invention, the KRAS ligand compound is a compound represented by the following formula (KIA) or (KIB):

[0140] or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein R 100 ,m,L1,n,R 1 , L3, R 2 , L2, R 3 、R 4 、R 5 、R 6 、R 7 、R 8 , Z, p, q are as defined above.

[0141] Furthermore, R 3 and R 4 At least one of them is F, Cl, -NO2 or -CN. In some embodiments, R 3 and R 4 One of them is hydrogen, and the other is F or Cl, more preferably F.

[0142] In some embodiments of the present invention, the KRAS ligand compound is a compound represented by the following formula (KIIA) or (KIIB):

[0143] or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein R 100 ,m,L1,n,R 1 , L3, R 2 , L2, R 3 、R 4 、R 5 、R 6 、R 7 、R8 , p, q are as defined above.

[0144] Furthermore, R 3 and R 4 At least one of them is F, Cl, -NO2 or -CN. In some embodiments, R 3 and R 4 One of them is hydrogen, and the other is F or Cl, more preferably F.

[0145] In some embodiments of the present invention, the KRAS ligand compound is a compound represented by the following formula (KIC)-(KIJ):

[0146] or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein L2, R 3 、R 4 、R 5 、R 6 、R 7 、R 8 , p, q, and Z are as defined above.

[0147] Furthermore, R 3 and R 4 At least one of them is F, Cl, -NO2 or -CN. In some embodiments, R 3 and R 4 One of them is hydrogen, and the other is F or Cl, more preferably F.

[0148] In some embodiments of the present invention, the KRAS ligand compound is a compound represented by the following formula (KIIC)-(KIIS):

[0149] or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein L2, R 3 、R 4 、R 5 、R 6 、R 7 、R 8 , p, q are as defined above.

[0150] Furthermore, R 3 and R 4 At least one of them is F, Cl, -NO2 or -CN. In some embodiments, R 3 and R 4 One of them is hydrogen, and the other is F or Cl, more preferably F.

[0151] In some embodiments of the present invention, the KRAS ligand compound is a compound represented by the following formula (KIK) or (KIL):

[0152] or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein R 100 ,m,X1,L3,R 2 、R 3 、R 4 As defined above.

[0153] Furthermore, R 3 and R 4 At least one of them is F, Cl, -NO2 or -CN. In some embodiments, R 3 and R 4 One of them is hydrogen, and the other is F or Cl, more preferably F.

[0154] The present invention provides the KRAS ligand compound described above, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the KRAS ligand compound is selected from the KRAS ligand compounds exemplified herein, as shown in Table 1 below:

[0155] , preferably

[0156] Degradation Label B

[0157] In some embodiments, B is a group that binds an E3 ligase, wherein the E3 ligase is selected from von Hippel-Lindau (VHL), Cereblon, XIAP, E3A, MDM2, anaphase-promoting complex (APC), UBR5 (EDD1), SOCS / BC-box / eloBC / CUL5 / RING, LNXp80, CBX4, CBLL1, HACE1, HECTD1, HECTD2, HECTD3, HECW1, HECW2, HERC1, HERC2, HERC3, HERC4, HUWE1, ITCH, NEDD4, NEDD4L, PPIL2, PRPF19, PIAS1, PIAS2, PIAS3, PIAS4, RANBP2, RNF4, RBX1, SMURF1, SMURF2, STUB1, TOPORS, TRIP12, UBE3A, UBE3B, UBE3C, UBE4A, UBE4B, UBOX5, UBR5, WWP1, WWP2, Parkin, A20 / TNFAIP3, AMFR / gp78, ARA54, β-TrCP1 / BT RC, BRCA1, CBL, CHIP / STUB1, E6, E6AP / UBE3A, F-box protein 15 / FBXO15, FBXW7 / Cdc4, GRAIL / RNF128, HOIP / RNF31, cIAP-1 / HIAP-2, cIAP-2 / HIAP-1, cIAP(pan), ITCH / AIP4, KAP1, MARCH8, MindBomb1 / MIB1, Min dBomb2 / MIB2, MuRF1 / TRIM63, NDFIP1, NEDD4, NleL, Parkin, RNF2, RNF4, RNF8, RNF168, RNF43, SART1, Skp2, SMURF2, TRAF-1, TRAF-2, TRAF-3, TRAF-4, TRAF-5, TRAF-6, TRIM5, TRIM21, TRIM32, UBR5, or ZNRF3.

[0158] Furthermore, the B is a group that binds to an E3 ligase selected from VHL, Cereblon, MDM2 or cIAP.

[0159] In some embodiments, B is selected from the structure represented by the following formula:

[0160] in,

[0161] V3 and V4 are each independently selected from absent, NH, O, S, SO, SO2, SO2NR h6 SRh6 、-R h6 CO-、-COR h6 -、CO、CO2、C(O)NR h6 、C(O)NR h6 R h6 、C(S)NR h6 NR h6 NR h6 CO, R h6 NR h6 CO、NR h6 CONR h7 、-C 1-8 Alkylene, -C 2-8 Alkenylene, -C 2-8 Alkyne, cycloalkyl, heterocyclic, aryl and heteroaryl, the -C 1-8 Alkylene, -C 2-8 Alkenylene, -C 2-8 Alkyne, cycloalkyl, heterocyclyl, aryl or heteroaryl are each optionally replaced by R h8 replace;

[0162] R H1 Independently selected from amino, NR h6 R h7 , heterocyclic, aryl and heteroaryl, wherein the aryl and heteroaryl are each optionally substituted by one or more R h8 replace;

[0163] R h independently selected from hydrogen, halogen, C 1-8 Alkyl, heterocyclic and heteroaryl, each of which is optionally substituted by 1, 2 or more R h5 replace;

[0164] R h1 and R h3 are independently selected from hydrogen, NR h6 R h7 、-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C 3-9 Cycloalkyl and C 3-9 Heterocyclic group, the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C 3-9 Cycloalkyl, or C 3-9 The heterocyclic groups are each optionally substituted by one or more R h9 replace;

[0165] R h2independently selected from hydrogen, deuterium, halogen, nitro, cyano, amino, hydroxyl, carboxyl, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR C6 、-SO2R h6 、-SO2NR h6 R h7 、-COR h6 、-CO2R h6 、-CONR h6 R h7 、-POR h6 R h7 、-NR h6 R h7 、-NR h6 COR h7 、-NR h6 CONR h7 R h8 、-NR h6 CO2R h7 、-NR h6 SO2NR h7 R h8 、-NR h6 SO2R h7 , the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are each optionally substituted with at least one substituent R h10 replace;

[0166] q1 is independently 1 or 2;

[0167] R h4 、R h5 、R h6 、R h7 independently selected from hydrogen, deuterium, halogen, nitro, cyano, amino, hydroxyl, carboxyl, -C 1-8 Alkyl, -C(O)R h12 , the -C 1-8 The alkyl group is optionally replaced by one or more R h11 replace;

[0168] R h8 、R h9 、R h10 、R h11 independently selected from hydrogen, deuterium, CN, halogen, carbonyl, nitro, amino, hydroxyl, carboxyl, oxo, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0169] R h12 Selected from C 3-9 Cycloalkyl, the C 3-9 The cycloalkyl group is optionally substituted with CN, halogen, nitro, amino, hydroxy, carboxyl, -C 1-3 Alkyl substitution.

[0170] In some embodiments, R H1 Independently selected from amino, NR h6 R h7 , heterocyclic, aryl and heteroaryl, wherein the aryl and heteroaryl are each optionally substituted by one or more R h8 replace.

[0171] In some embodiments, R h8 、R h9 、R h10 、R h11 independently selected from hydrogen, deuterium, CN, halogen, carbonyl, nitro, amino, hydroxyl, carboxyl, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.

[0172] In some further embodiments, R h1 are independently selected from hydrogen, -C 1-8 Alkyl and C 3-9 Cycloalkyl.

[0173] In some embodiments, R h2 Selected from hydrogen, deuterium, halogen, nitro, cyano, amino, hydroxyl, -C 1-8 Alkyl, deuterated-C 1-8 Alkyl and halo-C 1-8 alkyl.

[0174] In some embodiments, R h3 independently selected from hydrogen, hydroxy substituted -C 1-8 Alkyl, and C 3-9 Cycloalkyl.

[0175] In some embodiments, R h4 Selected from hydrogen, deuterium, halogen, nitro, cyano, amino, hydroxyl, -C 1-8 Alkyl, deuterated-C 1-8 Alkyl and halo-C 1-8 alkyl.

[0176] In some embodiments, R h independently selected from H, halogen, C 1-8 alkyl,

[0177] In some embodiments, R h5 Selected from hydrogen, deuterium, halogen, nitro, cyano, amino, hydroxyl, -C 1-8 Alkyl, deuterated-C 1-8 Alkyl and halo-C 1-8 alkyl.

[0178] In some embodiments, V3 is selected from C(O)NR h6 NR h6 CO, heterocyclic and heteroaryl, each of which is optionally replaced by R h8 replace.

[0179] In some embodiments, V4 is independently selected from absent, SR h6 、-R h6 CO-、-COR h6 -、C(O)NR h6 R h6 、R h6 NR h6 CO and -C 1-8 Alkylene, the -C 1-8 The alkylene group is optionally replaced by R h8 replace.

[0180] In some embodiments, R H1 Independently selected from amino, NR h6 R h7 , heterocyclic and heteroaryl, each of which is optionally substituted by one or more R h8 replace.

[0181] In some embodiments, R h6 and R h7 independently selected from hydrogen, deuterium, -C 1-8 Alkyl and -C(O)R h12 , the-C 1-8 The alkyl group is optionally replaced by one or more R h11 replace.

[0182] In some embodiments, R h8 independently selected from hydrogen, deuterium, CN, halogen, oxo, -C 1-8 Alkyl and cycloalkyl groups.

[0183] In some embodiments, R h11 are independently selected from hydrogen and deuterium.

[0184] In some embodiments, R h12 Selected from C 3-9Cycloalkyl, the C 3-6 Cycloalkyl is optionally substituted with CN or halogen.

[0185] Furthermore,

[0186] R h1 Selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, and / or

[0187] R h2 is selected from hydrogen, deuterium, halogen, nitro, cyano, amino, hydroxy, methyl, ethyl, deuterated methyl or halomethyl; and / or

[0188] R h3 Selected from hydrogen, methyl, ethyl, propyl, isopropyl or

[0189] R h4 is selected from hydrogen, deuterium, halogen, nitro, cyano, amino, hydroxy, methyl, ethyl, deuterated methyl or halomethyl; and / or

[0190] R h independently selected from H, halogen, C 1-8 alkyl, and / or

[0191] R h5 Selected from hydrogen, deuterium, halogen, nitro, cyano, amino, hydroxyl, C 1-8 Alkyl (such as methyl, ethyl, deuterated methyl) or halomethyl; and / or

[0192] V3 is selected from -C(O)NH-, -NHC(O)-, and / or

[0193] V4 is selected from the group consisting of absent, -CH2-, -CH2C(O)-, -C(O)CH2-, -CH2NHC(O)-, -C(O)NHCH2-, and / or

[0194] R H1 Selected from Further selected

[0195] C mentioned above 1-8 Alkyl refers to a straight or branched chain alkyl group having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, etc.; the halogen refers to fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

[0196] In some embodiments, B is selected from the structure represented by the general formula:

[0197] (Preferred )(BVJ),

[0198] where R h1 、R h3 、R h4 、R h 、R h5 、R H1 、CyV、R h6 As defined above for general formula (B-V1), formula (B-V2), formula (B-V3), and formula (B-V4).

[0199] Further, the formula (BVC) is where R h3 Not hydrogen.

[0200] Further, the formula (BVD) is where R h3 Not hydrogen.

[0201] Further, the formula (BVE) is where R h3 Not hydrogen.

[0202] Further, the formula (BVG) is where R h3 Not hydrogen.

[0203] In some further embodiments, R h1 Selected from isopropyl, tert-butyl,

[0204] R h3 Selected from H, methyl,

[0205] R h4 is selected from H, halogen;

[0206] R h Selected from hydrogen, halogen, C 1-8 alkyl,

[0207] R h5 Selected from hydrogen, C 1-8 Alkyl, preferably methyl or hydrogen;

[0208] R H1 Selected from

[0209] CyV is selected from

[0210] R h6 Selected from hydrogen, deuterium, halogen, nitro, cyano, amino, hydroxyl, carboxyl, -C 1-8 Alkyl, -C(O)R h12 , the -C 1-8 The alkyl group is optionally replaced by one or more R h11 replace;

[0211] R h11 independently selected from hydrogen, deuterium, CN, halogen, carbonyl, nitro, amino, hydroxyl, carboxyl, nitro, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0212] R h12 Selected from C 3-9 Cycloalkyl, the C 3-9 The cycloalkyl group is optionally substituted with CN, halogen, nitro, amino, hydroxy, carboxyl, nitro, -C 1-3 Alkyl substitution.

[0213] In some embodiments, R H1 Selected from

[0214] In some further embodiments, R h1 Selected from

[0215] R H1 Selected from

[0216] R h3 is selected from hydrogen, methyl,

[0217] R h4 is hydrogen;

[0218] R h Selected from

[0219] R h5 Selected from methyl and ethyl;

[0220] CyV is selected from as well as

[0221] Rh6 For hydrogen.

[0222] In some embodiments, the structure of B is shown in the following table:

[0223] In some embodiments, the structure of B is:

[0224] Linker L between B and KRAS ligand

[0225] In some embodiments of the present invention, L may be L4a, L4b, or L4c.

[0226] L4a

[0227] In some embodiments of the present invention, L is L4a.

[0228] In some embodiments of the invention, L4a is

[0229] Among them, here

[0230] X5 selected from CR L1 R L2 NR L1 , O, S or does not exist;

[0231] w and v are each independently selected from 1, 2, 3, 4, 5, 6, 7, 8, and 9;

[0232] R L 、R L1 、R L2 are each independently selected from hydrogen, halogen, C 1-8 Alkyl, hydroxyl.

[0233] Furthermore, L4a is

[0234] In some embodiments of the invention, L4a is

[0235] Among them, here

[0236] X5 is selected from the group consisting of: absent, -O-, -CH2-,

[0237] Ring CyL3 is a 3-9 membered cycloalkyl group, or a 3-9 membered heterocyclyl group;

[0238] R L 、R L1are each independently selected from hydrogen, halogen, C 1-8 Alkyl, hydroxyl;

[0239] s, w, and v are each independently selected from 0, 1, 2, 3, 4, and 5.

[0240] Furthermore, CyL3 is preferably a 4-9 membered cycloalkyl group, more preferably Additionally or alternatively, CyL3 is

[0241] Furthermore, CyL3 is preferably a 4-8 membered heterocyclic group, more preferably

[0242] Furthermore, L4a is

[0243] Additionally or alternatively, in some embodiments L4a is

[0244] In some embodiments of the invention, L4a is

[0245] Among them, here

[0246] X6 is selected from absent, -CH2-;

[0247] Ring CyL4 is a 5-9 membered aromatic ring, or a 5-9 membered aromatic heterocyclic ring;

[0248] R L 、R L1 are each independently selected from hydrogen, halogen, C 1-8 Alkyl, hydroxyl;

[0249] s, w, and v are each independently selected from 0, 1, 2, 3, 4, and 5.

[0250] Furthermore, CyL4 is preferably a 5-9 membered aromatic ring, more preferably a benzene ring.

[0251] Furthermore, CyL4 is preferably a 5-6 membered aromatic heterocycle, more preferably

[0252] Furthermore, L4a is

[0253] In some embodiments of the invention, L4a is

[0254] Among them, here

[0255] X6 is selected from absent, -CH2-;

[0256] Ring CyL4 is a 5-9 membered aromatic ring, or a 5-9 membered aromatic heterocyclic ring;

[0257] R L1 are each independently selected from hydrogen, halogen, C 1-8 Alkyl, hydroxyl;

[0258] s, w, and v are each independently selected from 0, 1, 2, 3, 4, and 5.

[0259] Furthermore, CyL4 is preferably a 5-9 membered aromatic ring, more preferably a benzene ring.

[0260] Furthermore, L4a is

[0261] In some embodiments of the invention, L4a is

[0262] Among them, here

[0263] X5 is selected from -O-, -CH2-;

[0264] w is selected from 0, 1, 2, 3, 4, 5;

[0265] Ring CyL1 is a 3-9 membered heterocyclic group;

[0266] R L1 independently selected from hydrogen, halogen, C 1-8 alkyl;

[0267] s is independently selected from 0, 1, 2, 3, 4.

[0268] Furthermore, L4a is

[0269] In some embodiments of the invention, L4a is

[0270] Among them, here

[0271] X5 is selected from -O-, -CH2-,

[0272] Ring CyL1 is a 3-9 membered heterocyclic group;

[0273] Ring CyL2 is a 3-9 membered heterocyclic group;

[0274] R L1 、R L2 are each independently selected from hydrogen, halogen, C 1-8 alkyl;

[0275] s and t are each independently selected from 0, 1, 2, 3, and 4.

[0276] Furthermore, CyL1 is preferably a 4-6 membered N-containing heterocyclic group, more preferably

[0277] Furthermore, CyL2 is preferably a 4-8 membered N-containing heterocyclic group, more preferably

[0278] Furthermore, L4a is

[0279] Furthermore, in some embodiments of the present invention, L4a is selected from

[0280] Additionally or alternatively, in some embodiments, L4a is selected from

[0281] L4b

[0282] In some embodiments of the present invention, L is L4b.

[0283] In some embodiments of the invention, L4b is

[0284] Among them, here

[0285] Each X5 is independently selected from CR L1 R L2 NR L1 , O, S or does not exist;

[0286] Each w and v are independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9;

[0287] s is selected from 1, 2, 3, 4, 5;

[0288] Each R L 、R L1 、R L2 are each independently selected from hydrogen, halogen, C 1-8 Alkyl, hydroxyl.

[0289] Furthermore, L4b is

[0290] Additionally or alternatively, in some embodiments, L4b is

[0291] In some embodiments of the invention, L4b is

[0292] Among them, here

[0293] X5 is selected from the group consisting of: absent, -O-, -CH2-,

[0294] X6 is selected from the group consisting of absent, -O-, -NR L2 -;

[0295] Ring CyL3 is a 3-9 membered cycloalkyl, phenyl or a 3-9 membered heterocyclyl;

[0296] R L 、R L1 、R L2 are each independently selected from hydrogen, halogen, C 1-8 Alkyl, hydroxyl;

[0297] s, w, and v are each independently selected from 0, 1, 2, 3, 4, and 5.

[0298] Furthermore, CyL3 is preferably a 4-9 membered cycloalkyl group, more preferably

[0299] Furthermore, CyL3 is preferably a 4-8 membered heterocyclic group, more preferably

[0300] Furthermore, L4b is (Preferred ),

[0301] Additionally or alternatively, in some embodiments, L4b is

[0302] In some embodiments of the invention, L4b is

[0303] Among them, here

[0304] X6 is selected from absent, -CH2-, O;

[0305] Ring CyL4 is a 5-9 membered aromatic ring, or a 5-9 membered aromatic heterocyclic ring;

[0306] R L1 are each independently selected from hydrogen, halogen, C 1-8 Alkyl, hydroxyl;

[0307] s, w, and v are each independently selected from 0, 1, 2, 3, 4, and 5.

[0308] Furthermore, CyL4 is preferably a 5-9 membered aromatic ring, more preferably a benzene ring.

[0309] Furthermore, L4b is Additionally or alternatively, in some embodiments, L4b is

[0310] In some embodiments of the invention, L4b is

[0311] Among them, here

[0312] X6 is selected from absent, -O-;

[0313] Ring CyL4 is a 5-9 membered aromatic ring, or a 5-9 membered aromatic heterocyclic ring;

[0314] R L 、R L1 are each independently selected from hydrogen, halogen, C 1-8 Alkyl, hydroxyl;

[0315] R A 、R B are each independently selected from hydrogen and C 1-3 alkyl;

[0316] s, w, and v are each independently selected from 0, 1, 2, 3, 4, and 5.

[0317] In some embodiments, L4b is

[0318] Furthermore, CyL4 is preferably a 5-9 membered aromatic ring, more preferably a benzene ring.

[0319] Furthermore, CyL4 is preferably a 5-6 membered aromatic heterocycle, more preferably

[0320] Furthermore, L4b is

[0321] Additionally or alternatively, in some embodiments, L4b is

[0322] In some embodiments of the invention, L4b is

[0323] Among them, here

[0324] X5 is selected from absent, -O-, -CH2-;

[0325] X6 is selected from absent, -O-;

[0326] X5 and X6 cannot exist at the same time;

[0327] w is selected from 0, 1, 2, 3, 4, 5;

[0328] Ring CyL1 is a 3-9 membered heterocyclic group;

[0329] R L1 independently selected from hydrogen, halogen, C 1-8 alkyl;

[0330] s is independently selected from 0, 1, 2, 3, 4.

[0331] Furthermore, L4b is

[0332] Additionally or alternatively, in some embodiments, L4b is

[0333] In some embodiments of the invention, L4b is

[0334] Among them, here

[0335] X5 is selected from -O-, -CH2-,

[0336] Ring CyL1 is a 3-9 membered heterocyclic group;

[0337] Ring CyL2 is a 3-9 membered heterocyclic group;

[0338] R L1 、R L2 are each independently selected from hydrogen, halogen, C 1-8 alkyl;

[0339] s and t are each independently selected from 0, 1, 2, 3, and 4.

[0340] Furthermore, CyL1 is preferably a 4-6 membered N-containing heterocyclic group, more preferably

[0341] Furthermore, CyL1 is preferably a 4-8 membered N-containing heterocyclic group, more preferably

[0342] Furthermore, L4b is

[0343] Furthermore, in some embodiments of the present invention, L4b is selected from (Preferred ),

[0344] Additionally or alternatively, in some embodiments, L4b is

[0345] L4c

[0346] In some embodiments of the present invention, L is L4c.

[0347] In some embodiments of the invention, L4c is

[0348] Among them, here

[0349] w and v are each independently selected from 1, 2, 3, 4, 5, 6, 7, 8, and 9;

[0350] R L 、R L1 are each independently selected from hydrogen, halogen, C 1-8 Alkyl, hydroxyl.

[0351] Furthermore, L4c is

[0352] In some embodiments of the invention, L4c is

[0353] Among them, here

[0354] X5 is selected from the group consisting of: absent, -O-, -CH2-,

[0355] Ring CyL3 is a 3-9 membered cycloalkyl, phenyl or a 3-9 membered heterocyclyl;

[0356] R L 、R L1 are each independently selected from hydrogen, halogen, C 1-8 Alkyl, hydroxyl;

[0357] s, w, and v are each independently selected from 0, 1, 2, 3, 4, and 5.

[0358] Furthermore, CyL3 is preferably a 4-9 membered cycloalkyl group, more preferably

[0359] Furthermore, CyL3 is preferably a 4-8 membered heterocyclic group, more preferably

[0360] Furthermore, L4c is

[0361] Additionally or alternatively, in some embodiments, L4c is

[0362] In some embodiments of the invention, L4c is

[0363] Among them, here

[0364] X6 is selected from absent, -CH2-;

[0365] Ring CyL4 is a 5-9 membered aromatic ring, or a 5-9 membered aromatic heterocyclic ring;

[0366] R L 、R L1 are each independently selected from hydrogen, halogen, C 1-8 Alkyl, hydroxyl;

[0367] s, w, and v are each independently selected from 0, 1, 2, 3, 4, and 5.

[0368] Furthermore, CyL4 is preferably a 5-9 membered aromatic ring, more preferably a benzene ring.

[0369] Furthermore, CyL4 is preferably a 5-6 membered aromatic heterocycle, more preferably

[0370] Furthermore, L4c is

[0371] In some embodiments of the invention, L4c is

[0372] Among them, here

[0373] X6 is selected from absent, -CH2-;

[0374] Ring CyL4 is a 5-9 membered aromatic ring, or a 5-9 membered aromatic heterocyclic ring;

[0375] R L 、R L1 are each independently selected from hydrogen, halogen, C 1-8 Alkyl, hydroxyl;

[0376] s, w, and v are each independently selected from 0, 1, 2, 3, 4, and 5.

[0377] Furthermore, CyL4 is preferably a 5-9 membered aromatic ring, more preferably a benzene ring.

[0378] Furthermore, L4c is

[0379] In some embodiments of the invention, L4c is

[0380] Among them, here

[0381] X5 is selected from absent, -O-, -CH2-;

[0382] w is selected from 0, 1, 2, 3, 4, 5;

[0383] Ring CyL1 is a 3-9 membered heterocyclic group;

[0384] R L1 independently selected from hydrogen, halogen, C 1-8 alkyl;

[0385] s is independently selected from 0, 1, 2, 3, 4.

[0386] Furthermore, L4c is

[0387] Furthermore, in some embodiments of the present invention, L4c is selected from Additionally or alternatively, in some embodiments, L4c is

[0388] In some embodiments of the present invention, L is selected from:

[0389] Additionally or alternatively, in some embodiments, L is selected from:

[0390] In some embodiments of the present invention, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is a compound of the following formula (II-C):

[0391] or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,

[0392] Among them, X1, X2, X3, R 100 ,m,L1,n,R 1 , L3, R 2 , L2, R 3 、R 4 、R 5 、R 6 、R 7 、R 8 , p, q, R h1 、R h3 、R h4 、R h and L4a are as defined above.

[0393] Further, here L4a is selected from

[0394] In some embodiments of the present invention, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is a compound of the following formula (II-D):

[0395] or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,

[0396] Among them, X1, X2, X3, R 100 ,m,L1,n,R 1 , L3, R 2 , L2, R 3 、R 4 、R 5 、R 6 、R 7 、R 8 , p, q, R h1 、R h3 、R h4 、R h , CyV and L4b are as defined above.

[0397] Further, here L4b is selected from

[0398] In some embodiments of the present invention, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is a compound of the following formula (II-E):

[0399] or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,

[0400] Among them, X1, X2, X3, R 100 ,m,L1,n,R 1 , L3, R 2 , L2, R 3 、R 4 、R 5 、R 6 、R 7 、R 8 , p, q, R h1 、R h3 、R h4 、R h 、R H1 and L4b are as defined above.

[0401] Further, here L4b is selected from

[0402] In some embodiments of the present invention, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is a compound of the following formula (II-F1) or (II-F2):

[0403] or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,

[0404] Among them, X1, X2, X3, R 100 ,m,L1,n,R 1 , L3, R 2 , L2, R 3 、R 4 、R 5 、R 6 、R 7 、R 8 , p, q, R h1 、R h3 、R h4 、R h , CyV and L4b are as defined above.

[0405] In some embodiments, the compound of formula (II-F2) is selected from:

[0406] Here each R h1 Not hydrogen.

[0407] Further, here L4b is selected from

[0408] In some embodiments of the present invention, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is a compound of the following formula (II-G):

[0409] or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,

[0410] Among them, X1, X2, X3, R 100 ,m,L1,n,R 1 , L3, R 2 , L2, R 3 、R 4 、R 5 、R 6 、R 7 、R 8 , p, q, R h3 、R h4 、R h 、R H1and L4c are as defined above.

[0411] Further, here L4c is selected from

[0412] In some embodiments of the present invention, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is a compound of the following formula (II-J):

[0413] or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,

[0414] Among them, X1, X2, X3, R 100 ,m,L1,n,R 1 , L3, R 2 , L2, R 3 、R 4 、R 5 、R 6 、R 7 、R 8 , p, q, R h1 、R h4 、R h 、R H1 、R h6 and L4a are as defined above.

[0415] Further, here L4a is selected from

[0416] The present invention provides the compound described above, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is selected from the exemplary compounds disclosed herein, as shown in Table 2 below:

[0417] Table 2:

[0418] or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

[0419] The present invention provides a composition comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof and a pharmaceutically acceptable carrier. In some embodiments, the composition is a pharmaceutical composition.

[0420] The present invention also provides use of the above-mentioned compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof in the preparation of drugs related to KRas G12D inhibition / degradation.

[0421] The present invention also provides the use of the compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or the pharmaceutical composition, in the preparation of a medicament for treating or preventing a disease associated with the KRas G12D mutant protein. Furthermore, the disease includes, but is not limited to, pancreatic cancer, colorectal cancer, endometrial cancer, or lung cancer. In some embodiments, the lung cancer is selected from non-small cell lung cancer or small cell lung cancer.

[0422] The present invention provides methods for treating or preventing diseases associated with the KRas G12D mutant protein, comprising administering to a patient in need thereof an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. Furthermore, the diseases include, but are not limited to, pancreatic cancer, colorectal cancer, endometrial cancer, or lung cancer. In some embodiments, the lung cancer is selected from non-small cell lung cancer or small cell lung cancer.

[0423] The present invention also provides a method for treating a cancer patient, comprising administering to the patient an effective amount of the compound of the present invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

[0424] Definition and Description

[0425] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be construed as indefinite or unclear unless specifically defined, but rather should be understood in accordance with its ordinary meaning. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0426] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0427] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention, which may be an acid addition salt or a base addition salt.

[0428] Unless otherwise specified, the term “C 1-8 "Alkyl" is used to refer to a straight or branched chain saturated hydrocarbon group having from 1 to 8 carbon atoms. In some embodiments, the alkyl group has from 1 to 6 carbon atoms (ie, "C 1-6 alkyl”), in other embodiments 1-4 carbon atoms (i.e., “C 1-4Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, 2-methylpentyl, n-heptyl, and n-octyl. The term “C 1-3 "Alkyl" is used to represent a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms. 1-3 Alkyl groups include C 1-2 and C 2-3 Alkyl, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 1-3 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.

[0429] Unless otherwise specified, “C 2-8 "Alkenyl" is used to represent a linear or branched hydrocarbon group consisting of 2 to 8 carbon atoms containing at least one carbon-carbon double bond, which may be located at any position of the group. 2-8 Alkenyl groups include C 2-6 、C 2-4 、C 2-3 , C4, C3 and C2 alkenyl, etc.; which may be monovalent, divalent or polyvalent. 2-8 Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, piperyl, hexadienyl, and the like.

[0430] Unless otherwise specified, “C 2-8 "Alkynyl" means a straight or branched chain hydrocarbon group having 1 to 8 carbon atoms, which contains one or more carbon-carbon triple bonds. 2-8 Alkynyl groups include C 2-6 、C 2-4 、C 2-3 , C4, C3 and C2 alkynyl, etc. Examples include, for example, -C≡CH, -CH2C≡CH, -C≡C-CH3, -CH2-C≡C-CH3, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 3-methyl-2-butynyl and 2-methyl-3-pentynyl.

[0431] Unless otherwise specified, the term “C 1-3 Alkoxy" and "-OC 1-3 "Alkyl" is used interchangeably to refer to those alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule through an oxygen atom. The C 1-3 Alkoxy groups include C 1-2 、C 2-3 , C3 and C2 alkoxy, etc. 1-3Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.

[0432] The term "cycloalkyl" refers to a hydrocarbon group selected from saturated cyclic hydrocarbon groups, including monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups, including fused cycloalkyl, bridged cycloalkyl or spirocycloalkyl. In some embodiments, the cycloalkyl group has 3-12, e.g., 7-12, 4-10, 3-9, 3-6, or 4-6 ring carbon atoms.

[0433] The term "spirocycloalkyl" refers to a cyclic structure containing carbon atoms and formed by at least two rings sharing one atom. For example, a 7- to 12-membered spirocycloalkyl refers to a cyclic structure containing 7 to 12 carbon atoms and formed by at least two rings sharing one atom.

[0434] The term "fused cycloalkyl" refers to a fused ring containing carbon atoms and formed by two or more rings sharing two adjacent atoms. For example, a 4- to 10-membered fused cycloalkyl refers to a fused ring containing 4 to 10 ring carbon atoms and formed by two or more rings sharing two adjacent atoms.

[0435] The term "bridged cycloalkyl" refers to a cyclic structure containing carbon atoms and formed by two rings sharing two non-adjacent atoms. For example, a 7- to 10-membered bridged cycloalkyl refers to a cyclic structure containing 7 to 12 carbon atoms and formed by two rings sharing two non-adjacent atoms.

[0436] The term "aryl" used alone or in combination with other terms refers to a group selected from:

[0437] - 5- and 6-membered carbocyclic aromatic rings, such as phenyl;

[0438] - bicyclic ring systems, such as 7- to 12-membered bicyclic ring systems, in which at least one ring is carbocyclic and aromatic, for example naphthyl and indanyl;

[0439] - a tricyclic ring system, such as a 10- to 15-membered tricyclic ring system, wherein at least one ring is carbocyclic and aromatic, for example fluorenyl.

[0440] The terms "aromatic hydrocarbon ring" and "aryl" are used interchangeably throughout the disclosure herein. In some embodiments, the monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 ring-forming carbon atoms (i.e., C5-10 aryl). Examples of monocyclic or bicyclic aromatic hydrocarbon rings include, but are not limited to, phenyl, naphthyl (e.g., naphthalene-1-yl, naphthalene-2-yl), anthracenyl, phenanthrenyl, etc.

[0441] The term "heteroaryl" refers to a group selected from:

[0442] - a 5-, 6-, or 7-membered aromatic monocyclic ring containing at least one heteroatom, for example 1 to 4 heteroatoms, or in some embodiments 1 to 3 heteroatoms, in some embodiments 1 to 2 heteroatoms, selected from nitrogen (N), sulfur (S), and oxygen (O), with the remaining ring atoms being carbon. Examples of such heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, thienyl, oxazolyl, furanyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, imidazolyl, triazinyl, oxadiazolyl, thiadiazolyl;

[0443] - a 7- to 12-membered (e.g., 8-, 9-, or 10-membered) bicyclic ring containing at least one heteroatom, e.g., 1 to 4 heteroatoms, or in some embodiments 1 to 3 heteroatoms, or in other embodiments 1 or 2 heteroatoms, selected from N, O, and S, the remaining ring atoms being carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring. Examples of such heteroaryl groups include, but are not limited to, benzothiazolyl, benzisothiazolyl, imidazopyridinyl, quinolinyl, indolyl, pyrrolopyridazinyl, benzofuranyl, benzothienyl, indazolyl, benzoxazolyl, benzisoxazolyl, quinazolinyl, pyrrolopyridinyl, pyrazolopyrimidinyl, imidazopyridazinyl, pyrazolopyridinyl, triazolopyridinyl, isoquinolinyl, tetrahydroisoquinolinyl, benzimidazolyl, cinnolinyl, indolizinyl, phthalazinyl, isoindolyl, pteridinyl, purinyl, furazanyl, benzofurazanyl, quinoxalinyl, naphthyridinyl, or furopyridinyl; and

[0444] - an 11- to 14-membered tricyclic ring containing at least one heteroatom, for example 1 to 4 heteroatoms, or in some embodiments 1 to 3 heteroatoms, or in other embodiments 1 or 2 heteroatoms, selected from N, O and S, the remaining ring atoms being carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring.

[0445] When the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in the heteroaryl group is no greater than 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle is no greater than 1. When the heteroaryl group contains more than one heteroatom ring member, the heteroatoms may be the same or different.

[0446] In some embodiments, the monocyclic or bicyclic aromatic heterocycle has 5, 6, 7, 8, 9 or 10 ring members, wherein 1, 2, 3 or 4 heteroatom ring members are independently selected from nitrogen (N), sulfur (S) and oxygen (O), and the remaining ring members are carbon. In some embodiments, the monocyclic or bicyclic aromatic heterocycle is a monocyclic or bicyclic ring comprising 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulfur (S) and oxygen (O). In some embodiments, the monocyclic or bicyclic aromatic heterocycle is a 5 to 6-membered heteroaryl ring, which is a monocyclic ring and has 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulfur (S) and oxygen (O). In some embodiments, the ring of the monocyclic or bicyclic aromatic heterocycle is an 8 to 10-membered heteroaryl ring, which is bicyclic and has 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.

[0447] "Heterocyclyl", "heterocycle" or "heterocyclic" are interchangeable and refer to non-aromatic heterocyclic groups comprising one or more heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring members and the remaining ring members being carbon, including monocyclic rings, fused rings, bridged rings and spirocycles, i.e., containing monocyclic heterocyclic groups, bridged heterocyclic groups, spiro heterocyclic groups and fused heterocyclic groups. The term "optionally oxidized sulfur" as used herein refers to S, SO or SO2. The heterocycle can be saturated (i.e., "heterocycloalkyl") or partially saturated. In some embodiments, the heterocyclyl is a 3-7 yuan (e.g., 4, 5 or 6 yuan) monocyclic group (i.e., "monocyclic heterocyclyl"); in some embodiments, the heterocyclyl is a 5-20 yuan polycyclic (e.g., bicyclic) group. In some embodiments, each ring in the polycyclic heterocyclyl is non-aromatic and at least one heteroatom is present in at least one ring, and the polycyclic heterocyclyl is connected to the rest of the molecule via the ring containing the heteroatom. In some embodiments, the polycyclic heterocyclyl may comprise an aromatic hydrocarbon ring but be attached to the remainder of the molecule through a non-aromatic ring containing a heteroatom.

[0448] The term "monocyclic heterocyclyl" refers to a monocyclic group in which at least one ring member is a heteroatom selected from nitrogen, oxygen, or optionally oxidized sulfur. The heterocycle can be saturated (i.e., a "heterocycloalkyl") or partially saturated. In some embodiments, the monocyclic heterocyclyl is a 3-7 membered (e.g., 4, 5, or 6 membered) monocyclic group. Examples that may be mentioned include, but are not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, dioxolinyl, pyrrolidinyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, hexahydropyrimidinyl, triazinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, azocanyl, dihydropyrrolyl, dihydroimidazolyl, azooctenyl.

[0449] The term "spiro heterocyclic radical " refers to a 5 to 20 yuan polycyclic heterocyclic radical with a ring connected by a shared carbon atom (called spiral atom), comprising one or more heteroatoms selected from nitrogen, oxygen or the optionally oxidized sulphur as ring members, and the remaining ring members are carbon. One or more rings of spiro heterocyclic radical can contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, spiro heterocyclic radical is 6 to 14 yuan, and more preferably 7 to 12 yuan. According to the number of shared spiral atoms, spiro heterocyclic radical is divided into single spiral heterocyclic radical, two spiral heterocyclic radicals or multiple spiral heterocyclic radicals, and preferably refers to single spiral heterocyclic radical or two spiral heterocyclic radicals, and more preferably 4 yuan / 4 yuan, 3 yuan / 5 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiral heterocyclic radicals.

[0450] The term "fused heterocyclic group" refers to a 5 to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms (carbon and carbon atoms or carbon and nitrogen atoms) with another ring, comprising one or more heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring members, and the remaining ring members are carbon. One or more rings of the fused heterocyclic group may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, the fused heterocyclic group is 6 to 14 members, preferably 7 to 12 members and more preferably 7 to 10 members. Depending on the number of member rings, the fused heterocyclic group is divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic fused heterocyclic group, and more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group. Examples of fused heterocycles include, but are not limited to, pyrrolidinyl and cyclopropyl, cyclopentyl and aziridine, pyrrolidinyl and cyclobutyl, pyrrolidinyl and pyrrolidinyl, pyrrolidinyl and piperidinyl, pyrrolidinyl and piperazinyl, piperidinyl and morpholinyl,

[0451] The term "bridged heterocyclic group" or "bridged heterocyclic group" refers to a 5- to 14-membered polycyclic heterocyclic group in which every two rings in the system share two non-connected atoms, containing one or more heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring members, and the remaining ring members are carbon. One or more rings of the bridged heterocyclic group may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, the bridged heterocyclic group is 6- to 14-membered, and more preferably 7- to 10-membered. Depending on the number of member rings, the bridged heterocyclic group is divided into a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group, and preferably refers to a bicyclic, tricyclic or tetracyclic bridged heterocyclic group, and more preferably a bicyclic or tricyclic bridged heterocyclic group.

[0452]

[0046] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.

[0453] Unless otherwise indicated, the term "isomer" is intended to include geometric isomers, cis-trans isomers, stereoisomers, enantiomers, optical isomers, diastereomers and tautomers.

[0454] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are encompassed within the scope of the present invention.

[0455] Unless otherwise indicated, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of one another.

[0456] Unless otherwise indicated, the term "cis-trans isomers" or "geometric isomers" arises from the inability to rotate freely about double bonds or single bonds forming ring carbon atoms.

[0457] Unless otherwise indicated, the term "diastereomer" refers to stereoisomers that have two or more chiral centers and that are not mirror images of each other.

[0458] Unless otherwise indicated, "(+)" indicates dextrorotatory, "(-)" indicates levorotatory, and "(±)" indicates racemic.

[0459] Unless otherwise specified, use a solid wedge key. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a wavy line Indicates the cis-trans configuration of geometric isomers, such as compound C003 Middle wavy line Indicates that the compound can be And so on.

[0460] The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, the compounds may be labeled with radioactive isotopes, such as deuterium ( 2 H), tritium ( 3 H), iodine-125( 125 I) or C-14( 14 C). For example, deuterated drugs can be formed by replacing hydrogen with heavy hydrogen. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs have advantages such as reduced toxic side effects, increased drug stability, enhanced efficacy, and prolonged drug biological half-life. All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of this invention.

[0461] The terms "optional" or "optionally" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0462] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it may be substituted or unsubstituted, and unless otherwise specified, the type and number of substituents can be any on the basis of chemical achievable.

[0463] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, with each occurrence of R being an independent choice. Furthermore, combinations of substituents and / or their variants are permissible only if such combinations result in stable compounds.

[0464] When the number of a linking group is 0, such as -(L1)0-, it means that the linking group is a single bond.

[0465] When the number of a substituent is 0, it means that the substituent does not exist, for example, -A-(R)0 means that the structure is actually -A.

[0466] When a substituent is vacant, it means that the substituent does not exist. For example, when X in AX is vacant, it means that the structure is actually A.

[0467] When one of the variables is selected from a single bond, it means that the two groups it connects are directly connected. For example, when L in ALZ represents a single bond, it means that the structure is actually AZ.

[0468] When a substituent's bond can cross-link to two or more atoms in a ring, the substituent can be bonded to any atom in the ring, e.g. The substituent R can be substituted at any position on the cyclohexyl group or cyclohexadiene. When the listed substituent does not specify the atom through which it is bonded to the substituted group, the substituent can be bonded through any atom. For example, a pyridyl substituent can be bonded to the substituted group through any carbon atom on the pyridine ring.

[0469] When the linking group is listed without specifying its linking direction, its linking direction is arbitrary, for example, The connecting group L is -MW-, in which case -MW- can connect ring A and ring B in the same direction as the reading order from left to right to form You can also connect ring A and ring B in the opposite direction of reading from left to right to form Combinations of linkers, substituents, and / or variations thereof are permissible only if such combinations result in stable compounds.

[0470] Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the chemical bond connection mode is non-positional and there are H atoms at the connectable sites, when the chemical bond is connected, the number of H atoms at the site will decrease accordingly with the number of connected chemical bonds, and become a group with a corresponding valence. The chemical bond connecting the site to other groups can be a straight solid bond. Straight solid key with * or wavy lines The two forms can be used interchangeably. For example, the straight solid bond in -OCH3 indicates that it is connected to other groups through the oxygen atom in the group; The wavy line in the figure indicates that it is connected to other groups through the carbon atom #1 in the phenyl group; The * in the figure indicates that the group is connected to other groups through the carbon atom #1 in the phenyl group.

[0471] Unless otherwise specified, the number of atoms in a ring is generally defined as the ring member number, for example, a "3-9 membered ring" refers to a "ring" having 3-9 atoms arranged around it.

[0472] As used herein, the terms "administration," "administering," "treating," and "treatment" refer to the contact of an exogenous agent, therapeutic agent, diagnostic agent, or composition with an animal, human, subject, cell, tissue, organ, or biological fluid. Treatment of cells encompasses contact of an agent with a cell, and contact of an agent with a fluid, wherein the fluid is in contact with the cell. The terms "administering" and "treating" also refer to in vitro and ex vivo treatment of, for example, a cell, by an agent, diagnostic agent, binding compound, or by another cell. The term "patient" herein includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, and rabbit), and most preferably a human.

[0473] The term "effective amount" or "therapeutically effective amount" refers to an amount of an active ingredient, such as a compound, which, when administered to a subject for treating a disease or at least one clinical symptom of a disease or disorder, is sufficient to affect such treatment of the disease, disorder or symptom.

[0474] The term "disease" refers to any illness, ailment, disease, symptom, or indication and is interchangeable with the terms "condition" or "disorder."

[0475] Throughout the specification and subsequent aspects, the term "C n-m " indicates a range including the endpoints, where n and m are integers and indicate the number of carbons. Examples include C 1-8 、C 1-6 、C 1-3 wait.

[0476] Unless explicitly defined elsewhere in this document, all other technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0477] The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present invention.

[0478] The solvent used in the present invention is commercially available.

[0479] Compounds are named according to the conventional nomenclature in the art or using Software naming, commercially available compounds use supplier catalog names. DETAILED DESCRIPTION

[0480] Example 1: Degradation experiment

[0481] 1. Experimental Materials

[0482] AsPC-1 (KRAS G12D mutation) cell line was purchased from Nanjing CoBiotech Co., Ltd. (CoBioer). AsPC-HiBit (stable strain), Nano-Glo Hibit Lytic (Promega, N3040), RMPI1640 medium (Cellmax, CGM112.05), DMER medium (Cellmax, CGM101.05), trypsin (Cellmax, CPT101.02), serum (GEMINI, 900-108), and CCK8 (Bimake, B34304) were purchased from Nanjing CoBiotech Co., Ltd.

[0483] Multifunctional microplate reader (SPARK, Tecan).

[0484] 2. Test methods

[0485] 1) Plate AsPC-1-HiBit cells into a 96-well plate at 12,000 cells per well and incubate at 37°C overnight. 2) Add compound to a maximum concentration of 10 μM in a 9-well gradient, with a control, and duplicate wells, incubating at 37°C for 24 h. 3) Add 50 μl of Nano-glo HiBit Lytic Reagent to each well of the 96-well plate and shake at 300 rpm in the dark for 3 min. 4) Incubate in the dark for 10 min and read the sample using a microplate reader.

[0486] Conclusion: The compounds of the present invention have a good degradation effect on KRAS G12D protein in AsPC-1 cells.

[0487] Example 2: Cell proliferation inhibition experiment

[0488] 1. Experimental Materials

[0489] AsPC-1 (KRAS G12D mutation) and GP2D (KRAS G12D mutation) cell lines were purchased from Nanjing CoBiotech Co., Ltd. (CoBioer). RMPI1640 medium (Cellmax, CGM112.05), DMER medium (Cellmax, CGM101.05), trypsin (Cellmax, CPT101.02), serum (GEMINI, 900-108), and CCK8 (Bimake, B34304) were used.

[0490] 2. Cell Viability Test Method

[0491] 1) Select cells in the logarithmic phase to prepare a cell suspension and count them. 2) Inoculate into a 96-well plate, 3000 cells / well, 100 μl of culture medium, and duplicate wells. 3) After incubation at 37°C for 18 hours, adhere to the wall and add the test substance (10 mM storage solution) according to experimental requirements. 4) Add 10 μl of CCK8 after 72 hours of compound incubation. After addition, suspend and shake for 2 minutes. Continue incubation at 37°C for 3 hours. 5) Measure the absorbance at 450 nM. Curve fitting is performed using Prism software (GraphPad 7.0) to obtain the IC 50 value.

[0492] Experimental results: The compounds of the present invention have strong inhibitory activity against AsPC-1 and GP2D cell lines with KRAS G12D mutation, indicating that the compounds of the present invention have strong inhibitory activity against KRas G12D.

[0493] Preparation Example

[0494] The present invention is further described in detail below with reference to specific examples, but these examples do not limit the scope of the present invention. The following examples are used to understand the methods and core ideas of the present invention. For those skilled in the art, any possible changes or substitutions without departing from the concept of the present invention are within the scope of protection of the present invention. The experimental methods for which specific conditions are not specified in the examples of the present invention are generally conventional conditions, or conditions recommended by the raw material or commodity manufacturer; reagents for which the source is not specified are generally conventional reagents available through commercial channels.

[0495] In the following examples, the experimental methods without specific conditions were carried out according to conventional methods and conditions, or selected according to the product instructions.

[0496] Intermediate Preparation Example 1: Preparation of Intermediate A:

[0497] Step 1: Preparation of A2

[0498] At room temperature, compound intermediate A1 (13.1 g, 5.0 eq) was dissolved in DMF (80 ml). Imidazole (3.0 g, 1.5 eq) was added, followed by dropwise addition of TBDPSCl (8.0 g, 1.0 eq). The reaction was stirred at room temperature for 4 h. The reaction was terminated upon disappearance of TBDPSCl by TLC. Water and MTBE were added for extraction, and the organic phase was concentrated and purified on a silica gel column to yield compound A2. LCMS: [M+Na] + =351.1.

[0499] Step 2: Preparation of A3

[0500] At room temperature, intermediate A2 (3.8 g, 1.0 eq) was dissolved in DCM (50 ml). Imidazole (1.2 g, 1.5 eq) was added, followed by dropwise addition of TBSCl (2.0 g, 1.2 eq). The reaction was stirred at room temperature for 2 h. The reaction was stopped upon disappearance of intermediate 1-2 by TLC. 100 ml of water was added, and the mixture was extracted with DCM. The combined organic phases were concentrated and purified on a silica gel column to obtain intermediate A3.

[0501] Step 3: Preparation of A4

[0502] At room temperature, (fluoromethyl) triphenylphosphine tetrafluoroborate (5.56 g, 1.5 eq) was suspended in anhydrous tetrahydrofuran (45 ml), cooled to -78°C, and NaHMDS (14.5 ml, 1.5 eq, 1 M) was added dropwise. After stirring for 30 minutes, a solution of intermediate A3 (4.3 g, 1.0 eq) in anhydrous tetrahydrofuran (25 ml) was added dropwise. After the addition was complete, the reaction solution was transferred to room temperature and allowed to react for 2 hours. The reaction was terminated by the disappearance of the starting material on TLC. The reaction solution was cooled to 0°C, and aqueous ammonium chloride and EA were added, stirred for 10 minutes, and the layers were separated. The organic phase was concentrated and purified on a silica gel column to obtain intermediate A4. LCMS: [M+Na] + =481.1.

[0503] Step 4: Preparation of A5

[0504] At room temperature, intermediate A4 (3.2 g, 1.0 eq) was dissolved in tetrahydrofuran (40 ml), and a 4M HCl solution in dioxane (21 ml, 12 eq) was added. The mixture was allowed to react at room temperature for 1.5 h. When TLC showed that the starting material had essentially disappeared, the reaction was stopped. The reaction solution was concentrated, and the crude product was purified on a silica gel column to obtain intermediate A5. LCMS: [M+Na] + =367.1.

[0505] Step 5: Preparation of Intermediate A

[0506] At room temperature, intermediate A5 (1.9 g, 1.0 eq) was dissolved in DCM (20 ml). DMAP (67 mg, 0.1 eq), DIEA (1.43 g, 2.0 eq), and TosCl (1.57 g, 1.5 eq) were added. The mixture was allowed to react at room temperature for 24 h. TLC analysis indicated that the starting material had essentially disappeared, and the reaction was stopped. Water and DCM were added to the reaction mixture, and the organic phase was concentrated and purified on a silica gel column to obtain intermediate A. LCMS: [M+Na] + =521.1.

[0507] Intermediate Preparation Example 2: Preparation of Intermediate B:

[0508] Step 1: Preparation of B2

[0509] Compound B1 (5.0 g, 23.2 mmol) was slowly added to a reaction flask containing POCl3 (50 mL) and DIEA (20 mL) under an ice bath. After the addition, the mixture was slowly heated to 110°C in an oil bath and reacted for three hours. The reaction was completed by plate scanning and LCMS. The mixture was returned to room temperature and concentrated in vacuo to obtain compound B2, which was used directly in the next step.

[0510] Step 2: Preparation of B4

[0511] Compound B2 (5.8 g, 23.2 mmol) was dissolved in 60 mL of DCM, and 20 mL of DIEA was added. The reaction was then cooled to -45°C and the DCM solution of B3 was added dropwise. The reaction was stirred for about 1 h. LCMS detected that the reaction was complete. The reaction flask was placed at room temperature and quenched with saturated ammonium chloride. The product was extracted three times with DCM and backwashed twice with saturated brine. The organic phase was dried and concentrated in vacuo. The product was purified by forward column chromatography to obtain compound B4.

[0512] Step 3: Preparation of B5

[0513] B4 (2.9 g, 6.78 mmol) and 30 mL of THF were added to a 250 mL single-necked flask and stirred at -10 °C for 10 min. NaSMe (520 mg, 7.46 mmol) was added and the temperature was slowly raised to room temperature. The reaction was allowed to react overnight. LCMS detected that the reaction was complete. Water was then added to quench the reaction, and the mixture was extracted three times with EA and backwashed twice with saturated brine. The organic phases were combined, dried, and concentrated to obtain the crude product, which was then purified by beating with EA / PE = 1 / 2 to obtain compound B5.

[0514] Step 4: Preparation of B7

[0515] B5 (1.6 g, 3.6 mmol), compound B6 (2.8 g, 5.45 mmol), K2CO3 (1.5 g, 10.9 mmol), catalyst (264 mg, 0.36 mmol), 20 mL of dioxane, and 5 mL of water were added to the reaction flask. The atmosphere was purged with nitrogen three times and the reaction was carried out at 95°C for 3 h. LCMS analysis revealed no MS signal, but a new spot appeared on the plate. Water was then added to quench the reaction. The reaction was extracted three times with EA, and the organic phases were combined, dried, concentrated, and purified on a normal phase column (EA / PE = 1 / 2) to obtain compound B7. MS m / z (ESI): 634.2 [M+H] + .

[0516] Step 5: Preparation of Intermediate B

[0517] Compound B7 (2.6 g, 3.3 mmol), 40 mL of DCM, and m-CPBA (680 mg, 3.93 mmol) were added to a single-necked flask and reacted at room temperature for 2 h. LCMS showed no peaks for either the starting material or the product, with a new peak appearing at a more polar position. The reaction was quenched with water, extracted three times with EA, and the combined organic phases were dried, concentrated, and purified by a forward column chromatography to obtain the product, Intermediate B. MS m / z (ESI): 650.2 [M+H] + .

[0518] Example 1: Preparation of C001

[0519] Step 1: Preparation 1_2

[0520] Compound 1_1 (2.5 g, 9.7 mmol) and potassium carbonate (4.0 g, 29.1 mmol) were dissolved in DMF (40 ml) at 25°C. Under nitrogen, iodomethane (1.45 g, 10.2 mmol) was added. Stirring was continued at room temperature for 4 hours. The reaction was monitored for completion by TLC. 200 ml of water was added to the reaction solution to quench and dilute it. The mixture was extracted with ethyl acetate (3 x 100 ml) and backwashed with saturated sodium chloride solution. The combined organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a residue, which was purified by silica gel column chromatography to obtain compound 1_2.

[0521] Step 2: Preparation 1_3

[0522] Compound 1_2 (2.0 g, 7.38 mmol) was dissolved in 1,4-dioxane (30 mL), and 4N HCl in dioxane (15 mL) was added at room temperature. The reaction was stirred at room temperature for 2 hours. The reaction was monitored by TLC until the starting material disappeared. The mixture was returned to room temperature and the solvent was dried to give the crude product, Compound 1_3.

[0523] Step 3: Preparation 1_4

[0524] Compound 1_3 (200 mg, 0.4 mmol), intermediate A (200 mg, 0.4 mmol), and potassium carbonate (221 mg, 1.6 mmol) were dissolved in DMF (5 ml) at 25°C and stirred at 60°C for 3 hours under nitrogen. Completion of the reaction was monitored by TLC. The reaction mixture was quenched and diluted with 20 ml of water, extracted with ethyl acetate (3 x 10 ml), and backwashed with saturated sodium chloride solution. The combined organic phases were dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography to yield compound 1_4.

[0525] Step 4: Preparation 1_5

[0526] Compound 1-4 (200 mg, 0.4 mmol) was dissolved in THF (4 ml), and 0.8 ml of TBAF (1.0 M in THF) was added dropwise at room temperature. Stirring was continued at room temperature for 2 hours after the addition. The reaction was monitored for completion by TLC. 20 ml of water was added to the reaction solution to quench and dilute it. The mixture was extracted with ethyl acetate (3 x 10 ml) and backwashed with saturated sodium chloride solution. The combined organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a residue, which was purified by silica gel column chromatography to obtain compound 1-5.

[0527] Step 5: Preparation 1_6

[0528] Compound 1-5 (80 mg, 0.31 mmol) and intermediate B (200 mg, 0.25 mmol) were dissolved in THF (5 ml) under nitrogen protection and an ice bath. NaH (21 mg, 0.50 mmol) was added dropwise at room temperature. The addition was continued at room temperature for 2 hours. LCMS monitored the reaction to completion. The reaction solution was poured into ice water to quench, extracted with ethyl acetate (3x5 ml), backwashed with saturated sodium chloride solution, and the combined organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a residue, which was purified by preparative plate to obtain compound 1-6.

[0529] Step 6: Preparation 1_7

[0530] Compound 1_6 (100 mg, 0.1 mmol) was dissolved in MeOH (3 ml) and water (0.6 ml), and LiOH (21 mg, 0.5 mmol) was added. Stirring was continued at room temperature for 16 hours. LCMS monitored the reaction for completion. The reaction solution was concentrated in vacuo, the methanol was dried, and then diluted with 5 ml of water. The pH was adjusted to 6 and extracted with ethyl acetate (3 x 5 ml). The mixture was backwashed with saturated sodium chloride solution. The combined organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by preparative plate yielded compound 1_7.

[0531] Step 7: Preparation 1_8

[0532] Compound 1-7 (60 mg, 0.061 mmol), Intermediate C (31 mg, 0.073 mmol), HATU (35 mg, 0.091 mmol), and DIEA (24 mg, 0.018 mmol) were dissolved in DMF (1.5 ml) and stirred at room temperature for 12 hours. LCMS monitored the reaction for completion. The reaction mixture was diluted with 5 ml of water to precipitate a solid product. The product was filtered with filter paper, dissolved in ethyl acetate, dried over anhydrous sodium sulfate, and concentrated in vacuo to yield pure Compound 1-8.

[0533] Step 8: Preparation 1_9

[0534] Compound 1-8 (50 mg, 0.033 mmol) was dissolved in THF (2 ml) and 0.07 ml of TBAF (1.0 M in THF) was added dropwise at room temperature. Stirring was continued at room temperature for 2 hours. LCMS monitored the reaction for completion. The reaction solution was quenched and diluted with 10 ml of water. The mixture was extracted with ethyl acetate (3 x 5 ml) and backwashed with saturated sodium chloride solution. The combined organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by preparative plate yielded compound 1-9.

[0535] Step 9: Prepare C001

[0536] 1-9 (30 mg, 0.024 mmol) was dissolved in DCM (10 mL), and 4N HCl in dioxane (0.3 mL) was added at room temperature. The reaction mixture was stirred at room temperature for 0.5 h. The reaction was monitored by LCMS until the starting material disappeared. The solid in the reaction solution was filtered with filter paper, redissolved in water, adjusted to pH = 8, and extracted with EA. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to obtain a residue, which was purified by preparative chromatography to obtain compound C001. MS m / z (ESI): 1099.5 [M+H] + .

[0537] Example 2: Preparation of C002

[0538] The preparation method of C001 described in Example 1 was followed except that 1-5 was replaced by 2-7 to obtain compound C002.

[0539] Compound C002: MS m / z (ESI): 1115.5 [M+H] + .

[0540] The preparation method of intermediate 2-7 is as follows:

[0541] Step 1: Preparation 2_2

[0542] Compound 2_1 (5.0 g, 50 mmol) was dissolved in THF (20 ml), and 2.0 M NaOH (100 ml) was added at room temperature. The reaction mixture was placed in an ice bath, and CbzCl (8.4 g, 50 mmol) was slowly added dropwise. The mixture was stirred at room temperature for 16 hours. LCMS monitored the reaction completion, and the mixture was extracted with ethyl acetate (3 x 40 ml), backwashed with saturated sodium chloride solution, and the combined organic phases were dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography to yield compound 2_2.

[0543] Step 2: Preparation 2_4

[0544] Compounds 2_2 (3.0 g, 12.8 mmol) and 2_3 (2.0 g, 15.4 mmol) were dissolved in ACN (30 ml), and Triton-B (641 mg, 15.3 mmol) was added. Stirring was continued for 24 hours after addition. LCMS monitored the reaction for completion. The mixture was concentrated in vacuo, 30 ml of ethyl acetate was added, and the mixture was backwashed with saturated sodium chloride solution. The combined organic phases were dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography to yield compound 2_4.

[0545] Step 3: Preparation 2_5

[0546] 2_4 (1.8 g, 5.0 mmol) was dissolved in methanol (30 mL), and Pd / C (600 mg) was added at room temperature. After hydrogen substitution, the mixture was stirred at room temperature for 16 hours. The reaction was monitored by TLC, and the reaction solution was filtered through celite. The filtrate was concentrated in vacuo, and the solvent was dried to give the crude product, Compound 2_5.

[0547] Step 4: Preparation 2_6

[0548] Compound 2_5 (200 mg, 0.4 mmol), intermediate A (184 mg, 0.8 mmol), and potassium carbonate (166 mg, 1.2 mmol) were dissolved in DMF (5 ml) at 25°C and stirred at 60°C under nitrogen for 4 hours. Completion of the reaction was monitored by TLC. The reaction mixture was quenched and diluted with 20 ml of water, extracted with ethyl acetate (3 x 10 ml), and backwashed with saturated sodium chloride solution. The organic phases were combined and purified by silica gel column chromatography to yield compound 2_6.

[0549] Step 5: Preparation 2_7

[0550] Compound 2-6 (190 mg, 0.34 mmol) was dissolved in THF (5 ml), and 0.7 ml of TBAF (1.0 M in THF) was added dropwise at room temperature. Stirring was continued at room temperature for 1 hour. The reaction was monitored for completion by TLC. The reaction mixture was quenched and diluted with 20 ml of water, extracted with ethyl acetate (3 x 10 ml), and backwashed with saturated sodium chloride solution. The combined organic phases were dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography to yield compound 2-7.

[0551] Example 3: Preparation of C003A and C003B

[0552] Step 1: Preparation 3_2

[0553] (Methoxymethyl)triphenylphosphonium chloride (1.4 g, 1.5 eq) was added to THF (12 ml), cooled to -78°C, and NaHMDS (4.07 ml, 1.5 eq) was added dropwise. After stirring at -78°C for 1 h, a solution of 3_1 (500 mg, 1.0 eq) in THF (8 ml) was added dropwise. The mixture was transferred to room temperature and allowed to react for 3 h. TLC analysis showed a small amount of residual starting material, and the reaction was stopped. The reaction mixture was added dropwise to icy ammonium chloride aqueous solution and extracted twice with EA. The organic phase was concentrated and purified on a silica gel column to obtain 3_2.

[0554] Step 2: Preparation 3_3

[0555] 3_2 (280 mg) was dissolved in THF (4 mL) at room temperature, and a solution of HCl in dioxane (3 ml, 4 M) was added. The reaction was allowed to react at room temperature for 1 h. When the starting material disappeared by TLC, the reaction was stopped. The reaction solution was spin-dried to obtain a crude product, which was dissolved in EA and washed twice with brine. The organic phase was concentrated to dryness to obtain 3_3.

[0556] Step 3: Preparation 3_4

[0557] Compound 3_3 (230 mg, 1.0 eq) was dissolved in DCM (10 ml) at room temperature. N-methylbenzylamine (183 mg, 1.3 eq) and AcOH (1 drop) were added. The mixture was allowed to react at room temperature for 30 minutes, followed by the addition of STAB (740 mg, 3.0 eq) in portions. The reaction was continued at room temperature for 2 hours. The reaction was stopped upon disappearance of the starting material 3_3 by TLC. Aqueous NaHCO3 solution and DCM were slowly added, and the layers separated. The organic phase was concentrated and isolated on a preparative TLC plate to yield compound 3_4. LCMS: [M+1] + =304.2.

[0558] Step 4: Preparation 3_5

[0559] Compound 3_4 (230 mg) was dissolved in EA (5 ml) at room temperature, and Pd / C (100 mg, 5 wt%) was added. The mixture was hydrogenated at room temperature for 24 h, filtered through celite, and the filter cake was washed with EA. The filtrate was concentrated to dryness to obtain crude product 3_5. LCMS: [M+1] + =214.3.

[0560] Step 5: Preparation 3_6

[0561] Compound 3_5 (83 mg, 1.3 eq) was dissolved in DMF (2 ml) at room temperature, and intermediate A (150 mg, 1.0 eq) and anhydrous potassium carbonate (70 mg, 3.0 eq) were added. The mixture was stirred at room temperature overnight. LCMS indicated that intermediate A had reacted completely. Water and EA were added to the reaction mixture, and the layers were separated. The aqueous layer was extracted twice with EA, and the organic phase was concentrated to dryness to obtain crude product 3_6, which was directly used in the next step. LCMS: [M+H] + =540.2.

[0562] Step 6: Preparation 3_7

[0563] The crude compound 3_6 from the previous step was dissolved in THF (4 ml) at room temperature, and TBAF (0.2 ml, 1 M in THF) was added. The reaction was allowed to react at room temperature for 2 h. LCMS monitored the reaction for completion. Water and EA were added for separation, and the organic layer was washed three times with saturated brine. The organic phase was adjusted to a pH of 1-2 with dilute hydrochloric acid and extracted with water to an aqueous phase. The organic phase was discarded, and the aqueous phase was adjusted to a pH of approximately 10 with potassium carbonate solution. The phase was extracted with EA, and the organic phase was concentrated to dryness to yield 3_7. LCMS: [M+H] + =302.2.

[0564] Step 7: Preparation 3_8

[0565] At room temperature, compound 3_7 (70 mg, 1.4 eq) was dissolved in anhydrous THF (5.0 mL), and intermediate B (133 mg, 1.0 eq) was added. The temperature was lowered to -10°C, and LiHMDS (0.25 ml, 3.0 eq, 2 M in THF) was added dropwise. After completion of the addition, the mixture was allowed to react at this temperature for 30 minutes. LCMS indicated that intermediate B had completely reacted. The reaction solution was added dropwise to an icy ammonium chloride solution, extracted with EA, and the organic phase was concentrated and purified using a preparative plate to obtain 3_8. LCMS: [M+H] + =1043.9.

[0566] Step 8: Preparation 3_9

[0567] At room temperature, compound 3_8 (35 mg) was dissolved in THF (1 ml) and MeOH (1 ml), and LiOH (100 mg + 1 ml water) solution was added dropwise. The reaction was allowed to proceed at room temperature for 1 h. LCMS monitored the complete reaction of the starting material. The reaction solution was concentrated to dryness to obtain the crude product 3_9, which was directly used for the next step. LCMS: [M+H] + =1015.6.

[0568] Step 9: Preparation 3_10

[0569] The crude product of compound 3_9 from the previous step was dissolved in DMF (2 ml) at room temperature. Intermediate C (24 mg, 1.5 eq), DIEA (13 mg, 3.0 eq), and HATU (38 mg, 3.0 eq) were added sequentially and reacted at room temperature for 2 h. LCMS monitored the reaction for completion. Water and EA were added for separation. The aqueous layer was extracted twice with EA. The organic phase was concentrated and separated on a preparative silica gel plate to obtain compound 3_10. LCMS: [M+H] + =1427.7.

[0570] Step 10: Preparation 3_11

[0571] To a solution of compound 3_10 (30 mg) in THF (4 mL) was added TBAF (0.2 mL, 1 M in THF) at 25°C. The mixture was allowed to react at room temperature for 1 h. LCMS monitored the reaction for completion. Water and EA were added, the layers separated, and the aqueous layer was extracted once with EA. The combined organic phases were concentrated to dryness to afford crude product 3_11, which was directly used in the next step. LCMS: [M+H]+ = 1271.6.

[0572] Step 11: Prepare C003A and C003B

[0573] The crude product of the previous step, compound 3-11, was dissolved in DCM (3.0 mL) at room temperature and TFA (1.0 mL) was added. The reaction was allowed to react at room temperature for 2 hours. LCMS monitoring indicated the disappearance of the starting material. The reaction solution was concentrated and the residue was purified by preparative HPLC to obtain products C003A and C003B.

[0574] C003A: LCMS: [M+H] + =1127.5.

[0575] C003B: LCMS: [M+H] + =1127.3.

[0576] Example 4: Preparation of C004

[0577] In addition to replacing 3_5 with 4_1, According to the preparation method described in Example 3, compound C004 was obtained.

[0578] C004: LCMS: [M+H] + =1113.5.

[0579] Example 5: Preparation of C005

[0580] The preparation method of C002 described in Example 2 was followed except that 2-4 was replaced by 5-2 to obtain compound C005.

[0581] Compound C005: MS m / z (ESI): 1101.6 [M+H] + .

[0582] The preparation method of intermediate 5-2 is as follows:

[0583] Compound 2_2 (1.1 g, 4.2 mmol) was dissolved in THF (15 ml) and NaH (252 mg, 6.4 mmol) was added under nitrogen in an ice bath. Stirring was continued for 0.5 h. Compound 5_1 (1.6 g, 8.4 mmol) was then slowly added dropwise in an ice bath. Stirring was continued at room temperature for 3 days. LCMS monitored the reaction for completion. Water was added to the reaction mixture under ice bath to quench and dilute the mixture. The mixture was extracted with ethyl acetate, and the organic phases were combined, concentrated, and purified by silica gel column chromatography to yield compound 5_2.

[0584] Example 6: Preparation of C006

[0585] In addition to replacing 3_5 with 6_1, According to the preparation method described in Example 3, compound C006 was obtained.

[0586] 1H NMR (400MHz, DMSO) δ10.15(s,1H),9.04(s,1H),8.98(s,1H),8.56(d,J=5.9Hz,1H),7.97(dd,J=9.3,6.0Hz,1H),7.82 (d,J=9.4Hz,1H),7.49–7.36(m,6H),7.18(s,1H),7.05(s,0.5H),6.84(s,0.5H),5.16(s,1H),4.87(d,J=41.0Hz,2H) ,4.56–4.39(m,4H),4.38–4.19(m,3H),3.93(s,1H),3.69–3.50(m,6H),2.90(s,1H),2.44(s,3H),2.25(d,J=7.6Hz,3 H),2.13–2.01(m,5H),1.89(s,1H),1.64(s,4H),1.36(s,4H),1.19(s,4H),0.91(s,9H).LCMS(ESI)m / z:1101.6(M+H) + .

[0587] Example 7: Preparation of C007

[0588] In addition to replacing 3_5 with 7_1, According to the preparation method described in Example 3, compound C007 was obtained.

[0589] C007:LCMS(ESI)m / z:1121.6(M+H) + .

[0590] Example 8: Preparation of C008

[0591] In addition to replacing 3_5 with 8_1, According to the preparation method described in Example 3, compound C008 was obtained.

[0592] LCMS (ESI) m / z: 1111.5 (M+H) + .

[0593] Example 9: Preparation of C009

[0594] In addition to replacing 1_1 with 9_1, Compound C009 was obtained according to the preparation method of C001 described in Example 1. LCMS (ESI) m / z: 1113.5 (M+H) + .

[0595] Example 10: Preparation of C010

[0596] In addition to replacing 3_5 with 10_1, Compound C010 was obtained according to the preparation method described in Example 3. LCMS (ESI) m / z: 1135.5 (M+H) + .

[0597] Example 11: Preparation of C011A and C011B

[0598] In addition to replacing 3_5 with 11_1, According to the preparation method described in Example 3, compounds C011A and C011B were obtained.

[0599] C011A: 1 H NMR (400MHz, DMSO) δ9.04 (s, 1H), 8.98 (s, 1H), 8.56 (dd, J = 10.9, 5.9Hz, 1H), 7 .95(dd,J=9.1,6.1Hz,1H),7.81(d,J=9.3Hz,1H),7.47-7.37(m,6H),7.26(s, 0.5H),7.17(t,J=2.4Hz,1H),7.05(s,0.5H),4.82(d,J=2.5Hz,2H),4.56–4.4 5(m,2H),4.45–4.38(m,2H),4.31(dd,J=11.5,9.1Hz,2H),4.21(dd,J=15.8,5. 5Hz,1H),3.92(s,1H),3.63(d,J=10.6Hz,3H),3.55(d,J=12.5Hz,3H),3.06(s ,2H),2.59(s,1H),2.44(s,3H),2.23(dt,J=22.3,7.3Hz,3H),2.11(s,3H),2. 08–1.98(m,2H),1.89(ddd,J=13.2,8.4,4.5Hz,1H),1.64(s,4H),1.52–1.34( m,4H),1.20(dd,J=14.4,7.2Hz,2H),0.91(s,9H).LCMS(ESI)m / z:1087.9(M+H) + .

[0600] C011B: 1H NMR (400MHz, DMSO) δ9.03(d,J=2.0Hz,1H),8.98(s,1H),8.56(t,J=6.4Hz,1H),8.03–7.91(m,1H),7.82(d,J=9.7Hz,1H),7.46–7.36 (m,6H),7.17(t,J=2.8Hz,1H),7.05(s,0.5H),6.84(s,0.5H),4.92(s,2H),4.54–4.39(m,4H),4.29-4.34(m,2H),4.25–4.18(m,1H) ,3.92(s,1H),3.64(t,J=6.1Hz,3H),3.55(d,J=13.7Hz,3H),2.91(s,2H),2.59(s,1H),2.44(s,3H),2.21-2.27(m,3H),2.10(s,3H) ,2.08–2.00(m,2H),1.86-1.92(m,1H),1.64(s,4H),1.48–1.35(m,4H),1.17-1.23(m,2H),0.91(s,9H).LCMS(ESI)m / z:1087.9(M+H) + .

[0601] Example 12: Preparation of C012A and C012B

[0602] Except that 3_5 was replaced by 12_2, the preparation method described in Example 3 was followed to obtain compounds C012A and C012B.

[0603] Compound C012A: 11H NMR (400 MHz, DMSO) δ 9.03 (s, 1H), 8.97 (s, 1H), 8.57 (dd, J = 11.8, 6.2 Hz, 1H), 7.96–7.87 (m, 1H), 7.80 (d, J = 9.3 Hz, 1H), 7.39 (dd, J = 16.2, 7.8 Hz, 6H), 7.31 (s, 1H), 7.14 (s, 1H), 7.04 (s, 0.5H), 6.83 (s, 0.5H), 4.93 (s, 2H), 4.54–4.46 (m, 2H), 4.43 (dd, J = 14.8, 6.6 Hz, 2H), 4.32 (d, J = 15.0 Hz, 2H), 4.23 (d, J = 4.6 Hz, 1H), 3.87 (s, 1H), 3.63 (d, J = 用 11.8 Hz, 3H), 3.55 (d, J = 16.7 Hz, 3H), 2.90 (s, 2H), 2.44 (s, 3H), 2.28–2.24 (m, 2H), 2.21–2.15 (m, 1H), 2.09 (s, 3H), 2.05 - 2.01 (m, 2H), 1.90 (dd, J = 12.2, 4.2 Hz, 1H), 1.64 (s, 4H), 1.45–1.33 (m, 4H), 1.17 (s, 6H), 0.91 (s, 9H). MS m / z (ESI): 1115.1 [M+H] + .

[0604] Compound C012B: 1 It should be noted that there seems to be a small error in the original text where "3.63 (d, J = 用 11.8 Hz, 3H)" has an extra "用" character. This has been left as is in the translation to maintain consistency with the original.H NMR (400MHz, DMSO) δ10.18(s,1H),9.05(s,1H),8.98(s,1H),8.54(t,J=6.0Hz,1H),7.97(dd,J=9.2,5.9Hz,1H),7.80(d,J=9.3Hz,1H),7.4 6(t,J=9.0Hz,1H),7.40(q,J=8.4Hz,5H),7.26(s,0.5H),7.17(d,J=2.0Hz,1H),7.05(s,0.5H),4.83(s,2H),4.56–4.46(m,2H),4.44–4.38 (m,2H),4.32(d,J=13.3Hz,2H),4.25-4.19(m,1H),3.90(s,1H),3.65(d,J=4.2Hz,3H),3.56(s,3H),3.05(s,2H),2.44(s,3H),2.30–2.25( m,2H),2.23–2.17(m,1H),2.10(s,3H),2.07–2.00(m,2H),1.94–1.86(m,1H),1.66(s,4H),1.47-1.40(m,4H),1.18(s,6H),0.91(s,9H)..MS m / z(ESI):1115.1[M+H] + .

[0605] The preparation method of intermediate 12_2 is as follows:

[0606] At room temperature, 12_1 (5.95 g, 25 mmol) was added to tetrahydrofuran (65 ml), and methylamine tetrahydrofuran (100 ml, 200 mmol) was added. The reaction mixture was reacted in a sealed tube at 40°C overnight. The reaction solution was concentrated and separated by column chromatography to obtain compound 12_2.

[0607] Example 13: Synthesis of C013

[0608] In addition to changing 3-5 to 13-1, Compound C013 was obtained according to the preparation method described in Example 3. MS m / z (ESI): 1097.5 [M+H] + .

[0609] Example 14: Synthesis of C014A and C014B

[0610] In addition to changing 3-5 to 14-1, According to the preparation method described in Example 3, compounds C014A and C014B were obtained.

[0611] C014A:MS m / z(ESI):1111.5[M+H] + .

[0612] C014B:MS m / z(ESI):1111.6[M+H] + .

[0613] Example 15: Synthesis of C015A and C015B

[0614] In addition to changing 3-5 to 15-1, According to the preparation method described in Example 3, compounds C015A and C015B were obtained.

[0615] C015A:MS m / z(ESI):1153.6[M+H] + .

[0616] C015B:MS m / z(ESI):1153.4[M+H] + .

[0617] Example 16: Synthesis of C016A and C016B

[0618] In addition to changing 3-5 to 16-1, According to the preparation method described in Example 3, compounds C016A and C016B were obtained.

[0619] C016A:MS m / z(ESI):1141.6[M+H] + .

[0620] C016B:MS m / z(ESI):1141.6[M+H] + .

[0621] Example 17: Synthesis of C017A and C017B

[0622] In addition to changing 3-5 to 17-1, According to the preparation method described in Example 3, compounds C017A and C017B were obtained.

[0623] C017A:MS m / z(ESI):1135.6[M+H] + .

[0624] C017B:MS m / z(ESI):1135.6[M+H] + .

[0625] Example 18: Synthesis of C018

[0626] In addition to changing 3-5 to 18-1, Compound C018 was obtained according to the preparation method described in Example 3. MS m / z (ESI): 1121.6 [M+H] + .

[0627] Example 19: Synthesis of C019

[0628] In addition to changing 3-5 to 19-1, Compound C019 was obtained according to the preparation method described in Example 3. MS m / z (ESI): 1139.6 [M+H] + .

[0629] Example 20: Synthesis of C020A and C020B

[0630] In addition to changing 3-5 to 20-1, According to the preparation method described in Example 3, compounds C020A and C020B were obtained.

[0631] C020A, MS m / z(ESI):1107.5[M+H] + .

[0632] C020B, MS m / z(ESI):1107.6[M+H] + .

[0633] Example 21: Synthesis of C021

[0634] Step 1: Prepare 21_2

[0635] 21_1 (110 mg, 1.0 eq) was dissolved in DCM (5 ml) in a 100 ml single-necked flask. TEA (120 mg, 3 eq) was added, and AllocCl (71 mg, 1.5 eq) was added dropwise. The reaction was allowed to proceed overnight at room temperature. LCMS monitoring indicated the disappearance of the starting material and the formation of the product as a major peak. Water and DCM were added, the layers separated, and the organic phase was concentrated to dryness to obtain the crude product 21_2, which was directly used in the next step.

[0636] Step 2: Prepare 21_3

[0637] 21_2 (130 mg, 1.0 eq) and THF (4 ml) were added to a 50 ml single-necked flask for dissolution. HCl in dioxane (0.88 ml, 10 eq) was added and the mixture was allowed to react at room temperature for 2 h. LCMS showed the disappearance of the starting material and the formation of the product as a major peak. The reaction solution was concentrated to dryness, and water and EA were added. The pH was adjusted to 9-10 with sodium carbonate solution. The layers were separated, and the aqueous layer was extracted twice with EA. The organic phases were combined and concentrated to yield 21_3, which was directly carried to the next step.

[0638] Step 3: Prepare 21_4

[0639] To a 100 ml single-necked flask were added intermediate A (90 mg, 1.0 eq), 21_3 (45 mg, 1.0 eq), DMF (3 ml), and KCO (75 mg, 3.0 eq). The mixture was allowed to react overnight at room temperature. LCMS analysis indicated a small amount of starting material remaining, and the reaction was stopped. Water and EA were added, the layers separated, and the aqueous layer was extracted with EA. The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain the crude product 21_4, which was directly used in the next step.

[0640] Step 4: Prepare 21_5

[0641] To a 100ml single-necked flask, 21_4 (90mg, 1.0eq) and THF (3ml) were added, followed by 2 drops of TBAF solution. The mixture was reacted at 32°C for 8h. LCMS analysis indicated the disappearance of the starting material and the product as the main peak. Water and EA were added, and the layers were separated. The organic layer was washed twice with saturated brine and the pH was adjusted to 1-2 with dilute HCl. The organic phase was discarded, and the aqueous phase was adjusted to pH 11-12 with K2CO3 solution. The product was extracted with EA, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain the product 21_5, which was directly carried into the next step.

[0642] Step 5: Prepare 21_6

[0643] To a 100 ml single-necked flask, intermediate B (100 mg, 1.0 eq) and 21_5 (46 mg, 1.1 eq) were added, along with THF (5 ml) as solvent. The temperature was lowered to -10°C, and LiHMDS (0.36 ml, 3.0 eq, 1 M in THF) was added dropwise. The mixture was reacted at -10°C for 0.5 h. LCMS showed that the starting material disappeared and the reaction was complete. The reaction solution was quenched by adding dropwise to an icy NH4Cl aqueous solution, extracted with EA, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried and isolated on a preparative plate to obtain product 21_6.

[0644] Step 6: Prepare 21_7

[0645] 21_6 (35 mg, 1.0 eq) was added to an 8 ml vial and dissolved in 2 ml of DCM. Tetrakistriphenylphosphine palladium (14.4 mg, 0.5 eq) and morpholine (22 mg, 10 eq) were added and reacted at room temperature for 1 h. LCMS showed that the starting material disappeared. 21_7 was directly isolated using a preparative plate. LCMS: [M+1] + =1012.6.

[0646] Step 7: Prepare 21_8

[0647] 21_7 (20 mg, 1.0 eq) and DMF (2 ml) were added to an 8 ml vial and dissolved. Intermediate C (17 mg, 2.0 eq) and CDI (10 mg, 3.0 eq) were added and reacted at room temperature for 2 h. LCMS showed the presence of the desired product. Water and EA were added, the layers were separated, and the organic layer was concentrated to dryness and isolated on a preparative plate to obtain 21_8.

[0648] Step 8: Prepare 21_9

[0649] To a 50 ml single-necked flask were added 21_8 (12 mg, 1.0 eq) and THF (3 ml), followed by the addition of 2 drops of TBAF solution. The mixture was allowed to react at room temperature for 1 h. LCMS analysis showed the disappearance of the starting material and the main peak was the product. Water and EA were added, the layers were separated, and the organic layer was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to afford crude 21_9, which was directly used in the next step.

[0650] Step 9: Prepare C021

[0651] 21_9 (12 mg, 1.0 eq) and DCM (3 ml) were added to a 50 ml single-necked bottle, and TFA (1 ml) was added at room temperature. The reaction was allowed to proceed at room temperature for 1 h. After the reaction was complete, the reaction solution was concentrated to dryness and purified by preparative HPLC to obtain C021. LCMS: [M+H] + =1167.6.

[0652] Example 22: Synthesis of C022

[0653] In addition to replacing intermediate C with intermediate D According to the preparation method described in Example 5, compound C022 was obtained.

[0654] MS m / z(ESI):1131.5[M+H] + .

[0655] Example 23: Synthesis of C023A and C023B

[0656] In addition to replacing intermediate C with intermediate E, According to the preparation method described in Example 5, compounds C023A and C023B were obtained.

[0657] C023A:MS m / z(ESI):1115.4[M+H] + .

[0658] C023B:MS m / z(ESI):1115.3[M+H] + .

[0659] Example 24: Synthesis of D001

[0660] Step 1: Synthesis of D1_1

[0661] Intermediate A (1.06 g, 2.36 mmol) was dissolved in tetrahydrofuran (5 mL), cooled to 0°C, and sodium hydride (282.83 mg, 7.07 mmol) was added. The mixture was stirred at 0°C for 30 minutes. Intermediate B (1.9 g, 2.36 mmol) was then added, and the mixture was stirred at 0°C for 30 minutes. After the reaction was complete, ethyl acetate and water were added for extraction. The organic phase was concentrated and purified by silica gel column chromatography to obtain product D1_1. MS m / z (ESI): 1086.5 [M+H] + .

[0662] Step 2: Synthesis of D1_2

[0663] D1_1 (1.1 g, 1.01 mmol) was dissolved in N,N-dimethylformamide (15 mL), and cesium fluoride (1.54 g, 10.12 mmol) was added. The mixture was stirred at 60°C for 1 hour. The reaction was monitored for completion by LCMS. The reaction solution was extracted with ethyl acetate and water. The organic phase was concentrated and purified by silica gel column chromatography to obtain product D1_2. MS m / z (ESI): 692.3 [M+H] + .

[0664] Step 3: Synthesis of D1_3

[0665] D1_2 (160 mg, 0.231 mmol) was dissolved in dichloromethane (1 mL), cooled to 0°C, and triethylamine (70.22 mg, 0.693 mmol) and methanesulfonyl chloride were added. The mixture was stirred at 0°C for 1 hour. The reaction was monitored for completion by LCMS. The reaction solution was concentrated to give compound D1_3. MS m / z (ESI): 770.2 [M+H] + .

[0666] Step 4: Synthesis of D1_5

[0667] D1_3 (600 mg, 0.67 mmol) was dissolved in N,N-dimethylformamide (6 mL) at room temperature. D1_4 (93 mg, 0.67 mmol), potassium carbonate (370 mg, 2.68 mmol), and sodium iodide (200 mg, 1.34 mmol) were added. The reaction mixture was allowed to react at room temperature for 3 hours. LCMS monitoring indicated that the reaction was complete. Ethyl acetate and water were then added for extraction. The organic phase was concentrated and purified by silica gel column chromatography to obtain compound D1_5.

[0668] Step 5: Synthesis of D1_6

[0669] At room temperature, a solution of CuSO4.5H2O (412 mg, 1.65 mmol) in water (10 mL) was added to a solution of compound D1_5 (320 mg, 0.33 mmol), intermediate F (187 mg, 0.396 mmol), Vc-Na (327 mg, 1.65 mmol) and t-BuOH (10 mL) in DMSO (10 mL). The reaction mixture was stirred at 20°C for 1 h. LCMS showed that most of the starting material was converted into product. Ethyl acetate (500 mL) was added to dilute the mixture, and the organic layer was washed with brine and sodium potassium tartrate aqueous solution, respectively. The organic phase was dried over Na2SO4, concentrated, and further purified by column chromatography to obtain compound D1_6. LCMS (ESI) m / z: 1441.4 (M+H) + .

[0670] Step 6: Synthesis of D1_7

[0671] Cesium fluoride (368 mg, 2.43 mmol) was added to a solution of compound D1_6 (350 mg, 0.243 mmol) in N,N-dimethylformamide (10 mL). The reaction mixture was stirred at 20°C for 2 hours. LCMS analysis showed that most of the starting material was converted to product. The residue was diluted with ethyl acetate (200 mL), and the organic phase was washed three times with saturated brine and then separated. The organic phase was dried over anhydrous sodium sulfate, concentrated, and then purified by column chromatography to obtain compound D1_7. LCMS (ESI) m / z: 1285.3 (M+H) + .

[0672] Step 7: Synthesis of Compound D001

[0673] Trifluoroacetic acid (2 mL) was added to a solution of compound D1_7 (197 mg, 0.153 mmol) in dichloromethane (6 mL), and the reaction mixture was stirred at 20°C for 2 hours. LCMS analysis showed that most of the starting material was converted into product. The reaction mixture was concentrated at low temperature to remove trifluoroacetic acid, and the crude product obtained after beating with diethyl ether was separated and purified by preparative chromatography to obtain compound D001.

[0674] 1 H NMR (400MHz, DMSO) δ9.04(d,J=9.0Hz,1H),8.97(d,J=4.0Hz,1H),7.93(s,1H),7.87–7.71(m,1H),7.46–7.28(m,6H),7.14(s, 0.5H),7.12–7.01(m,1H),6.86(d,J=11.6Hz,0.5H),5.21–5.11(m,1H),5.06–4.65(m,4H),4.46(dd,J=21.2,10.0Hz,1H),4.28 (t,J=22.8Hz,3H),3.87(d,J=9.6Hz,1H),3.78–3.69(m,1H),3.63-3.50(m,6H),2.98–2.81(m,2H),2.47–2.27(m,7H),2.06(dd ,J=16.5,11.0Hz,4H),1.79(s,1H),1.66–1.16(m,12H),1.00(t,J=7.1Hz,3H),0.66–0.51(m,3H).LCMS(ESI)m / z:1141.5(M+H) + .

[0675] Example 25: Synthesis of D002

[0676] In addition to replacing intermediate D1_4 with intermediate D2_1, Compound D002 was obtained according to the preparation method of D001 described in Example 24. MS (ESI) m / z: 1127.5 (M+H) + .

[0677] Example 26: Synthesis of D003A and D003B

[0678] In addition to replacing intermediate D1_4 with intermediate D3_1, According to the preparation method of D001 described in Example 24, compounds D003A and D003B were obtained.

[0679] D003A: 1H NMR(400MHz,CDCl3)δ9.11–9.02(m,1H),8.99(s,1H),8.59(d,J=1.5Hz,1H),8.50(dd,J=8.1,4.7Hz,1H),7.97(dd,J=9.1,6.0Hz,1H),7.72(t,J=8.1Hz,2H),7.49–7.42(m,3H),7.38(dt,J=8.4,3.1Hz,3H),7.30-7.24(m,2.5H),7.17(d,J=8.4Hz,1H),7.06(s,0.5H),5.33(d,J=10.5Hz,1H),4.87(dd,J=11.6,5.8Hz,3H),4.48(dd,J=14.1,6.3Hz,2H),4.32(d,J=9.7Hz,2H),3.93(s,1H),3.79(dd,J=10.8,4.0Hz,1H),3.70(d,J=11.1Hz,1H),3.61(dd,J=9.0,6.5Hz,3H),3.53(s,2H),3.03(s,2H),2.76–2.71(m,2H),2.59(d,J=8.3Hz,2H),2.46(s,3H),2.22(d,J=1.5Hz,4H),2.12–2.04(m,1H),1.83–1.77(m,1H),1.63(s,4H),1.08(d,J=6.3Hz,3H),0.71(dd,J=6.4,4.3Hz,3H).LCMS(ESI)m / z:1161.3(M+H) + 。

[0680] D003B: 1H NMR (400MHz, DMSO) δ9.06 (d, J = 3.2 Hz, 1H), 8.99 (s, 1H), 8.60 (s, 1H), 8.49 (d, J =4.5Hz,1H),7.98(dd,J=9.0,6.1Hz,1H),7.73(t,J=8.3Hz,2H),7.50–7. 40(m,3H),7.40–7.34(m,3H),7.30–7.24(m,2H),7.20(dd,J=8.6,2.0Hz, 1H),7.07(s,0.5H),6.86(s,0.5H),5.33(d,J=10.1Hz,1H),4.87(dd,J=1 4.8,6.8Hz,3H),4.63–4.41(m,2H),4.35(d,J=16.3Hz,2H),3.93(s,1H),3 .79(dd,J=10.5,4.1Hz,1H),3.72(s,1H),3.67–3.59(m,5H),3.01(d,J=1 4.2Hz,2H),2.74(t,J=6.9Hz,2H),2.58(t,J=7.3Hz,2H),2.46(s,3H),2. 22(s,4H),2.08(dd,J=12.3,9.8Hz,1H),1.83-1.76(m,1H),1.69(s,4H), 1.08(d,J=6.4Hz,3H),0.71(t,J=5.4Hz,3H).LCMS(ESI)m / z:1161.3(M+H) + .

[0681] Example 27: Synthesis of D004A and D004B

[0682] In addition to replacing intermediate D1_4 with intermediate D4_1, According to the preparation method of D001 described in Example 24, compounds D004A and D004B were obtained.

[0683] D004A: 1H NMR(400MHz,DMSO-d6)δ10.18(s,1H),9.04(s,1H),8.99(s,1H),8.49(d,J=7.8Hz,1H),8.10(s,1H),7.96(dd,J=9.1,6.1Hz,1H),7.49–7.41(m,3H),7.37(d,J=7.8Hz,3H),7.17(d,J=2.3Hz,1H),7.05(s,0.5H),6.84(s,0.5H),5.28(d,J=10.4Hz,1H),5.23–5.04(m,1H),4.95(s,2H),4.89–4.83(m,1H),4.53–4.42(m,4H),4.33–4.27(m,2H),3.93(s,1H),3.76(dd,J=10.5,3.8Hz,1H),3.66–3.56(m,4H),3.53(s,2H),3.44–3.36(m,1H),2.91(s,2H),2.70–2.60(m,2H),2.46(s,3H),2.42–2.39(m,1H),2.10–2.03(m,2H),1.83–1.77(m,2H),1.65(s,4H),1.40(d,J=8.1Hz,2H),1.04(d,J=6.6Hz,3H),0.65(d,J=6.6Hz,3H).LCMS for(ESI)m / z:1141.3(M+H) + 。

[0684] D004B: 1H NMR (400MHz, DMSO-d6) δ8.97 (s, 2H), 8.03 (d, J = 12.7Hz, 1H), 7.88 (s, 1H), 7.47–7.33 (m, 6H), 7.26 (s, 0.5H), 7.15 (s, 1H), 7.04 (s, 0.5H), 5. 21(dd,J=10.7,5.5Hz,1H),5.03–4.77(m,3H),4.72(s,1H),4.61(s,1H),4.55–4.45(m,3H),4.29(s,3H),3.82(d,J=11.3Hz,1H),3.73(dd,J =7.0,4.1Hz,2H),3.65–3.53(m,5H),3.07(d,J=9.0Hz,2H),2.63(s,1H),2.58–2.53(m,1H),2.46(s,3H),2.41(dd,J=6.2,2.0Hz,1H),2.13( s,1H),2.03–1.93(m,2H),1.84–1.77(m,2H),1.68–1.52(m,4H),1.38(s,1H),1.23(s,1H),1.02(d,J=6.5Hz,3H),0.62(d,J=6.4Hz,3H).LCMS for(ESI)m / z:1141.0(M+H) + .

[0685] Example 28: Synthesis of D005A and D005B

[0686] In addition to replacing intermediate D1_4 with intermediate D5_1, and replace intermediate F with intermediate G, According to the preparation method of D001 described in Example 24, compounds D005A and D005B were obtained.

[0687] D005A: 1H NMR(400MHz,DMSO-d6)δ10.17(s,1H),9.14–8.94(m,2H),8.57(dd,J=21.4,9.5Hz,2H),7.98(dd,J=9.3,5.8Hz,1H),7.71(dd,J=20.1,11.7Hz,2H),7.42(dt,J=16.1,9.0Hz,6H),7.26(d,J=6.0Hz,2H),7.20(d,J=8.2Hz,1H),6.96(d,J=84.1Hz,1H),5.35–5.16(m,2H),4.91(dd,J=18.5,6.9Hz,2H),4.50(d,J=10.5Hz,1H),4.41(t,J=8.3Hz,1H),4.32(s,2H),3.93(s,1H),3.79(d,J=10.8Hz,1H),3.72–3.63(m,2H),3.59(s,3H),3.03(s,2H),2.74(t,J=7.5Hz,2H),2.59(s,1H),2.46(s,2H),2.22(s,3H),2.03(dd,J=20.0,12.7Hz,2H),1.84–1.75(m,1H),1.66(s,2H),1.63(s,1H),1.55–1.42(m,1H),1.38(d,J=7.0Hz,2H),1.30(s,1H),1.24(s,3H),1.08(d,J=6.6Hz,3H),0.85(t,J=6.9Hz,1H),0.76–0.66(m,3H).LCMS(ESI)m / z:1145.6(M+H) + .

[0688] D005B: 1HNMR (400MHz, DMSO-d6) δ10.18(s,1H),9.06(t,J=5.7Hz,1H),8.99(d,J=2.1Hz,1H),8.59(dd, J=10.1,2.3Hz,1H),8.53(dd,J=7.4,4.5Hz,1H),7.98(dd,J=9.2,6.0Hz,1H),7.71(m,2H),7.45 (m,3H),7.38(m,4H),7.27(m,2.5H),7.20(dd,J=10.3,2.4Hz,1H),7.09(s,0.5H),5.33(d,J=10 .3Hz,1H),4.93(t,J=7.2Hz,1H),4.79(d,J=6.6Hz,2H),4.47(m,1H),4.40(d,J=7.8Hz,1H),4.3 4(s,2H),3.92(s,1H),3.79(d,J=6.9Hz,1H),3.67(dd,J=28.4,11.4Hz,2H),3.56(s,3H),3.18( s,4H),2.73(dd,J=22.1,14.3Hz,3H),2.44(m,4H),2.23(d,J=2.4Hz,4H),2.03(dd,J=22.3,10. 1Hz,2H),1.80(m,1H),1.64(s,4H),1.39(d,J=7.0Hz,3H),1.24(s,2H),1.08(d,J=6.5Hz,3H),0 .85(d,J=7.0Hz,1H),0.71(t,J=6.2Hz,3H),0.71(t,J=6.2Hz,3H).LCMS(ESI)m / z:1146.0(M+H) + .

[0689] Example 29: Synthesis of D006

[0690] In addition to replacing intermediate D1_4 with intermediate D6_1, and replacing intermediate F with intermediate H, According to the preparation method of D001 described in Example 24, compounds D006A and D006B were obtained.

[0691] 1H NMR (400MHz, DMSO-d6) δ10.22(s,1H),9.33(s,1H),9.16(s,1H),8.99(s,1H),7.94(d,J=45 .4Hz,2H),7.49–7.42(m,4H),7.22-6.96(m,1H),5.25–4.99(m,3H),4.61(d,J=62.3Hz,2H), 4.39-3.67(m,15H),2.79-2.70(m,4H),2.51-2.40(m,5H),2.34–2.32(m,1H),2.01- 1.69(m,12H),1.41-1.02(m,7H),0.63(d,J=5.8Hz,3H).LCMS(ESI)m / z:1123.2(M+H) + .

[0692] Example 30: Synthesis of D007

[0693] In addition to replacing intermediate D1_4 with intermediate D7_1, According to the preparation method of D001 described in Example 24, compound D007 was obtained.

[0694] 1 H NMR (400MHz, DMSO-d6) δ10.16(s,1H),9.07–8.97(m,2H),8.50(s,1H),8.15(s,1H),7.98(d,J=9.0Hz,1H ),7.72(s,1H),7.46–7.37(m,5H),7.27-6.96(m,3H),5.33(d,J=10.7Hz,1H),4.99(s,1H),4.86(s,1H),4 .51-4.48(m,4H),3.79-3.55(m,11H),3.09-2.94(m,3H),2.67(s,2H),2.46(s,4H),2.33(s,5H),2.15-2 .11(m,5H),1.80-1.65(m,7H),1.08(d,J=6.5Hz,3H),0.72(d,J=5.4Hz,3H).LCMS(ESI)m / z:1175.2(M+H) + .

[0695] Example 31: Synthesis of D008

[0696] In addition to replacing intermediate D1_4 with intermediate D8_1, According to the preparation method of D001 described in Example 24, compound D008 was obtained.

[0697] MS (ESI) m / z: 1179.2 (M+H) +.

[0698] Example 32: Synthesis of D009A and D009B

[0699] In addition to replacing intermediate D5_1 with intermediate D9_1, According to the preparation method described in Example 28, compounds D009A and D009B were obtained.

[0700] D009A: 1 H NMR (400MHz, DMSO-d6) δ10.16(s,1H),9.02(d,J=2.8Hz,1H),8.99(s,1H),8.60(s,1H),8.51(d,J=2.8Hz,1H),7. 97(dd,J=9.1,6.0Hz,1H),7.86–7.71(m,2H),7.48–7.34(m,5H),7.20-7.18(m,2H),7.06(s,0.5H),6.86(s,0.5H ),5.37(d,J=10.2Hz,1H),4.88(dt,J=26.1,9.3Hz,3H),4.52–4.28(m,4H),3.93(s,1H),3.79–3.42(m,8H),3.03 (s,2H),2.77(d,J=6.8Hz,2H),2.69-2.60(m,4H),2.46(s,3H),2.22(d,J=2.3Hz,3H),2.06(s,1H),1.79-1.75(m 1H),1.70-1.51(m,4H),1.39(d,J=7.0Hz,3H),1.07(d,J=6.5Hz,3H),0.74–0.66(m,3H).LCMS(ESI)m / z:1159.6(M+H) + .

[0701] D009B: 1H NMR (400MHz, DMSO-d6) δ10.16(s,1H),9.02(d,J=2.8Hz,1H),8.99(s,1H),8.60(s,1H),8.56–8.46(m,1H),7.97(dd,J =9.1,6.0Hz,1H),7.72(dd,J=8.1,3.1Hz,2H),7.51-7.43(m,3H),7.39-7.32(m,3H),7.29–7.06(m,4H),5.36-5.30(m 1H),5.11-5.25(m,1H),4.97–4.82(m,3H),4.49–4.37(m,2H),4.34-4.30(m,2H),3.87(s,1H),3.79(d,J=6.9Hz,1H) ,3.70(d,J=11.2Hz,1H),3.61(d,J=11.4Hz,1H),3.55(s,1H),3.50(s,2H),3.09(s,2H),2.58–2.55(m,2H),2.51(s,1 H),2.49–2.49(m,1H),2.46(s,3H),2.33(t,J=6.6Hz,2H),2.13(s,3H),2.11–2.03(m,1H),1.83–1.68(m,3H),1.61( s,3H),1.56(s,1H),1.38(d,J=7.0Hz,3H),1.08(d,J=6.4Hz,3H),0.72(d,J=4.4Hz,3H).LCMS(ESI)m / z:1159.8(M+H) + .

[0702] Example 33: Synthesis of D010A and D010B

[0703] In addition to replacing intermediate D1_4 with intermediate D10_1, According to the preparation method of D001 described in Example 24, compounds D010A and D010B were obtained.

[0704] D010A: 1H NMR(400MHz,DMSO-d6)δ10.16(s,1H),9.05(s,1H),8.98(s,1H),8.64–8.55(m,1H),8.50(d,J=4.7Hz,1H),8.21(s,1H),7.97(dd,J=9.2,6.0Hz,1H),7.74-7.69(m,3H),7.49–7.42(m,3H),7.42–7.33(m,4H),7.29-2.21(m,4H),7.01(s,0.5H),6.80(s,0.5H),5.32(d,J=9.8Hz,1H),5.16(s,1H),4.98–4.70(m,4H),4.53–4.26(m,5H),3.91(s,1H),3.79-3.70(m,3H),3.61-3.56(m,6H),2.96(s,5H),2.67(s,1H),2.44(d,J=11.7Hz,6H),2.33(s,1H),2.16(s,4H),2.07(s,1H),1.80(s,2H),1.64(s,5H),1.38(d,J=6.9Hz,4H),1.11(dd,J=25.2,6.6Hz,8H),0.70(dd,J=11.0,6.3Hz,4H).LCMS(ESI)m / z:1175.5(M+H) + 。

[0705] D010B: 1H NMR(400MHz,DMSO-d6)δ10.15(s,1H),9.06(s,1H),8.99(s,1H),8.62–8.55(m ,1H),8.52(s,1H),8.04–7.93(m,1H),7.76–7.63(m,2H),7.50–7.41(m,3H),7 .42–7.33(m,4H),7.31-7.25(m,3H),7.18(s,0.5H),7.07(s,0.5H),5.32(d,J =10.5Hz,1H),5.19-5.11(m,1H),4.98–4.87(m,1H),4.79-4.70(m,2H),4.49(s ,1H),4.41-4.37(m,3H),3.90(d,J=4.2Hz,1H),3.78(s,1H),3.74-3.665(m,5 H),3.12(s,2H),2.96(s,1H),2.44(d,J=11.7Hz,6H),2.15(d,J=6.1Hz,3H),2 .06(s,1H),1.79(s,1H),1.68(s,4H),1.51(s,1H),1.38(d,J=7.0Hz,3H),1.1 1(dd,J=26.9,6.2Hz,7H),0.69(t,J=11.3Hz,4H).LCMS(ESI)m / z:1175.5(M+H) + .

[0706] Example 34: Synthesis of D011A and D011B

[0707] In addition to replacing intermediate D5_1 with intermediate D11_1, According to the preparation method described in Example 28, compounds D011A and D011B were obtained.

[0708] D011A: 1H NMR(400MHz,DMSO-d6)δ10.20(s,1H),9.05(s,1H),8.99(s,1H),8.59-8.53(m,1H),8.32(s,1H),8.05–7.79(m,2H),7.44-7.37(m,6H),7.30(s,0.5H),7.21(d,J=12.4Hz,2H),7.16(s,1H),7.09(s,0.5H),5.39(d,J=10.4Hz,1H),5.23-5.15(m,1H),5.12–4.60(m,4H),4.51–4.38(m,2H),4.33(s,2H),3.90(s,1H),3.77(s,1H),3.69(d,J=11.1Hz,1H),3.61(d,J=10.0Hz,2H),3.55(s,1H),3.51(s,3H),3.18(s,2H),2.79(s,2H),2.63(s,2H),2.46(s,2H),2.22(s,3H),2.07(s,1H),1.79(s,1H),1.61(s,3H),1.52(s,1H),1.39(d,J=6.7Hz,2H),1.24(s,1H),1.07(d,J=5.6Hz,3H),0.69(s,3H).LCMS(ESI)m / z:1163.5(M+H) + .

[0709] D011B: 1H NMR (400MHz, DMSO-d6) δ10.15(s,1H),9.02(d,J=12Hz,1H),8.98(s,1H),8.63–8.47(s,1H),8.31(d,J=12Hz,1H),7.93-7.89(m,1H),7.45 -7.37(m,6H),7.33-7.14(m,2H),7.06(s,0.5H),6.86(s,0.5H),5.38(d,J=10.4Hz,1H).5.23-5.15(m,1H),4.94–4.86(m,3H),4.45–4.32 (m,3H),3.90(s,1H),3.77(s,1H),3.78-3.50(m,7H),3.03(s,2H),2.79-2.73(m,2H),2.67-2.51(m,5H),2.46-2.40(m,4H),2.21(s,3H), 2.17-2.06(m,1H),1.74(s,1H),1.69-1.50(m,4H),1.39(d,J=8.0Hz,3H),1.07(d,J=5.6Hz,3H),0.69(s,3H).LCMS(ESI)m / z:1163.3(M+H) + .

[0710] Example 35: Synthesis of D012A and D012B

[0711] In addition to replacing intermediate D5_1 with intermediate D12_1, According to the preparation method described in Example 28, compounds D012A and D012B were obtained.

[0712] D012A: 1H NMR(400MHz,DMSO-d6)δ9.04(s,1H),8.98(s,1H),8.60–8.37(m,3H),7.97(dd,J=9.1,6.0Hz,1H),7.86–7.71(m,2H),7.48–7.34(m,6H),7.21(d,J=12Hz,1H),7.06(s,0.5H),6.86(s,0.5H),5.37(d,J=10.2Hz,1H),4.95-4.83(m,3H),4.52–4.28(m,4H),3.93(s,1H),3.79–3.42(m,8H),3.03(s,2H),2.77(d,J=6.8Hz,2H),2.64(d,J=22.7Hz,4H),2.46(s,3H),2.22(d,J=2.3Hz,3H),2.06(s,1H),1.77(d,J=12.9Hz,1H),1.57(d,J=27.7Hz,4H),1.39(d,J=7.0Hz,3H),1.07(d,J=6.5Hz,3H),0.74–0.66(m,3H).LCMS(ESI)m / z:1146.0(M+H) + 。

[0713] D012B: 1H NMR(400MHz,DMSO-d6)δ10.16(s,1H),9.05(s,1H),8.98(s,1H),8.56–8.4 3(m,3H),7.97(dd,J=9.0,6.0Hz,1H),7.84–7.71(m,2H),7.45–7.36(m,5H ),7.29(s,0.5H),7.21(d,J=12Hz,1H),7.08(s,0.5H),5.37(d,J=10.2Hz, 1H),5.22-512(m,1H),4.98–4.87(m,1H),4.73(d,J=13.8Hz,2H),4.47–4.2 8(m,4H),3.92(s,1H),3.78–3.48(m,6H),3.18(s,2H),2.78(s,2H),2.65( d,J=16.6Hz,3H),2.44(d,J=11.1Hz,4H),2.22(d,J=3.0Hz,3H),2.05(s,1H ),1.77(d,J=12.6Hz,1H),1.67–1.47(m,5H),1.38(d,J=7.0Hz,3H),1.07( d,J=6.6Hz,3H),0.70(dd,J=10.3,6.6Hz,3H).LCMS(ESI)m / z:1146.0(M+H) + .

[0714] Example 36: Synthesis of D013A and C013B

[0715] In addition to replacing intermediate D6_1 with intermediate D13_1, According to the preparation method described in Example 29, compounds D013A and C013B were obtained.

[0716] D013A: 1H NMR(400MHz,DMSO-d6)δ10.14(s,1H),9.03(d,J=4.3Hz,1H),8.99(s,1H),8.76(s,1H),8.60(t,J=5.7Hz,1H),8.04–7.94(m,1H),7.91(d,J=5.3Hz,1H),7.72(t,J=8.1Hz,1H),7.42(dt,J=12.1,7.7Hz,8H),7.18(dd,J=3.6,2.9Hz,1H),7.06(s,0.5H),6.85(s,0.5H),5.36(d,J=10.1Hz,1H),5.20(s,1H),4.89(s,2H),4.47(d,J=12.8Hz,1H),4.42–4.28(m,5H),3.92(s,1H),3.85(d,J=7.1Hz,1H),3.72(d,J=10.5Hz,1H),3.62(s,1H),3.55(s,3H),3.04(s,3H),2.84(d,J=7.1Hz,2H),2.59(s,2H),2.45(s,3H),2.25(s,3H),2.08(t,J=10.8Hz,1H),1.92(s,1H),1.61(s,4H),1.07(d,J=6.3Hz,3H),0.79–0.69(m,3H).LCMS for(ESI)m / z:1165.6(M+H) + 。

[0717] D013B: 1H NMR(400MHz,DMSO-d6)δ10.15(s,1H),9.03(d,J=5.5Hz,1H),8.99(s,1H),8 .76(d,J=0.7Hz,1H),8.60(t,J=6.0Hz,1H),7.97(dd,J=9.2,6.0Hz,1H),7.9 1(dd,J=6.9,1.6Hz,1H),7.71(t,J=9.4Hz,1H),7.49–7.35(m,7H),7.29(s, 0.5H),7.19(dd,J=7.8,2.2Hz,1H),7.08(s,0.5H),5.36(d,J=10.1Hz,1H),5 .20(s,1H),4.79(s,2H),4.50–4.25(m,6H),3.91(s,1H),3.85(dd,J=10.8, 3.9Hz,1H),3.72(d,J=11.0Hz,1H),3.62-3.53(m,4H),3.19(s,2H),2.93–2. 78(m,2H),2.59(d,J=5.4Hz,2H),2.45(s,3H),2.08(t,J=9.6Hz,1H),1.98- 1.80(m,1H),1.60(s,4H),1.07(d,J=6.5Hz,3H),0.72(t,J=6.2Hz,3H).LCMS for(ESI)m / z:1165.9(M+H) + .

[0718] Example 37: Synthesis of D014A and D014B

[0719] In addition to replacing intermediate D5_1 with intermediate D14_1, According to the preparation method of D001 described in Example 24, compounds D014A and D014B were obtained.

[0720] D014A: 1H NMR(400MHz,DMSO-d6)δ10.15(s,1H),9.05(s,1H),8.98(s,1H),8.51(d,J=7.1Hz,1H),8.31(s,1H),7.97(dd,J=9.2,6.0Hz,1H),7.44(d,J=9.5Hz,2H),7.39–7.36(m,2H),7.20(dd,J =13.1,5.1Hz,2H),7.12–7.00(m,2.5H),6.91(s,0.5H),5.33(d,J=10.0Hz,1H),5.15(s,3H),5.03–4.89(m,3H),4.52–4.28(m,4H),3.90(d,J=1.2Hz,1H),3.67-3.42(m,6H),3.42(s,2H),2.99(s,2H),2.51(s,2H),2.44(d,J=11.6Hz,4H),2.06(s,4H),1.79(td,J=8.4,4.2Hz,1H),1.63(s,4H),1.37(d,J=7.0Hz,3H),1.04(d,J=6.5Hz,3H),0.65(d,J=6.6Hz,3H).LCMS(ESI)m / z:1179.4(M+H) + 。

[0721] D014B: 1 H NMR(400MHz,DMSO-d6)δ10.16(s,1H),9.06(s,1H),8.98(s,1H),8.51(d,J=7.6Hz,1H),8.31(s,1H),7.97(dd,J=9.2,6.0Hz,1H),7.44(d,J=8.4Hz,2H),7.39-7.36(m,3H),7.27(s,0.5H),7.25-7.19(m,2H),7.08(s,0.5H),7.06-7.02(m,2H),5.33(d,J=10.1Hz,1H),5.14(s,3H),4.97–4.83(m,3H),4.44-4.31(m,4H),3.89(d,J=1.7Hz,1H),3.77–3.41(m,8H),3.13(s,2H),2.51(s,3H),2.46(s,3H),2.09(s,4H),1.79(s,1H),1.63(s,4H),1.37(d,J=7.0Hz,3H),1.04(d,J=6.5Hz,3H),0.65(d,J=6.6Hz,3H).LCMS(ESI)m / z:1179.4(M+H) + 。

[0722] Example 38: Synthesis of D015

[0723] In addition to replacing intermediate D6_1 with intermediate D15_1, According to the preparation method described in Example 29, compound D015 was obtained.

[0724] D015: 1 H NMR(400MHz,DMSO-d6)δ10.15(s,1H),9.06(s,1H),8.98(s,1H),8.58(t,J =6.1Hz,1H),7.97(dd,J=9.2,5.9Hz,1H),7.88(s,1H),7.49–7.43(m,2H),7 .40(d,J=8.7Hz,2H),7.37(s,2H),7.35(s,1H),7.28(s,0.5H),7.18(d,J= 7.5Hz,3H),7.13-7.07(m,2.5H),5.24(d,J=10.1Hz,1H),5.18(s,1H),4.90 (s,2H),4.49(d,J=12.2Hz,1H),4.40–4.22(m,5H),3.92(s,3H),3.81(d,J =6.4Hz,1H),3.64(d,J=6.8Hz,2H),3.57(s,1H),3.52(s,3H),3.42(s,2H), 3.12(s,2H),2.44(s,3H),2.05(s,4H),1.91(d,J=4.9Hz,1H),1.63(s,4H) ,1.00(d,J=6.6Hz,3H),0.61(d,J=5.0Hz,3H).LCMS(ESI)m / z:1131.7(M+H) + .

[0725] Example 39: Synthesis of D016A and D016B

[0726] In addition to replacing intermediate D5_1 with intermediate D16_1, According to the preparation method of D001 described in Example 24, compounds D016A and D016B were obtained.

[0727] D016A:MS(ESI)m / z:1179.4(M+H) + .

[0728] D016B:MS(ESI)m / z:1179.4(M+H) + .

[0729] Example 40: Synthesis of D017A and D017B

[0730] In addition to replacing intermediate D5_1 with intermediate D17_1, According to the preparation method of D001 described in Example 24, compounds D017A and D017B were obtained.

[0731] D017A: 1 H NMR (400MHz, DMSO-d6) δ9.06 (s, 1H), 8.98 (s, 1H), 8.60 (d, J = 3.6Hz, 1H), 8.5 5(s,1H),8.06–7.89(m,1H),7.83–7.66(m,2H),7.48–7.35(m,8H),7.22(d,J =9.3Hz,1H),6.89(d,J=84.2Hz,1H),5.32(d,J=10.2Hz,1H),5.06(d,J=69.4 Hz,1H),4.92(dd,J=19.2,6.6Hz,3H),4.50(d,J=12.0Hz,1H),4.42(t,J=8.1 Hz,1H),4.34(s,2H),3.91(s,1H),3.79(d,J=7.7Hz,1H),3.67(d,J=23.6Hz, 3H),3.54(s,3H),2.90(s,2H),2.54(s,2H),2.46(s,2H),2.07(s,1H),1.91( d,J=2.8Hz,3H),1.78(d,J=13.4Hz,1H),1.66(s,4H),1.39(d,J=6.7Hz,3H), 1.24(s,6H),1.08(d,J=5.9Hz,3H),0.71(s,3H).LCMS(ESI)m / z:1173.4(M+H) + .

[0732] D017B: 1H NMR (400MHz, DMSO-d6) δ10.20(s,1H),9.06(s,1H),8.99(s,1H),8.61(d,J=4.9Hz, 1H),8.54(dd,J=15.9,4.2Hz,1H),7.98(dd,J=9.2,6.0Hz,1H),7.79–7.73(m,2H), 7.49–7.36(m,8.5H),7.24-7.2(m,1H),7.01(s,0.5H)5.32(d,J=10.3Hz,1H),5.29 –4.96(m,2H),4.96–4.89(m,1H),4.82(s,2H),4.49(d,J=11.0Hz,1H),4.41(t,J=8 .1Hz,1H),4.35(d,J=13.9Hz,2H),3.90(s,1H),3.79(d,J=6.9Hz,1H),3.73–3.60( m,3H),3.55(s,3H),3.05(s,2H),2.56(s,2H),2.46(s,2H),2.06(d,J=8.9Hz,1H), 1.91(d,J=2.2Hz,3H),1.79(t,J=12.8Hz,1H),1.66(s,4H),1.38(d,J=7.0Hz,3H), 1.25(s,6H),1.08(d,J=6.4Hz,3H),0.75–0.66(m,3H).LCMS(ESI)m / z:1173.4(M+H) + .

[0733] Example 41: Synthesis of D018A and D018B

[0734] In addition to replacing intermediate H with intermediate D18_1, According to the preparation method described in Example 36, compounds D018A and D018B were obtained.

[0735] D018A: 1H NMR(400MHz,DMSO-d6)δ10.17(s,1H),9.03(d,J=4.8Hz,1H),8.77(t,J=5.7Hz,1H),8.52(d,J=4.7Hz,1H),8.02–7.84(m,2H),7.77-7.71(m,1H),7.51–7.33(m,8H),7.19(dd,J=6.7,2.0Hz,1H),7.07(s,0.5H),6.86(s,0.5H),6.32(d,J=1.5Hz,1H),5.35(d,J=10.0Hz,1H),5.18(s, 1H),4.99–4.78(m,3H),4.56–4.38(m,2H),4.31(d,J=12.9Hz,2H),4.11(dd,J=14.4,7.3Hz,2H),3.92(s,1H),3.75(dd,J=28.4,9.4Hz,2H),3.57(dd,J=35.3,15.4Hz,4H),3.04(s,2H),2.89–2.79(m,2H),2.62–2.56(m,2H),2.25(s,3H),2.07(t,J=12.6Hz,1H),1.84–1.75(m,1H),1.58(d,J=25.3Hz,4H),1.39(d,J=6.9Hz,3H),1.30(t,J=7.2Hz,3H),1.09(d,J=6.3Hz,3H),0.72(t,J=5.5Hz,3H).LCMS for(ESI)m / z:1176.7(M+H) + 。

[0736] D018B: 1H NMR (400MHz, DMSO-d6) δ10.18(s,1H),9.03(d,J=5.7Hz,1H),8.77(d,J=3.3Hz,1H),8.52(d,J= 4.5Hz,1H),7.97(dd,J=9.0,6.0Hz,1H),7.91(d,J=7.2Hz,1H),7.77–7.68(m,1H),7.49–7.38( m,8H),7.29(s,0.5H),7.20(d,J=9.0Hz,1H),7.08(s,0.5H),6.32(d,J=1.4Hz,1H),5.35(d,J= 10.1Hz,1H),5.18(s,1H),4.95(t,J=7.3Hz,1H),4.79(d,J=7.1Hz,2H),4.44(dd,J=17.7,10.5 Hz,2H),4.30(d,J=13.0Hz,2H),4.11(q,J=7.1Hz,2H),3.91(s,1H),3.79(d,J=7.4Hz,1H),3.7 2(d,J=10.5Hz,1H),3.61(d,J=12.0Hz,1H),3.53(d,J=16.8Hz,3H),3.20(s,2H),2.89–2.82(m ,2H),2.59(d,J=3.7Hz,2H),2.26(s,3H),2.10–2.04(m,1H),1.83–1.74(m,1H),1.61(s,4H),1 .39(d,J=7.0Hz,3H),1.30(t,J=7.2Hz,3H),1.08(d,J=6.3Hz,3H),0.72(t,J=6.2Hz,3H).LCMS for(ESI)m / z:1177.0(M+H) + .

[0737] Example 42: Synthesis of D019A and D019B

[0738] Except that intermediate B was replaced by intermediate D19_1, and replacing intermediate D1_4 with intermediate D9_1, According to the method described in Example 24, compounds D019A and D019B were obtained.

[0739] Intermediate D19_1 was prepared according to the method described in Intermediate Preparation Example 2, except that B6 Replace

[0740] D019A: 1H NMR (400MHz, DMSO-d6) δ10.46–9.94(m,1H),9.05(s,1H),8.98(s,1H),8.59(d,J=2.9Hz,1H),8.50(s,1H),7.83(d,J=7. 6Hz,1H),7.69(s,2H),7.45-7.35(m,6H),7.28(s,0.5H),7.15(d,J=4.0Hz,2H),7.05(s,.5H),5.33(d,J=10.3Hz,1H),5. 11-4.85(m,4H),4.47-4.34(m,4H),3.80–3.45(m,8H),2.92(s,2H),2.67(s,1H),2.46(s,4H),2.33(s,3H),2.11(s,4H), 1.62(d,J=49.1Hz,7H),1.38(d,J=6.8Hz,3H),1.08(d,J=6.3Hz,3H),0.71(d,J=6.4Hz,3H).LCMS(ESI)m / z:1151.4(M+H) + .

[0741] D019B: 1 H NMR (400MHz, DMSO-d6) δ10.46–9.94(m,1H),9.02(d,J=24.3Hz,2H),8.59(d,J=2.9Hz,1H),8.50(s,1H),7.83(d,J=7.6Hz,1H),7.69(s,2H),7. 47-7.33(m,6H),7.17-7.14(m,2H),7.07(s,.5H),6.86(s,0.5H),5.32 (d,J=10.5Hz,1H),5.05-4.87(m,4H),4.45-4.35(m,4H),3.85–3.42(m, 8H),2.91(s,2H),2.64(s,1H),2.47-2.44(m,4H),2.33(s,3H),2.11(s,4H),1.65-1.62(m,7H), 1.38(d,J=7.0Hz,3H),1.08(d,J=6.4Hz,3H),0.71(d,J=6.4Hz,3H).LCMS(ESI)m / z:1151.4(M+H) + .

[0742] Example 43: Synthesis of D020

[0743] Except that intermediate B is replaced by intermediate D20_1, and replacing intermediate D1_4 with intermediate D9_1, According to the method described in Example 24, compound D020 was obtained.

[0744] Intermediate D20_1 was prepared according to the method described in Intermediate Preparation Example 2, except that Intermediate B6 Replace

[0745] D020: 1 HNMR(400MHz,DMSO-d6)δ9.92(s,1H),9.08(d,J=1.9Hz,1H),8.99(s,1H),8.59(s,1H),8.54-8.51(m,1H),7.77-7.67(m,3 H),7.45(d,J=8.3Hz,2H),7.38-7.31(m,4H),7.25-7.01(m,3H),5.32(d,J=9.7Hz,1H),4.94-4.91(m,3H),4.49-4.31(m,4H ),3.78(s,1H),3.70(d,J=11.5Hz,1H),3.59(s,4H),3.08(s,2H),2.46(s,4H),2.32(s,4H),2.13(s,3H),1.38(d,J=7.0Hz ,3H),1.24(s,5H),1.08(d,J=6.4Hz,3H),0.85(d,J=6.9Hz,1H),0.69(dd,J=11.7,4.9Hz,6H).LCMS(ESI)m / z:1163.4(M+H) + .

[0746] Example 44: Synthesis of D021

[0747] Step 1: Synthesis of D21_3

[0748] At room temperature, compound D21_1 (400 mg, 1.43 mmol), D21_2 (342 mg, 1.72 mmol), and potassium carbonate (108 mg, 2.86 mmol) were dissolved in DMF (8 ml), heated to 60 degrees, and stirred for 2 hours. The reaction was monitored for completion by TLC. 20 ml of water was added to the reaction solution to quench and dilute it, and the mixture was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a residue, which was purified by silica gel column chromatography to obtain compound D21_3.

[0749] Step 2: Synthesis of D21_4

[0750] D21_3 (260 mg, 0.68 mmol) was dissolved in DCM (6 mL), TFA (2 mL) was added at room temperature, and stirring was continued at room temperature for 1 hour. The reaction was monitored by TLC until the starting material disappeared. The room temperature was restored and the solvent was spin-dried to obtain crude compound D21_4, which was used directly in the next step without purification.

[0751] Step 3: D21_5

[0752] Compound D21_4 (crude product), Intermediate A (200 mg, 0.4 mmol), and potassium carbonate (221 mg, 1.6 mmol) were dissolved in DMF (5 ml) at 25°C and stirred under nitrogen at room temperature for 16 hours. The reaction was monitored for completion by TLC. The reaction mixture was quenched and diluted with 20 ml of water, extracted with ethyl acetate, and the combined organic phases dried over anhydrous sodium sulfate and concentrated in vacuo to yield a residue, which was purified by silica gel column chromatography to yield Compound D21_5.

[0753] Step 4: Synthesis of D21_6

[0754] Compound D21_5 (290 mg, 0.48 mmol) was dissolved in THF (4 ml) and 1 ml of TBAF (1.0 M THF solution) was added dropwise at room temperature. Stirring was continued at room temperature for 1 hour after the addition. The reaction was monitored for completion by TLC. 20 ml of water was added to the reaction solution to quench the dilution, and the mixture was extracted with ethyl acetate (3 x 10 ml). The mixture was backwashed with saturated sodium chloride solution, and the combined organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a residue, which was purified by silica gel column chromatography to obtain compound D21_6.

[0755] Step 5: Synthesis of D21_7

[0756] Compound D21_6 (100 mg, 0.32 mmol) and intermediate B (218 mg, 0.27 mmol) were dissolved in THF (5 ml) under nitrogen protection and cooled to -10 degrees. LiHMDS (0.54 ml, 1.0 M THF, 0.54 mmol) was slowly added dropwise and stirred for 1 hour after addition. TLC monitored the reaction completion. The reaction solution was poured into ice water to quench, extracted with ethyl acetate (3 x 10 ml), backwashed with saturated sodium chloride solution, and the combined organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a residue, which was purified by preparative plate to obtain compound D21_7.

[0757] Step 6: Synthesis of D21_8

[0758] Compound D21_7 (70 mg, 0.06 mmol) was dissolved in MeOH (3 ml) and water (0.6 ml), and LiOH (25 mg, 0.6 mmol) was added. Stirring was continued at room temperature for 16 hours. LCMS monitored the reaction for completion. The reaction solution was concentrated in vacuo, the methanol was spin-dried, and diluted with 5 ml of water. The pH was adjusted to 6 and extracted with ethyl acetate (3 x 5 ml). The mixture was backwashed with saturated sodium chloride solution, and the combined organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a residue, which was purified by preparative plate to obtain compound D21_8.

[0759] Step 7: Synthesis of D21_10

[0760] Compound D21_8 (40 mg, 0.036 mmol), D21_9 (14 mg, 0.044 mmol), HATU (20 mg, 0.054 mmol), and DIEA (14 mg, 0.011 mmol) were dissolved in DMF (1.5 ml) and stirred at room temperature for 2 hours. LCMS monitored the reaction for completion. The reaction mixture was diluted with 5 ml of water to precipitate a solid product. The product was filtered with filter paper, dissolved in ethyl acetate, dried over anhydrous sodium sulfate, and concentrated in vacuo to afford pure compound D21_10.

[0761] Step 8: Synthesis of D21_11

[0762] Compound D21_10 (40 mg, 0.029 mmol) was dissolved in THF (2 ml) and 0.06 ml of TBAF (1.0 M in THF solution) was added dropwise at room temperature. The reaction mixture was stirred for 1 hour after addition. LCMS monitored the reaction to completion. 10 ml of water was added to the reaction solution to quench the dilution, and the mixture was extracted with ethyl acetate (3 x 5 ml) and backwashed with saturated sodium chloride solution. The combined organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a residue, which was purified by preparative plate to obtain compound D21_11.

[0763] Step 9: Synthesis of D021A and D021B

[0764] D21_11 (30 mg, 0.024 mmol) was dissolved in DCM (1.5 mL), TFA (0.5 mL) was added at room temperature, and the reaction mixture was stirred at room temperature for 1 h. The reaction was monitored by LCMS until the starting material disappeared. The reaction solution was concentrated in vacuo, and the crude product was purified by preparative HPLC to obtain compounds D021A and D021B.

[0765] D021A: 1H NMR(400MHz,DMSO-d6)δ9.05(d,J=3.0Hz,1H),8.99(s,1H),8.53(t,J=6.0Hz,1H),8.23(s,1H),7.97(dd,J=9.2,5.9Hz,1H),7.51–7.32(m,4H),7.27(s,0.5H),7.18(d,J=2.5Hz,1H),7.10(s,0.5H),6.08(s,1H),4.85(s,1H),4.56–4.41(m,2H),4.41–4.26(m,4H),3.97–3.90(m,2H),3.66(d,J=9.8Hz,2H),3.62–3.58(m,4H),3.55–3.14(m,5H),3.09(d,J=9.3Hz,3H),2.70–2.56(m,2H),2.45(s,3H),2.31–2.12(m,4H),2.09–1.85(m,4H),1.65(s,3H),1.65–1.57(m,2H),0.94(d,J=6.6Hz,3H),0.80(dd,J=6.7,3.7Hz,3H).MS(ESI)m / z:1197.8(M+H) + 。

[0766] D021B: 1 H NMR(400MHz,DMSO-d6)δ9.05(d,J=3.0Hz,1H),8.96(s,1H),8.47(t,J=6.0Hz,1H),8.23(s,1H),7.97(dd,J=9.2,5.9Hz,1H),7.51–7.32(m,4H),7.18(d,J=2.5Hz,1H),7.09(s,0.5H),6.89(s,0.5H),6.05(s,1H),4.84(s,1H),4.50–4.41(m,2H),4.36–4.26(m,4H),3.94–3.93(m,2H),3.66(d,J=9.8Hz,2H),3.58–3.54(m,4H),3.47–3.25(m,5H),3.09(d,J=9.3Hz,3H),2.64–2.54(m,2H),2.43(s,3H),2.328–2.12(m,4H),2.08–1.85(m,4H),1.67(s,3H),1.67–1.56(m,2H),0.94(d,J=6.6Hz,3H),0.80(dd,J=6.7,3.7Hz,3H).MS(ESI)m / z:1197.8(M+H) + 。

[0767] Example 45: Synthesis of D022

[0768] In addition to replacing intermediate D21_1 with intermediate D22_1, Compound D022 was obtained according to the preparation method described in Example 44. MS (ESI) m / z: 1111.8 (M+H) + .

[0769] Example 46: Synthesis of D023

[0770] In addition to replacing intermediate D21_1 with intermediate D23_1, Compound D023 was obtained according to the preparation method described in Example 44. LCMS (ESI) m / z: 1153.6 (M+H) + .

[0771] Example 47: Synthesis of D024

[0772] In addition to replacing intermediate D21_1 with intermediate D24_1, Compound D024 was obtained according to the preparation method described in Example 44. MS (ESI) m / z: 1139.6 (M+H) + .

[0773] Example 48: Synthesis of D025

[0774] In addition to replacing intermediate D21_1 with intermediate D25_1, Compound D025 was obtained according to the preparation method described in Example 44. LCMS (ESI) m / z: 1147.4 (M+H) + .

[0775] Example 49: Synthesis of E001

[0776] Step 1: Preparation of E1_2

[0777] E1_1 is dissolved in dichloromethane (10mL), tert-butyldiphenylchlorosilane (1.3g, 4.755mmol) and imidazole (0.324g, 4.755mmol) are added, and the mixture is stirred at room temperature for 2 hours. The reaction is monitored by LCMS. The reaction solution is diluted with ethyl acetate (60mL) and extracted with water (100mL) and repeated three times. The organic phase is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated in vacuo. The obtained residue is purified by silica gel column chromatography to obtain product E1_2.

[0778] Step 2: Preparation of E1_3

[0779] E1_2 (2 g, 4.25 mmol) was dissolved in N,N-dimethylformamide (20 mL). Sodium hydride (850 mg, 21.25 mmol) and iodomethane (1.5 mL, 21.25 mmol) were added at 0°C, and the mixture was stirred at 25°C for 2 hours. The reaction was monitored for completion by LCMS. The reaction solution was diluted with ethyl acetate (60 mL) and extracted with water (100 mL), and the mixture was repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain product E1_3.

[0780] Step 3: Preparation of E1_4

[0781] To E1_3 (780 mg, 1.612 mmol) was added tetrahydrofuran (10 mL) and tetra-n-butylammonium fluoride (0.9 mL, 3.244 mmol), and the mixture was stirred at 25°C for 2 hours. The reaction was monitored for completion by LCMS. The reaction solution was diluted with ethyl acetate (30 mL) and extracted with water (100 mL), and this was repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain product E1_4.

[0782] Step 4: Preparation of E1_5

[0783] E1_4 (360 mg, 1.556 mmol) was dissolved in dichloromethane (5 mL), triethylamine (472 mg, 4.668 mmol) and p-toluenesulfonyl chloride (593 mg, 3.112 mmol) were added, and the mixture was stirred at room temperature for 0.5 hours. The reaction was monitored by LCMS. The reaction solution was diluted with ethyl acetate (60 mL) and extracted with water (100 mL), and the mixture was repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain product E1_5.

[0784] Step 5: Preparation of E1_6

[0785] E1_5 (20 mg, 0.065 mmol) was dissolved in acetonitrile (5 mL), cesium carbonate (63.53 mg, 0.665 mmol) and intermediate I were added, and the mixture was stirred at 80 ° C for 2 hours. The reaction was monitored by LCMS. The reaction solution was diluted with ethyl acetate (60 mL) and extracted with water (100 mL), and the reaction mixture was repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (dichloromethane: methanol = 15: 1) to obtain product E1_6.

[0786] Step 6: Preparation of E1_7

[0787] E1_6 (770 mg) was dissolved in dichloromethane (10 mL) and 1,4-dioxane hydrochloride (5 mL), and the mixture was stirred at room temperature for 0.5 hours. The reaction was monitored for completion by LCMS. The reaction solution was diluted with ethyl acetate (50 mL) and extracted with water (90 mL), and the mixture was repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by silica gel column chromatography to obtain product E1_7.

[0788] Step 7: Preparation of E1_8

[0789] Intermediate D1_3 (150 mg, 0.194 mmol) was dissolved in N,N-dimethylformamide (2 mL), E1_7 (152.54 mg, 0.233 mmol) and potassium carbonate (269.30 mg, 1.95 mmol) were added, and the mixture was stirred at 60 ° C for 16 hours. The reaction was monitored by LCMS. The reaction solution was diluted with ethyl acetate (100 mL) and extracted with water (100 mL), and the mixture was repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by silica gel column chromatography to obtain product E1_8. MS m / z (ESI) / 2: 660.4 [M+H] + .

[0790] Step 8: Prepare E001

[0791] E1_8 (60 mg, 0.045 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (2 mL) was added, and the mixture was stirred at 25 ° C for 1 hour. The reaction was monitored by LCMS. The reaction solution was concentrated in vacuo and then the pH value was adjusted to 8 using 7M ammonia methanol solution. The residue was then purified by preparative HPLC to obtain product E001.

[0792] 1H NMR(400MHz,DMSO-d6)δ8.94(s,1H),8.37(s,1H),8.13(s,1H),7.62(s,1H),7.41–7.32(m,1H),7.29– 7.17(m,3H),7.11–7.04(m,2.5H),6.95-6.90(m,3H),6.51(s,0.5H),5.11-5,07(m,1H),4.60(s,1H),4 .51(s,1H),4.34(s,1H),4.20–4.05(m,1H),3.99(s,3H),3.61(s,1H),2.67(s,1H),2.41(s,3H),2.33( s,3H),2.26–1.97(m,10H),1.96–1.81(m,4H),1.71(s,6H),1.35(s,10H),0.95(s,9H),0.85(s,2H).MS m / z(ESI) / 2:588.3[M+H] + .

[0793] Example 50: Synthesis of E002

[0794] In addition to replacing intermediate E1_1 with intermediate E2_1, According to the method described in Example 49, compound E002 was obtained.

[0795] 1 H NMR (400MHz, DMSO-d6) δ10.14(s,1H),9.05(s,1H),8.96(s,1H),8.48(s,1H),7.96(s,1H),7.45(s,1H),7.39(d,J=7.4Hz,2H) ,7.27(s,1H),7.17(s,1H),7.06(s,0.5H),6.96-6.93(m,2H),6.52(s,0.5H),5.17(s,1H),4.84(s,1H),4.65–4.41(m,3H),4. 34(s,2H),4.29-4.18(m,2H),3.97(s,2H),3.91(s,1H),3.69-3.57(m,5H),3.29(s,3H),3.06(s,1H),2.43(s,3H),2.33(s,1H ),2.28(s,2H),2.10(s,4H),1.91(s,1H),1.73(s,2H),1.69–1.65(m,2H),1.37(s,8H),1.22(d,J=10.2Hz,8H),0.95(s,9H).MS m / z(ESI):1189.4[M+H]+ .

[0796] Example 51: Synthesis of E003

[0797] In addition to replacing intermediate E1_1 with intermediate E3_1, According to the method described in Example 49, compound E003 was obtained.

[0798] 1 H NMR(400MHz,DMSO-d6)δ10.22(s,1H),9.33(s,2H),9.16(s,1H),9.05(s,1H ),8.98(s,1H),8.51(s,1H),8.01–7.96(m,1H),7.47(t,J=8.8Hz,1H),7.41 (s,2H),7.28(d,J=6.4Hz,1H),7.18(s,1H),7.09(s,0.5H),6.97(d,J=4.8H z,2H),6.95(s,0.5H),5.12-5.03(m,1H),5.01-4.98(m,1H),4.68(s,1H),4. 59(d,J=9.2Hz,1H),4.54-4.49(m,2H),4.35(s,1H),4.27(s,1H),4.22(s,2 H),4.02(s,2H),3.92(d,J=4.8Hz,2H),3.87(s,2H),3.62(s,4H),2.79(s,2 H),2.74(s,1H),2.45(s,3H),2.08(d,J=7.6Hz,1H),1.96(s,4H),1.71(s,2 H),1.68–1.59(m,2H),1.45–1.36(m,4H),1.30–1.21(m,8H),0.95(s,9H).MS m / z(ESI) / 2:602.4[M+H] + .

[0799] Example 52: Synthesis of E004

[0800] In addition to replacing intermediate E1_1 with intermediate E4_1, According to the method described in Example 49, compound E004 was obtained.

[0801] 1H NMR(400MHz,DMSO-d6)δ10.21(s,1H),9.37–9.25(m,1H),9.16(s,2H),8.9 9(s,2H),8.50(s,1H),8.00(s,1H),7.64–7.60(m,1H),7.49(d,J=8.8Hz,1 H),7.45(s,1H),7.41(s,2H),7.40–7.36(m,1H),7.28(s,1H),7.21(s,1H) ,7.17(s,1H),7.08(s,1H),7.05(s,1H),6.98(d,J=8.4Hz,1H),6.95(s,1H) ,5.11(d,J=48.0Hz,1H),5.01–4.86(m,1H),4.68(s,1H),4.61–4.45(m,3H ),4.34(s,2H),4.21(s,6H),3.90(s,2H),3.83(d,J=24.6Hz,6H),3.62(s,3 H),3.16–2.95(m,3H),2.46(s,3H),2.12–2.00(m,2H),1.95(s,4H),1.92– 1.82(m,2H),1.35(d,J=17.8Hz,2H),1.22(d,J=8.0Hz,2H),0.94(s,9H).MS m / z(ESI):1189.4[M+H] + .

[0802] Example 53: Synthesis of E005A and E005B

[0803] In addition to replacing intermediate E1_1 with intermediate E5_1, According to the method described in Example 49, compounds E005A and E005B were obtained.

[0804] E005A: 1H NMR(400MHz,DMSO-d6)δ10.74(s,1H),9.72(s,1H),8.98(s,1H),8.54(s,1H),8.41(s,1H),8.16–8.07(m,1H),7.76-7.69(m,2H),7.39(s,1H),7.28(s,1H),6.96(s,2H),6.93–6.88(m,1H),6.52(s,1H),6.28–6.21(m,1H),5.19(s,2H),4.95–4.75(m,1H),4.59(d,J=9.3Hz,1H),4.52(s,1H),4.35(s,2H),4.21(s,4H),4.12–4.01(m,1H),3.88(s,3H),3.62(s,2H),3.08(s,1H),2.83(s,2H),2.67(s, 1H),2.44(s,3H),2.43–2.40(m,2H),2.33(s,1H),2.13(s,2H),2.10–2.04(m,1H),1.91(s,5H),1.79(s,6H),1.37(d,J=9.2Hz,2H),1.22(d,J=9.6Hz,4H),1.15–1.03(m,3H),0.95(s,10H).MS m / z(ESI):1201.6[M+H] + 。

[0805] E005B: 1 H NMR(400MHz,DMSO-d6)δ10.22(s,2H),9.60–9.39(m,1H),9.15(s,4H),8.99(s,1H),8.53(s,1H),8.09–7.87(m,1H),7.41(d,J=8.3Hz,6H),6.95(s,3H),5.19(s,3H),4.72–4.46(m,5H),4.39–4.16(m,7H),3.92(d,J=5.2Hz,3H),3.85(s,6H),3.63(s,4H),3.14–2.99(m,2H),2.80(d,J=10.6Hz,3H),2.67(s,1H),2.45(s,5H),2.33(s,1H),2.11(s,2H),1.96(s,5H),1.94–1.87(m,4H),1.86–1.74(m,5H),1.37(d,J=8.2Hz,3H),1.23(s,2H),1.21(s,2H),1.09–1.00(m,3H),0.95(s,13H).MS m / z(ESI):1201.6[M+H]+ .

[0806] Example 54: Synthesis of E006A and E006B

[0807] In addition to replacing intermediate E1_1 with intermediate E6_1, According to the method described in Example 49, compounds E006A and E006B were obtained.

[0808] E006A:MS m / z(ESI):1173.2[M+H] + .

[0809] E006B:MS m / z(ESI):1173.6[M+H] + .

[0810] Example 55: Synthesis of E007

[0811] In addition to replacing intermediate E1_1 with intermediate E7_1, Compound E007 was obtained according to the method described in Example 49. MS m / z (ESI): 1171.6 [M+H] + .

[0812] Example 56: Synthesis of E008A and E008B

[0813] In addition to replacing intermediate E1_1 with intermediate E8_1, According to the method described in Example 49, compounds E008A and E008B were obtained.

[0814] E008A: 1H NMR(400MHz,DMSO-d6)δ10.70(s,1H),9.70(s,1H),8.95(s,1H),8.56(s,1H),8.39(s,1H),8.11(s,1H),7.75(t,J=10.1Hz,1H),7.65(s,1H),7.64–7.61(m,1H),7.42(d,J=7.2Hz,1H),7.27(d,J=9.1Hz,1H),7.01(d,J=36.5Hz,2H),6.38(d,J=95.0Hz,1H),5.27(s,2H),5.15(s,3H),4.85(s,2H),4.59(d,J=8.4Hz,1H),4.51(d,J=8.0Hz,1H),4.34(s,2H),4.22(s,2H),4.04(s,3H),3.62(s,4H),3.59–3.53(m,6H),2.67(s,3H),2.33(s,4H),2.07(s,1H),1.92(s,3H),1.79(s,2H),1.37(dd,J=18.7,9.8Hz,2H),1.22(d,J=8.3Hz,2H),0.95(s,9H).MS m / z(ESI):1195.4[M+H] + 。

[0815] E008B: 1H NMR (400MHz, MeOD) δ9.01(d,J=2.7Hz,1H),8.81(d,J=5.2Hz,1H),7.82(dd,J=8.9,5.9Hz,1H),7.48(d,J=7.6Hz,1H),7.33(s,5H),7.30 (s,0.5H),7.26(d,J=9.2Hz,1H),7.20(s,1H),7.15(s,0.5H),7.00–6.95(m,1H),6.94(s,1H),5.12(d,J=12.0Hz,3H),5.01(s,2H),4.7 3(s,1H),4.67–4.53(m,3H),4.45(d,J=11.4Hz,2H),3.87–3.76(m,2H),3.72(d,J=20.7Hz,2H),3.63(s,3H),3.53(s,2H),3.48(s,1H), 3.22(s,2H),2.32(t,J=5.2Hz,3H),2.20(s,4H),2.07(d,J=8.8Hz,1H),1.89–1.68(m,4H),1.41–1.21(m,6H),1.01(d,J=9.9Hz,9H).MS m / z(ESI):1195.6[M+H] + .

[0816] Example 57: Synthesis of E009A and E009B

[0817] In addition to replacing intermediate I with intermediate E9_1, According to the method described in Example 53, compounds E009A and E009B were obtained.

[0818] E009A: 1H NMR(400MHz,DMSO-d6)δ9.02(s,1H),8.96(s,1H),8.36(s,1H),7.94(s,1H),7.52–7.39(m,2H),7.37(s,1H),7.26(s,2H),7.17(s,1H),7.05(s,1H),7.00(d,J=7.5Hz,1H),6.93(s,1H),5.12(s,1H),4.86(s,2H),4.56(d,J=8.6Hz,2H),4.49(s,3H),4.32(s,2H),4.28(s,2H),3.87(s,2H),3.77(s,4H),3.63(s,3H),3.05(s,2H),2.44(s,3H),2.10(s,4H),2.08(s,2H),1.77(d,J=11.3Hz,6H),1.63(s,4H),1.42(s,1H),1.37(s,1H),1.32(s,1H),1.28(d,J=5.9Hz,3H),1.21(s,2H),1.17(s,1H),1.02(s,2H),0.93(s,9H),0.83(s,2H).LCMS(ESI)m / z:1215.7(M+H) + 。

[0819] E009B: 1H NMR (400MHz, DMSO-d6) δ10.11(s,1H),9.03(s,1H),8.96(s,1H),8.46(d,J=7.1Hz,1H),7.96(d, J=6.2Hz,1H),7.55(d,J=8.3Hz,1H),7.44(t,J=8.9Hz,1H),7.37(d,J=2.3Hz,1H),7.28(s,1H), 7.27(s,1H),7.17(s,1H),7.06(s,1H),6.91(d,J=5.8Hz,2H),5.15(s,1H),4.99–4.91(m,1H),4 .86(s,2H),4.55(d,J=6.6Hz,2H),4.47(d,J=12.9Hz,1H),4.33(s,2H),3.88(d,J=6.9Hz,1H),3 .79(s,2H),3.63(s,1H),3.59(d,J=9.3Hz,2H),3.55(s,1H),3.52(s,2H),3.06(s,2H),2.43(s, 3H),2.11(s,4H),2.10–2.08(m,1H),2.04(s,1H),1.92(s,1H),1.79(d,J=9.9Hz,4H),1.66(s,1 H),1.63(s,4H),1.43(s,1H),1.39(d,J=8.8Hz,1H),1.34(d,J=8.9Hz,1H),1.31–1.25(m,3H),1 .22(d,J=3.2Hz,2H),1.04(s,2H),0.87(s,9H),0.85–0.77(m,2H).LCMS(ESI)m / z:1215.6(M+H) + .

[0820] Example 58: Synthesis of E010A and E010B

[0821] In addition to replacing intermediate I with intermediate E10_1, According to the method described in Example 56, compounds E010A and E010B were obtained.

[0822] E10A:LCMS(ESI)m / z:1215.6(M+H) + .

[0823] E10B:LCMS(ESI)m / z:1215.4(M+H) + .

[0824] Example 59: Synthesis of E011A and E011B

[0825] In addition to replacing intermediate I with intermediate E11_1, According to the method described in Example 56, compounds E011A and E011B were obtained.

[0826] E011A:MS(ESI)m / z:1175.6(M+H) + .

[0827] E011B:MS(ESI)m / z:1175.68(M+H) + .

[0828] Example 60: Synthesis of E012A and E012B

[0829] In addition to the intermediate Replaced with intermediate E12_1, According to the method described in Example 57, compounds E012A and E012B were obtained.

[0830] E012A:LCMS(ESI)m / z:1223.6(M+H) + .

[0831] E012B:LCMS(ESI)m / z:1223.6(M+H) + .

[0832] Example 61: Synthesis of E013A and E013B

[0833] In addition to the intermediate Replaced with intermediate E13_1, According to the method described in Example 57, compounds E013A and E013B were obtained.

[0834] E013A:LCMS(ESI)m / z:1210.6(M+H) + .

[0835] E013B:LCMS(ESI)m / z:1210.3(M+H) + .

[0836] Example 62: Synthesis of E014A and E014B

[0837] In addition to the intermediate Replaced with intermediate E14_1, According to the method described in Example 57, compounds E014A and E014B were obtained.

[0838] E014A:MS(ESI)m / z:1227.4(M+H) + .

[0839] E014B:MS(ESI)m / z:1227.3(M+H) + .

[0840] Example 63: Synthesis of E015A and E015B

[0841] In addition to the intermediate Replaced with intermediate E15_1, According to the method described in Example 57, compounds E015A and E015B were obtained.

[0842] E015A:LCMS(ESI)m / z:1227.5(M+H) + .

[0843] E015B:LCMS(ESI)m / z:1227.4(M+H) + .

[0844] Example 64: Synthesis of E016A and E016B

[0845] In addition to replacing intermediate E_1 with intermediate E16_1, According to the method described in Example 49, compounds E016A and E016B were obtained.

[0846] E016A:MS(ESI)m / z:1229.3(M+H) + .

[0847] E016B:MS(ESI)m / z:1229.6(M+H) + .

[0848] Example 65: Synthesis of E017A and E017B

[0849] In addition to replacing intermediate E1_1 with intermediate E15_1, According to the method described in Example 49, compounds E017A and E017B were obtained.

[0850] E017A, MS(ESI)m / z:1213.5(M+H) + .

[0851] E017B,MS(ESI)m / z:1213.4(M+H) + .

[0852] Example 66: Synthesis of E018

[0853] In addition to replacing intermediate E1_1 with intermediate E10_1, According to the method described in Example 49, compound E018 was obtained. LCMS (ESI) m / z: 1201.5 (M+H) + .

[0854] Example 67: Synthesis of E019A and E019B

[0855] In addition to replacing intermediate E9_1 with intermediate E8_1, According to the method described in Example 57, compounds E019A and E019B were obtained.

[0856] E019A: 1 H NMR (400MHz, DMSO-d6) δ10.17(s,1H),9.05(s,1H),8.95(s,1H),8.41(d,J=7.7Hz,1H),7.99–7.93(m,1H),7.44(td,J=9.0,2.3Hz,1H ),7.38(d,J=2.1Hz,2H),7.33–7.29(m,3H),7.24(d,J=6.5Hz,1H),7.18(d,J=2.4Hz,1H),7.09(s,0.5H),7.03(s,1H),7.01(s,0.5H), 5.27–5.08(m,4H),4.93(s,2H),4.61–4.43(m,3H),4.34–4.23(m,2H),3.92(s,1H),3.66–3.47(m,8H),3.17(s,2H),2.51(s,2H),2.34 (s,3H),2.08(s,4H),1.80–1.73(m,1H),1.63(s,4H),1.41–1.29(m,5H),1.25–1.16(m,2H),0.95(s,9H).LCMS(ESI)m / z:1209.2(M+H) + .

[0857] E019B: 1H NMR (400MHz, DMSO-d6) δ10.15(s,1H),9.05(s,1H),8.95(s,1H),8.48(d,J=7.3Hz,1H),8.01–7 .93(m,1H),7.58(d,J=7.8Hz,1H),7.47–7.41(m,1H),7.38(d,J=2.3Hz,1H),7.36(s,1H),7.33 (s,1H),7.31(s,1H),7.28(d,J=8.8Hz,1H),7.18(d,J=2.3Hz,1H),7.03(s,1H),6.94(d,J=7.9 Hz,1H),5.16(s,3H),5.08–5.01(m,1H),4.93(s,2H),4.59–4.53(m,2H),4.48(d,J=11.9Hz,1H) ,4.31(d,J=17.6Hz,2H),3.91(d,J=1.4Hz,1H),3.63(d,J=12.2Hz,1H),3.59(d,J=10.8Hz,2H) ,3.54(s,1H),3.51(s,2H),3.49(s,2H),3.17(s,2H),2.54(s,2H),2.36(s,3H),2.08(s,3H),2. 03(d,J=8.3Hz,1H),1.92(d,J=8.7Hz,1H),1.68–1.60(m,4H),1.41–1.36(m,1H),1.36–1.33(m ,1H),1.31(dd,J=6.8,2.6Hz,3H),1.24–1.19(m,2H),0.88(s,9H).LCMS(ESI)m / z:1209.1(M+H) + .

[0858] Example 68: Synthesis of E020

[0859] Except that intermediate I was replaced by intermediate E20_1, Compound E020 was obtained according to the method described in Example 56. MS (ESI) m / z: 1224.3 (M+H) + .

[0860] Example 69: Synthesis of E021

[0861] In addition to replacing intermediate E1_1 with intermediate E21_1, Compound E021 was obtained according to the method described in Example 49. MS (ESI) m / z: 1229.3 (M+H) + .

[0862] Example 700: Synthesis of E022

[0863] In addition to replacing intermediate E1_1 with intermediate E3_1, Compound E022 was obtained according to the method described in Example 49. MS (ESI) m / z: 1182.3 (M+H) + .

[0864] Example 71: Synthesis of F001

[0865] Step 1: Synthesize F1_2

[0866] At room temperature, F1_1 (6 g, 14.2 mmol) was dissolved in ultra-dry 1,4-dioxane (60 mL). N,N-diisopropylethylamine (5.5 g, 42.6 mmol) was added, the mixture was cooled to 0°C, and stirred for 10 minutes. Tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.1 g, 15.6 mmol) was then slowly added. The mixture was allowed to react at room temperature for 1 hour. LCMS showed that most of the starting material had been converted to product. The reaction mixture was concentrated in vacuo and then added with a mixture of petroleum ether and ethyl acetate (10:1). The mixture was stirred at room temperature until the oil was completely converted to a yellow powder. The mixture was filtered through a Buchner funnel to obtain compound F1_2.

[0867] Step 2: Synthesize F1_4

[0868] F1_2 (7 g, 11.9 mmol) and F1_3 (2.16 g, 23.9 mmol) were dissolved in N,N-dimethylformamide (80 mL) and tetrahydrofuran (80 mL). Cesium carbonate (11.7 g, 35.9 mmol) and 1,4-diaza[2.2.2]bicyclooctane (672 mg, 5.9 mmol) were added to the reaction mixture, which was allowed to react at room temperature for 16 hours. LCMS showed that most of the starting material had been converted to product. The reaction mixture was diluted with ethyl acetate, washed with brine, and the organic phase was separated, dried, concentrated, and purified by column chromatography to yield F1_4.

[0869] Step 3: Synthesize F1_5

[0870] F1_4 (3 g, 4.71 mmol) and cyclopropaneboronic acid (2.69 g, 23.50 mmol) were dissolved in anhydrous toluene (60 mL). Potassium phosphate (2.66 g, 9.41 mmol) was dissolved in water (8 mL) and added to the mixture. Finally, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (1.01 g, 0.94 mmol) was added. The reaction mixture was reacted at 90°C for 3 hours. LCMS showed that most of the starting material was converted to product. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic phase was concentrated and then purified by column chromatography to obtain F1_5.

[0871] Step 4: Synthesize F1_7

[0872] F1_6 (1.8 g, 37.59 mmol) was dissolved in anhydrous tetrahydrofuran (60 mL) and cooled to 0°C. Potassium tert-butoxide (2.44 g, 21.75 mmol) was slowly added and stirred at 0°C for half an hour. F1_5 (1.5 g, 2.70 mmol) was then slowly added. The reaction mixture was allowed to react at 0°C for 3 hours. LCMS showed that most of the starting material had been converted to product. The reaction mixture was quenched with ammonium chloride, diluted with ethyl acetate, washed with brine, and the organic phase was separated, dried, concentrated, and then purified by column chromatography to obtain F1_7.

[0873] Step 6: Synthesize F1_9

[0874] F1_7 (260 mg, 0.361 mmol) and F1_8 (255.7 mg, 0.541 mmol) were added to tert-butanol (10 mL) and dimethyl sulfoxide (10 mL). Copper sulfate pentahydrate (270.2 mg, 1.082 mmol) and sodium ascorbate (214.4 mg, 1.082 mmol) were added to water (10 mL) and then added dropwise to the above reaction solution. The reaction mixture was reacted at room temperature for 2 hours. LCMS detection showed that the product was the main product. The product was extracted with ethyl acetate (50 mL), washed with brine, and the organic phase was concentrated and purified by thin layer chromatography to obtain compound F1_9. LCMS (ESI) m / z: 1194.0 (M+H) + .

[0875] Step 7: Synthesize F1_11

[0876] F1_9 (150 mg, 0.126 mmol) was added to 1,4-dioxane (16 mL) and water (4 mL). To the reaction solution were added F1_10 (104.9 mg, 0.377 mmol), potassium phosphate (80.1 mg, 0.377 mmol), and chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (36.2 mg, 0.050 mmol). The reaction mixture was reacted at 50°C under nitrogen for 20 minutes. The product was extracted with ethyl acetate (30 mL), washed with brine, and the organic phase was separated, dried, concentrated, and purified by thin-layer chromatography to obtain compound F1_11. LCMS (ESI) m / z: 1346.2 (M+H) +.

[0877] Step 8: Synthesize F001

[0878] Compound F1_11 (70 mg, 0.052 mmol) was dissolved in anhydrous dichloromethane (3 mL) and trifluoroacetic acid (1 mL) was added under an ice bath. The reaction mixture was allowed to react at room temperature for 2 hours. The trifluoroacetic acid was removed by cryogenic concentration, and the remaining oil was added dropwise to ammonia methanol solution under an ice bath. The crude product was spin-dried and purified by preparative HPLC to yield F001.

[0879] 1H NMR (400MHz, DMSO-d6) δ13.10(s,1H),8.98(s,1H),8.62(s,1H),8.49(d,J=7.7Hz ,1H),7.63(d,J=8.0Hz,2H),7.51(s,1H),7.43(t,J=6.8Hz,3H),7.37(d,J=8.4Hz ,3H),7.26(s,1H),7.03(s,0.5H),6.82(s,0.5H),6.78(d,J=6.6Hz,2H),5.31(d, J=10.4Hz,1H),5.30–5.24(m,1H),5.20(s,1H),4.92(s,4H),4.92-4.80(m,2H),4 .45(t,J=7.9Hz,2H),4.32(s,2H),4.16(d,J=11.7Hz,2H),3.78(d,J=7.2Hz,3H), 3.68(s,2H),2.83(s,2H),2.46(s,4H),2.08(s,6H),1.98(s,4H),1.83–1.73(m,2 H),1.71(s,4H),1.35(d,J=5.3Hz,1H),1.07(d,J=6.4Hz,4H),0.71(d,J=6.4Hz,3 H),0.66(s,1H),0.62(s,2H),0.55(t,J=8.7Hz,1H).LCMS(ESI)m / z:1162.7(M+H) + .

[0880] Example 72: Synthesis of G001A and G001B

[0881] Step 1: Synthesize G1_2

[0882] D1_3 (50 mg, 1.0 eq) and G1_1 (15 mg, 1.6 eq) were added to an 8 ml vial and dissolved in 0.5 ml of DMF. Potassium carbonate (41 mg, 5 eq) was added and the mixture was allowed to react at 30°C overnight. LCMS showed the main peak was the product. Water and EA were added, the layers were separated, and the organic layer was concentrated to dryness to obtain the crude product. The product G1_2 was isolated on a preparative plate. LCMS: [M+1] + =867.4.

[0883] Step 2: Synthesize G1_3

[0884] To a 100ml single-necked flask, add G1_2 (20mg, 1.0eq) and THF (2ml). Add a solution of LiOH (100mg + 1ml water) dropwise at room temperature. Reaction was carried out at 30°C for 24h. LCMS indicated the disappearance of the starting material and the main peak was the product. Dilute with water, adjust the pH to 2-3 with dilute hydrochloric acid, extract with EA, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness to obtain G1_3, which was directly carried into the next step. LCMS: [M+1] + =825.4.

[0885] Step 3: Synthesis of G1_4

[0886] To an 8 ml vial, add G1_3 (30 mg, 1.0 eq), DCM (2 ml), DMAP (2.0 mg, 1.0 eq), DIPEA (14 mg, 3.0 eq), and TosCl (10 mg, 2.0 eq) and react at room temperature for 24 h. The reaction was stopped after the starting material had essentially disappeared, as monitored by TLC. Separate on a preparative plate to obtain G1_4. LCMS: [M+1] + =979.4.

[0887] Step 4: Synthesis of G1_6

[0888] G1_4 (15 mg, 1.0 eq) and G1_5 (16 mg, 2.0 eq) were added to an 8 ml vial and dissolved in 1 ml of DMF. Cesium carbonate (15 mg, 3 eq) was added and the mixture was reacted at 55°C for 1 h. LCMS indicated the main peak was the product. Water and EA were added, the layers were separated, and the organic layer was concentrated to dryness and isolated on a preparative plate to obtain G1_6. LCMS: [M+1] + =1341.5.

[0889] Step 5: Synthesis of G001:

[0890] To a 50ml single-necked flask, add G1_6 (13mg, 1.0eq) and DCM (3ml). Add TFA (1ml) at room temperature and allow to react for 1h. Upon completion, concentrate the reaction mixture to dryness, dissolve it in DCM and methanolic ammonia, and separate and purify it using preparative TLC to obtain G001A and G001B.

[0891] G001A: 1H NMR(400MHz,DMSO-d6)δ10.17(s,1H),9.06(d,J=2.5Hz,1H),8.97(s,1H),8.63(t, J=6.1Hz,1H),7.98(dd,J=9.2,5.9Hz,1H),7.59–7.51(m,1H),7.46(t,J=9.0Hz,1H),7.42–7.30(m,5H),7.28(s,0.5H),7.19(d,J=2.9Hz,1H),7.17–7.12(m,3H),7.11(s,0.5H),5.20(s,1H),4.97–4.84(m,3H),4.57–4.45(m,2H),4.45–4.29(m,3H),4.20(dd,J=15.8,5.4Hz,1H),3.92(s,1H),3.79–3.58(m,7H),3.45–3.39(m,2H),3.37-3.33(m,5H),3.12(s,2H),2.41(d,J=1.1Hz,2H),2.13–2.06(m,1H),2.05(s,2H),1.91(tt,J=9.1,4.5Hz,1H),1.69(s,3H),1.44(d,J=3.1Hz,2H),1.40–1.32(m,4H),1.24(d,J=7.9Hz,4H).LCMS(ESI)m / z:1197.7(M+H) + 。

[0892] G001B: 1H NMR(400MHz,DMSO-d6)δ10.16(s,1H),9.06(d,J=1.8Hz,1H),8.97(s,1H),8.62(t,J =5.9Hz,1H),7.97(dd,J=9.2,6.0Hz,1H),7.53(d,J=9.1Hz,1H),7.46(t,J=9.0Hz,1H ),7.37(dd,J=21.6,2.7Hz,5H),7.19(d,J=2.6Hz,1H),7.14(s,3H),7.09(s,0.5H), 6.92(s,0.5H),5.20(s,1H),5.01(d,J=14.2Hz,2H),4.87(dd,J=9.1,4.2Hz,1H),4.4 9(q,J=11.2,8.2Hz,2H),4.44–4.27(m,3H),4.20(dd,J=15.7,5.4Hz,1H),3.92(s,1 H),3.79–3.53(m,7H),3.42(s,2H),3.38-3.34(m,5H),2.97(s,2H),2.41(s,2H),2.0 9(t,J=10.5Hz,1H),2.03(s,2H),1.91(td,J=8.5,4.4Hz,1H),1.67(s,3H),1.44(d, J=3.2Hz,3H),1.36(d,J=5.6Hz,4H),1.27–1.19(m,4H).LCMS(ESI)m / z:1197.5(M+H) + .

[0893] Example 73: Synthesis of G002A and G002B

[0894] In addition to replacing intermediate G1_1 with intermediate E2_1, According to the method described in Example 72, G002A and G002B were obtained.

[0895] G002A:LCMS(ESI)m / z:1203.6(M+H) + .

[0896] G002B:LCMS(ESI)m / z:1203.4(M+H) + .

[0897] Example 74: Synthesis of H001A and H001B

[0898] Step 1: Prepare H1_2

[0899] D1_3 (600 mg, 0.67 mmol) was dissolved in N,N-dimethylformamide (6 mL) at room temperature. H1_1 (78 mg, 0.67 mmol), potassium carbonate (370 mg, 2.68 mmol), and sodium iodide (200 mg, 1.34 mmol) were added. The reaction mixture was allowed to react at room temperature for 3 hours. LCMS monitoring indicated complete reaction. Ethyl acetate and water were then added for extraction. The organic phase was concentrated and purified by silica gel column chromatography to yield compound H1_2.

[0900] Step 2: Prepare H1_3

[0901] At room temperature, a solution of lithium hydroxide (27 mg, 1.184 mmol) in water (1 mL) was added to a solution of H1_2 (140 mg, 0.148 mmol) in tetrahydrofuran (4 mL). After the reaction mixture was allowed to react at room temperature for 2 hours, most of the starting material had been converted to product. The reaction mixture was concentrated and purified by column chromatography to yield compound H1_3.

[0902] Step 3: Prepare H1_4

[0903] At room temperature, DMTMM (137 mg, 0.465 mmol) was added to a solution of H1_3 (124 mg, 0.133 mmol), intermediate J (72 mg, 0.133 mmol), and N,N-diisopropylethylamine (52 mg, 0.399 mmol) in N,N-dimethylformamide (10 mL). The reaction mixture was allowed to react at room temperature for 3 hours, and most of the starting material was converted to product. The residue was diluted with ethyl acetate (200 mL), and the organic phase was washed three times with saturated brine and then separated. The organic phase was concentrated and purified by thin-layer chromatography to obtain compound H1_4. LCMS (ESI) m / z: 1460.2 (M+H) + .

[0904] Step 4: Prepare H1_5

[0905] Cesium fluoride (104 mg, 0.68 mmol) was added to H1_4 (100 mg, 0.068 mmol) in N,N-dimethylformamide (4 mL). The reaction mixture was stirred at 20°C for 2 hours. LCMS analysis indicated that most of the starting material had been converted to product. The residue was diluted with ethyl acetate (200 mL), and the organic phase was washed three times with saturated brine and separated. The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by thin-layer chromatography to yield compound H1_5.

[0906] Step 5: Preparation of compound H001

[0907] Trifluoroacetic acid (3 mL) was added to a solution of compound H1_5 (70 mg, 0.054 mmol) in dichloromethane (9 mL). The reaction mixture was stirred at 20°C for 1 hour. LCMS analysis indicated that most of the starting material had been converted to product. The reaction mixture was concentrated at low temperature to remove the solvent and trifluoroacetic acid. The resulting crude product was purified by preparative chromatography to yield H001.

[0908] H001A: 1 H NMR (400MHz, DMSO-d6)) δ10.17(s,1H),9.02(d,J=4.9Hz,1H),8.96(s,1H),8.52(dd,J=8 .0,4.5Hz,1H),7.97(dd,J=9.2,6.0Hz,1H),7.83(dd,J=11.4,6.6Hz,1H),7.49–7.44(m, 1H),7.44–7.37(m,4H),7.34(dd,J=8.4,1.9Hz,2H),7.26(s,0.5H),7.23–7.16(m,2H),7 .05(s,0.5H),5.16(s,1H),4.93(dd,J=14.2,7.0Hz,1H),4.78(s,2H),4.57(d,J=8.7Hz,1 H),4.44(dd,J=17.5,9.3Hz,2H),4.28(s,2H),3.92(d,J=1.9Hz,1H),3.61(dd,J=11.1,7 .8Hz,3H),3.53(d,J=17.1Hz,4H),3.46-3.41(m,1H),3.07(s,2H),2.43(d,J=1.9Hz,3H) ,2.31–2.25(m,1H),2.24-2.20(m,1H),2.10(s,3H),2.05(d,J=11.7Hz,1H),1.76(t,J=8 .8Hz,1H),1.62(s,4H),1.39–1.31(m,2H),1.20(dd,J=8.8,2.7Hz,2H),0.96(s,9H).LCMS for(ESI)m / z:1160.2(M+H) + .

[0909] H001B: 1H NMR (400MHz, DMSO-d6)) δ10.17(s,1H),9.02(d,J=4.7Hz,1H),8.97(s,1H),8.54(s,1H),8.05–7.93(m,1H),7.85(s,1H),7.5 0–7.31(m,6H),7.27–7.15(m,2H),7.03(s,0.5H),6.82(s,0.5H),5.17(s,1H),4.92-4.81(m,3H),4.57(d,J=8.3Hz,1H),4.51 –4.37(m,2H),4.28(s,2H),3.94(d,J=1.8Hz,1H),3.67–3.48(m,6H),3.47–3.39(m,2H),2.91(s,2H),2.43(s,3H),2.24(dd,J =9.9,6.6Hz,2H),2.12–2.02(m,4H),1.80–1.73(m,1H),1.63(s,4H),1.42–1.30(m,2H),1.24–1.17(m,2H),0.96(s,9H).LCMS for(ESI)m / z:1160.2(M+H) + .

[0910] The compounds and applications provided by the present invention are introduced in detail above.

[0911] Specific examples are used herein to illustrate the principles and implementation methods of the present invention. The above examples are merely intended to facilitate understanding of the methods and central concepts of the present invention. It should be noted that those skilled in the art may make various improvements and modifications to the present invention without departing from the principles of the present invention, and such improvements and modifications are also protected by the claims of the present invention.

Claims

1. Compound represented by formula (I): [BL] n -KRAS ligand (I), or a pharmaceutically acceptable salt or stereoisomer thereof, Among them, KRAS ligand is KRAS inhibitor, B is a degradation tag, such as an E3 ligase ligand, L is a linker between B and the KRAS ligand, n is the number of the degradation tags attached to the KRAS ligand, selected from 1, 2 or 3, preferably n is 1, and The KRAS ligand is a compound represented by formula (KI) or formula (KII): or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, in: X1 is N or C; X2 and X3 are independently N or CR 100 ; R 100 are independently hydrogen, deuterium, halogen, hydroxyl, amino, -CN, -C 1-8 Alkyl, -OC 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -CONR 100a R 100b , cycloalkyl, heterocyclic, aryl or heteroaryl, the -C 1-8 Alkyl, -OC 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are each optionally substituted with one or more deuterium, halogen, cyano, hydroxyl, -C 1-8 Alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl substitution; R 100a 、R 100b are each independently hydrogen, deuterium, halogen, cyano, hydroxyl or -C 1-8 alkyl; m is an integer from 0 to 3; L1, L2 and L3 are independently a single bond, -C 1-8 Alkylene-, -O-, -S-, -NR 1a -、 -R 1b C=CR 1c -、-C(R 1a R 1b )-、-C(=O)-、-S(=O)-、-S(=O)2-、-PR 1a -、-P(=O)R 1a 、-C(=O)O-、-OC(=O)-、-C(=O)NR 1a -、-NR 1a C(=O)-、S(=O)O-、-OS(=O)-、-OS(=O)2-、-S(=O)NR 1a -、-NR 1a S(=O)-、-S(=O)2NR 1a -、-NR 1a S(=O)2- 、-OC(=O)O-、-OC(=O)NR 1a -、-NR 1a C(=O)O- or -NR 1a C(=O)NR 1b -; Note: In the English translation, for the chemical formula -OC(=O)O- and -OC(=O)NR, I added a space before "or" in the translation of line 28 to make the expression more in line with the English language habit. Also, for the line 24, there was a missing space between "S(=O)2-" and "、", which was corrected in the translation. These are minor adjustments to improve the readability of the English text while strictly following the translation rules. n is an integer from 1 to 10; R 1 Selected from hydrogen, halogen, amino, hydroxy, -C 1-8 Alkyl, -SC 1-8 Alkyl, -OC 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR 1a 、-SO2R 1a 、-COR 1a 、-CO2R 1a 、-CONR 1a R 1b 、-CH2C(=O)NR 1a R 1b 、-C 2-8 Alkynyl (NR 1a )2、-C(=NR 1a )NR 1b R 1c 、-NR 1a R 1b 、-NR 1a COR 1b 、-NR 1a CONR 1b R 1c 、-NR 1a CO2R 1b 、-NR 1a SONR 1b R 1c 、-NR 1a SO2NR 1b R 1c , or -NR 1a SO2R 1b , the -C 1-8 Alkyl, -SC 1-8 Alkyl, -OC 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are each optionally substituted by hydrogen, deuterium, halogen, hydroxyl, -C 1-8 Alkoxy, -NR 1d R 1e , cycloalkyl, heterocyclyl, aryl, or heteroaryl substituted; Each R 1a 、R 1b , and R 1c are independently hydrogen, deuterium, halogen, cyano, amino, hydroxyl, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups are each optionally substituted with at least one substituent R 1d Replace; or (R 1a and R 1b )、(R 1b and R 1c ), or (R 1c and R 1a ) together with the atom or atoms to which they are attached form a 3- to 9-membered ring comprising 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, said ring optionally substituted with at least one substituent R 1e replace; where R 1d and R 1e are independently hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR 1f 、-SO2R 1f 、-COR 1f 、-CO2R 1f 、-CONR 1f R 1g 、-C(=NR 1f )NR 1g R 1h 、-NR 1f R 1g 、-NR 1f COR 1g 、-NR 1f CONR 1g R 1h 、-NR 1f CO2R 1g 、-NR 1f SONR 1g R 1h 、-NR 1f SO2NR 1g R 1h , or -NR 1f SO2R 1g , the-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one selected from halogen, -C 1-8 Alkyl, -OR 1i 、-NR 1i R 1j , cycloalkyl, heterocyclyl, aryl, or heteroaryl substituents; R 1f 、R 1g 、R 1h 、R 1i and R 1j are independently hydrogen, -C 1-8 Alkyl, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R 2 is aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted by one or more R 2a replace; Each R 2a are independently hydrogen, halogen, amino, hydroxy, -C 1-8 Alkyl, -SC 1-8 Alkyl, -OC 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR 2b 、-SO2R 2b 、-COR 2b 、-CO2R 2b 、-CONR 2b R 2c 、-CH2C(=O)NR 2b R 2c 、-C(=NR 2b )NR 2c R 2d 、-NR 2b R 2c 、-NR 2b COR 2c 、-NR 2b CONR 2c R 2d 、-NR 2b CO2R 2c 、-NR 2b SONR 2c R 2d 、-NR 2b SO2NR 2c R 2d , or -NR 2b SO2R 2c , the -C 1-8 Alkyl, -SC 1-8 Alkyl, -OC 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are each optionally substituted with deuterium, halogen, cyano, hydroxyl, -NR 2e R 2f , amino, -C 1-8 Alkyl, -C 1-8 Alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl substitution; Each R 2b 、R 2c 、R 2d 、R 2e 、R 2f are independently hydrogen, deuterium, halogen or C 1-8 alkyl; R 3 and R 4 are independently hydrogen, halogen, hydroxy, amino, -C 1-8 Alkyl, -OC 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR 4a 、-SO2R 4a 、-SO2NR 4a R 4b 、-COR 4a 、-CO2R 4a 、-CONR 4a R 4b 、-C(=NR 4a )NR 4b R 4c 、-NR 4a R 4b 、-NR 4a COR 4b 、-NR 4a CONR 4b R 4c 、-NR 4a CO2R 4b 、-NR 4a SONR 4b R 4c 、-NR 4a SO2NR 4b R 4c , or -NR 4a SO2R 4b , the-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups are each optionally substituted with at least one substituent R 4d replace; R 4a 、R 4b , and R 4c are independently hydrogen, hydroxyl, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups are each optionally substituted with at least one substituent R 4e Replace; or (R 4a and R 4b )、(R 4b and R 4c ), or (R 4c and R 4a ) together with the atom or atoms to which they are attached form a 3 to 12 membered ring comprising 0, 1, 2 or 3 further heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, said ring optionally substituted with at least one substituent R 4e Replace; or R 4d and R 4e are independently hydrogen, deuterium, halogen, hydroxyl, amino, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR 4f 、-SO2R 4f 、-SO2NR 4f R 4g 、-COR 4f 、-CO2R 4f 、-CONR 4f R 4g 、-C(=NR 4f )NR 4g R 4h 、-NR 4f R 4g 、-NR 4f COR 4g 、-NR 4f CONR 4g R 4h 、-NR 4f CO2R 4f 、-NR 4f SONR 4f R 4g 、-NR 4f SO2NR 4g R 4h , or -NR 4f SO2R 4g , the-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one selected from halogen, -C 1-8 Alkyl, -OR 4i 、-NR 4i R 4j , cycloalkyl, heterocyclyl, aryl, or heteroaryl substituents; R 4f 、R 4g 、R 4h 、R 4i , and R 4j are independently hydrogen, -C 1-8 Alkyl, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R 5 、R 6 、R 7 、R 8 are independently hydrogen, deuterium, halogen, hydroxyl, amino, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR 5a 、-SO2R 5a 、-SO2NR 5a R 5b 、-COR 5a 、-CO2R 5a 、-CONR 5a R 5b 、-C(=NR 5a )NR 5b R 5c 、-NR 5a R 5b 、-NR 5a COR 5b 、-NR 5a CONR 5b R 5c 、-NR 5a CO2R 5b 、-NR 5a SONR 5b R 5c 、-NR 5a SO2NR 5b R 5c , or -NR 5a SO2R 5b , the-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups are each optionally substituted with at least one substituent R 5d replace; R 5a 、R 5b , and R 5c are independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups are each optionally substituted with at least one substituent R 5e replace; R 5d and R 5e are independently hydrogen, hydroxy, amino, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR 5f 、-SO2R 5f 、-SO2NR 5f R 5g 、-COR 5f 、-CO2R 5f 、-CONR 5f R 5g 、-C(=NR 5f )NR 5g R 5h 、-NR 5f R 5g 、-NR 5f COR 5g 、-NR 5f CONR 5g R 5h 、-NR 5f CO2R 5f 、-NR 5f SONR 5f R 5g 、-NR 5f SO2NR 5g R 5h , or -NR 5f SO2R 5g , the-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one selected from halogen, hydroxy, amino, cyano, -C 1-8 Alkyl, -C 1-8 Alkyl-OH, -OR 5i 、-NR 5i R 5j , cycloalkyl, heterocyclyl, aryl, or heteroaryl substituents; R 5f 、R 5g 、R 5h 、R 5i , and R 5j are independently hydrogen, -C 1-8 Alkyl, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; p is independently an integer from 1 to 5; q is independently an integer from 1 to 5; Z is selected from hydrogen, amino, hydroxy, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR 9 、-SR 9 、-SO2R 9 、-COR 9 、-CO2R 9 、-CONR 9 R 10 、-C(=NR 9 )NR 10 R 11 、-NR 9 R 10 、-NR 9 COR 10 、-NR 9 CONR 10 R 11 、-NR 9 CO2R 10 、-NR 9 SONR 10 R 11 、-NR 9 SO2NR 10 R 11 , or -NR 9 SO2R 10 , the-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with hydrogen, deuterium, oxo, halogen, cyano, hydroxyl, amino, -C 1-8 Alkyl, -OR 9a 、-NR 9a R 9b 、-NR 9a COR 9b 、-C 1-8 Alkoxy, -C 1-8 Alkyl-OR 9a , cycloalkyl, heterocyclyl, aryl, or heteroaryl substituted; R 9 、R 10 , and R 11 are independently hydrogen, -C 1-8 Alkyl, -OC 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, the -C 1-8 Alkyl, -OC 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups are each optionally substituted with at least one substituent R 9a Replace; or (R 9 and R 10 )、(R 10 and R 11 ), or (R 11 and R 9 ) together with the atom or atoms to which they are attached form a 3 to 12 membered ring comprising 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, said ring optionally substituted with at least one substituent R 9b replace; or When q is 1, (R 8 and Z) together with the atom or atoms to which they are attached form a 3 to 12 membered ring comprising 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, said ring optionally substituted with at least one substituent R 9b replace; where R 9a and R 9b are each independently hydrogen, deuterium, halogen, hydroxyl, amino, carbonyl, carbonyl-C 1-8 Alkyl, -C 1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR 9c 、-SO2R 9c 、-C 1-8 Alkyl-OR 9c 、-COR 9c 、-CO2R 9c 、-CONR 9c R 9d 、-C(=NR 9c )NR 9d R 9e 、-NR 9c R 9d 、-NR 9c COR 9d 、-NR 9c CONR 9d R 9e 、-NR 9c CO2R 9d 、-NR 9c SONR 9d R 9e 、-NR 9c SO2NR 9d R 9e , or -NR 9c SO2R 9d , the-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one selected from halogen, -C 1-8 Alkyl, -OR 9f 、-NR 9f R 9g , cycloalkyl, heterocyclyl, aryl, or heteroaryl substituents; R 9c 、R 9d 、R 9e 、R 9f and R 9g are independently hydrogen, -C 1-8 Alkyl, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; Furthermore, R 3 and R 4 At least one of them is F, Cl, -NO2 or -CN.

2. The compound according to claim 1, wherein B is a group that binds to an E3 ligase, wherein the E3 ligase is selected from von Hippel-Lindau (VHL), Cereblon, XIAP, E3A, MDM2, anaphase-promoting complex (APC), UBR5 (EDD1), SOCS / BC-box / eloBC / CUL5 / RING, LNXp80, CBX4, CBLL1, HACE1, HECTD1, HECTD2, HECTD3, HECW1, HECW2, HERC1, HERC2, HERC3, HERC4, HUWE1, ITCH, NEDD4, NEDD4L, PPIL2, PRPF19, PIAS1, PIAS2, PIAS3, PIAS4, RANBP2, RNF4, RBX1, SMURF1, SMURF2, STUB1, TOPORS, TRIP 12. UBE3A, UBE3B, UBE3C, UBE4A, UBE4B, UBOX5, UBR5, WWP1, WWP2, Parkin, A20 / TNFAIP3, AMFR / gp78, ARA54, β-TrCP1 / BTRC, BRCA1, CBL, CHIP / STUB1, E6, E6AP / UBE3A, F-box protein 1 5 / FBXO15, FBXW7 / Cdc4, GRAIL / RNF128, HOIP / RNF31, cIAP-1 / HIAP-2, cIAP-2 / HIAP-1, cIAP(pan), ITCH / AIP4, KAP1, MARCH8, MindBomb1 / MIB1, MindBomb2 / MIB2, MuRF1 / TRIM6 3. NDFIP1, NEDD4, NleL, Parkin, RNF2, RNF4, RNF8, RNF168, RNF43, SART1, Skp2, SMURF2, TRAF-1, TRAF-2, TRAF-3, TRAF-4, TRAF-5, TRAF-6, TRIM5, TRIM21, TRIM32, UBR5 or ZNRF3; Furthermore, the B is a group that binds to an E3 ligase selected from VHL, Cereblon, MDM2 or cIAP, Furthermore, the B is a group that binds to VHL.

3. The compound according to claim 1 or 2, wherein B is selected from the structure represented by the following general formula: in, V3 and V4 are each independently selected from absent, NH, O, S, SO, SO2, SO2NR h6 SR h6 、-R h6 CO-、-COR h6 -、CO、CO2、C(O)NR h6 、C(O)NR h6 R h6 、C(S)NR h6 NR h6 NR h6 CO, R h6 NR h6 CO、NR h6 CONR h7 、-C 1-8 Alkylene, -C 2-8 Alkenylene, -C 2-8 Alkyne, cycloalkyl, heterocyclic, aryl and heteroaryl, the -C 1-8 Alkylene, -C 2-8 Alkenylene, -C 2-8 Alkyne, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally replaced by R h8 replace; R H1 Independently selected from amino, NR h6 R h7 , heterocyclic, aryl and heteroaryl, wherein the aryl, or heteroaryl are each optionally substituted by one or more R h8 replace; R h independently selected from hydrogen, halogen, C 1-8 Alkyl, heterocyclic and heteroaryl, each of which is optionally substituted by 1, 2 or more R h5 replace; R h1 and R h3 are independently selected from hydrogen, NR h6 R h7 、-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C 3-9 Cycloalkyl and C 3-9 Heterocyclic group, the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C 3-9 Cycloalkyl, or C 3-9 The heterocyclic groups are each optionally substituted by one or more R h9 replace; R h2 independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, carboxyl, nitro, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR C6 、-SO2R h6 、-SO2NR h6 R h7 、-COR h6 、-CO2R h6 、-CONR h6 R h7 、-POR h6 R h7 、-NR h6 R h7 、-NR h6 COR h7 、-NR h6 CONR h7 R h8 、-NR h6 CO2R h7 、-NR h6 SO2NR h7 R h8 、-NR h6 SO2R h7 , the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are each optionally substituted with at least one substituent R h10 replace; q1 is independently 1 or 2; R h4 、R h5 、R h6 、R h7 are independently selected from hydrogen, deuterium, halogen, nitro, cyano, amino, hydroxyl, carboxyl, -C 1-8 Alkyl, -C(O)R h12 , the -C 1-8 The alkyl group is optionally replaced by one or more R h11 replace; R h8 、R h9 、R h10 、R h11 independently selected from hydrogen, deuterium, CN, halogen, carbonyl, nitro, amino, hydroxyl, carboxyl, oxo, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; R h12 Selected from C 3-9 Cycloalkyl, the C 3-9 The cycloalkyl group is optionally substituted with CN, halogen, nitro, amino, hydroxy, carboxyl, -C 1-3 Alkyl substitution; Further, R h1 are independently selected from hydrogen, -C 1-8 Alkyl and C 3-9 Cycloalkyl; and / or R h2 Selected from hydrogen, deuterium, halogen, nitro, cyano, amino, hydroxyl, -C 1-8 Alkyl, deuterated-C 1-8 Alkyl and halo-C 1-8 Alkyl; and / or R h3 independently selected from hydrogen, hydroxy substituted -C 1-8 Alkyl, and C 3-9 Cycloalkyl; and / or R h4 Selected from hydrogen, deuterium, halogen, nitro, cyano, amino, hydroxyl, -C 1-8 Alkyl, deuterated-C 1-8 Alkyl and halo-C 1-8 Alkyl; and / or R h independently selected from H, halogen, C 1-8 alkyl, and / or R h5 Selected from hydrogen, deuterium, halogen, nitro, cyano, amino, hydroxyl, -C 1-8 Alkyl, deuterated-C 1-8 Alkyl and halo-C 1-8 Alkyl; and / or V3 is selected from C(O)NR h6 NR h6 CO, heterocyclic and heteroaryl, each of which is optionally replaced by R h8 Replace; and / or V4 is independently selected from the group consisting of absent, SR h6 、-R h6 CO-、-COR h6 -、C(O)NR h6 R h6 、R h6 NR h6 CO and -C 1-8 Alkylene, the -C 1-8 The alkylene group is optionally replaced by R h8 Replace; and / or R H1 Independently selected from amino, NR h6 R h7 , heterocyclic and heteroaryl, each of which is optionally substituted by one or more R h8 Replace; and / or R h6 and R h7 independently selected from hydrogen, deuterium, -C 1-8 Alkyl and -C(O)R h12 , the-C 1-8 The alkyl group is optionally replaced by one or more R h11 Replace; and / or R h8 independently selected from hydrogen, deuterium, CN, halogen, oxo, -C 1-8 Alkyl and cycloalkyl groups; and / or R h11 independently selected from hydrogen and deuterium; and / or R h12 Selected from C 3-9 Cycloalkyl, the C 3-6 Cycloalkyl is optionally substituted with CN or halogen; Furthermore, R h1 Selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, and / or R h2 is selected from hydrogen, deuterium, halogen, nitro, cyano, amino, hydroxy, methyl, ethyl, deuterated methyl or halomethyl; R h3 Selected from hydrogen, methyl, ethyl, propyl, isopropyl, and / or R h4 is selected from hydrogen, deuterium, halogen, nitro, cyano, amino, hydroxy, methyl, ethyl, deuterated methyl or halomethyl; and / or R h independently selected from H, halogen, C 1-8 alkyl, and / or R h5 Selected from hydrogen, deuterium, halogen, nitro, cyano, amino, hydroxyl, C 1-8 Alkyl (such as methyl, ethyl, deuterated methyl) or halomethyl; and / or V3 is selected from -C(O)NH-, -NHC(O)-, and / or V4 is selected from the group consisting of absent, -CH2-, -CH2C(O)-, -C(O)CH2-, -CH2NHC(O)-, -C(O)NHCH2-, and / or R H1 Selected from Further selected 4. The compound according to any one of claims 1 to 3, wherein B is selected from the structure represented by the following general formula: where R h1 、R h3 、R h4 、R h 、R h5 、R H1 、CyV、R h6 As defined in claim 3 for general formula (B-V1), formula (B-V2), formula (B-V3), and formula (B-V4); in: The formula (BVC) is further where R h3 Not hydrogen; The formula (BVD) is further where R h3 Not hydrogen; The formula (BVE) is further where R h3 Not hydrogen; The formula (BVG) is further where R h3 Not hydrogen; Further, R h1 Selected from isopropyl, tert-butyl, R h3 Selected from H, methyl, R h4 is selected from H, halogen; R h Selected from hydrogen, halogen, C 1-8 alkyl, R h5 Selected from hydrogen, C 1-8 Alkyl, preferably methyl or hydrogen; R H1 Selected from CyV is selected from R h6 Selected from hydrogen, deuterium, halogen, nitro, cyano, amino, hydroxyl, carboxyl, -C 1-8 Alkyl, -C(O)R h12 , the -C 1-8 The alkyl group is optionally replaced by one or more R h11 replace; R h11 independently selected from hydrogen, deuterium, CN, halogen, carbonyl, nitro, amino, hydroxyl, carboxyl, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; and R h12 Selected from C 3-9 Cycloalkyl, the C 3-9 The cycloalkyl group is optionally substituted with CN, halogen, nitro, amino, hydroxy, carboxyl, -C 1-3 Alkyl substitution; Furthermore, R h1 Selected from R H1 for R h3 Selected from hydrogen, methyl, R h4 is hydrogen; R h Selected from R h5 Selected from methyl and ethyl; CyV is selected from as well as R h6 is hydrogen; Even further, the structure of B is selected from:

5. The compound according to any one of claims 1 to 4, wherein L is L4a, wherein: (1) L4a is: Among them, here X5 selected from CR L1 R L2 NR L1 , O, S or does not exist; w and v are each independently selected from 1, 2, 3, 4, 5, 6, 7, 8, and 9; R L 、R L1 、R L2 are each independently selected from hydrogen, halogen, C 1-8 Alkyl, hydroxyl; Furthermore, L4a is or, (2) L4a is Among them, here X5 is selected from the group consisting of: absent, -O-, -CH2-, Ring CyL3 is a 3-9 membered cycloalkyl group, or a 3-9 membered heterocyclyl group; R L 、R L1 are each independently selected from hydrogen, halogen, C 1-8 Alkyl, hydroxyl; s, w, and v are each independently selected from 0, 1, 2, 3, 4, and 5; Furthermore, CyL3 is preferably a 4-9 membered cycloalkyl group, more preferably Furthermore, CyL3 is preferably a 4-8 membered heterocyclic group, more preferably Furthermore, L4a is or (3) L4a is Among them, here X6 is selected from absent, -CH2-; Ring CyL4 is a 5-9 membered aromatic ring, or a 5-9 membered aromatic heterocyclic ring; R L 、R L1 are each independently selected from hydrogen, halogen, C 1-8 Alkyl, hydroxyl; s, w, and v are each independently selected from 0, 1, 2, 3, 4, and 5; Furthermore, CyL4 is preferably a 5-9 membered aromatic ring, more preferably a benzene ring; Furthermore, CyL4 is preferably a 5-6 membered aromatic heterocycle, more preferably Furthermore, L4a is or (4) L4a is Among them, here X6 is selected from absent, -CH2-; Ring CyL4 is a 5-9 membered aromatic ring, or a 5-9 membered aromatic heterocyclic ring; R L1 are each independently selected from hydrogen, halogen, C 1-8 Alkyl, hydroxyl; s, w, and v are each independently selected from 0, 1, 2, 3, 4, and 5; Furthermore, CyL4 is preferably a 5-9 membered aromatic ring, more preferably a benzene ring; Furthermore, L4a is or (5) L4a is Among them, here X5 is selected from -O-, -CH2-; w is selected from 0, 1, 2, 3, 4, 5; Ring CyL1 is a 3-9 membered heterocyclic group; R L1 independently selected from hydrogen, halogen, C 1-8 alkyl; s is independently selected from 0, 1, 2, 3, 4; Furthermore, L4a is or (6) L4a is Among them, here X5 is selected from -O-, -CH2-, Ring CyL1 is a 3-9 membered heterocyclic group; Ring CyL2 is a 3-9 membered heterocyclic group; R L1 、R L2 are each independently selected from hydrogen, halogen, C 1-8 alkyl; s and t are each independently selected from 0, 1, 2, 3, and 4; Furthermore, CyL1 is preferably a 4-6 membered N-containing heterocyclic group, more preferably Furthermore, CyL2 is preferably a 4-8 membered N-containing heterocyclic group, more preferably Furthermore, L4a is Furthermore, L4a is selected from 6. The compound according to any one of claims 1 to 4, wherein L is L4b, wherein: (1) L4b is Among them, here Each X5 is independently selected from CR L1 R L2 NR L1 , O, S or does not exist; Each w and v are independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9; s is selected from 1, 2, 3, 4, 5; Each R L 、R L1 、R L2 are each independently selected from hydrogen, halogen, C 1-8 Alkyl, hydroxyl; Furthermore, L4b is or (2) L4b is Among them, here X5 is selected from the group consisting of: absent, -O-, -CH2-, X6 is selected from the group consisting of absent, -O-, -NR L2 -; Ring CyL3 is a 3-9 membered cycloalkyl, phenyl or a 3-9 membered heterocyclyl; R L 、R L1 、R L2 are each independently selected from hydrogen, halogen, C 1-8 Alkyl, hydroxyl; s, w, and v are each independently selected from 0, 1, 2, 3, 4, and 5; Furthermore, CyL3 is preferably a 4-9 membered cycloalkyl group, more preferably Furthermore, CyL3 is preferably a 4-8 membered heterocyclic group, more preferably Furthermore, L4b is (Preferred )、 or (3) L4b is Among them, here X6 is selected from absent, -CH2-, O; Ring CyL4 is a 5-9 membered aromatic ring, or a 5-9 membered aromatic heterocyclic ring; R L1 are each independently selected from hydrogen, halogen, C 1-8 Alkyl, hydroxyl; s, w, and v are each independently selected from 0, 1, 2, 3, 4, and 5; Furthermore, CyL4 is preferably a 5-9 membered aromatic ring, more preferably a benzene ring; Furthermore, L4b is or (4) L4b is Among them, here X6 is selected from absent, -O-; Ring CyL4 is a 5-9 membered aromatic ring, or a 5-9 membered aromatic heterocyclic ring; R L 、R L1 are each independently selected from hydrogen, halogen, C 1-8 Alkyl, hydroxyl; R A 、R B are each independently selected from hydrogen and C 1-3 alkyl; s, w, and v are each independently selected from 0, 1, 2, 3, 4, and 5; Furthermore, CyL4 is preferably a 5-9 membered aromatic ring, more preferably a benzene ring; Furthermore, CyL4 is preferably a 5-6 membered aromatic heterocycle, more preferably Furthermore, L4b is or (5) L4b is Among them, here X5 is selected from absent, -O-, -CH2-; X6 is selected from absent, -O-; X5 and X6 cannot exist at the same time; w is selected from 0, 1, 2, 3, 4, 5; Ring CyL1 is a 3-9 membered heterocyclic group; R L1 independently selected from hydrogen, halogen, C 1-8 alkyl; s is independently selected from 0, 1, 2, 3, 4; Furthermore, L4b is or (6) L4b is Among them, here X5 is selected from -O-, -CH2-, Ring CyL1 is a 3-9 membered heterocyclic group; Ring CyL2 is a 3-9 membered heterocyclic group; R L1 、R L2 are each independently selected from hydrogen, halogen, C 1-8 alkyl; s and t are each independently selected from 0, 1, 2, 3, and 4; Furthermore, CyL1 is preferably a 4-6 membered N-containing heterocyclic group, more preferably Furthermore, CyL1 is preferably a 4-8 membered N-containing heterocyclic group, more preferably Furthermore, L4b is Furthermore, L4b is selected from (Preferred )、 7. The compound according to any one of claims 1 to 4, wherein L is L4c, wherein: (1) L4c is: Among them, here w and v are each independently selected from 1, 2, 3, 4, 5, 6, 7, 8, and 9; R L 、R L1 are each independently selected from hydrogen, halogen, C 1-8 Alkyl, hydroxyl; Furthermore, L4c is or (2) L4c is Among them, here X5 is selected from the group consisting of: absent, -O-, -CH2-, Ring CyL3 is a 3-9 membered cycloalkyl, phenyl or a 3-9 membered heterocyclyl; R L 、R L1 are each independently selected from hydrogen, halogen, C 1-8 Alkyl, hydroxyl; s, w, and v are each independently selected from 0, 1, 2, 3, 4, and 5; Furthermore, CyL3 is preferably a 4-9 membered cycloalkyl group, more preferably Furthermore, CyL3 is preferably a 4-8 membered heterocyclic group, more preferably Furthermore, L4c is or (3) L4c is wherein X6 is selected from absent, -CH2-; Ring CyL4 is a 5-9 membered aromatic ring, or a 5-9 membered aromatic heterocyclic ring; R L 、R L1 are each independently selected from hydrogen, halogen, C 1-8 Alkyl, hydroxyl; s, w, and v are each independently selected from 0, 1, 2, 3, 4, and 5; Furthermore, CyL4 is preferably a 5-9 membered aromatic ring, more preferably a benzene ring; Furthermore, CyL4 is preferably a 5-6 membered aromatic heterocycle, more preferably Furthermore, L4c is or (4) L4c is Among them, here X6 is selected from absent, -CH2-; Ring CyL4 is a 5-9 membered aromatic ring, or a 5-9 membered aromatic heterocyclic ring; R L 、R L1 are each independently selected from hydrogen, halogen, C 1-8 Alkyl, hydroxyl; s, w, and v are each independently selected from 0, 1, 2, 3, 4, and 5; Furthermore, CyL4 is preferably a 5-9 membered aromatic ring, more preferably a benzene ring; Furthermore, L4c is or (5) L4c is Among them, here X5 is selected from absent, -O-, -CH2-; w is selected from 0, 1, 2, 3, 4, 5; Ring CyL1 is a 3-9 membered heterocyclic group; R L1 independently selected from hydrogen, halogen, C 1-8 alkyl; s is independently selected from 0, 1, 2, 3, 4; Furthermore, L4c is Furthermore, L4c is selected from 8. The compound according to any one of claims 1 to 4, wherein said L is selected from 9. The compound according to any one of claims 1 to 5, wherein the compound is a compound of the following formula (II-C): or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, in: X1, X2, X3, R 100 ,m,L1,n,R 1 , L3, R 2 , L2, R 3 、R 4 、R 5 、R 6 、R 7 、R 8 , p, q as defined in claim 1; R h1 、R h3 、R h4 、R h As defined in claim 3 for general formula (B-V1), formula (B-V2), formula (B-V3), and formula (B-V4); L4a as defined in claim 5; Further, L4a is selected from 10. The compound according to any one of claims 1 to 4 and 6, wherein the compound is a compound of the following formula (II-D): or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, in: X1, X2, X3, R 100 ,m,L1,n,R 1 , L3, R 2 , L2, R 3 、R 4 、R 5 、R 6 、R 7 、R 8 , p, q as defined in claim 1; R h1 、R h3 、R h4 、R h , CyV is as defined in claim 3 for general formula (B-V1), formula (B-V2), formula (B-V3), and formula (B-V4); L4b as defined in claim 6; Further, L4b is selected from 11. The compound according to any one of claims 1 to 4 and 6, wherein the compound is a compound of the following formula (II-E): or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, in: X1, X2, X3, R 100 ,m,L1,n,R 1 , L3, R 2 , L2, R 3 、R 4 、R 5 、R 6 、R 7 、R 8 , p, q as defined in claim 1; R h1 、R h3 、R h4 、R h 、R H1 As defined in claim 3 for general formula (B-V1), formula (B-V2), formula (B-V3), and formula (B-V4); L4b as defined in claim 6; Further, L4b is selected from 12. The compound according to any one of claims 1 to 4 and 6, wherein the compound is a compound of the following formula (II-F1) or (II-F2): (Preferred Here each R h1 Not hydrogen) or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, in: X1, X2, X3, R 100 ,m,L1,n,R 1 , L3, R 2 , L2, R 3 、R 4 、R 5 、R 6 、R 7 、R 8 , p, q as defined in claim 1; R h1 、R h3 、R h4 、R h , CyV is as defined in claim 3 for general formula (B-V1), formula (B-V2), formula (B-V3), and formula (B-V4); L4b as defined in claim 6; Further, L4b is selected from 13. The compound according to any one of claims 1 to 4 and 7, wherein the compound is a compound of the following formula (II-G): or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, in: X1, X2, X3, R 100 ,m,L1,n,R 1 , L3, R 2 , L2, R 3 、R 4 、R 5 、R 6 、R 7 、R 8 , p, q as defined in claim 1; R h3 、R h4 、R h 、R H1 As defined in claim 3 for general formula (B-V1), formula (B-V2), formula (B-V3), and formula (B-V4); L4c as defined in claim 7; Further, L4c is selected from 14. The compound according to any one of claims 1 to 5, wherein the compound is a compound of the following formula (II-J): or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, in: X1, X2, X3, R 100 ,m,L1,n,R 1 , L3, R 2 , L2, R 3 、R 4 、R 5 、R 6 、R 7 、R 8 , p, q as defined in claim 1; R h1 、R h4 、R h 、R H1 、R h6 As defined in claim 3 for general formula (B-V1), formula (B-V2), formula (B-V3), and formula (B-V4); L4a as defined in claim 5; Further, L4a is selected from 15. The compound according to any one of claims 1 to 14, wherein: X1 is N or C; X2 and X3 are independently N; R 100 are independently halogen, hydroxy, amino, -CN, or cycloalkyl, preferably halogen or cycloalkyl, more preferably F, Cl and cyclopropyl; m is 0 or 1; n is 1; L1 and L3 are independently a single bond; L2 is independently -O- or -S-; R 1 Selected from wherein M is N, Cy3 is a 4-10 membered heterocyclyl and said heterocyclyl contains as one or more ring members 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur; R 2 is naphthyl or heteroaryl (preferably ), wherein the naphthyl or the heteroaryl group is replaced by one or more (eg, 2 or 3) R 2a replace; Each R 2a are independently halogen, amino, hydroxy, -C 1-8 Alkyl, -C 2-8 Alkynyl, or -CN, preferably F, Cl, hydroxy, methyl, ethyl, or ethynyl; R 3 and R 4 One of them is hydrogen, and the other is halogen, -CN, or -NO2, preferably F or Cl, more preferably F; R 5 、R 6 、R 7 、R 8 independently hydrogen; p is independently 1; q is independently 1; Z is selected from -NR 9 R 10 ; R 9 and R 10 are each independently hydrogen or -C 1-8 Alkyl, preferably methyl or ethyl; Further, R 1 for (Preferred )； R 2 for Furthermore, described Part of described Part of it is:

16. The compound according to claim 1, wherein the compound is selected from the compounds listed in Table 2 in the specification, or pharmaceutically acceptable salts thereof, or stereoisomers thereof.

17. A pharmaceutical composition comprising the compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and a pharmaceutically acceptable carrier.

18. Use of the compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof in the preparation of drugs related to KRas G12D inhibition or degradation.

19. Use of the compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or the composition according to claim 17 in the preparation of a medicament for treating and / or preventing a disease associated with the KRas G12D mutant protein, wherein the disease includes but is not limited to pancreatic cancer, colorectal cancer, endometrial cancer, or lung cancer; and wherein the lung cancer is selected from non-small cell lung cancer or small cell lung cancer.

20. A method for treating or preventing a disease associated with KRas G12D mutant protein, comprising administering to a patient in need thereof an effective amount of the compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or the pharmaceutical composition according to claim 17.