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WO2024131777A1 - Composé chimérique de kras-protac, son procédé de préparation et son utilisation - Google Patents

Composé chimérique de kras-protac, son procédé de préparation et son utilisation Download PDF

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Publication number
WO2024131777A1
WO2024131777A1 PCT/CN2023/139822 CN2023139822W WO2024131777A1 WO 2024131777 A1 WO2024131777 A1 WO 2024131777A1 CN 2023139822 W CN2023139822 W CN 2023139822W WO 2024131777 A1 WO2024131777 A1 WO 2024131777A1
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Prior art keywords
alkyl
hydrogen
cycloalkyl
halogen
heterocyclyl
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Chinese (zh)
Inventor
孙伟
翟文强
叶久勇
王令
邓涛
孙栗楠
刘东舟
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Hangzhou Zhongmei Huadong Pharmaceutical Co Ltd
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Hangzhou Zhongmei Huadong Pharmaceutical Co Ltd
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Priority to CN202380086854.3A priority Critical patent/CN120344540A/zh
Publication of WO2024131777A1 publication Critical patent/WO2024131777A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • 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.
  • 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.
  • Ub ubiquitin
  • 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.
  • KRAS Kirsten Rat Sarcoma Viral Oncogene Homolog
  • 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.
  • KRAS mutants Drug development targeting KRAS mutants is one of the important means of intervening or treating the above cancers.
  • 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.
  • GTP guanosine triphosphate
  • PROTACs technology 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.
  • KRAS-PROTAC chimeric compounds of the present invention are attractive drugs for cancers with this mutation.
  • 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),
  • 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.
  • the KRAS ligand according to the present invention is a compound represented by the following formula (KI):
  • 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;
  • n is an integer from 0 to 3;
  • 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
  • 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 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 2
  • R 2b , R 2c , R 2d , R 2e , and R 2f is independently hydrogen, deuterium, halogen, or C 1-8 alkyl;
  • 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 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 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 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;
  • 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 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 ;
  • 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.
  • R 3 and R 4 is F, Cl, -NO 2 or -CN.
  • one of R 3 and R 4 is hydrogen, and the other is F or Cl, more preferably F.
  • the KRAS ligand according to the present invention is a compound represented by the following formula (KII):
  • 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).
  • R 3 and R 4 is F, Cl, -NO 2 or -CN.
  • one of R 3 and R 4 is hydrogen, and the other is F or Cl, more preferably F.
  • Xi is N, and the other variables are as defined herein.
  • Xi is C, and the other variables are as defined herein.
  • X2 and X3 are N, and the other variables are as defined herein.
  • 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.
  • R 100 is independently halogen, hydroxy, amino, -CN, or cycloalkyl, preferably halogen or cycloalkyl, more preferably F, Cl and cyclopropyl.
  • 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.
  • 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.
  • 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.
  • 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.
  • n is an integer from 1 to 10.
  • L3 is selected from a single bond, and the other variables are as defined herein.
  • L 2 is selected from a single bond, -NH-, -CH 2 -, -O-, -S-, and other variables are as defined in the present invention.
  • L 2 is selected from -O-, -NH-, -CH 2 -, and the other variables are as defined herein.
  • L2 is selected from -O-, and the other variables are as defined herein.
  • 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
  • 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 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.
  • 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
  • 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.
  • R 1 is In some preferred embodiments, R 1 is Best
  • 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
  • R 1 is selected from -NR 1a R 1b , preferably
  • R1 is selected from Other variables are as defined herein.
  • -(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.
  • L 1 is a single bond
  • said R 1 is
  • 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
  • -(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
  • 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 2
  • R 2b , R 2c , R 2d , R 2e , and R 2f is independently hydrogen, deuterium, halogen, or C 1-8 alkyl.
  • 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 .
  • 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
  • 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
  • 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 .
  • R2 is selected from Other variables are as defined herein.
  • R2 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • 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 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.
  • R 5 , R 6 , R 7 , and R 8 are independently hydrogen, deuterium, or C 1-8 alkyl.
  • R 5 is selected from hydrogen, and the other variables are as defined herein.
  • R6 is selected from hydrogen, and the other variables are as defined herein.
  • R7 is selected from hydrogen, and the other variables are as defined herein.
  • R 8 is selected from hydrogen, and the other variables are as defined herein.
  • p is independently selected from 1 and 2, and other variables are as defined in the present invention.
  • q is independently selected from 1 and 2, and other variables are as defined in the present invention.
  • Z is selected from hydrogen, amino, hydroxy , halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -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
  • 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 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 ;
  • 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.
  • 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;
  • 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.
  • Z is selected from -OR 9 , -SR 9 , -NR 9 R 10 , -NR 9 COR 10 ,
  • 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 9c are each independently hydrogen, deuterium or -C 1-8 alkyl.
  • Z is selected from -NR 9 COR 10 , wherein R 9 and R 10 are independently hydrogen, methyl, or ethyl.
  • 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.
  • 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
  • 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
  • Z is selected from -OR 9 , wherein R 9 is selected from hydrogen, methyl, ethyl substituted by hydroxyl, C 3 cycloalkyl; further selected from
  • Z is selected from Other variables are as defined herein.
  • the KRAS ligand compound is a compound represented by the following formula (KIA) or (KIB):
  • 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.
  • R 3 and R 4 is F, Cl, -NO 2 or -CN.
  • one of R 3 and R 4 is hydrogen, and the other is F or Cl, more preferably F.
  • the KRAS ligand compound is a compound represented by the following formula (KIIA) or (KIIB):
  • 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.
  • R 3 and R 4 is F, Cl, -NO 2 or -CN.
  • one of R 3 and R 4 is hydrogen, and the other is F or Cl, more preferably F.
  • the above-mentioned KRAS ligand compound is a compound represented by the following formula (KIC)-(KIJ):
  • R 3 and R 4 is F, Cl, -NO 2 or -CN.
  • one of R 3 and R 4 is hydrogen, and the other is F or Cl, more preferably F.
  • the above-mentioned KRAS ligand compound is a compound represented by the following formula (KIIC)-(KIIS):
  • R 3 and R 4 is F, Cl, -NO 2 or -CN.
  • one of R 3 and R 4 is hydrogen, and the other is F or Cl, more preferably F.
  • the KRAS ligand compound is a compound represented by the following formula (KIK) or (KIL):
  • R 100 , m, X 1 , L 3 , R 2 , R 3 , and R 4 are as defined above.
  • R 3 and R 4 is F, Cl, -NO 2 or -CN.
  • one of R 3 and R 4 is hydrogen, and the other is F or Cl, more preferably F.
  • 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:
  • 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,
  • the B is a group that binds to an E3 ligase selected from VHL, Cereblon, MDM2 or cIAP.
  • B is selected from the following structures:
  • 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 and heteroaryl, wherein the -C1-8alkylene, -C2-8alkenylene
  • 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 -
  • 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.
  • 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 .
  • 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.
  • R h1 is independently selected from hydrogen, -C 1-8 alkyl, and C 3-9 cycloalkyl.
  • 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.
  • R h3 is independently selected from hydrogen, hydroxy-substituted-C 1-8 alkyl, and C 3-9 cycloalkyl.
  • 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.
  • Rh is independently selected from H, halogen, C1-8 alkyl,
  • 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.
  • 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 .
  • V4 is independently selected from absent, SRh6 , -Rh6CO- , -CORh6- , C(O) NRh6Rh6 , Rh6NRh6CO , and -C1-8alkylene , said -C1-8alkylene being optionally substituted with Rh8 .
  • 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 .
  • 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 .
  • R h8 is independently selected from hydrogen, deuterium, CN, halogen, oxo, -C 1-8 alkyl, and cycloalkyl.
  • R h11 is independently selected from hydrogen and deuterium.
  • R h12 is selected from C 3-9 cycloalkyl, said C 3-6 cycloalkyl optionally substituted with CN or halogen.
  • 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.
  • B is selected from the structure shown by the general formula:
  • 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).
  • 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.
  • R H1 is selected from
  • 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
  • the structure of B is shown in the following table:
  • the structure of B is:
  • L may be L4a, L4b, or L4c.
  • L is L4a.
  • L4a is N-(2-a)-2-a
  • 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.
  • L4a is N-(2-a)-2-a
  • 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.
  • CyL3 is preferably a 4-9 membered cycloalkyl, more preferably Additionally or alternatively, CyL3 is
  • CyL3 is preferably a 4-8 membered heterocyclic group, more preferably
  • L4a is
  • L4a is N-(2-a)-2-a
  • 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.
  • CyL4 is preferably a 5-9 membered aromatic ring, more preferably a benzene ring.
  • CyL4 is preferably a 5-6 membered aromatic heterocycle, more preferably
  • L4a is N-(2-a)-2-a
  • 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.
  • CyL4 is preferably a 5-9 membered aromatic ring, more preferably a benzene ring.
  • L4a is N-(2-a)-2-a
  • 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.
  • L4a is N-(2-a)-2-a
  • 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.
  • CyL1 is preferably a 4-6 membered N-containing heterocyclic group, more preferably
  • CyL2 is preferably a 4-8 membered N-containing heterocyclic group, more preferably
  • L4a is selected from
  • L4a is selected from
  • L is L4b.
  • L4b is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • 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.
  • L4b is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • L4b is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • 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.
  • CyL3 is preferably a 4-9 membered cycloalkyl group, more preferably
  • CyL3 is preferably a 4-8 membered heterocyclic group, more preferably
  • L4b is (Preferred ),
  • L4b is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • L4b is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • 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.
  • CyL4 is preferably a 5-9 membered aromatic ring, more preferably a benzene ring.
  • L4b is Additionally or alternatively, in some embodiments, L4b is
  • L4b is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • 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.
  • L4b is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • CyL4 is preferably a 5-9 membered aromatic ring, more preferably a benzene ring.
  • CyL4 is preferably a 5-6 membered aromatic heterocycle, more preferably
  • L4b is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • L4b is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • X 5 is selected from absent, -O-, -CH 2 -;
  • X 6 is selected from absent, -O-;
  • 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.
  • L4b is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • L4b is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • 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.
  • CyL1 is preferably a 4-6 membered N-containing heterocyclic group, more preferably
  • CyL1 is preferably a 4-8 membered N-containing heterocyclic group, more preferably
  • L4b is selected from (Preferred ),
  • L4b is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • L is L4c.
  • L4c is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • 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.
  • L4c is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • 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.
  • CyL3 is preferably a 4-9 membered cycloalkyl, more preferably
  • CyL3 is preferably a 4-8 membered heterocyclic group, more preferably
  • L4c is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • L4c is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • 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.
  • CyL4 is preferably a 5-9 membered aromatic ring, more preferably a benzene ring.
  • CyL4 is preferably a 5-6 membered aromatic heterocycle, more preferably
  • L4c is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • 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.
  • CyL4 is preferably a 5-9 membered aromatic ring, more preferably a benzene ring.
  • L4c is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • 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.
  • L4c is selected from Additionally or alternatively, in some embodiments, L4c is
  • said L is selected from:
  • L is selected from:
  • 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):
  • 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.
  • L4a is selected from
  • 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):
  • 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.
  • L4b is selected from
  • 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):
  • 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.
  • L4b is selected from
  • 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):
  • 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.
  • the compound of formula (II-F2) is selected from:
  • each R h1 here is not hydrogen.
  • L4b is selected from
  • 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):
  • 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.
  • L4c is selected from
  • 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):
  • 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.
  • 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:
  • 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.
  • 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.
  • the disease includes but is not limited to pancreatic cancer, colorectal cancer, endometrial cancer or lung cancer.
  • 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.
  • the disease includes but is not limited to pancreatic cancer, colorectal cancer, endometrial cancer, or lung cancer.
  • 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.
  • pharmaceutically acceptable 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.
  • 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.
  • C 1-8 alkyl is used to refer to a straight or branched saturated hydrocarbon group having 1 to 8 carbon atoms.
  • 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").
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the cycloalkyl group has 3-12, e.g., 7-12, 4-10, 3-9, 3-6, or 4-6 ring carbon atoms.
  • spirocycloalkyl refers to a cyclic structure containing carbon atoms and formed by at least two rings sharing one atom.
  • 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.
  • fused cycloalkyl refers to a fused ring containing carbon atoms and formed by two or more rings sharing two adjacent atoms.
  • 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.
  • 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.
  • 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.
  • aryl used alone or in combination with other terms, refers to a group selected from:
  • 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;
  • 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.
  • aromatic hydrocarbon ring and “aryl” are used interchangeably throughout the disclosure herein.
  • the monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 ring-forming carbon atoms (i.e., C5-10 aryl).
  • 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.
  • 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.
  • 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;
  • 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.
  • 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, naphth
  • 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.
  • the heteroaryl group 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.
  • 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.
  • 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).
  • 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).
  • 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.
  • optionally oxidized sulfur refers to S, SO or SO 2.
  • the heterocycle can be saturated (i.e., "heterocycloalkyl") or partially saturated.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a spiral atom shared carbon atom
  • One or more rings of a spiral heterocyclic group may contain one or more double bonds, but no ring has a completely conjugated ⁇ electron system.
  • the spiral heterocyclic group is 6 to 14 yuan, and more preferably 7 to 12 yuan.
  • 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.
  • 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 ⁇ electron system.
  • the fused heterocyclic group is 6 to 14 yuan, preferably 7 to 12 yuan and more preferably 7 to 10 yuan.
  • 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.
  • 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,
  • 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 ⁇ electron system.
  • the bridged heterocyclic group is 6- to 14-membered, and more preferably 7- to 10-membered.
  • 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.
  • halo or halogen, by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
  • 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.
  • enantiomer or “optical isomer” refers to stereoisomers that are mirror images of one another.
  • 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.
  • diastereomer refers to stereoisomers that have two or more chiral centers and that are not mirror images of each other.
  • 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.
  • the compound may be labeled with a radioactive isotope, such as deuterium ( 2H ), tritium ( 3H ), iodine-125 ( 125I ) or C-14 ( 14C ).
  • 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.
  • 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.
  • 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.
  • oxygen it means that two hydrogen atoms are replaced.
  • Oxygen substitution does not occur on aromatic groups.
  • 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.
  • any variable e.g., R
  • its definition at each occurrence is independent.
  • the group may be optionally substituted with up to two Rs, and each occurrence of R is an independent choice.
  • substituents and/or variants thereof are permitted only if such combinations result in stable compounds.
  • linking group When the number of a linking group is 0, such as -(L 1 ) 0 -, it means that the linking group is a single bond.
  • the substituent 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.
  • the substituent can be bonded through any atom thereof.
  • a pyridyl substituent can be connected to the substituted group through any carbon atom on the pyridine ring.
  • linking group L 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.
  • any one or more of the sites of the group may be Connected to other groups through chemical bonds.
  • 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.
  • 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.
  • 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.
  • administering 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.
  • 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.
  • 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.
  • an 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.
  • disease refers to any illness, ailment, disease, symptom, or indication, and is interchangeable with the terms “condition” or "disorder.”
  • 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.
  • 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.
  • 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)
  • 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 ⁇ M, 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 ⁇ l 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.
  • the compounds of the present invention have a good degradation effect on KRAS G12D protein in AsPC-1 cells.
  • 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
  • CCK8 Beimake, B34304
  • 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.
  • 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.
  • 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.
  • compound 1_3 200 mg, 0.4 mmol
  • intermediate A 200 mg, 0.4 mmol
  • potassium carbonate 221 mg, 1.6 mmol
  • 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.
  • compound 2_5 200 mg, 0.4 mmol
  • intermediate A 184 mg, 0.8 mmol
  • potassium carbonate 166 mg, 1.2 mmol
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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) + .
  • 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.
  • 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.

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Abstract

La présente invention concerne un composé tel que représenté par la formule (I) ou un sel pharmaceutiquement acceptable et un stéréoisomère de celui-ci, et son utilisation dans le traitement de tumeurs, de maladies immunologiques, d'inflammations et d'autres maladies; et une préparation pharmaceutique du composé, une composition pharmaceutique et son utilisation.
PCT/CN2023/139822 2022-12-19 2023-12-19 Composé chimérique de kras-protac, son procédé de préparation et son utilisation Ceased WO2024131777A1 (fr)

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WO2025034702A1 (fr) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Rmc-6291 destiné à être utilisé dans le traitement d'une maladie ou d'un trouble lié à une protéine ras
WO2025061079A1 (fr) * 2023-09-22 2025-03-27 杭州中美华东制药有限公司 Composé chimérique kras-protac et son utilisation
WO2025080946A2 (fr) 2023-10-12 2025-04-17 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025171296A1 (fr) 2024-02-09 2025-08-14 Revolution Medicines, Inc. Inhibiteurs de ras
US12448399B2 (en) 2023-01-26 2025-10-21 Arvinas Operations, Inc. Cereblon-based KRAS degrading PROTACs and uses related thereto
WO2025228285A1 (fr) * 2024-04-28 2025-11-06 杭州中美华东制药有限公司 Composé ayant un effet inhibiteur de kras
WO2025240847A1 (fr) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025242027A1 (fr) * 2024-05-20 2025-11-27 杭州中美华东制药有限公司 Agent de dégradation de protéine ciblée ayant un effet inhibiteur sur kras

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CN115028680A (zh) * 2022-08-11 2022-09-09 深圳湾实验室 一种靶向降解Cyclophilin A的PROTAC化合物及其制备方法与应用
CN115028679A (zh) * 2022-08-11 2022-09-09 深圳湾实验室 一种具有Cyclophilin A降解活性的PROTAC化合物及其制备方法与应用
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CN114127067A (zh) * 2019-07-17 2022-03-01 百济神州有限公司 作为hpk1抑制剂的三环化合物及其用途
WO2021139678A1 (fr) * 2020-01-07 2021-07-15 广州百霆医药科技有限公司 Inhibiteur pyridopyrimidine de protéine mutante kras g12c
WO2021163064A2 (fr) * 2020-02-14 2021-08-19 Jounce Therapeutics, Inc. Anticorps et protéines de fusion se liant à ccr8, et leurs utilisations
WO2022087149A2 (fr) * 2020-10-22 2022-04-28 Gilead Sciences, Inc. Protéines de fusion d'interleukine-2-fc et méthodes d'utilisation
WO2022105857A1 (fr) * 2020-11-20 2022-05-27 Jacobio Pharmaceuticals Co., Ltd. Inhibiteurs de kras g12d
WO2022148421A1 (fr) * 2021-01-08 2022-07-14 Beigene, Ltd. Composés pontés en tant qu'inhibiteur et dégradeur de kras g12d et leur utilisation
WO2022217691A1 (fr) * 2021-04-14 2022-10-20 中山大学 Protéine de fusion, son procédé de préparation et son utilisation
CN115028680A (zh) * 2022-08-11 2022-09-09 深圳湾实验室 一种靶向降解Cyclophilin A的PROTAC化合物及其制备方法与应用
CN115028679A (zh) * 2022-08-11 2022-09-09 深圳湾实验室 一种具有Cyclophilin A降解活性的PROTAC化合物及其制备方法与应用

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12448399B2 (en) 2023-01-26 2025-10-21 Arvinas Operations, Inc. Cereblon-based KRAS degrading PROTACs and uses related thereto
WO2025034702A1 (fr) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Rmc-6291 destiné à être utilisé dans le traitement d'une maladie ou d'un trouble lié à une protéine ras
WO2025061079A1 (fr) * 2023-09-22 2025-03-27 杭州中美华东制药有限公司 Composé chimérique kras-protac et son utilisation
WO2025080946A2 (fr) 2023-10-12 2025-04-17 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025171296A1 (fr) 2024-02-09 2025-08-14 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025228285A1 (fr) * 2024-04-28 2025-11-06 杭州中美华东制药有限公司 Composé ayant un effet inhibiteur de kras
WO2025240847A1 (fr) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025242027A1 (fr) * 2024-05-20 2025-11-27 杭州中美华东制药有限公司 Agent de dégradation de protéine ciblée ayant un effet inhibiteur sur kras

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