WO2024131777A1

WO2024131777A1 - Kras-protac chimeric compound, preparation method therefor and use thereof

Info

Publication number: WO2024131777A1
Application number: PCT/CN2023/139822
Authority: WO
Inventors: 孙伟; 翟文强; 叶久勇; 王令; 邓涛; 孙栗楠; 刘东舟
Original assignee: 杭州中美华东制药有限公司
Priority date: 2022-12-19
Filing date: 2023-12-19
Publication date: 2024-06-27

Abstract

The present invention relates to a compound as represented by formula (I) or a pharmaceutically acceptable salt and a stereoisomer thereof, and the use thereof in the treatment of tumors, immunological diseases, inflammation and other diseases; and a pharmaceutical preparation of the compound, a pharmaceutical composition and the use thereof.

Description

KRAS-PROTAC chimeric compounds and preparation methods and uses thereof

Technical Field

The present invention belongs to the field of medicine, and specifically relates to PROTAC chimeric compounds and uses thereof in preparing drugs for treating or preventing diseases such as tumors.

Background technique

The protein degradation targeted chimera (PROTAC) technology originated from scientists' discovery of the protein degradation process regulated by ubiquitin (Ub). Eukaryotic cells have been working hard to maintain appropriate protein levels, and they are generating and degrading thousands of proteins at every moment. The key factor in maintaining protein balance is a small protein molecule called ubiquitin. When it is linked to proteins, it causes these proteins to be transported to the proteasome for degradation.

Targeted protein degradation is an emerging direction in the field of drug research and development. Protein-targeted degradation drugs attempt to design small molecules into a new type of drug. Traditional small molecules block the function of proteins, while protein-targeted degraders degrade these proteins by sending them into the proteasome.

Dr. Craig Crews and Dr. Raymond Deshaies designed a series of bifunctional chimeric molecules based on peptide compounds to induce the degradation of methionyl aminopeptidase 2 (MetAP-2), and formally proposed the PROTAC concept and applied for the relevant patent WO2002020740A3. However, since these compounds based on large and bulky peptides are difficult to enter cells, the first generation of PROTACs failed.

In 2008, Crews' team designed the second-generation PROTACs based on the E3 ubiquitin protein ligase MDM2, which can be used to degrade the androgen receptor (AR).

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

The KRAS (Kirsten Rat Sarcoma Viral Oncogene Homolog) gene is one of the most common 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 cancer, ^10-12 % of colorectal cancer, 4% of lung adenocarcinoma, 11% of bile duct cancer, 5% of endometrial cancer, and several other cancers. It is clearly a solid cancer target, however, to effectively target other KRAS mutants, a series of challenges need to be overcome.

Drug development targeting KRAS mutants is one of the important means of intervening or treating the above cancers. For a long time, KRAS has been cursed as "undruggable" and "untargetable" due to its extremely high affinity for guanosine triphosphate (GTP) and the "smooth" surface of the KRAS protein, which is difficult to target.

One of the biggest advantages of PROTACs technology is that it can 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 corners and gaps.

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.

Summary of the invention

One object of the present invention is to provide protein degradation targeted chimeric compounds having good KRAS G12D inhibition/degradation activity and capable of inducing KRAS degradation, and their pharmaceutically acceptable salts, stereoisomers, and their use in the treatment of tumor, immune or inflammatory diseases.

The present invention provides compounds of general formula (I):
[BL] _n -KRAS ligand (I),

or a pharmaceutically acceptable salt or stereoisomer thereof,

wherein the KRAS ligand is, for example, a KRAS inhibitor, further a KRAS G12D 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 connected to the KRAS ligand, selected from 1, 2 or 3.

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

KRAS ligands

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

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 is 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, heterocyclyl, aryl or heteroaryl, wherein the -C _1-8 alkyl, -OC _1-8 alkyl, -C _2-8 alkenyl, -C _2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is each optionally substituted with one or more deuterium, halogen, cyano, hydroxyl, -C _1-8 alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl;

R ^100a and R ^100b are each independently hydrogen, deuterium, halogen, cyano, hydroxyl or -C _1-8 alkyl;

m is an integer from 0 to 3;

L ₁ , L ₂ and L ₃ 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) ₂ NR ^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 -;

n is an integer from 1 to 10;

R ¹ is selected from hydrogen, halogen, amino, hydroxyl, -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, -NO ₂ , -OR ^1a , -SO ₂ R ^1a , -COR ^1a , -CO ₂ R ^1a , -CONR ^1a R ^1b , -CH ₂ C(═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 CO ₂ R ^1b , -NR ^1a SONR ^1b R ^1c , -NR ^1a SO ₂ NR ^1b R ^1c , or -NR ^1a SO ₂ R ^1b , wherein 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 is each optionally substituted with hydrogen, deuterium, halogen, cyano, hydroxy, -C _1-8 alkoxy, -NR ^1d R ^1e , cycloalkyl, heterocyclyl, aryl or heteroaryl;

Each of R ^1a , R ^1b , and R ^1c is independently hydrogen, deuterium, halogen, cyano, amino, hydroxy, -C _1-8 alkyl, -C _2-8 alkenyl, -C _2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and the -C _1-8 alkyl, -C _2-8 alkenyl, -C _2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R ^1d ; 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 being optionally substituted with at least one substituent R ^1e ;

wherein R ^1d and R ^1e are each independently hydrogen, halogen, -C _1-8 alkyl, -C _{2-8 alkenyl, -C 2-8} _alkynyl , cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO ₂ , -OR ^1f , -SO ₂ R ^1f , -COR ^1f , -CO ₂ R ^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 CO ₂ R ^1g , -NR ^1f SONR ^1g R ^1h , -NR ^1f SO ₂ NR ^1g R ^1h , or -NR ^1f SO ₂ R ^1g ; the -C each of -C _1-8 alkyl, -C _2-8 alkenyl, -C _2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with at least one substituent selected from halogen, -C _1-8 alkyl, -OR ¹ⁱ , -NR ¹ⁱ R ^1j , cycloalkyl, heterocyclyl, aryl, or heteroaryl;

R ^1f , R ^1g , R ^1h , R ¹ⁱ and R ^1j are each 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 with one or more R ^2a ;

each R ^2a is 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, -NO ₂ , -OR ^2b , -SO ₂ R ^2b , -COR ^2b , -CO ₂ R ^2b , -CONR ^2b R ^2c , -CH ₂ C(═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 CO ₂ R ^2c , -NR ^2b SONR ^2c R ^2d , -NR ^2b SO ₂ NR ^2c R ^2d , or -NR ^2b SO ₂ R ^2c , wherein 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 is each optionally substituted with deuterium, halogen, cyano, hydroxy, -NR ^2e R ^2f , amino, -C _1-8 alkyl, -C _1-8 alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl;

Each of R ^2b , R ^2c , R ^2d , R ^2e , and R ^2f is independently hydrogen, deuterium, halogen, or C _1-8 alkyl;

^R3 and ^R4 are each independently hydrogen, halogen, hydroxy, amino, _-C1-8 alkyl, _-OC1-8 alkyl, _-C2-8 alkenyl, _-C2-8 alkynyl, cycloalkyl, heterocyclyl _, _aryl ^, ^heteroaryl _, ^oxo , -CN, _-NO2 , ^-OR4a , ^-SO2R4a ^, ^-SO2NR4aR4b ^, ^-COR4a ^, ^-CO2R4a , -CONR4aR4b, ^-C ( ^＝ ^NR4a ) ^NR4bR4c ^, ^-NR4aR4b ^, ^-NR4aCOR4b _, ^{-NR4aCONR4bR4c} ^, ^-NR4aCO2R4b ^, ^{-NR4aSONR4bR4c} _, ^{-NR4aSO2NR4bR} ^4c , or -NR ^4a SO ₂ R ^4b , wherein the -C _1-8 alkyl, -C _2-8 alkenyl, -C _2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R ^4d ;

R ^4a , R ^4b , and R ^4c are each independently hydrogen, hydroxy, -C _1-8 alkyl, -C _2-8 alkenyl, -C _2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and the -C _1-8 alkyl, -C _2-8 alkenyl, -C _2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R ^4e ; 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 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, which ring is optionally substituted with at least one substituent R ^4e ; or

R ^4d and R ^4e are each independently hydrogen, deuterium, halogen, hydroxyl, amino, -C _1-8 alkyl, -C _2-8 alkenyl, -C _2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO ₂ , -OR 4f , -SO ₂ R ^4f , -SO ₂ NR ^4f R ^4g , -COR ^4f , -CO ₂ R ^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 CO ₂ R ^4f , -NR ^4f SONR ^4f R ^4g , ^{-NR 4f} ^SO ₂ NR ^4g R ^4h , or -NR ^4f SO ₂ R ^4g , wherein the -C _1-8 alkyl, -C _2-8 alkenyl, -C _2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent selected from halogen, -C _1-8 alkyl, -OR ⁴ⁱ , -NR ⁴ⁱ R ^4j , cycloalkyl, heterocyclyl, aryl, or heteroaryl;

R ^4f , R ^4g , R ^4h , R ⁴ⁱ , and R ^4j are each 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 , and R ⁸ are independently hydrogen, deuterium, halogen, hydroxy, amino, -C _1-8 alkyl, -C _2-8 alkenyl, -C _2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO ₂ , -OR ^5a , -SO ₂ R ^5a , -SO ₂ NR ^5a R ^5b , -COR ^5a , -CO ₂ R ^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 CO ₂ R ^5b , -NR ^5a SONR ^5b R ^5c , -NR ^5a _SO NR ^5b R ^5c , or -NR ^5a SO ₂ R ^5b , wherein the -C _1-8 alkyl, -C _2-8 alkenyl, -C _2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group is each optionally substituted with at least one substituent R ^5d ;

R ^5a , R ^5b , and R ^5c are each independently hydrogen, -C _1-8 alkyl, -C _{2-8 alkenyl, -C 2-8} _alkynyl , cycloalkyl _, heterocyclyl, aryl, or heteroaryl, and the -C 1-8 alkyl, -C _2-8 alkenyl, -C _2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R ^5e ;

R ^5d and R ^5e are each independently hydrogen, hydroxy, amino _, halogen, -C _1-8 alkyl, -C 2-8 alkenyl, -C _2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO ₂ , -OR ^5f , -SO ₂ R ^5f , -SO ₂ NR ^5f R ^5g , -COR ^5f , -CO ₂ R ^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 CO ₂ R ^5f , -NR ^5f SONR ^5f R ^5g , -NR ^5f SO ₂ NR ^5g R ^5h , or -NR ^5f SO ₂ R ^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 substituent 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;

R ^5f , R ^5g , R ^5h , R ⁵ⁱ , and R ^5j are each 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, -NO ₂ , -OR ⁹ , -SR ⁹ , -SO ₂ R ⁹ , -COR ⁹ , -CO ₂ R 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 CO ₂ R ¹⁰ , -NR ⁹ SONR ¹⁰ R ¹¹ , -NR ⁹ SO ₂ NR ¹⁰ R ¹¹ , or -NR ⁹ SO ₂ R ¹⁰ , said -C _1-8 alkyl, -C _2-8 alkenyl, -C _2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group each being optionally substituted with hydrogen, deuterium, oxo, halogen, cyano, hydroxy, 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;

R ⁹ , R ¹⁰ , and R ¹¹ are each independently hydrogen, -C _1-8 alkyl, -OC _1-8 alkyl, -C _2-8 alkenyl, -C _2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and 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 at least one substituent R ^9a ; 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, as one or more ring members, 1 , 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur, which ring is optionally substituted with at least one substituent R ^9b ;

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 being optionally substituted with at least one substituent R ^9b ;

wherein R ^9a and R ^9b are each independently hydrogen, deuterium, halogen, hydroxy, 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, -NO ₂ , -OR ^9c , -SO ₂ R ^9c , -C _1-8 alkyl-OR ^9c , -COR ^9c , -CO ₂ R ^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 CO ₂ R ^9d , -NR ^9c SONR ^9d R ^9e , -NR ^9c SO ₂ NR ^9d R ^9e , or -NR ^9c SO ₂ R ^9d , said -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 selected from halogen, -C _1-8 alkyl, -OR ^9f , -NR ^9f R ^9g , cycloalkyl, heterocyclyl, aryl, or heteroaryl;

R ^9c , R ^9d , R ^9e , R ^9f and R ^9g are each 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.

Further, at least one of R ³ and R ⁴ is F, Cl, -NO ₂ or -CN. In some embodiments, one of R ³ and R ⁴ is hydrogen, and the other is F or Cl, more preferably F.

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

or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,

wherein X ₁ , X ₂ , X ₃ , R ¹⁰⁰ , m, L ₁ , n, R ¹ , L ₃ , R ² , L ₂ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , p and q are as defined above for formula (KI).

In some embodiments of the present invention, _Xi is N, and the other variables are as defined herein.

In some embodiments of the present invention, _Xi is C, and the other variables are as defined herein.

In some embodiments of the present invention, _X2 and _X3 are N, and the other variables are as defined herein.

In some embodiments of the present invention, R ¹⁰⁰ is selected from 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.

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

In some embodiments of the present invention, ^R3 and ^R4 are each independently hydrogen, halogen, cyano, _-OC1-8 alkyl, _C1-8 alkyl, cycloalkyl, and the _-C1-8 alkyl, _-OC1-8 alkyl, cycloalkyl, are each optionally substituted by deuterium, halogen, cyano, hydroxyl, amino, _-OC1-8 alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, with the proviso that at least one of ^R3 or ^R4 is F, Cl, _-NO2 or -CN; other variables are as defined herein.

Further, R ³ and R ⁴ are independently selected from halogen, hydrogen, C _1-6 alkyl, cyano, -NO ₂ , provided that at least one of R ³ or R ⁴ is F, Cl, -NO ₂ or -CN.

Further, R ³ and R ⁴ are independently selected from -F, hydrogen, methyl, -CN, Cl, -NO ₂ , provided that at least one of R ³ or R ⁴ is F, Cl, -NO ₂ or -CN.

Further, ^R3 and ^R4 are independently selected from -F, hydrogen, methyl, -CN, Cl, _-NO2 , provided that at least one of ^R3 or ^R4 is F or -CN. In some embodiments, one of ^R3 and ^R4 is hydrogen, and the other is F or Cl, more preferably F.

In some embodiments of the present invention, L ₁ , L ₂ and L ₃ 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) ₂ NR ^1a -, -NR ^1a S(＝O) ₂ -, -OC(＝O)O-, -OC(＝O)NR ^1a -, -NR ^1a C(＝O)O-, -NR ^1a C(＝O)NR ^1b -; and

n is an integer from 1 to 10.

In some embodiments of the present invention, _L3 is selected from a single bond, and the other variables are as defined herein.

In some embodiments of the present invention, L ₂ is selected from a single bond, -NH-, -CH ₂ -, -O-, -S-, and other variables are as defined in the present invention.

In some embodiments of the present invention, L ₂ is selected from -O-, -NH-, -CH ₂ -, and the other variables are as defined herein.

In some embodiments of the present invention, _L2 is selected from -O-, and the other variables are as defined herein.

In some embodiments of the present invention, _L1 is selected from a single bond, -NH-, -O-, -S-, -NHC(=O)-, -CH ₂ -, -(CH ₂ ) ₂ -, n=1 or 2, and other variables are as defined in the present invention.

In some embodiments of the present invention, -(L ₁ ) _n - is selected from a single bond, -NH-, -O-, -S-, _-OCH2- , -S- _CH2- , -NHC(=O)-, -CH ₂ -, -(CH ₂ ) ₂ -, and other variables are as defined in the present invention.

In some embodiments of the present invention, R ¹ is selected from hydrogen, halogen, amino, hydroxyl, -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, -NO ₂ , -OR ^1a , -SO ₂ R ^1a , -COR ^1a , -CO ₂ R ^1a , -CONR ^1a R ^1b , -CH ₂ C(＝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 CO ₂ R ^1b , -NR ^1a SONR ^1b R ^1c , -NR ^1a SO ₂ NR ^1b R ^1c , or -NR ^1a SO ₂ R ^1b , wherein 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, hydroxy, -C _1-8 alkoxy, -NR ^1d R ^1e , cycloalkyl, heterocyclyl, aryl, or heteroaryl;

R ^1a , R ^1b , and R ^1c are each independently hydrogen, deuterium, halogen, cyano, amino, hydroxy, -C _1-8 alkyl, -C _2-8 alkenyl, -C _2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and the -C _1-8 alkyl, -C _2-8 alkenyl, -C _2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R ^1d ; or

In some embodiments of the present invention, R ¹ is selected from C _3-10 cycloalkyl, C _3-10 heterocyclyl, C _6-10 aryl, C _6-10 heteroaryl, and the cycloalkyl, heterocyclyl, aryl, heteroaryl are each optionally substituted by deuterium, halogen, cyano, hydroxyl, -C _1-8 alkoxy, -NR ^1d R ^1e , cycloalkyl, heterocyclyl, aryl, or heteroaryl.

In some embodiments of the present invention, ^R1 is selected from _C3-10 heterocyclic groups, preferably _C3-10 heterocyclic groups containing N, preferably In some embodiments of the present invention, the N-containing C _3-10 heterocyclic group is Best

In some embodiments of the present invention, ^R1 is selected from _C4-10 heterocyclic group or _C4-10 heteroaryl group, 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, the heterocyclic or heteroaryl group containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, the heterocyclic or heteroaryl group is optionally substituted by hydrogen, deuterium, halogen, cyano, hydroxyl, -C _1-8 alkoxy, -NR ^1d R ^1e , cycloalkyl, heterocyclic, aryl, or heteroaryl. In some preferred embodiments, R ¹ is In some preferred embodiments, R ¹ is Best

In some embodiments of the present invention, R ¹ is selected from C _3-10 cycloalkyl (such as C ₄ cycloalkyl), each of which is optionally substituted by -NR ^1d R ^1e , preferably

In some embodiments of the present invention, R ¹ is selected from -NR ^1a R ^1b , preferably

In some embodiments of the present invention, ^R1 is selected from Other variables are as defined herein.

In some embodiments of the present invention, -(L ₁ ) _n -R ¹ is selected from -R ¹ , i.e. L ₁ is a single bond, and said R ¹ is selected from C _4-10 heterocyclic group or C _4-10 heteroaryl group, said 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 heterocyclyl or heteroaryl group, the heterocyclyl or heteroaryl group containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, the heterocyclyl 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, -(L ₁ ) _n -R ¹ is In some preferred embodiments, -(L ₁ ) _n -R ¹ is Best

In some embodiments of the present invention, -(L ₁ ) _n is selected from -NH-, -O-, -S-, _-OCH2- , -S- _CH2- , -NHC(=O)-, -CH ₂ -, -(CH ₂ ) ₂ -; and/or

R ¹ is selected from -NR ^1a R ^1b , C _3-10 cycloalkyl ^, each of which is optionally substituted by -NR ^1d R ^1e , preferably

Furthermore, -(L ₁ ) _n -R ¹ is selected from

In some embodiments of the present invention, -(L ₁ ) _n -R ¹ is selected from The other variables are as defined herein. Alternatively or additionally, in some embodiments, -(L ₁ ) _n -R ¹ is

In some embodiments of the present invention, R ² is aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more R ^2a ;

each R ^2a is 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, -NO ₂ , -OR ^2b , -SO ₂ R ^2b , -COR ^2b , -CO ₂ R ^2b , -CONR ^2b R ^2c , -CH ₂ C(═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 CO ₂ R ^2c , -NR ^2b SONR ^2c R ^2d , -NR ^2b SO ₂ NR ^2c R ^2d , or -NR ^2b SO ₂ R ^2c , wherein 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 by deuterium, halogen, cyano, hydroxy, -NR ^2e R ^2f , amino, -C _1-8 alkyl, -C _1-8 alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

Each of R ^2b , R ^2c , R ^2d , R ^2e , and R ^2f is independently hydrogen, deuterium, halogen, or C _1-8 alkyl.

In some embodiments of the present invention, R ² is C _6-12 aryl or C _6-12 heteroaryl, and the aryl or heteroaryl is optionally substituted with one or more R ^2a .

In some embodiments of the present invention, R ² is a C _6-12 aryl group, which is substituted by one or more R ^2a , wherein the C _6-12 aryl group is selected from a benzene ring Naphthalene ring

In some embodiments of the present invention, R ² is a C _6-12 heteroaryl group, which is substituted by one or more R ^2a , wherein the C _6-12 heteroaryl group is selected from

The above R ^2a is selected from halogen, hydroxyl, C _1-8 alkyl, -C _2-8 alkynyl, amino, cyano, -C _1-8 alkyl substituted by halogen; preferably selected from -F, -Cl, methyl, hydroxyl, ethynyl, ethyl, amino, cyano, -CF ₃ .

In some embodiments of the present invention, ^R2 is selected from Other variables are as defined herein.

In some embodiments of the present invention, ^R2 is

In some embodiments of the invention, R ⁵ , R ⁶ , R ⁷ and 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, -NO ₂ , -OR ^5a , -SO ₂ R ^5a , -SO ₂ NR ^5a R ^5b , -COR ^5a , -CO ₂ R ^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 CO ₂ R ^5b , -NR ^5a SONR ^5b R ^5c , -NR ^5a SO ₂ NR ^5b R ^5c , or -NR ^5a SO ₂ R ^5b , wherein the -C _1-8 alkyl, -C _2-8 alkenyl, -C _2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group is each optionally substituted with at least one substituent R ^5d ;

R ^5f , R ^5g , R ^5h , R ⁵ⁱ , and R ^5j are each 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.

In some embodiments of the present invention, R ⁵ , R ⁶ , R ⁷ , and R ⁸ are independently hydrogen, deuterium, or C _1-8 alkyl.

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

In some embodiments of the present invention, ^R6 is selected from hydrogen, and the other variables are as defined herein.

In some embodiments of the present invention, ^R7 is selected from hydrogen, and the other variables are as defined herein.

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

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

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

In some embodiments of the 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, -NO ₂ , -OR ⁹ , -SR 9 , -SO 2 R 9 , -COR ⁹ , -CO ₂ R 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 CO 2 R 10 , -NR ⁹ SONR 10 R ¹¹ , -NR ⁹ SO 2 NR ¹⁰ R ¹¹ , or -NR ⁹ SO 2 R 10 , wherein the -C 1-8 ^alkyl ^, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2 , -OR ⁹ , -SR ⁹ , -SO 2 R ⁹ , -COR 9 , -CO ₂ R 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 CO ₂ R 10 , -NR 9 SONR ¹⁰ R 11 , -NR 9 SO 2 NR ₁₀ R 11 , or -NR ⁹ SO ₂ R ¹⁰ -C _2-8 alkenyl, -C _2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with hydrogen, deuterium, oxo, halogen, cyano, hydroxy, 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;

or

In some embodiments of the 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, the ring being optionally substituted with at least one substituent R ^9b ;

Further, R ⁸ and Z form a C _3-9 heterocyclic group, and the heterocyclic group is optionally substituted by at least one substituent R ^9b , and R ^9b is selected from hydrogen, methyl, and ethyl;

Furthermore, the C _3-9 heterocyclic group formed by R ₈ and Z is It is optionally substituted with methyl, further

In some embodiments of the present invention, Z is selected from hydrogen, amino, hydroxy, -OR ⁹ , -SR ⁹ , -NR ⁹ R ¹⁰ , -NR ⁹ COR ¹⁰ , cycloalkyl, heterocyclyl, aryl, heteroaryl, and the cycloalkyl, heterocyclyl, aryl, heteroaryl are each optionally substituted with hydrogen, deuterium, oxo, halogen, cyano, hydroxy, 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;

R ⁹ and R ¹⁰ are independently (in accordance with valence bond theory) hydrogen, C _1-8 alkyl, -OC _1-8 alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and the C _1-8 alkyl, -OC _1-8 alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted by hydrogen, deuterium, halogen, cyano, hydroxyl, amino, -C _1-8 alkoxy, -OR ^9c , cycloalkyl, heterocyclyl, aryl, or heteroaryl; or

R ⁹ and R ¹⁰ 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, 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;

R ^9a , R ^9b , and R ^9c are each independently hydrogen, deuterium, or -C _1-8 alkyl.

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

R ^9c are each independently hydrogen, deuterium or -C _1-8 alkyl.

In some embodiments of the present invention, Z is selected from -NR ⁹ COR ¹⁰ , wherein R ⁹ and R ¹⁰ are independently hydrogen, methyl, or ethyl.

In some embodiments of the present invention, Z is preferably selected from -NR ⁹ R ¹⁰ , wherein R ⁹ and R ¹⁰ are independently hydrogen, methyl, ethyl, ethyl substituted by -OCH ₃ ; or wherein R ⁹ and R ¹⁰ form a 3- to 12-membered heterocyclic group.

In some embodiments of the present invention, Z is selected from -NR ⁹ R ¹⁰ , wherein R ⁹ and R ¹⁰ are independently hydrogen, methyl, ethyl, ethyl substituted by -OCH ₃ ; further selected from

In some embodiments of the present invention, Z is selected from -NR ⁹ R ¹⁰ , wherein R ⁹ and R ¹⁰ form a 3- to 12-membered heterocyclic group selected from Further, the heterocyclic group is optionally substituted by oxo, halogen, methyl, -OCH ₃ , -CH ₂ -OH, heterocyclic group, and can be selected from

In some embodiments of the present invention, Z is selected from -OR ⁹ , wherein R ⁹ is selected from hydrogen, methyl, ethyl substituted by hydroxyl, C ₃ cycloalkyl; further selected from

In some embodiments of the present invention, Z is selected from Other variables are as defined herein.

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

or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein R ¹⁰⁰ , m, L ₁ , n, R ¹ , L ₃ , R ² , L ₂ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , Z, p and q are as defined above.

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

or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein R ¹⁰⁰ , m, L ₁ , n, R ¹ , L ₃ , R ² , L ₂ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , p and q are as defined above.

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

or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein L ₂ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , p, q, and Z are as defined above.

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

or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein L ₂ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , p, and q are as defined above.

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

or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein R ¹⁰⁰ , m, X ₁ , L ₃ , R ² , R ³ , and R ⁴ are as defined above.

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:

, preferably

Degradation Tag B

In some embodiments, 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, TRIP12, 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 15/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/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.

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

In some embodiments, B is selected from the following structures:

in,

_V3 and _V4 are each independently selected from absent, NH, O, S, SO, SO2, _SO2NRh6 , ^SRh6 , _-Rh6CO- , ^-CORh6- , CO, _CO2 , C(O) ^NRh6 , C(O) ^NRh6Rh6 , C(S ^)NRh6 ^, ^NRh6 , ^NRh6CO , ^Rh6NRh6CO , ^NRh6CONRh7 ^, -C1-8alkylene ^, _{-C2-8alkenylene} , _{-C2-8alkynylene, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the -C1-8alkylene, -C2-8alkenylene} _, ^{-C2-8alkynylene} ^, _cycloalkyl _, _heterocyclyl , aryl or heteroaryl is each optionally substituted by ^Rh8 ;

R ^H1 is independently selected from amino, NR ^h6 R ^h7 , heterocyclyl, aryl and heteroaryl, and the aryl and heteroaryl are each optionally substituted by one or more R ^h8 ;

R ^h is independently selected from hydrogen, halogen, C _1-8 alkyl, heterocyclyl and heteroaryl, each of which is optionally substituted with 1, 2 or more R ^h5 ;

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 heterocyclyl, wherein the -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, C 3-9} _cycloalkyl _, _or _C _3-9 _heterocyclyl _is each optionally substituted with one or more R ^h9 ;

R ^h2 is independently 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 , -SO ₂ R ^h6 , -SO ₂ NR ^h6 R ^h7 , -COR ^h6 , -CO ₂ R ^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 CO ₂ R ^h7 , -NR ^h6 SO ₂ NR ^h7 R ^h8 , -NR ^h6 SO ₂ R ^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 ;

q1 is independently 1 or 2;

R ^h4 , R ^h5 , R ^h6 , and R ^h7 are independently selected from hydrogen, deuterium, halogen, nitro, cyano, amino, hydroxyl, carboxyl, -C _1-8 alkyl, and -C(O)R ^h12 , wherein the -C _1-8 alkyl is optionally substituted by one or more R ^h11 ;

R ^h8 , R ^h9 , R ^h10 , and R ^h11 are 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, and heteroaryl;

R ^h12 is selected from C _3-9 cycloalkyl, and the C _3-9 cycloalkyl is optionally substituted by CN, halogen, nitro, amino, hydroxy, carboxyl, or -C _1-3 alkyl.

In some embodiments, R ^H1 is independently selected from amino, NR ^h6 R ^h7 , heterocyclyl, aryl and heteroaryl, each of which is optionally substituted with one or more R ^h8 .

In some embodiments, R ^h8 , R ^h9 , R ^h10 , and R ^h11 _are 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, and heteroaryl.

In some further embodiments, R ^h1 is independently selected from hydrogen, -C _1-8 alkyl, and C _3-9 cycloalkyl.

In some embodiments, R ^h2 is selected from hydrogen, deuterium, halogen, nitro, cyano, amino, hydroxyl, -C _1-8 alkyl, deuterated-C _1-8 alkyl, and halo-C _1-8 alkyl.

In some embodiments, R ^h3 is independently selected from hydrogen, hydroxy-substituted-C _1-8 alkyl, and C _3-9 cycloalkyl.

In some embodiments, R ^h4 is selected from hydrogen, deuterium, halogen, nitro, cyano, amino, hydroxyl, -C _1-8 alkyl, deuterated-C _1-8 alkyl, and halo-C _1-8 alkyl.

In some embodiments, ^{Rh is} independently selected from H, halogen, _C1-8 alkyl,

In some embodiments, R ^h5 is selected from hydrogen, deuterium, halogen, nitro, cyano, amino, hydroxyl, -C _1-8 alkyl, deuterated-C _1-8 alkyl, and halo-C _1-8 alkyl.

In some embodiments, V ₃ is selected from C(O)NR ^{h 6} , NR ^{h 6} CO, heterocyclyl, and heteroaryl, each of which is optionally substituted with R ^{h 8} .

In some embodiments, _V4 is independently selected from absent, ^SRh6 , ^-Rh6CO- , ^-CORh6- , C(O) ^NRh6Rh6 , ^Rh6NRh6CO ^, and ^{-C1-8alkylene} , said _{-C1-8alkylene} being optionally substituted ^{with Rh8} _.

In some embodiments, R ^H1 is independently selected from amino, NR ^h6 R ^h7 , heterocyclyl, and heteroaryl, each of which is optionally substituted with one or more R ^h8 .

In some embodiments, R ^h6 and R ^h7 are independently selected from hydrogen, deuterium, -C _1-8 alkyl, and -C(O)R ^h12 , wherein the -C _1-8 alkyl is optionally substituted with one or more R ^h11 .

In some embodiments, R ^h8 is independently selected from hydrogen, deuterium, CN, halogen, oxo, -C _1-8 alkyl, and cycloalkyl.

In some embodiments, R ^h11 is independently selected from hydrogen and deuterium.

In some embodiments, R ^h12 is selected from C _3-9 cycloalkyl, said C _3-6 cycloalkyl optionally substituted with CN or halogen.

go a step further,

R ^h1 is 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; and/or

R ^h3 is selected from hydrogen, methyl, ethyl, propyl, isopropyl or

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

R ^h is independently selected from H, halogen, C _1-8 alkyl, and / or

R ^h5 is 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

V ₄ is selected from the group consisting of absent, -CH ₂ -, -CH ₂ C(O)-, -C(O)CH ₂ -, -CH ₂ NHC(O)-, -C(O)NHCH ₂ -, and / or

R ^H1 is selected from Further selected from

The C _1-8 alkyl mentioned above refers to a straight or branched 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.

In some embodiments, B is selected from the structure shown by the general formula:

(Preferred )(BVJ),

wherein R ^h1 , R ^h3 , R ^h4 , R ^h , R ^h5 , R ^H1 , CyV and R ^h6 are as defined above for Formula (B-V1), Formula (B-V2), Formula (B-V3) and Formula (B-V4).

Further, the formula (BVC) is wherein R ^h3 is not hydrogen.

Further, the formula (BVD) is wherein R ^h3 is not hydrogen.

Further, the formula (BVE) is wherein R ^h3 is not hydrogen.

Further, the formula (BVG) is wherein R ^h3 is not hydrogen.

In some further embodiments, R ^h1 is selected from isopropyl, tert-butyl,

R ^h3 is selected from H, methyl,

R ^h4 is selected from H, halogen;

^Rh is selected from hydrogen, halogen, _C1-8 alkyl,

R ^h5 is selected from hydrogen, C _1-8 alkyl, preferably methyl or hydrogen;

R ^H1 is selected from

CyV is selected from

R ^h6 is selected from hydrogen, deuterium, halogen, nitro, cyano, amino, hydroxyl, carboxyl, -C _1-8 alkyl, -C(O)R ^h12 , wherein the -C _1-8 alkyl is optionally substituted with one or more R ^h11 ;

R ^h11 is 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;

R ^h12 is selected from C _3-9 cycloalkyl, and the C _3-9 cycloalkyl is optionally substituted by CN, halogen, nitro, amino, hydroxy, carboxyl, nitro, or -C _1-3 alkyl.

In some embodiments, R ^H1 is selected from

In some further embodiments, R ^h1 is selected from

R ^H1 is selected from

R ^h3 is selected from hydrogen, methyl,

R ^h4 is hydrogen;

R ^h is selected from

R ^h5 is selected from methyl and ethyl;

CyV is selected from as well as

R ^h6 is hydrogen.

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

In some embodiments, the structure of B is:

Linker L between B and KRAS ligand

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

L4a

In some embodiments of the invention, L is L4a.

In some embodiments of the invention, L4a is

Among them, here

_X5 is selected from CR ^L1 R ^L2 , NR ^L1 , O, S or absent;

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

^RL , ^RL1 and ^RL2 are each independently selected from hydrogen, halogen, _C1-8 alkyl and hydroxy.

Furthermore, L4a is

In some embodiments of the invention, 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;

^RL , ^RL1 are each independently selected from hydrogen, halogen, _C1-8 alkyl, hydroxyl;

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

Further, CyL3 is preferably a 4-9 membered cycloalkyl, more preferably Additionally or alternatively, CyL3 is

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

Furthermore, L4a is

Additionally or alternatively, in some embodiments L4a is

In some embodiments of the invention, L4a is

Among them, here

X ₆ is selected from absent, -CH ₂ -;

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

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

In some embodiments of the invention, L4a is

Among them, here

X ₆ is selected from absent, -CH ₂ -;

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, L4a is

In some embodiments of the invention, 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 is independently selected from hydrogen, halogen, C _1-8 alkyl;

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

Furthermore, L4a is

In some embodiments of the invention, 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 and R ^L2 are each independently selected from hydrogen, halogen, and 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, in some embodiments of the present invention, L4a is selected from

Additionally or alternatively, in some embodiments, L4a is selected from

L4b

In some embodiments of the invention, L is L4b.

In some embodiments of the invention, L4b is

Among them, here

Each _X5 is independently selected from CR ^L1 R ^L2 , NR ^L1 , O, S or absent;

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 of ^RL , ^RL1 , and ^RL2 is independently selected from hydrogen, halogen, _C1-8 alkyl, and hydroxy.

Furthermore, L4b is

Additionally or alternatively, in some embodiments, L4b is

In some embodiments of the invention, L4b is

Among them, here

_X5 is selected from the group consisting of absent, -O-, _-CH2- ,

_X6 is selected from absent, -O-, -NR ^L2 -;

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

^RL , ^RL1 , ^RL2 are each independently selected from hydrogen, halogen, _C1-8 alkyl, hydroxyl;

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

Further, CyL3 is preferably a 4-9 membered cycloalkyl group, more preferably

Furthermore, L4b is (Preferred ),

Additionally or alternatively, in some embodiments, L4b is

In some embodiments of the invention, L4b is

Among them, here

X ₆ is selected from absent, -CH ₂ -, O;

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

Furthermore, L4b is Additionally or alternatively, in some embodiments, L4b is

In some embodiments of the invention, L4b is

Among them, here

X ₆ is selected from absent, -O-;

^RA and ^RB are each independently selected from hydrogen and _C1-3 alkyl;

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

In some embodiments, L4b is

Furthermore, L4b is

Additionally or alternatively, in some embodiments, L4b is

In some embodiments of the invention, L4b is

Among them, here

X ₅ is selected from absent, -O-, -CH ₂ -;

X ₆ is selected from absent, -O-;

X ₅ and X ₆ cannot both not exist;

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

Ring CyL1 is a 3-9 membered heterocyclic group;

R ^L1 is independently selected from hydrogen, halogen, C _1-8 alkyl;

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

Furthermore, L4b is

Additionally or alternatively, in some embodiments, L4b is

In some embodiments of the invention, 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;

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

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

Furthermore, L4b is

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

Additionally or alternatively, in some embodiments, L4b is

L4c

In some embodiments of the invention, L is L4c.

In some embodiments of the invention, L4c is

Among them, here

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

^RL and ^RL1 are each independently selected from hydrogen, halogen, _C1-8 alkyl, and hydroxy.

Furthermore, L4c is

In some embodiments of the invention, 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;

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

Further, CyL3 is preferably a 4-9 membered cycloalkyl, more preferably

Furthermore, L4c is

Additionally or alternatively, in some embodiments, L4c is

In some embodiments of the invention, L4c is

Among them, here

X ₆ is selected from absent, -CH ₂ -;

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

Furthermore, L4c is

In some embodiments of the invention, L4c is

Among them, here

X ₆ is selected from absent, -CH ₂ -;

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

Furthermore, L4c is

In some embodiments of the invention, L4c is

Among them, here

X ₅ is selected from absent, -O-, -CH ₂ -;

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

Ring CyL1 is a 3-9 membered heterocyclic group;

R ^L1 is independently selected from hydrogen, halogen, C _1-8 alkyl;

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

Furthermore, L4c is

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

In some embodiments of the present invention, said L is selected from:

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

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):

or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,

wherein _X1 , _X2 , _X3 , ^R100 , m, _L1 , n, ^R1 , L3, _R2 , ^L2 , _R3 , ^R4 , ^R5 , ^R6 ^{, R7, R8, p, q, Rh1, Rh3, Rh4} ^, ^Rh ^and ^L4a ^are ^as defined above.

Further, here L4a is selected from

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):

or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,

wherein _X1 , _X2 , _X3 , ^R100 , m, _L1 , n, ^R1 , L3, _R2 , ^L2 , _R3 , ^R4 , ^R5 , ^R6 ^{, R7, R8, p, q, Rh1, Rh3, Rh4} ^, ^Rh ^, ^CyV ^and ^L4b are as defined above.

Further, here L4b is selected from

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):

or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,

wherein _X1 , _X2 , _X3 , ^R100 , m, _L1 , n, ^R1 , L3, _R2 , ^L2 , _R3 , ^R4 , ^R5 ^{, R6, R7, R8, p, q, Rh1, Rh3, Rh4} ^, ^Rh ^, ^RH1 ^and ^L4b ^are ^as defined above.

Further, here L4b is selected from

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):

or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,

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

wherein each R ^h1 here is not hydrogen.

Further, here L4b is selected from

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):

or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,

wherein _X1 , _X2 , _X3 , ^R100 , m, _L1 , n, ^R1 , L3, _R2 , ^L2 , _R3 , ^R4 , ^R5 , ^R6 , ^R7 , ^R8 , p, q, ^Rh3 , ^Rh4 , ^Rh , ^RH1 and ^L4c are as defined above.

Further, here L4c is selected from

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):

or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,

wherein _X1 , _X2 , _X3 , ^R100 , m, _L1 , n, ^R1 , L3, _R2 , ^L2 , _R3 , ^R4 ^{, R5, R6, R7, R8, p, q, Rh1, Rh4} ^, ^Rh ^, ^RH1 ^, ^Rh6 ^and ^L4a ^are as defined above.

Further, here L4a is selected from

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:

Table 2:

or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

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.

The present invention also provides the use of the above-mentioned compounds, or pharmaceutically acceptable salts thereof, or stereoisomers thereof in the preparation of KRas G12D inhibition/degradation related drugs.

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 drug for treating or preventing a disease associated with the KRas G12D mutant protein. Further, 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.

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

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

Definition and Description

Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered to be uncertain or unclear in the absence of a special definition, but should be understood according to its ordinary meaning. When a trade name appears in this article, it is intended to refer to its corresponding commercial product or its active ingredient.

The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, 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.

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

Unless otherwise specified, the term "C _1-8 alkyl" is used to refer to a straight or branched saturated hydrocarbon group having 1 to 8 carbon atoms. In some embodiments, the alkyl group has 1-6 carbon atoms (i.e., "C _1-6 alkyl"), and in other embodiments 1-4 carbon atoms (i.e., "C _1-4 alkyl"). Examples 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 refer to a straight or branched saturated hydrocarbon group consisting of 1 to 3 carbon atoms. The C _1-3 alkyl group includes 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). Examples of C _1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), etc.

Unless otherwise specified, " _C2-8 alkenyl" is used to refer to a straight 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. The _C2-8 alkenyl includes _C2-6 , _C2-4 , _C2-3 , _C4 , _C3 and _C2 alkenyl, etc.; it may be monovalent, divalent or polyvalent. Examples of _C2-8 alkenyl include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, etc.

Unless otherwise specified, " _C2-8 alkynyl" means a straight or branched hydrocarbon group having 1 to 8 carbon atoms, which contains one or more carbon-carbon triple bonds. _C2-8 alkynyl includes _C2-6 , _C2-4 , _C2-3 , _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.

Unless otherwise specified, the terms "C _1-3 alkoxy" and "-OC _1-3 alkyl" are interchangeable and refer to those alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule via an oxygen atom. The C _1-3 alkoxy group includes C _1-2 , C _2-3 , C ₃ and C ₂ alkoxy groups, etc. Examples of C _1-3 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), etc.

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.

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.

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.

The term "bridged cycloalkyl" refers to a cyclic structure containing carbon atoms and formed by two rings sharing two atoms that are not adjacent to each other. 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 atoms that are not adjacent to each other.

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

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

- 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;

- 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.

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.

The term "heteroaryl" refers to a group selected from:

- a 5-, 6- or 7-membered aromatic monocyclic ring comprising 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), The remaining ring atoms are 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;

- 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

- an 11- to 14-membered tricyclic ring comprising 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.

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.

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 containing 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 5-6 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 8-10 membered heteroaryl ring, which is bicyclic and has 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.

"Heterocyclyl", "heterocycle" or "heterocyclic" are interchangeable and refer to non-aromatic heterocyclic groups containing one or more heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring members and the remaining ring members are carbon, including monocyclic rings, fused rings, bridged rings and spiro rings, 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 SO _2. The heterocycle can be saturated (i.e., "heterocycloalkyl") or partially saturated. In some embodiments, the heterocyclic group is a 3-7 member (e.g., 4, 5 or 6 member) monocyclic group (i.e., "monocyclic heterocyclic group"); in some embodiments, the heterocyclic group is a 5-20 member polycyclic (e.g., bicyclic) group. In some embodiments, each ring in the polycyclic heterocyclic group is non-aromatic and at least one heteroatom is present in at least one ring, and the polycyclic heterocyclic group is connected to the rest of the molecule through the ring containing the heteroatom. In some embodiments, the polycyclic heterocyclyl may contain an aromatic hydrocarbon ring but be attached to the remainder of the molecule through a non-aromatic ring containing a heteroatom.

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., "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, oxirane, 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.

The term "spiro heterocyclic group" refers to a 5 to 20 yuan polycyclic heterocyclic group having a ring connected by a shared carbon atom (called a spiral atom), 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 a spiral heterocyclic group may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, the spiral heterocyclic group is 6 to 14 yuan, and more preferably 7 to 12 yuan. According to the number of shared spiral atoms, the spiral heterocyclic group is divided into a monospiro heterocyclic group, a dispiro heterocyclic group or a polyspiro heterocyclic group, and preferably refers to a monospiro heterocyclic group or a dispiro heterocyclic group, 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 monospiro heterocyclic group.

The term "fused heterocyclic group" refers to a 5 to 20-membered polycyclic heterocyclic group in which each ring in the system shares a pair of adjacent 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 yuan, preferably 7 to 12 yuan and more preferably 7 to 10 yuan. According to 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 yuan/5 yuan or 5 yuan/6 yuan 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,

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.

[0043] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.

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

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. All of these isomers and their mixtures are included within the scope of the present invention.

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

Unless otherwise indicated, the term "cis-trans isomers" or "geometric isomers" arises from the inability of a double bond or single bond forming a ring carbon atom to rotate freely.

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.

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

Unless otherwise specified, the key is a solid wedge. 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 Medium wave line It means that the compound can be And so on.

The compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more atoms constituting the compound. For example, the compound may be labeled with a radioactive isotope, such as deuterium ( ^2H ), tritium ( ^3H ), iodine-125 ( ^125I ) or C-14 ( ^14C ). For another example, deuterium may be substituted for hydrogen to form a deuterated drug. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic effects, and extending the biological half-life of drugs. All isotopic composition changes of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.

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.

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 not substituted, and unless otherwise specified, the type and number of the substituent can be arbitrary on the basis of chemical achievable.

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, and each occurrence of R is an independent choice. In addition, combinations of substituents and/or variants thereof are permitted only if such combinations result in stable compounds.

When the number of a linking group is 0, such as -(L ₁ ) ₀ -, it means that the linking group is a single bond.

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.

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

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 A-L-Z represents a single bond, it means that the structure is actually A-Z.

When a substituent has bonds that cross-link to two or more atoms in a ring, the substituent may be bonded to any atom in the ring, e.g. Indicates that the substituent R can be substituted at any position on the cyclohexyl group or cyclohexadiene. When the listed substituents do not specify which atom is connected to the substituted group, the substituent can be bonded through any atom thereof. For example, a pyridyl substituent can be connected to the substituted group through any carbon atom on the pyridine ring.

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 the reading order from left to right to form Combinations of linkers, substituents, and/or variations thereof are permissible only if such combinations result in stable compounds.

Unless otherwise specified, when a group has one or more attachable sites, any one or more of the sites of the group may 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 site, when the chemical bond is connected, the number of H atoms at the site will decrease accordingly with the number of connected chemical bonds to become a group of corresponding valence. The chemical bond connecting the site to other groups can be represented by a straight solid bond. Straight solid key with * or wavy line The two forms can be used interchangeably. For example, the straight solid bond in -OCH ₃ indicates that it is connected to other groups through the oxygen atom in the group; The wavy line in the phenyl group indicates that it is connected to other groups through the carbon atom #1 in the phenyl group; The * in the phenyl group indicates that it is connected to other groups through the #1 carbon atom in the phenyl group.

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

When applied to animals, humans, experimental subjects, cells, tissues, organs or biological fluids, the terms "administration", "administering", "treating" and "treatment" refer to the contact of an exogenous agent, therapeutic agent, diagnostic agent or composition with the 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 "treatment" also refer to in vitro and ex vivo treatment of, for example, a cell by an agent, a diagnostic agent, a binding compound or by another cell. The term "patient" herein includes any organism, preferably an animal, more preferably a mammal (e.g., rats, mice, dogs, cats, and rabbits) and most preferably a human.

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 to treat 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.

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

Throughout the specification and subsequent aspects, the term "C _nm " indicates a range including endpoints, where n and m are integers and indicate the number of carbons. Examples include C _1-8 , C _1-6 , C _1-3 , etc.

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.

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 synthetic 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.

The solvent used in the present invention is commercially available.

Compounds are named according to the conventional nomenclature in the art or using The software names were used, and commercially available compounds were named using the supplier's catalog names.

Detailed ways

Example 1: Degradation experiment

1. Experimental Materials

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), CCK8 (Bimake, B34304)

Multifunctional microplate reader (SPARK, Tecan).

2. Test methods

1) AsPC-1-HiBit cells were plated into 96-well plates, 12,000 cells per well, and incubated at 37°C overnight; 2) Compounds were added, with the highest concentration being 10 μM, 9 gradients, one control, and 2 replicates, and incubated at 37°C for 24 h; 3) Nano-glo HiBit Lytic reagent was added to the 96-well plate at 50 μl per well, and shaken at 300 rpm for 3 min in the dark; 4) Incubated in the dark for 10 min, and then read using a microplate reader.

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

Example 2: Cell proliferation inhibition experiment

1. Experimental Materials

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 purchased from Nanjing CoBiotech Co., Ltd.

2. Cell activity test method

1) Select cells in logarithmic phase to prepare cell suspension and count. 2) Inoculate into 96-well plate, 3000 cells/well, 100μl culture medium, 2 replicates. 3) After 18h of incubation at 37℃, adhere to the wall and add the test substance (10mM storage solution) according to the experimental requirements. 4) Add 10μl CCK8 when the compound is incubated for 72h. After addition, suspend and shake for 2min. Continue incubation at 37℃ for 3h. 5) Measure the absorbance at 450nM. Curve fitting is performed using Prism software (GraphPad7.0) to obtain the IC ₅₀ value.

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.

Preparation Example

The present invention is further described in detail below in conjunction with 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 in the embodiments of the present invention that do not specify specific conditions are usually conventional conditions, or according to the conditions recommended by the raw material or commodity manufacturer; reagents that do not specify the source are usually conventional reagents that can be purchased through commercial channels.

The experimental methods in the following examples without specifying specific conditions were carried out according to conventional methods and conditions, or selected according to the product instructions.

Intermediate Preparation Example 1: Preparation of Intermediate A:

Step 1: Preparation of A2

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, and TBDPSCl (8.0 g, 1.0 eq) was added dropwise. The mixture was stirred at room temperature for 4 h. TBDPSCl disappeared after TLC detection, and the reaction was stopped. Water and MTBE were added for extraction, the organic phase was concentrated, and compound A2 was obtained after purification by silica gel column. LCMS: [M+Na] ⁺ = 351.1.

Step 2: Preparation of A3

At room temperature, compound intermediate A2 (3.8 g, 1.0 eq) was dissolved in DCM (50 ml), imidazole (1.2 g, 1.5 eq) was added, and TBSCl (2.0 g, 1.2 eq) was added dropwise. The mixture was stirred at room temperature for 2 h. The intermediate 1-2 disappeared after TLC detection, and the reaction was stopped. 100 ml of water was added, and the mixture was extracted with DCM. The organic phases were combined, concentrated, and purified by silica gel column to obtain intermediate A3.

Step 3: Preparation of A4

At room temperature, (fluoromethyl) tetrafluoroboryl triphenylphosphine (5.56g, 1.5eq) was suspended in anhydrous tetrahydrofuran (45ml), cooled to -78°C, and NaHMDS (14.5ml, 1.5eq, 1M) was added dropwise. After stirring for 30 minutes, an anhydrous tetrahydrofuran solution (25ml) of intermediate A3 (4.3g, 1.0eq) was added dropwise. After the addition was completed, the reaction solution was transferred to room temperature for reaction for 2h. The TLC raw material disappeared and the reaction was stopped. The reaction solution was cooled to 0°C, and an aqueous ammonium chloride solution and EA were added and stirred for 10 minutes. The liquids were separated, the organic phase was concentrated, and the intermediate A4 was purified by silica gel column. LCMS: [M+Na] ⁺ = 481.1.

Step 4: Preparation of A5

At room temperature, the intermediate A4 (3.2 g, 1.0 eq) was dissolved in tetrahydrofuran (40 ml), and a 4M HCl dioxane solution (21 ml, 12 eq) was added. The mixture was reacted at room temperature for 1.5 h. When the raw material was almost gone by TLC, the reaction was stopped. After the reaction solution was concentrated, the crude product was purified by silica gel column to obtain the intermediate A5. LCMS: [M+Na] ⁺ = 367.1.

Step 5: Preparation of Intermediate A

At room temperature, intermediate A5 (1.9 g, 1.0 eq) was dissolved in DCM (20 ml), and DMAP (67 mg, 0.1 eq), DIEA (1.43 g, 2.0 eq) and TosCl (1.57 g, 1.5 eq) were added. The reaction was continued at room temperature for 24 h. The raw material was basically disappeared by TLC detection, and the reaction was stopped. Water and DCM were added to the reaction solution for extraction. After the organic phase was concentrated, it was purified by silica gel column to obtain intermediate A. LCMS: [M+Na] ⁺ = 521.1.

Intermediate Preparation Example 2: Preparation of Intermediate B:

Step 1: Preparation of B2

Compound B1 (5.0 g, 23.2 mmol) was slowly added to a reaction bottle containing POCl ₃ (50 mL) and DIEA (20 mL) under 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 spotting and LCMS. After returning to room temperature, the mixture was concentrated in vacuo to obtain compound B2, which was used directly in the next step.

Step 2: Preparation of B4

Compound B2 (5.8 g, 23.2 mmol) was dissolved in 60 mL DCM, and 20 mL 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 bottle was placed at room temperature and quenched with saturated ammonium chloride. The reaction was extracted three times with DCM and backwashed twice with saturated brine. The organic phase was dried and concentrated in vacuo. Compound B4 was obtained by forward column purification.

Step 3: Preparation of B5

B4 (2.9 g 6.78 mmol) and 30 mL THF were added to a 250 mL single-necked bottle 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. 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. The product was purified by beating with EA/PE = 1/2 to obtain compound B5.

Step 4: Preparation of B7

B5 (1.6 g, 3.6 mmol) and compound B6 (2.8 g, 5.45 mmol), K ₂ CO ₃ (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, and nitrogen was replaced three times. The reaction was carried out at 95°C for 3 h. After LCMS detection, there was no MS signal, and a new spot appeared on the spot plate. Water was then added to quench the reaction, and EA was extracted three times. The organic phases were combined, dried and concentrated, and then purified on a normal phase column (EA/PE=1/2) to obtain compound B7. MS m/z (ESI): 634.2 [M+H] ⁺ .

Step 5: Preparation of Intermediate B

Compound B7 (2.6 g, 3.3 mmol), 40 mL DCM and m-CPBA (680 mg, 3.93 mmol) were added to a single-mouth bottle and reacted at room temperature for 2 h. LCMS showed that the raw material and the product had no peaks, and a new point appeared at a more polar position. Water was added to quench the reaction, and the organic phases were combined after EA extraction three times, dried and concentrated, and purified by a forward column to obtain the product intermediate B. MS m/z (ESI): 650.2 [M + H] ⁺ .

Example 1: Preparation of C001

Step 1: Preparation 1_2

At 25°C, compound 1_1 (2.5 g, 9.7 mmol) and potassium carbonate (4.0 g, 29.1 mmol) were dissolved in DMF (40 ml), and iodomethane (1.45 g, 10.2 mmol) was added under nitrogen protection. After the addition, stirring was continued at room temperature for 4 hours. The reaction was monitored by TLC plate to complete. 200 ml of water was added to the reaction solution to quench and dilute, and ethyl acetate was extracted (3x100 ml), backwashed with saturated sodium chloride solution, and the combined organic phase was 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.

Step 2: Preparation 1_3

Dissolve 1_2 (2.0 g, 7.38 mmol) in 1,4-dioxane (30 mL), add 4N HCl dioxane solution (15 mL) at room temperature, and stir the reaction at room temperature for 2 hours. Monitor the reaction by TLC until the starting material disappears. Return to room temperature, spin dry the solvent, and obtain crude compound 1_3.

Step 3: Preparation 1_4

At 25°C, 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) and stirred at 60 degrees for 3 hours under nitrogen protection. The reaction was monitored by TLC plate. 20 ml of water was added to the reaction solution to quench and dilute, and ethyl acetate was extracted (3x10 ml), backwashed with saturated sodium chloride solution, and the combined organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo, and purified by silica gel column chromatography to obtain compound 1_4.

Step 4: Preparation 1_5

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 solution) was added dropwise at room temperature. After the addition, stirring was continued at room temperature for 2 hours. The reaction was monitored by TLC plate. 20 ml of water was added to the reaction solution to quench and dilute, and ethyl acetate was extracted (3x10 ml), backwashed with saturated sodium chloride solution, and the combined organic phase was 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.

Step 5: Preparation 1_6

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

Step 6: Preparation 1_7

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. The mixture was stirred at room temperature for 16 hours. The reaction was completed by LCMS monitoring. The reaction solution was concentrated in vacuo, the methanol was dried, and then diluted with 5 ml of water. The mixture was extracted with ethyl acetate (3x5 ml) at pH=6 and backwashed with saturated sodium chloride solution. The combined organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo. Compound 1_7 was obtained after purification by preparative plate.

Step 7: Preparation 1_8

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 completion of the reaction. 5 ml of water was added to the reaction solution to dilute it, and a solid product was precipitated. The product was filtered out with filter paper, dissolved in ethyl acetate, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain pure compound 1_8.

Step 8: Preparation 1_9

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 solution) was added dropwise at room temperature. After addition, stirring was continued at room temperature for 2 hours. LCMS monitored the reaction to be complete. 10 ml of water was added to the reaction solution to quench and dilute, and the mixture was extracted with ethyl acetate (3x5 ml), backwashed with saturated sodium chloride solution, and the combined organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The mixture was purified by preparative plate to obtain compound 1_9.

Step 9: Preparation of C001

1_9 (30 mg, 0.024 mmol) was dissolved in DCM (10 mL), 4N HCl dioxane solution (0.3 mL) was added at room temperature, and 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 out with filter paper, dissolved in water, adjusted to pH = 8, extracted with EA, and 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] ⁺ .

Example 2: Preparation of C002

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

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

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

Step 1: Preparation 2_2

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 solution was placed in an ice bath, and CbzCl (8.4 g, 50 mmol) was slowly added dropwise. After the addition, the mixture was stirred at room temperature for 16 hours. The reaction was monitored by LCMS. The mixture was extracted with ethyl acetate (3x40 ml), backwashed with saturated sodium chloride solution, and the combined organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The mixture was purified by silica gel column chromatography to obtain compound 2_2.

Step 2: Preparation 2_4

Compound 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. After addition, stirring was continued for 24 hours. LCMS monitored the reaction to be complete. The mixture was concentrated in vacuo, 30 ml of ethyl acetate was added, and the mixture was backwashed with a saturated sodium chloride solution. The combined organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo, and purified by silica gel column chromatography to obtain compound 2_4.

Step 3: Preparation 2_5

2_4 (1.8 g, 5.0 mmol) was dissolved in methanol (30 mL), Pd/C (600 mg) was added at room temperature, and after hydrogen replacement, the mixture was stirred at room temperature for 16 hours. After the reaction was completed by TLC monitoring, the reaction solution was filtered through diatomaceous earth. The filtrate was concentrated in vacuo, and the solvent was dried to obtain a crude product. Compound 2_5.

Step 4: Preparation 2_6

At 25°C, 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), and stirred at 60 degrees for 4 hours under nitrogen protection. The reaction was monitored by TLC plate. 20 ml of water was added to the reaction solution to quench and dilute, and ethyl acetate was extracted (3x10 ml), backwashed with saturated sodium chloride solution, and the organic phases were combined and purified by silica gel column chromatography to obtain compound 2_6.

Step 5: Preparation 2_7

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 solution) was added dropwise at room temperature. After the addition, stirring was continued at room temperature for 1 hour. The reaction was monitored by TLC plate. 20 ml of water was added to the reaction solution to quench and dilute, and ethyl acetate was extracted (3x10 ml), backwashed with saturated sodium chloride solution, and the combined organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. Compound 2_7 was obtained by purification by silica gel column chromatography.

Example 3: Preparation of C003A and C003B

Step 1: Preparation 3_2

(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 the addition was completed, a solution of 3_1 (500 mg, 1.0 eq) in THF (8 ml) was added dropwise after stirring at -78 °C for 1 h. The mixture was transferred to room temperature for reaction for 3 h. TLC detection showed that a small amount of raw materials remained, and the reaction was stopped. The reaction mixture was added dropwise to an icy aqueous solution of ammonium chloride, extracted twice with EA, and the organic phase was concentrated and purified on a silica gel column to obtain 3_2.

Step 2: Preparation 3_3

At room temperature, 3_2 (280 mg) was dissolved in THF (4 mL), 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 on 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.

Step 3: Preparation 3_4

At room temperature, compound 3_3 (230 mg, 1.0 eq) was dissolved in DCM (10 ml), N-methylbenzylamine (183 mg, 1.3 eq) and AcOH (1 drop) were added, and STAB (740 mg, 3.0 eq) was added in batches after reacting at room temperature for 30 min. The reaction was stopped after TLC detection of the disappearance of raw material 3_3. NaHCO ₃ aqueous solution and DCM were slowly added, and the organic phase was concentrated and separated using a preparative TLC plate to obtain 3_4. LCMS: [M+1] ⁺ = 304.2.

Step 4: Preparation 3_5

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

Step 5: Preparation 3_6

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

Step 6: Preparation 3_7

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

Step 7: Preparation 3_8

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 the addition was completed, the reaction was continued at this temperature for 30 minutes. LCMS showed that intermediate B was completely reacted. The reaction solution was added dropwise to an iced ammonium chloride solution, extracted with EA, and the organic phase was concentrated and separated and purified using a preparative plate to obtain 3_8. LCMS: [M+H] ⁺ = 1043.9.

Step 8: Preparation 3_9

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 carried out at room temperature for 1 h. LCMS monitored that the raw material was completely reacted. The reaction solution was concentrated to dryness to obtain the crude product 3_9, which was directly used for the next step of reaction. LCMS: [M+H] ⁺ =1015.6.

Step 9: Preparation 3_10

At room temperature, the crude compound 3_9 of the previous step was dissolved in DMF (2 ml), and intermediate C (24 mg, 1.5 eq), DIEA (13 mg, 3.0 eq) and HATU (38 mg, 3.0 eq) were added in sequence and reacted at room temperature for 2 h. The reaction was complete after LCMS monitoring. Water and EA were added for separation. The aqueous layer was extracted twice with EA. After the organic phase was concentrated, 3_10 was separated by preparative silica gel plate. LCMS: [M+H] ⁺ = 1427.7.

Step 10: Preparation 3_11

At 25°C, TBAF (0.2 ml, 1 M in THF) was added to a solution of compound 3_10 (30 mg) in THF (4 mL), and the mixture was reacted at room temperature for 1 h. The reaction was completed after monitoring by LCMS. Water and EA were added, and the liquids were separated. The aqueous layer was extracted once with EA, and the organic phases were combined and concentrated to dryness to obtain the crude product 3_11, which was directly subjected to the next step of reaction. LCMS: [M+H]+=1271.6.

Step 11: Preparation of C003A and C003B

At room temperature, the crude compound 3_11 from the previous step was dissolved in DCM (3.0 mL) solution, and TFA (1.0 mL) was added. The reaction was carried out at room temperature for 2 hours, and LCMS monitoring showed that the raw material disappeared. The reaction solution was concentrated, and the residue was purified by preparative HPLC to obtain products C003A and C003B.

C003A: LCMS: [M+H] ⁺ =1127.5.

C003B: LCMS: [M+H] ⁺ =1127.3.

Example 4: Preparation of C004

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

C004: LCMS: [M+H] ⁺ =1113.5.

Example 5: Preparation of C005

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

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

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

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 protection and ice bath. After addition, stirring was continued for 0.5 hours. In ice bath, 5_1 (1.6 g, 8.4 mmol) was slowly added dropwise, and stirred at room temperature for 3 days after addition. LCMS monitored the completion of the reaction. In ice bath, water was added to the reaction solution to quench and dilute, and ethyl acetate was used for extraction. The organic phases were combined, concentrated, and purified by silica gel column chromatography to obtain compound 5_2.

Example 6: Preparation of C006

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

¹ H NMR (400 MHz, DMSO) δ 10.15 (s, 1H), 9.04 (s, 1H), 8.98 (s, 1H), 8.56 (d, J = 5.9 Hz, 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 = 7.6 Hz, 3H), 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) ⁺ .

Example 7: Preparation of C007

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

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

Example 8: Preparation of C008

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

LCMS (ESI) m/z: 1111.5 (M+H) ⁺ .

Example 9: Preparation of C009

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) ⁺ .

Example 10: Preparation of C010

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

Example 11: Preparation of C011A and C011B

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

C011A: ¹ H NMR (400 MHz, DMSO) δ 9.04 (s, 1H), 8.98 (s, 1H), 8.56 (dd, J = 10.9, 5.9 Hz, 1H), 7.95 (dd, J = 9.1, 6.1 Hz ,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,0.5 H), 4.82 (d, J = 2.5 Hz, 2H), 4.56–4.45 (m, 2H), 4.45–4.38 (m, 2H), 4.31 (dd, J = 11.5, 9.1 Hz, 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, 7.3 Hz, 3H), 2.11 (s, 3H), 2.08–1.98 (m, 2H), 1.89 (ddd, J = 13.2, 8.4, 4.5 Hz, 1H), 1.64 (s, 4H), 1.52–1.34 (m, 4H), 1.20 (dd, J=14.4, 7.2 Hz, 2H), 0.91 (s, 9H). LCMS (ESI) m/z: 1087.9 ( M+H) ⁺ .

C011B: ¹ H NMR (400 MHz, DMSO) δ9.03 (d, J = 2.0 Hz, 1H), 8.98 (s, 1H), 8.56 (t, J = 6.4 Hz, 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) ⁺ .

Example 12: Preparation of C012A and C012B

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

Compound C012A: ¹ H NMR (400 MHz, DMSO) δ9.03 (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 .0Hz,2H),4.23(d,J＝4.6Hz,1H),3.87(s,1H),3.63(d,J＝11.8Hz,3H),3.55(d,J＝16.7Hz,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＝12.2,4.2Hz,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] ⁺ .

Compound C012B: ¹ H NMR (400 MHz, DMSO) δ 10.18 (s, 1H), 9.05 (s, 1H), 8.98 (s, 1H), 8.54 (t, J = 6.0 Hz, 1H), 7.97 (dd, J＝9.2,5.9Hz,1H),7.80(d,J＝9.3Hz,1H),7.46(t,J＝9.0Hz,1H),7.40(q,J＝8.4Hz,5H),7.26(s, 0.5H), 7.17 (d, J = 2.0 Hz, 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 = 13.3 Hz, 2H), 4.25-4.19 (m, 1H), 3.90 (s, 1H), 3.65 (d, J = 4.2 Hz, 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] ⁺ .

The preparation method of intermediate 12_2 is as follows:

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.

Example 13: Synthesis of C013

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

Example 14: Synthesis of C014A and C014B

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

C014A: MS m/z(ESI):1111.5[M+H] ⁺ .

C014B: MS m/z(ESI):1111.6[M+H] ⁺ .

Example 15: Synthesis of C015A and C015B

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

C015A: MS m/z(ESI):1153.6[M+H] ⁺ .

C015B: MS m/z(ESI):1153.4[M+H] ⁺ .

Example 16: Synthesis of C016A and C016B

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

C016A: MS m/z(ESI):1141.6[M+H] ⁺ .

C016B: MS m/z(ESI):1141.6[M+H] ⁺ .

Example 17: Synthesis of C017A and C017B

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

C017A: MS m/z(ESI):1135.6[M+H] ⁺ .

C017B: MS m/z(ESI):1135.6[M+H] ⁺ .

Example 18: Synthesis of C018

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

Example 19: Synthesis of C019

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

Example 20: Synthesis of C020A and C020B

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

C020A, MS m/z(ESI):1107.5[M+H] ⁺ .

C020B, MS m/z(ESI):1107.6[M+H] ⁺ .

Example 21: Synthesis of C021

Step 1: Preparation 21_2

21_1 (110 mg, 1.0 eq) and DCM (5 ml) were added to a 100 ml single-mouth bottle to dissolve, 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 showed that the starting material disappeared and the main peak was the product. Water and DCM were added, the liquids were separated, and the organic phase was concentrated to dryness to obtain the crude product 21_2, which was directly used for the next step of reaction.

Step 2: Preparation 21_3

21_2 (130 mg, 1.0 eq) and THF (4 ml) were added to a 50 ml single-mouth bottle to dissolve, and a dioxane solution of HCl (0.88 ml, 10 eq) was added. The reaction was allowed to react at room temperature for 2 h. LCMS showed that the raw material disappeared and the main peak was the product. The reaction solution was concentrated to dryness, water and EA were added, and the pH was adjusted to 9-10 with sodium carbonate solution. The liquid was separated, the aqueous layer was extracted twice with EA, the organic phases were combined, and concentrated to obtain 21_3, which was directly subjected to the next step of reaction.

Step 3: Preparation 21_4

In a 100 ml single-mouth bottle, intermediate A (90 mg, 1.0 eq), 21_3 (45 mg, 1.0 eq), DMF (3 ml) and K2CO3 (75 mg, 3.0 eq) were added, and the reaction was continued overnight at room temperature. LCMS detection showed that a small amount of raw materials remained, and the reaction was stopped. Water and EA were added, and the liquid was separated. The aqueous layer was extracted with EA, and the organic phases were combined and washed once with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain the crude product 21_4, which was directly subjected to the next step of reaction.

Step 4: Preparation 21_5

Add 21_4 (90 mg, 1.0 eq) and THF (3 ml) to a 100 ml single-mouth bottle, add TBAF solution (2 drops), react at 32 ° C for 8 h, LCMS detection shows that the raw material disappears and the main peak is the product. Add water and EA, separate the liquids, wash the organic layer with saturated brine twice, adjust the pH to 1-2 with dilute HCl solution, discard the organic phase, adjust the pH of the aqueous phase to 11-12 with K2CO3 solution, extract with EA, dry over anhydrous sodium sulfate, filter, and concentrate to obtain the product 21_5, which is directly used for the next step of reaction.

Step 5: Preparation 21_6

In a 100 ml single-mouth bottle, add intermediate B (100 mg, 1.0 eq) and 21_5 (46 mg, 1.1 eq) and solvent THF (5 ml), cool to -10 ° C, add LiHMDS (0.36 ml, 3.0 eq, 1M in THF) dropwise, react at -10 ° C for 0.5 h, LCMS shows that the starting material disappears and the reaction is complete. The reaction solution is added dropwise to an icy NH ₄ Cl aqueous solution to quench, extracted with EA, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is spin-dried and separated using a preparative plate to obtain the product 21_6.

Step 6: Preparation 21_7

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

Step 7: Preparation 21_8

21_7 (20 mg, 1.0 eq) and DMF (2 ml) were added to an 8 ml vial to dissolve, and intermediate C (17 mg, 2.0 eq) and CDI (10 mg, 3.0 eq) were added, and the reaction was carried out at room temperature for 2 h. LCMS showed the presence of the target product. Water and EA were added, the liquid was separated, the organic layer was concentrated to dryness, and 21_8 was obtained by separation using a preparative plate.

Step 8: Preparation 21_9

21_8 (12 mg, 1.0 eq) and THF (3 ml) were added to a 50 ml single-mouth bottle, and a solution of TBAF (2 drops) was added, and the reaction was carried out at room temperature for 1 h. LCMS detection showed that the raw material disappeared and the main peak was the product. Water and EA were added, and the liquid was separated. The organic layer was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain a crude product of 21_9, which was directly subjected to the next step of reaction.

Step 9: Prepare C021

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

Example 22: Synthesis of C022

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

MS m/z(ESI):1131.5[M+H] ⁺ .

Example 23: Synthesis of C023A and C023B

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

C023A: MS m/z(ESI):1115.4[M+H] ⁺ .

C023B: MS m/z(ESI):1115.3[M+H] ⁺ .

Example 24: Synthesis of D001

Step 1: Synthesis of D1_1

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, and 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, and 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] ⁺ .

Step 2: Synthesis of D1_2

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, and the mixture was stirred at 60°C for 1 hour. The reaction was monitored by LCMS. Ethyl acetate and water were added to the reaction solution for extraction, and 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] ⁺ .

Step 3: Synthesis of D1_3

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, and the mixture was stirred at 0°C for 1 hour. The reaction was monitored by LCMS. The reaction solution was concentrated to obtain compound D1_3. MS m/z (ESI): 770.2 [M+H] ⁺ .

Step 4: Synthesis of D1_5

At room temperature, D1_3 (600 mg, 0.67 mmol) was dissolved in N, N-dimethylformamide (6 mL), and D1_4 (93 mg, 0.67 mmol), potassium carbonate (370 mg, 2.68 mmol) and sodium iodide (200 mg, 1.34 mmol) were added, and the reaction mixture was reacted at room temperature for 3 hours. LCMS monitoring showed that the raw material had reacted completely, and ethyl acetate and water were added for extraction. The organic phase was concentrated and separated and purified by silica gel column chromatography to obtain compound D1_5.

Step 5: Synthesis of D1_6

At room temperature, a solution of CuSO ₄ .5H ₂ O (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), and the reaction mixture was stirred at 20° C. for 1 h. LCMS detected that most of the raw materials were converted into products. Ethyl acetate (500 mL) was added for dilution, and the organic layer was washed with brine and sodium potassium tartrate aqueous solution, respectively. The organic phase was dried over Na ₂ SO ₄ , concentrated and further purified by column chromatography to obtain compound D1_6. LCMS (ESI) m/z: 1441.4 (M+H) ⁺ .

Step 6: Synthesis of D1_7

Cesium fluoride (368 mg, 2.43 mmol) was added to N,N-dimethylformamide (10 mL) of compound D1_6 (350 mg, 0.243 mmol), and the reaction mixture was stirred at 20°C for 2 hours. LCMS detected that most of the raw materials were converted into products. The residue was diluted with ethyl acetate (200 mL), and the organic phase was washed 3 times with saturated brine and then separated. The organic phase was dried over anhydrous sodium sulfate, concentrated, and then column chromatography Analysis was performed to obtain compound D1_7. LCMS (ESI) m/z: 1285.3 (M+H) ⁺ .

Step 7: Synthesis of Compound D001

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 detected that most of the raw materials were converted into products. The reaction was concentrated at low temperature, trifluoroacetic acid was removed, and the crude compound obtained after slurrying with ether was separated and purified by preparative chromatography to obtain compound D001.

¹ H NMR (400 MHz, DMSO) δ9.04 (d, J = 9.0 Hz, 1H), 8.97 (d, J = 4.0 Hz, 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＝11.6 Hz, 0.5H), 5.21–5.11 (m, 1H), 5.06– 4.65 (m, 4H), 4.46 (dd, J = 21.2, 10.0 Hz, 1H), 4.28 (t, J = 22.8 Hz, 3H), 3.87 (d, J = 9.6 Hz, 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, 11.0 Hz, 4H), 1.79 (s, 1H), 1.66–1.16 (m, 12H), 1.00 (t, J = 7.1 Hz, 3H) ,0.66–0.51(m,3H).LCMS(ESI)m/z:1141.5(M+H) ⁺ .

Example 25: Synthesis of D002

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) ⁺ .

Example 26: Synthesis of D003A and D003B

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.

D003A: ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.11–9.02 (m, 1H), 8.99 (s, 1H), 8.59 (d, J=1.5 Hz, 1H), 8.50 (dd, J=8.1, 4.7 Hz, 1H), 7.97 (dd, J = 9.1, 6.0 Hz, 1H), 7.72 (t, J = 8.1 Hz, 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, 2 H), 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＝6.3 Hz, 3H), 0.71 (dd, J＝6.4, 4.3 Hz, 3H). LCMS (ESI) m/z: 1161.3 (M+H) ⁺ .

D003B: ¹ H NMR (400 MHz, 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＝14.8,6.8Hz,3H),4.63–4.41(m,2H),4.35(d,J＝16.3Hz,2H),3.93(s,1H),3 .79 (dd, J = 10.5, 4.1 Hz, 1H), 3.72 (s, 1H), 3.67-3.59 (m, 5H), 3.01 (d, J = 14.2 Hz, 2H), 2.74 (t, J = 6.9 Hz, 2H), 2.58 (t, J = 7.3 Hz, 2H), 2.46 (s, 3H), 2.22 (s, 4H), 2.08 (dd, J = 12.3, 9.8 Hz, 1H), 1.83-1.76 (m, 1H), 1.69 (s, 4H), 1.08 (d, J = 6.4 Hz, 3H), 0.71 (t, J = 5.4 Hz, 3H). LCMS (ESI) m/z: 1161.3 (M+H) ⁺ .

Example 27: Synthesis of D004A and D004B

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.

D004A: ¹ H NMR (400 MHz, DMSO-d6) δ 10.18 (s, 1H), 9.04 (s, 1H), 8.99 (s, 1H), 8.49 (d, J = 7.8 Hz, 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, 3.8 Hz, 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) ⁺ .

D004B: ¹ H NMR (400 MHz, DMSO-d6) δ 8.97 (s, 2H), 8.03 (d, J = 12.7 Hz, 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, 2.0 Hz, 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) ⁺ .

Example 28: Synthesis of D005A and D005B

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.

D005A: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.17 (s, 1H), 9.14–8.94 (m, 2H), 8.57 (dd, J=21.4, 9.5 Hz, 2H), 7.98 (dd, J=9.3, 5.8 Hz, 1H), 7.71 (dd, J=20.1, 11.7 Hz, 2H), 7.42 (dt, J=16.1, 9.0 Hz, 6H), 7.26 (d, J=6.0 Hz, 2H), 7.20 (d, J = 8.2 Hz, 1H), 6.96 (d, J = 84.1 Hz, 1H), 5.35–5.16 (m, 2H), 4.91 (dd, J = 18.5, 6.9 Hz, 2H), 4.50 (d, J = 10.5 Hz, 1H), 4.41 (t, J = 8.3 Hz, 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=7.0 Hz, 2H), 1.30 (s, 1H), 1.24 (s, 3H), 1.08 (d, J=6.6 Hz, 3H), 0.85 (t, J=6.9 Hz, 1H), 0.76–0.66 (m, 3H). LCMS (ESI) m/z: 1145.6 (M+H) ⁺ .

D005B: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.18 (s, 1H), 9.06 (t, J＝5.7 Hz, 1H), 8.99 (d, J＝2.1 Hz, 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,4 H), 7.27 (m, 2.5H), 7.20 (dd, J = 10.3, 2.4 Hz, 1H), 7.09 (s, 0.5H), 5.33 (d, J = 10.3 Hz, 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),4.34(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, 14.3 Hz, 3H), 2.44 (m, 4H), 2.23 (d, J = 2.4 Hz, 4H), 2.03 (dd, J = 22.3, 10.1 Hz, 2 H), 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 = 7.0 Hz, 1H), 0.71 (t, J = 6.2 Hz, 3H), 0.71 (t, J = 6.2 Hz, 3H). LCMS (ESI) m/z: 1146.0 (M+H) ⁺ .

Example 29: Synthesis of D006

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.22 (s, 1H), 9.33 (s, 1H), 9.16 (s, 1H), 8.99 (s, 1H), 7.94 (d, J = 45.4 Hz, 2H), 7.49–7.42 (m, 4H), 7.22-6.96 (m, 1H), 5.25–4.99 (m, 3H), 4.61 (d, J = 62.3 Hz, 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) ⁺ .

Example 30: Synthesis of D007

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.

¹ H NMR (400 MHz, DMSO-d ₆ )δ10.16(s,1H),9.07–8.97(m,2H),8.50(s,1H),8.15(s,1H),7.98(d,J＝9.0 Hz, 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 = 6.5 Hz, 3H), 0.72 (d, J = 5.4 Hz, 3H). LCMS (ESI) m/z: 1175.2 (M+H) ⁺ .

Example 31: Synthesis of D008

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.

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

Example 32: Synthesis of D009A and D009B

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.

D009A: ¹ H NMR (400 MHz, DMSO-d ₆ )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＝7.0 Hz, 3H), 1.07 (d, J＝6.5 Hz, 3H), 0.74–0.66 (m, 3H). LCMS (ESI) m/z: 1159.6 (M+H) ⁺ .

D009B: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.16 (s, 1H), 9.02 (d, J = 2.8 Hz, 1H), 8.99 (s, 1H), 8.60 (s, 1H), 8.56–8.46 (m, 1H), 7.97 (dd, J = 9.1, 6.0 Hz, 1H), 7.72 (dd, J = 8.1, 3.1 Hz, 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=6.6 Hz, 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=7.0 Hz, 3H), 1.08 (d, J=6.4 Hz, 3H), 0.72 (d, J=4.4 Hz, 3H). LCMS (ESI) m/z: 1159.8 (M+H) ⁺ .

Example 33: Synthesis of D010A and D010B

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.

D010A: ¹ H NMR (400 MHz, DMSO-d ₆ )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),4.5 3–4.26 (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=11.7 Hz, 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=6.9 Hz, 4H), 1.11 (dd, J=25.2, 6.6 Hz, 8H), 0.70 (dd, J=11.0, 6.3 Hz, 4H). LCMS (ESI) m/z: 1175.5 (M+H) ⁺ .

D010B: ¹ H NMR (400 MHz, DMSO-d ₆ )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 = 4.2 Hz, 1H), 3.78 (s, 1H), 3.74-3.665 (m, 5H), 3.12 (s, 2H), 2.96 (s, 1H), 2.44 (d, J = 11.7 Hz, 6H), 2.15 (d, J = 6.1 Hz, 3H), 2.06 (s, 1H), 1.79 (s, 1H), 1.68 (s, 4H), 1.51 (s, 1H), 1.38 (d, J = 7.0 Hz, 3H), 1.11 (dd, J = 26.9, 6.2 Hz, 7H), 0.69 (t, J = 11.3 Hz, 4H). LCMS (ESI) m/z: 1175.5 (M+H) ⁺ .

Example 34: Synthesis of D011A and D011B

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.

D011A: ¹ H NMR (400 MHz, DMSO-d ₆ )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 = 11.1 Hz, 1H), 3.61 (d, J = 10.0 Hz, 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 = 6.7 Hz, 2H), 1.24 (s, 1H), 1.07 (d, J = 5.6 Hz, 3H), 0.69 (s, 3H). LCMS (ESI) m/z: 1163.5 (M+H) ⁺ .

D011B: ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.15(s,1H),9.02(d,J＝12Hz,1H),8.98(s,1H),8.63–8.47(s,1H),8.31 (d, J = 12 Hz, 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, 0.5 H), 5.38 (d, J = 10.4 Hz, 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 = 8.0 Hz, 3H) ,1.07(d,J＝5.6Hz,3H),0.69(s,3H).LCMS(ESI)m/z:1163.3(M+H) ⁺ .

Example 35: Synthesis of D012A and D012B

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.

D012A: ¹ H NMR (400 MHz, DMSO-d ₆ )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 = 10.2 Hz, 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 = 6.5 Hz, 3H), 0.74–0.66 (m, 3H). LCMS (ESI) m/z: 1146.0 (M+H) ⁺ .

D012B: ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.16(s,1H),9.05(s,1H),8.98(s,1H),8.56–8.43(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 = 10.2 Hz, 1H), 5.22-512 (m, 1H), 4.98-4.87 (m, 1H), 4.73 (d, J = 13.8 Hz, 2H), 4.47-4.28 ( 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＝11.1 Hz, 4H), 2.22 (d, J = 3.0 Hz, 3H), 2.05 (s, 1H), 1.77 (d, J = 12.6 Hz, 1H), 1.67–1.47 (m, 5H), 1.38 (d, J =7.0 Hz, 3H), 1.07 (d, J=6.6 Hz, 3H), 0.70 (dd, J=10.3, 6.6 Hz, 3H). LCMS (ESI) m/z: 1146.0 (M+H) ⁺ .

Example 36: Synthesis of D013A and C013B

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.

D013A: ¹ H NMR (400 MHz, DMSO-d6) δ 10.14 (s, 1H), 9.03 (d, J = 4.3 Hz, 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 = 12.8 Hz, 1H), 4.42–4.28 (m, 5H), 3.92 (s, 1H), 3.85 (d, J = 7.1 Hz, 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) ⁺ .

D013B: ¹ H NMR (400 MHz, DMSO-d6) δ 10.15 (s, 1H), 9.03 (d, J = 5.5 Hz, 1H), 8.99 (s, 1H), 8.76 (d, J = 0.7 Hz, 1H ),8.60(t,J＝6.0Hz,1H),7.97(dd,J＝9.2,6.0Hz,1H),7.91(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, 2.2 Hz, 1H), 7.08 (s, 0.5H), 5.36 (d, J＝10.1 Hz,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) ⁺ .

Example 37: Synthesis of D014A and D014B

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.

D014A: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.15 (s, 1H), 9.05 (s, 1H), 8.98 (s, 1H), 8.51 (d, J = 7.1 Hz, 1H), 8.31 (s, 1H), 7.97 (dd, J = 9.2, 6.0 Hz, 1H), 7.44 (d, J = 9.5 Hz, 2H), 7.39–7.36 (m, 2H), 7.20 (dd, J = 9. =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) ⁺ .

D014B: ¹ H NMR (400 MHz, DMSO-d ₆ )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, 6.0 Hz, 1H), 7.44 (d, J = 8.4 Hz, 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 = 10.1 Hz, 1H), 5.14 (s, 3H), 4.97–4.83 (m, 3H), 4.44-4.31 (m, 4H), 3.89 (d, J＝1.7 Hz, 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＝6.5 Hz, 3H), 0.65 (d, J＝6.6 Hz, 3H). LCMS (ESI) m/z: 1179.4 (M+H) ⁺ .

Example 38: Synthesis of D015

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

D015: ¹ H NMR (400 MHz, DMSO-d ₆ )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, 5.9 Hz, 1H), 7.88 (s, 1H), 7.49–7.43 (m, 2H), 7.40 (d, J = 8.7 Hz, 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 = 12.2 Hz, 1H), 4.40–4.22 (m, 5H), 3.92 (s, 3H), 3.81 (d, J = 6.4 Hz, 1H), 3.64 (d, J = 6.8 Hz, 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＝ 4.9 Hz, 1H), 1.63 (s, 4H), 1.00 (d, J = 6.6 Hz, 3H), 0.61 (d, J = 5.0 Hz, 3H). LCMS (ESI) m/z: 1131.7 (M+H ) ⁺ .

Example 39: Synthesis of D016A and D016B

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.

D016A: MS (ESI) m/z: 1179.4 (M+H) ⁺ .

D016B: MS (ESI) m/z: 1179.4 (M+H) ⁺ .

Example 40: Synthesis of D017A and D017B

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.

D017A: ¹ H NMR (400 MHz, DMSO-d ₆ )δ9.06(s,1H),8.98(s,1H),8.60(d,J＝3.6Hz,1H),8.55(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＝69.4Hz,1H),4.92(dd,J＝19.2,6.6Hz,3H),4.50(d,J＝12.0Hz,1H),4.42(t,J＝8.1Hz,1H),4. 34 (s, 2H), 3.91 (s, 1H), 3.79 (d, J = 7.7 Hz, 1H), 3.67 (d, J = 23.6 Hz, 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 = 2.8 Hz, 3H), 1.78 (d, J = 13.4 Hz, 1H), 1.66 (s, 4H), 1.39 (d, J = 6.7 Hz, 3H), 1.24 (s, 6H), 1.08 (d, J = 5.9 Hz, 3H), 0.71 (s, 3H). LCMS (ESI) m/z: 1173.4 (M+H) ⁺ .

D017B: ¹ H NMR (400 MHz, DMSO-d ₆ )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 = 13.9 Hz, 2H), 3.90 (s, 1H), 3.79 (d, J = 6.9 Hz, 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 = 8.9 Hz, 1H), 1.91 (d, J = 2.2 Hz, 3H), 1.79 (t, J = 12.8 Hz, 1H), 1.66 (s, 4H), 1.38 (d, J = 7.0 Hz, 3H), 1.25 (s, 6H), 1.08 (d, J = 6.4 Hz, 3H), 0.75–0.66 (m, 3H). LCMS (ESI) m/z: 1173.4 (M+H) ⁺ .

Example 41: Synthesis of D018A and D018B

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.

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

D018B: ¹ H NMR (400 MHz, DMSO-d6) δ 10.18 (s, 1H), 9.03 (d, J = 5.7 Hz, 1H), 8.77 (d, J = 3.3 Hz, 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 = 9.0 Hz, 1H), 7.08 (s, 0.5H), 6.32 (d, J = 1.4 Hz, 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 = 13.0 Hz, 2H), 4.11 (q, J = 7.1 Hz, 2H), 3.91 (s, 1H), 3.79 (d, J = 7.4 Hz, 1H), 3.72 ( d, J = 10.5 Hz, 1H), 3.61 (d, J = 12.0 Hz, 1H), 3.53 (d, J = 16.8 Hz, 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 = 7.0 Hz, 3H), 1.30 (t, J = 7.2 Hz, 3H), 1.08 (d, J = 6.3 Hz, 3H), 0.72 (t, J = 6.2 Hz, 3H). LCMS for (ESI )m/z:1177.0(M+H) ⁺ .

Example 42: Synthesis of D019A and D019B

In addition to replacing intermediate B with 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.

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

D019A: ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.46–9.94 (m, 1H), 9.05 (s, 1H), 8.98 (s, 1H), 8.59 (d, J＝2.9 Hz, 1H), 8.50 (s, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.69 (s, 2H), 7.45-7.35 (m, 6H), 7.28 (s, 0.5H), 7.15 (d, J = 4.0 Hz, 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 = 49.1 Hz, 7H), 1.38 (d, J = 6.8 Hz, 3H), 1.08 (d, J = 6.3 Hz, 3H), 0.71 (d, J = 6.4 Hz, 3H). LCMS (ESI) m/z: 1151.4 (M+H) ⁺ .

D019B: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.46–9.94 (m, 1H), 9.02 (d, J = 24.3 Hz, 2H), 8.59 (d, J = 2.9 Hz, 1H), 8.50 (s, 1H), 7.83 (d, J = 7.6 Hz, 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 = 10.5 Hz, 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＝7.0 Hz, 3H), 1.08 (d, J＝6.4 Hz, 3H), 0.71 (d, J＝6.4 Hz, 3H). LCMS (ESI) m/z: 1151.4 (M+H) ⁺ .

Example 43: Synthesis of D020

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.

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

D020: ¹ HNMR (400 MHz, DMSO-d ₆ )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, 3H), 7.45 (d, J = 8.3 Hz, 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 = 7.0 Hz, 3H), 1.24 (s, 5H), 1.08 (d, J = 6.4 Hz, 3H), 0.85 (d, J = 6.9 Hz, 1H), 0.69 (dd, J = 11.7 ,4.9Hz,6H).LCMS(ESI)m/z:1163.4(M+H) ⁺ .

Example 44: Synthesis of D021

Step 1: Synthesis of D21_3

At room temperature, compound D21_1 (400 mg, 1.43 mmol), D21_2 (342 mg, 1.72 mmol), potassium carbonate (108 mg, 2.86 mmol) were dissolved in DMF (8 ml), and the temperature was raised to 60 degrees and stirred for 2 hours. The reaction was monitored by TLC plate. 20 ml of water was added to the reaction solution to quench and dilute, and ethyl acetate was extracted. The combined organic phase was 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.

Step 2: Synthesis of D21_4

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 a crude compound D21_4, which was used directly in the next step without purification.

Step 3: D21_5

At 25°C, 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) and stirred at room temperature for 16 hours under nitrogen protection. The reaction was monitored by TLC plate. 20 ml of water was added to the reaction solution to quench and dilute, and ethyl acetate was extracted. The combined organic phase was 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_5.

Step 4: Synthesis of D21_6

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. After the addition, stirring was continued at room temperature for 1 hour. The reaction was monitored by TLC plate. 20 ml of water was added to the reaction solution to quench and dilute, and ethyl acetate was extracted (3x10 ml), backwashed with saturated sodium chloride solution, and the combined organic phase was 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.

Step 5: Synthesis of D21_7

Compound D21_6 (100 mg, 0.32 mmol) and intermediate B (218 mg, 0.27 mmol) were dissolved in THF (5 ml), nitrogen was protected, the temperature was lowered to -10 degrees, and LiHMDS (0.54 ml, 1.0 M THF, 0.54 mmol) was slowly added dropwise, and stirring was continued for 1 hour after the addition. TLC monitored the completion of the reaction. The reaction solution was poured into ice water for quenching, extracted with ethyl acetate (3x10 ml), backwashed with saturated sodium chloride solution, and the combined organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a residue, which was purified by preparative plate to obtain compound D21_7.

Step 6: Synthesis of D21_8

Compound D21_7 (70 mg, 0.06 mmol) was dissolved in MeOH (3 ml) and water (0.6 ml), LiOH (25 mg, 0.6 mmol) was added, and stirring was continued at room temperature for 16 hours. LCMS monitored the reaction to be complete. The reaction solution was concentrated in vacuo, and after the methanol was spin-dried, 5 ml of water was added for dilution, and the pH was adjusted to 6, and ethyl acetate was extracted (3x5 ml), backwashed with saturated sodium chloride solution, and the combined organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a residue, which was purified by preparative plate to obtain compound D21_8.

Step 7: Synthesis of D21_10

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 completion of the reaction. 5 ml of water was added to the reaction solution to dilute it, and a solid product was precipitated. The product was filtered out with filter paper, dissolved in ethyl acetate, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain pure compound D21_10.

Step 8: Synthesis of D21_11

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. After addition, stirring was continued at room temperature for 1 hour. LCMS monitored the reaction to be complete. 10 ml of water was added to the reaction solution to quench and dilute, and the mixture was extracted with ethyl acetate (3x5 ml), backwashed with saturated sodium chloride solution, and the combined organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a residue, which was purified by preparative plate to obtain compound D21_11.

Step 9: Synthesis of D021A and D021B

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.

D021A: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.05 (d, J = 3.0 Hz, 1H), 8.99 (s, 1H), 8.53 (t, J = 6.0 Hz, 1H), 8.23 (s, 1H), 7.97 (dd, J = 9.2, 5.9 Hz, 1H), 7.51–7.32 (m, 4H), 7.27 (s, 0.5H), 7.18 (d, J = 2.5 Hz, 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 = 9.8 Hz, 2H), 3.62–3.58 (m, 4H), 3.55–3.14 (m, 5H), 3.09 (d, J = 9.3 Hz, 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, 3.7 Hz, 3H). MS (ESI) m/z: 1197.8 (M+H) ⁺ .

D021B: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.05 (d, J = 3.0 Hz, 1H), 8.96 (s, 1H), 8.47 (t, J = 6.0 Hz, 1H), 8.23 (s, 1H), 7.97 (dd, J = 9.2, 5.9 Hz, 1H), 7.51–7.32 (m, 4H), 7.18 (d, J = 2.5 Hz, 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 = 9.8 Hz, 2H), 3.58–3.54 (m, 4H), 3.47–3.25 (m, 5H), 3.09 (d, J = 9.3 Hz, 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, 3.7 Hz, 3H). MS (ESI) m/z: 1197.8 (M+H) ⁺ .

Example 45: Synthesis of D022

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) ⁺ .

Example 46: Synthesis of D023

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

Example 47: Synthesis of D024

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) ⁺ .

Example 48: Synthesis of D025

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

Example 49: Synthesis of E001

Step 1: Preparation of E1_2

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

Step 2: Preparation of E1_3

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 by LCMS. The reaction solution was diluted with ethyl acetate (60 mL) and extracted with water (100 mL), and 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 the product E1_3.

Step 3: Preparation of E1_4

E1_3 (780 mg, 1.612 mmol) was added with 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 by LCMS. The reaction solution was diluted with ethyl acetate (30 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 obtained residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain the product E1_4.

Step 4: Preparation of E1_5

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 to complete. The reaction solution was diluted with ethyl acetate (60 mL) and extracted with water (100 mL), and 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.

Step 5: Preparation of E1_6

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 repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The obtained residue was purified by silica gel column chromatography (dichloromethane: methanol = 15: 1) to obtain product E1_6.

Step 6: Preparation of E1_7

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 by LCMS to completion. The reaction solution was diluted with ethyl acetate (50 mL) and extracted with water (90 mL), and 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 the product E1_7.

Step 7: Preparation of E1_8

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 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] ⁺ .

Step 8: Preparation of E001

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 to completion. 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.

¹ H NMR (400 MHz, 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] ⁺ .

Example 50: Synthesis of E002

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

¹ H NMR (400 MHz, DMSO-d6) δ 10.14 (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] ⁺ .

Example 51: Synthesis of E003

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

¹ H NMR (400 MHz, DMSO-d6) δ 10.22 (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＝4.8Hz,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,2H),4.02(s,2H),3.92 (d, J = 4.8 Hz, 2H), 3.87 (s, 2H), 3.62 (s, 4H), 2.79 (s, 2H), 2.74 (s, 1H), 2.45 (s, 3H), 2.08 (d, J＝7.6Hz,1H),1.96(s,4H),1.71(s,2H),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] ⁺ .

Example 52: Synthesis of E004

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

¹ H NMR (400 MHz, DMSO-d6) δ 10.21 (s, 1H), 9.37–9.25 (m, 1H), 9.16 (s, 2H), 8.99 (s, 2H), 8.50 (s, 1H), 8.00 (s, 1H), 7.64–7.60 (m, 1H), 7.49 (d, J＝8.8Hz, 1H), 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,3H),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] ⁺ .

Example 53: Synthesis of E005A and E005B

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.

E005A: ¹ H NMR (400 MHz, DMSO-d ₆ )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 = 9.2 Hz, 2H), 1.22 (d, J = 9.6 Hz, 4H), 1.15–1.03 (m, 3H), 0.95 (s, 10H). MS m/z (ESI):1201.6[M+H] ⁺ .

E005B: ¹ H NMR (400 MHz, DMSO-d ₆ )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＝10.6 Hz, 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] ⁺ .

Example 54: Synthesis of E006A and E006B

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.

E006A: MS m/z (ESI): 1173.2 [M+H] ⁺ .

E006B: MS m/z (ESI): 1173.6 [M+H] ⁺ .

Example 55: Synthesis of E007

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] ⁺ .

Example 56: Synthesis of E008A and E008B

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.

E008A: ¹ H NMR (400 MHz, DMSO-d6) δ 10.70 (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 = 10.1 Hz, 1H), 7.65 (s, 1H), 7.64–7.61 (m, 1H), 7.42 (d, J = 7.2 Hz, 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 = 8.4 Hz, 1H), 4.51 (d, J = 8.0 Hz, 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] ⁺ .

E008B: ¹ H NMR (400 MHz, MeOD) δ 9.01 (d, J = 2.7 Hz, 1H), 8.81 (d, J = 5.2 Hz, 1H), 7.82 (dd, J = 8.9, 5.9 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.33 (s, 5H), 7.30 (s, 0.5H), 7.26 (d, J = 9.2 Hz, 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 = 5.2 Hz, 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] ⁺ .

Example 57: Synthesis of E009A and E009B

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

E009A: ¹ H NMR (400 MHz, DMSO-d ₆ )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 = 8.6 Hz, 2H), 4.49 (s, 3H), 4.32 (s, 2H), 4.28 (s, 2H), 3.87 (s, 2H),3.7 7(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) ⁺ .

E009B: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.11 (s, 1H), 9.03 (s, 1H), 8.96 (s, 1H), 8.46 (d, J＝7.1 Hz, 1H), 7.96 ( d, J = 6.2 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.44 (t, J = 8.9 Hz, 1H), 7.37 (d, J = 2.3 Hz, 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 = 6.6 Hz, 2H), 4.47 (d, J = 12.9 Hz, 1H), 4.33 (s, 2H), 3.88 (d, J = 6.9 Hz, 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, 1H), 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 = 3.2 Hz, 2H), 1.04 (s, 2H), 0.87 (s, 9H), 0.85-0.77 (m, 2H). LCMS (ESI) m/z: 1215.6 (M+H) ⁺ .

Example 58: Synthesis of E010A and E010B

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

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

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

Example 59: Synthesis of E011A and E011B

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

E011A: MS (ESI) m/z: 1175.6 (M+H) ⁺ .

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

Example 60: Synthesis of E012A and E012B

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

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

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

Example 61: Synthesis of E013A and E013B

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

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

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

Example 62: Synthesis of E014A and E014B

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

E014A: MS (ESI) m/z: 1227.4 (M+H) ⁺ .

E014B: MS (ESI) m/z: 1227.3 (M+H) ⁺ .

Example 63: Synthesis of E015A and E015B

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

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

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

Example 64: Synthesis of E016A and E016B)

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.

E016A: MS (ESI) m/z: 1229.3 (M+H) ⁺ .

E016B: MS (ESI) m/z: 1229.6 (M+H) ⁺ .

Example 65: Synthesis of E017A and E017B

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.

E017A, MS (ESI) m/z: 1213.5 (M+H) ⁺ .

E017B, MS (ESI) m/z: 1213.4 (M+H) ⁺ .

Example 66: Synthesis of E018

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) ⁺ .

Example 67: Synthesis of E019A and E019B

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.

E019A: ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.17 (s, 1H), 9.05 (s, 1H), 8.95 (s, 1H), 8.41 (d, J＝7.7 Hz, 1H), 7.99– 7.93 (m, 1H), 7.44 (td, J = 9.0, 2.3 Hz, 1H), 7.38 (d, J = 2.1 Hz, 2H), 7.33–7.29 (m, 3H), 7.24 (d, J = 6.5 Hz ,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) ⁺ .

E019B: ¹ H NMR (400 MHz, DMSO-d ₆ )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 = 7.8 Hz, 1H), 7.47–7.41 (m, 1H), 7.38 (d, J = 2.3 Hz, 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＝7.9Hz,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, 2.6 Hz, 3H), 1.24-1.19 (m, 2H), 0.88 (s, 9H). LCMS (ESI) m/z: 1209.1 (M+H) ⁺ .

Example 68: Synthesis of E020

In addition to replacing intermediate I with intermediate E20_1, According to the method described in Example 56, compound E020 was obtained. MS (ESI) m/z: 1224.3 (M+H) ⁺ .

Example 69: Synthesis of E021

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) ⁺ .

Example 700: Synthesis of E022

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) ⁺ .

Example 71: Synthesis of F001

Step 1: Synthesize F1_2

At room temperature, F1_1 (6 g, 14.2 mmol) was dissolved in ultra-dry 1,4-dioxane (60 mL), and N,N-diisopropylethylamine (5.5 g, 42.6 mmol) was added, and the temperature was lowered to 0°C and stirred for 10 minutes, and (1R, 5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (3.1 g, 15.6 mmol) was slowly added. The mixture was reacted at room temperature for 1 hour. LCMS showed that most of the raw materials were converted to products. The reaction mixture was concentrated in vacuo and a mixed solution of petroleum ether: ethyl acetate (10:1) was added, and stirred at room temperature until the oil was completely converted into yellow powder. The mixture was filtered through a Buchner funnel to obtain compound F1_2.

Step 2: Synthesize F1_4

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), and 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 and reacted at room temperature for 16 hours. LCMS showed that most of the raw materials were converted into products. 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 obtain F1_4.

Step 3: Synthesize F1_5

F1_4 (3 g, 4.71 mmol) and cyclopropane boronic 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 above system, and finally [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (1.01 g, 0.94 mmol) was added, and the reaction mixture was reacted at 90 ° C for 3 hours. LCMS showed that most of the raw materials were converted to products. The reaction mixture was diluted with ethyl acetate and washed with brine, and the organic phase was concentrated and then purified by column chromatography to obtain F1_5.

Step 4: Synthesize F1_7

F1_6 (1.8 g, 37.59 mmol) was dissolved in anhydrous tetrahydrofuran (60 mL) and then 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. Then F1_5 (1.5 g, 2.70 mmol) was slowly added. The reaction mixture was reacted at 0°C for 3 hours. LCMS showed that most of the raw materials were converted into products. The reaction mixture was quenched with ammonium chloride, diluted with ethyl acetate, washed with brine, and then the organic phase was separated, dried, concentrated, and then column chromatographed to obtain F1_7.

Step 6: Synthesize F1_9

F1_7 (260 mg, 0.361 mmol) and F1_8 (255.7 mg, 0.541 mmol) were added to tert-butyl alcohol (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 dropped into the above reaction solution. The reaction mixture was reacted at room temperature for 2 hours. LCMS detected that the product was mainly. 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) ⁺ .

Step 7: Synthesize F1_11

F1_9 (150 mg, 0.126 mmol) was added to 1,4-dioxane (16 mL) and water (4 mL), and 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) were added to the reaction solution. The reaction mixture was reacted at 50°C under nitrogen protection 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) ^+.

Step 8: Synthesize F001

Compound F1_11 (70 mg, 0.052 mmol) was dissolved in anhydrous dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added under ice bath. The reaction solution was reacted at room temperature for 2 hours. The reaction was concentrated at low temperature to remove trifluoroacetic acid, and the remaining oil was added dropwise to ammonia methanol solution under ice bath. The crude compound obtained by spin drying was purified by preparative HPLC to obtain F001.

¹ H NMR (400 MHz, DMSO-d ₆ )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,2H),1.71(s,4H),1.35(d,J＝5.3Hz,1H),1.07(d,J＝6.4Hz,4H),0.71(d,J＝6.4Hz,3H),0.66(s,1H),0.62(s,2H),0.55(t,J＝8.7Hz,1H).LCMS(ESI)m/z:1162.7(M+H) ⁺ .

Example 72: Synthesis of G001A and G001B

Step 1: Synthesize G1_2

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

Step 2: Synthesize G1_3

Add G1_2 (20 mg, 1.0 eq) and THF (2 ml) to a 100 ml single-mouth bottle, add a LiOH aqueous solution (100 mg + 1 ml water) dropwise at room temperature, react at 30°C for 24 h, LCMS shows that the raw material disappears, and the main peak is the product. Add water to dilute, adjust the pH to 2-3 with dilute hydrochloric acid, extract with EA, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness to obtain G1_3, which is directly used for the next step of reaction. LCMS: [M+1] ⁺ = 825.4.

Step 3: Synthesis of G1_4

G1_3 (30 mg, 1.0 eq) and DCM (2 ml), DMAP (2.0 mg, 1.0 eq), DIPEA (14 mg, 3.0 eq) and TosCl (10 mg, 2.0 eq) were added to an 8 ml vial and reacted at room temperature for 24 h. The starting material was basically disappeared by TLC monitoring, and the reaction was stopped. G1_4 was obtained by separation using a preparative plate, LCMS: [M+1] ⁺ = 979.4.

Step 4: Synthesis of G1_6

Add G1_4 (15 mg, 1.0 eq) and G1_5 (16 mg, 2.0 eq) to an 8 ml vial, dissolve in 1 ml of DMF, add cesium carbonate (15 mg, 3 eq), and react at 55°C for 1 h. LCMS shows that the main peak is the product. Add water and EA, separate the liquids, concentrate the organic layer to dryness, and separate G1_6 using a preparative plate. LCMS: [M+1] ⁺ = 1341.5.

Step 5: Synthesis of G001:

G1_6 (13 mg, 1.0 eq) and DCM (3 ml) were added to a 50 ml single-mouth bottle, and TFA (1 ml) was added at room temperature, and the mixture was reacted at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated to dryness, and DCM and ammonia methanol solution were added to dissolve the mixture, and the mixture was separated and purified using a preparative TLC plate to obtain G001A and G001B.

G001A: ¹ H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 9.06 (d, J = 2.5 Hz, 1H), 8.97 (s, 1H), 8.63 (t, 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) ⁺ .

G001B: ¹ H NMR (400 MHz, DMSO-d6) δ 10.16 (s, 1H), 9.06 (d, J = 1.8 Hz, 1H), 8.97 (s, 1H), 8.62 (t, J = 5.9 Hz, 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,1H),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＝5.6 Hz, 4H), 1.27–1.19 (m, 4H). LCMS (ESI) m/z: 1197.5 (M+H) ⁺ .

Example 73: Synthesis of G002A and G002B

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

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

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

Example 74: Synthesis of H001A and H001B

Step 1: Prepare H1_2

At room temperature, D1_3 (600 mg, 0.67 mmol) was dissolved in N,N-dimethylformamide (6 mL), H1_1 (78 mg, 0.67 mmol), potassium carbonate (370 mg, 2.68 mmol) and sodium iodide (200 mg, 1.34 mmol) were added, and the reaction mixture was reacted at room temperature for 3 hours. LCMS monitoring showed that the raw material had reacted completely, ethyl acetate and water were added for extraction, and the organic phase was concentrated and separated and purified by silica gel column chromatography to obtain compound H1_2.

Step 2: Preparation of H1_3

At room temperature, a solution of lithium hydroxide (27 mg, 1.184 mmol) in water (1 mL) was added to H1_2 (140 mg, 0.148 mmol) in tetrahydrofuran (4 mL). After the reaction mixture was reacted at room temperature for 2 hours, most of the raw materials were converted into products. The reaction mixture was concentrated and column chromatography was performed to obtain compound H1_3.

Step 3: Preparation of H1_4

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). After the reaction mixture was reacted at room temperature for 3 hours, it was detected that most of the raw materials had been converted into products. The residue was diluted with ethyl acetate (200 mL), and the organic phase was washed with saturated brine three times and then separated; after the organic phase was concentrated, it was purified by thin layer chromatography to obtain compound H1_4. LCMS (ESI) m/z: 1460.2 (M+H) ⁺ .

Step 4: Preparation of H1_5

Cesium fluoride (104 mg, 0.68 mmol) was added to H1_4 (100 mg, 0.068 mmol) in N,N-dimethylformamide (4 mL), and the reaction mixture was stirred at 20°C for 2 hours. LCMS detected that most of the raw materials were converted into products. The residue was diluted with ethyl acetate (200 mL), and the organic phase was washed with saturated brine three times and then separated; the organic phase was dried and concentrated over anhydrous sodium sulfate, and purified by thin layer chromatography to obtain compound H1_5.

Step 5: Preparation of compound H001

Trifluoroacetic acid (3 mL) was added to a solution of compound H1_5 (70 mg, 0.054 mmol) in dichloromethane (9 mL), and the reaction mixture was stirred at 20°C for 1 hour. LCMS detected that most of the raw materials were converted into products. The reaction was concentrated at low temperature to remove the solvent and trifluoroacetic acid, and the obtained crude compound was purified by preparative chromatography to obtain H001.

H001A: ¹ H NMR (400 MHz, DMSO-d6)) δ 10.17 (s, 1H), 9.02 (d, J = 4.9 Hz, 1H), 8.96 (s, 1H), 8.52 (dd, J = 8.0, 4.5 Hz, 1H), 7.97 (dd, J = 9.2, 6.0 Hz, 1H), 7.83 (dd, J = 11.4, 6.6 Hz, 1H), 7.49–7.44 (m, 1H), 7.44–7.37 (m, 4H), 7.34 (dd, J＝8.4, 1.9 Hz, 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, 9.3 Hz, 2H), 4.28 (s, 2H), 3.92 (d, J = 1.9 Hz, 1H), 3.61 (dd, J = 11.1, 7.8 Hz, 3H), 3.53 (d, J = 17.1 Hz, 4H), 3.46-3.41 (m, 1H), 3.07 (s, 2H), 2.43 (d, J = 1.9 Hz, 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, 2.7 Hz, 2H), 0.96 (s, 9H). LCMS for (ESI) m/z: 1160.2 (M+ H) ⁺ .

H001B: ¹ H NMR (400 MHz, DMSO-d6)) δ 10.17 (s, 1H), 9.02 (d, J = 4.7 Hz, 1H), 8.97 (s, 1H), 8.54 (s, 1H), 8.05– 7.93(m,1H),7.85(s,1H),7.50–7.31(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 = 8.3 Hz, 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) ⁺ .

The compounds and applications of the present invention are described in detail above.

The principles and implementation methods of the present invention are described in this article using specific embodiments. The description of the above embodiments is only used to help understand the method and its central idea of the present invention. It should be pointed out that for ordinary technicians in this field, several improvements and modifications can be made to the present invention without departing from the principles of the present invention, and these improvements and modifications also fall within the protection of the claims of the present invention.

Claims

The 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 is independently hydrogen, deuterium, halogen, hydroxy, amino, -CN, -C 1-8 alkyl, -OC 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -CONR 100a R 100b , cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein 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, hydroxy, -C 1-8 alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl;

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

m is an integer from 0 to 3;

L 1 , L 2 and L 3 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) 2 NR 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 -;

n is an integer from 1 to 10;

R 1 is selected from hydrogen, halogen, amino, hydroxyl, -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, -NO 2 , -OR 1a , -SO 2 R 1a , -COR 1a , -CO 2 R 1a , -CONR 1a R 1b , -CH 2 C(═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 CO 2 R 1b , -NR 1a SONR 1b R 1c , -NR 1a SO 2 NR 1b R 1c , or -NR 1a SO 2 R 1b , wherein 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 is each optionally substituted with hydrogen, deuterium, halogen, hydroxy, -C 1-8 alkoxy, -NR 1d R 1e , cycloalkyl, heterocyclyl, aryl or heteroaryl;

Each of R 1a , R 1b , and R 1c is independently hydrogen, deuterium, halogen, cyano, amino, hydroxy, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and the -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R 1d ; 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 being optionally substituted with at least one substituent R 1e ;

wherein R 1d and R 1e are each independently hydrogen, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl , cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2 , -OR 1f , -SO 2 R 1f , -COR 1f , -CO 2 R 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 CO 2 R 1g , -NR 1f SONR 1g R 1h , -NR 1f SO 2 NR 1g R 1h , or -NR 1f SO 2 R 1g ; the -C each of -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with at least one substituent selected from halogen, -C 1-8 alkyl, -OR 1i , -NR 1i R 1j , cycloalkyl, heterocyclyl, aryl, or heteroaryl;

R 1f , R 1g , R 1h , R 1i and R 1j are each 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 with one or more R 2a ;

each R 2a is 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, -NO 2 , -OR 2b , -SO 2 R 2b , -COR 2b , -CO 2 R 2b , -CONR 2b R 2c , -CH 2 C(═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 CO 2 R 2c , -NR 2b SONR 2c R 2d , -NR 2b SO 2 NR 2c R 2d , or -NR 2b SO 2 R 2c , wherein 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 is each optionally substituted with deuterium, halogen, cyano, hydroxy, -NR 2e R 2f , amino, -C 1-8 alkyl, -C 1-8 alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl;

Each of R 2b , R 2c , R 2d , R 2e , and R 2f is independently hydrogen, deuterium, halogen, or C 1-8 alkyl;

R3 and R4 are each independently hydrogen, halogen, hydroxy, amino, -C1-8 alkyl, -OC1-8 alkyl, -C2-8 alkenyl, -C2-8 alkynyl, cycloalkyl, heterocyclyl , aryl , heteroaryl , oxo , -CN, -NO2 , -OR4a , -SO2R4a , -SO2NR4aR4b , -COR4a , -CO2R4a , -CONR4aR4b, -C ( ＝ NR4a ) NR4bR4c , -NR4aR4b , -NR4aCOR4b , -NR4aCONR4bR4c , -NR4aCO2R4b , -NR4aSONR4bR4c , -NR4aSO2NR4bR 4c , or -NR 4a SO 2 R 4b , wherein the -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R 4d ;

R 4a , R 4b , and R 4c are each independently hydrogen, hydroxy, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and the -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R 4e ; 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 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, which ring is optionally substituted with at least one substituent R 4e ; or

R 4d and R 4e are each independently hydrogen, deuterium, halogen, hydroxyl, amino, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2 , -OR 4f , -SO 2 R 4f , -SO 2 NR 4f R 4g , -COR 4f , -CO 2 R 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 CO 2 R 4f , -NR 4f SONR 4f R 4g , -NR 4f SO 2 NR 4g R 4h , or -NR 4f SO 2 R 4g , wherein the -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent selected from halogen, -C 1-8 alkyl, -OR 4i , -NR 4i R 4j , cycloalkyl, heterocyclyl, aryl, or heteroaryl;

R 4f , R 4g , R 4h , R 4i , and R 4j are each 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 , and R 8 are independently hydrogen, deuterium, halogen, hydroxy, amino, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2 , -OR 5a , -SO 2 R 5a , -SO 2 NR 5a R 5b , -COR 5a , -CO 2 R 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 CO 2 R 5b , -NR 5a SONR 5b R 5c , -NR 5a SO NR 5b R 5c , or -NR 5a SO 2 R 5b , wherein the -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group is each optionally substituted with at least one substituent R 5d ;

R 5a , R 5b , and R 5c are each independently hydrogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl , cycloalkyl , heterocyclyl, aryl, or heteroaryl, and the -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent R 5e ;

R 5d and R 5e are each independently hydrogen, hydroxy, amino , halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2 , -OR 5f , -SO 2 R 5f , -SO 2 NR 5f R 5g , -COR 5f , -CO 2 R 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 CO 2 R 5f , -NR 5f SONR 5f R 5g , -NR 5f SO 2 NR 5g R 5h , or -NR 5f SO 2 R 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 substituent 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;

R 5f , R 5g , R 5h , R 5i , and R 5j are each 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, -NO 2 , -OR 9 , -SR 9 , -SO 2 R 9 , -COR 9 , -CO 2 R 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 CO 2 R 10 , -NR 9 SONR 10 R 11 , -NR 9 SO 2 NR 10 R 11 , or -NR 9 SO 2 R 10 , wherein the -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl , cycloalkyl , heterocyclyl, aryl, heteroaryl, oxo, -CN , -NO 2 , -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with hydrogen, deuterium, oxo, halogen, cyano, hydroxy, 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;

R 9 , R 10 , and R 11 are each independently hydrogen, -C 1-8 alkyl, -OC 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and 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 at least one substituent R 9a ; 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, as one or more ring members, 1 , 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur, which ring is optionally substituted with at least one substituent R 9b ;

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 being optionally substituted with at least one substituent R 9b ;

wherein R 9a and R 9b are each independently hydrogen, deuterium, halogen, hydroxy, 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, -NO 2 , -OR 9c , -SO 2 R 9c , -C 1-8 alkyl-OR 9c , -COR 9c , -CO 2 R 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 CO 2 R 9d , -NR 9c SONR 9d R 9e , -NR 9c SO 2 NR 9d R 9e , or -NR 9c SO 2 R 9d , said -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 selected from halogen, -C 1-8 alkyl, -OR 9f , -NR 9f R 9g , cycloalkyl, heterocyclyl, aryl, or heteroaryl;

R 9c , R 9d , R 9e , R 9f and R 9g are each 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, at least one of R 3 and R 4 is F, Cl, -NO 2 or -CN.
The compound according to claim 1, wherein B is a group that binds to an E3 ligase, wherein the E3 ligase is selected from vonHippel-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/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/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;

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.
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, SO2NRh6 , SRh6 , -Rh6CO- , -CORh6- , CO, CO2 , C(O) NRh6 , C(O )NRh6Rh6, C(S)NRh6, NRh6 , NRh6CO , Rh6NRh6CO , NRh6CONRh7 , -C1-8alkylene , -C2-8alkenylene, -C2-8alkynylene, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the -C1-8alkylene, -C2-8alkenylene, -C2-8alkynylene , cycloalkyl , heterocyclyl , aryl or heteroaryl is each optionally substituted with Rh8 ;

R H1 is independently selected from amino, NR h6 R h7 , heterocyclyl, aryl and heteroaryl, wherein the aryl or heteroaryl is each optionally substituted with one or more R h8 ;

R h is independently selected from hydrogen, halogen, C 1-8 alkyl, heterocyclyl and heteroaryl, each of which is optionally substituted with 1, 2 or more R h5 ;

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 heterocyclyl, wherein the -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, C 3-9 cycloalkyl , or C 3-9 heterocyclyl is each optionally substituted with one or more R h9 ;

R h2 is 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 , -SO 2 R h6 , -SO 2 NR h6 R h7 , -COR h6 , -CO 2 R 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 CO 2 R h7 , -NR h6 SO 2 NR h7 R h8 , -NR h6 SO 2 R 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 ;

q1 is independently 1 or 2;

R h4 , R h5 , R h6 , and R h7 are independently selected from hydrogen, deuterium, halogen, nitro, cyano, amino, hydroxyl, carboxyl, -C 1-8 alkyl, and -C(O)R h12 , wherein the -C 1-8 alkyl is optionally substituted by one or more R h11 ;

R h8 , R h9 , R h10 , and R h11 are 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, and heteroaryl;

R h12 is selected from C 3-9 cycloalkyl, wherein the C 3-9 cycloalkyl is optionally substituted by CN, halogen, nitro, amino, hydroxyl, carboxyl, -C 1-3 alkyl;

further,

R h1 is independently selected from hydrogen, -C 1-8 alkyl and C 3-9 cycloalkyl; and/or

R h2 is 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 is independently selected from hydrogen, hydroxy-substituted-C 1-8 alkyl, and C 3-9 cycloalkyl; and/or

R h4 is 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 is independently selected from H, halogen, C 1-8 alkyl, and / or

R h5 is 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) NRh6 , NRh6CO , heterocyclyl and heteroaryl, each of which is optionally substituted by Rh8 ; and/or

V4 is independently selected from absent, SRh6 , -Rh6CO- , -CORh6- , C(O) NRh6Rh6 , Rh6NRh6CO and -C1-8alkylene , said -C1-8alkylene being optionally substituted with Rh8 ; and/or

R H1 is independently selected from amino, NR h6 R h7 , heterocyclyl and heteroaryl, each of which is optionally substituted with one or more R h8 ; and/or

R h6 and R h7 are independently selected from hydrogen, deuterium, -C 1-8 alkyl and -C(O)R h12 , wherein the -C 1-8 alkyl is optionally substituted with one or more R h11 ; and/or

R h8 is independently selected from hydrogen, deuterium, CN, halogen, oxo, -C 1-8 alkyl and cycloalkyl; and/or

R h11 is independently selected from hydrogen and deuterium; and/or

R h12 is selected from C 3-9 cycloalkyl, wherein the C 3-6 cycloalkyl is optionally substituted by CN or halogen;

go a step further,

R h1 is 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 is 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 is independently selected from H, halogen, C 1-8 alkyl, and / or

R h5 is 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

V 4 is selected from the group consisting of absent, -CH 2 -, -CH 2 C(O)-, -C(O)CH 2 -, -CH 2 NHC(O)-, -C(O)NHCH 2 -, and / or

R H1 is selected from Further selected from
The compound according to any one of claims 1 to 3, wherein B is selected from the structure shown by the following general formula:

wherein R h1 , R h3 , R h4 , R h , R h5 , R H1 , CyV and R h6 are as defined in claim 3 for Formula (B-V1), Formula (B-V2), Formula (B-V3) and Formula (B-V4);

in:

The formula (BVC) is further wherein R h3 is not hydrogen;

The formula (BVD) is further wherein R h3 is not hydrogen;

The formula (BVE) is further wherein R h3 is not hydrogen;

The formula (BVG) is further wherein R h3 is not hydrogen;

further,

R h1 is selected from isopropyl, tert-butyl,

R h3 is selected from H, methyl,

R h4 is selected from H, halogen;

Rh is selected from hydrogen, halogen, C1-8 alkyl,

R h5 is selected from hydrogen, C 1-8 alkyl, preferably methyl or hydrogen;

R H1 is selected from

CyV is selected from

R h6 is selected from hydrogen, deuterium, halogen, nitro, cyano, amino, hydroxyl, carboxyl, -C 1-8 alkyl, -C(O)R h12 , wherein the -C 1-8 alkyl is optionally substituted with one or more R h11 ;

R h11 is 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 is selected from C 3-9 cycloalkyl, wherein the C 3-9 cycloalkyl is optionally substituted by CN, halogen, nitro, amino, hydroxyl, carboxyl, -C 1-3 alkyl;

go a step further,

R h1 is selected from

R H1

R h3 is selected from hydrogen, methyl,

R h4 is hydrogen;

R h is selected from

R h5 is selected from methyl and ethyl;

CyV is selected from as well as

R h6 is hydrogen;

Even further, the structure of said B is selected from:
The compound according to any one of claims 1 to 4, wherein L is L4a, wherein:

(1) L4a is:

Among them, here

X5 is selected from CR L1 R L2 , NR L1 , O, S or absent;

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

RL , RL1 , RL2 are each independently selected from hydrogen, halogen, C1-8 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;

RL , RL1 are each independently selected from hydrogen, halogen, C1-8 alkyl, hydroxyl;

s, w, and v are each independently selected from 0, 1, 2, 3, 4, and 5;

Further, CyL3 is preferably a 4-9 membered cycloalkyl, more preferably

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

Furthermore, L4a is

or

(3) L4a is

Among them, here

X 6 is selected from absent, -CH 2 -;

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

RL , RL1 are each independently selected from hydrogen, halogen, C1-8 alkyl, hydroxyl;

s, w, and v are each independently selected from 0, 1, 2, 3, 4, and 5;

Further, 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

X 6 is selected from absent, -CH 2 -;

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;

Further, 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 is 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 and R L2 are each independently selected from hydrogen, halogen, and 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
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 absent;

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 RL , RL1 , RL2 is independently selected from hydrogen, halogen, C1-8 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 absent, -O-, -NR L2 -;

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

RL , RL1 , RL2 are each independently selected from hydrogen, halogen, C1-8 alkyl, hydroxyl;

s, w, and v are each independently selected from 0, 1, 2, 3, 4, and 5;

Further, 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

X 6 is selected from absent, -CH 2 -, 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;

Further, CyL4 is preferably a 5-9 membered aromatic ring, more preferably a benzene ring;

Furthermore, L4b is

or

(4) L4b is

Among them, here

X 6 is selected from absent, -O-;

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

RL , RL1 are each independently selected from hydrogen, halogen, C1-8 alkyl, hydroxyl;

RA and RB are each independently selected from hydrogen and C1-3 alkyl;

s, w, and v are each independently selected from 0, 1, 2, 3, 4, and 5;

Further, 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

X 5 is selected from absent, -O-, -CH 2 -;

X 6 is selected from absent, -O-;

X 5 and X 6 cannot both not exist;

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

Ring CyL1 is a 3-9 membered heterocyclic group;

R L1 is 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 and R L2 are each independently selected from hydrogen, halogen, and 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 ),
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, 9;

RL , RL1 are each independently selected from hydrogen, halogen, C1-8 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;

RL , RL1 are each independently selected from hydrogen, halogen, C1-8 alkyl, hydroxyl;

s, w, and v are each independently selected from 0, 1, 2, 3, 4, and 5;

Further, CyL3 is preferably a 4-9 membered cycloalkyl, more preferably

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

Furthermore, L4c is

or

(3) L4c is

wherein X 6 is selected from absent, -CH 2 -;

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

RL , RL1 are each independently selected from hydrogen, halogen, C1-8 alkyl, hydroxyl;

s, w, and v are each independently selected from 0, 1, 2, 3, 4, and 5;

Further, 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

X 6 is selected from absent, -CH 2 -;

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

RL , RL1 are each independently selected from hydrogen, halogen, C1-8 alkyl, hydroxyl;

s, w, and v are each independently selected from 0, 1, 2, 3, 4, and 5;

Further, CyL4 is preferably a 5-9 membered aromatic ring, more preferably a benzene ring;

Furthermore, L4c is

or

(5) L4c is

Among them, here

X 5 is selected from absent, -O-, -CH 2 -;

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

Ring CyL1 is a 3-9 membered heterocyclic group;

R L1 is 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
The compound according to any one of claims 1 to 4, wherein said L is selected from
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:

X 1 , X 2 , X 3 , R 100 , m, L 1 , n, R 1 , L 3 , R 2 , L 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , p, q are as defined in claim 1 ;

R h1 , R h3 , R h4 , and R h are as defined in claim 3 for Formula (B-V1), Formula (B-V2), Formula (B-V3), and Formula (B-V4);

L4a as defined in claim 5;

Further, L4a is selected from
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:

X 1 , X 2 , X 3 , R 100 , m, L 1 , n, R 1 , L 3 , R 2 , L 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , p, q are as defined in claim 1 ;

R h1 , R h3 , R h4 , R h , and CyV are as defined in claim 3 for Formula (B-V1), Formula (B-V2), Formula (B-V3), and Formula (B-V4);

L4b as defined in claim 6;

Further, L4b is selected from
The compound according to any one of claims 1-4 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:

X 1 , X 2 , X 3 , R 100 , m, L 1 , n, R 1 , L 3 , R 2 , L 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , p, q are as defined in claim 1 ;

R h1 , R h3 , R h4 , R h , and RH1 are as defined in claim 3 for Formula (B-V1), Formula (B-V2), Formula (B-V3), and Formula (B-V4);

L4b as defined in claim 6;

Further, L4b is selected from
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 wherein each R h1 is not hydrogen)

or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,

in:

X 1 , X 2 , X 3 , R 100 , m, L 1 , n, R 1 , L 3 , R 2 , L 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , p, q are as defined in claim 1 ;

R h1 , R h3 , R h4 , R h , and CyV are as defined in claim 3 for Formula (B-V1), Formula (B-V2), Formula (B-V3), and Formula (B-V4);

L4b as defined in claim 6;

Further, L4b is selected from
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:

X 1 , X 2 , X 3 , R 100 , m, L 1 , n, R 1 , L 3 , R 2 , L 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , p, q are as defined in claim 1 ;

R h3 , R h4 , R h , and RH1 are as defined in claim 3 for Formula (B-V1), Formula (B-V2), Formula (B-V3), and Formula (B-V4);

L4c as defined in claim 7;

Further, L4c is selected from
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:

X 1 , X 2 , X 3 , R 100 , m, L 1 , n, R 1 , L 3 , R 2 , L 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , p, q are as defined in claim 1 ;

R h1 , R h4 , R h , R H1 , and R h6 are as defined in claim 3 for Formula (B-V1), Formula (B-V2), Formula (B-V3), and Formula (B-V4);

L4a as defined in claim 5;

Further, L4a is selected from
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 is 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 is selected from wherein M is N, Cy3 is a 4-10 membered heterocyclyl and the heterocyclyl contains 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members;

R2 is naphthyl or heteroaryl (preferably ), wherein the naphthyl or the heteroaryl group is substituted by one or more (eg, 2 or 3) R 2a ;

Each R 2a is independently halogen, amino, hydroxy, -C 1-8 alkyl, -C 2-8 alkynyl, or -CN, preferably F, Cl, hydroxy, methyl, ethyl, or ethynyl;

One of R 3 and R 4 is hydrogen, and the other is halogen, -CN, or -NO 2 , preferably F or Cl, more preferably F;

R 5 , R 6 , R 7 , and R 8 are 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,

R1 is (Preferred );

R2 is

go a step further,

Said Part of

Said Parts are:
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.
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.
Use of the compound according to any one of claims 1-16, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof in the preparation of KRas G12D inhibition or degradation-related drugs.
Use of the compound according to any one of claims 1-16, 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 diseases associated with KRas G12D mutant protein, further wherein the diseases include but are not limited to pancreatic cancer, colorectal cancer, endometrial cancer or lung cancer; further wherein the lung cancer is selected from non-small cell lung cancer or small cell lung cancer.
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 a compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutical composition according to claim 17.