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WO2023116934A1 - Régulateur d'hydrolyse de protéine krasg12d, son procédé de préparation et son utilisation - Google Patents

Régulateur d'hydrolyse de protéine krasg12d, son procédé de préparation et son utilisation Download PDF

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Publication number
WO2023116934A1
WO2023116934A1 PCT/CN2022/142077 CN2022142077W WO2023116934A1 WO 2023116934 A1 WO2023116934 A1 WO 2023116934A1 CN 2022142077 W CN2022142077 W CN 2022142077W WO 2023116934 A1 WO2023116934 A1 WO 2023116934A1
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alkyl
substituted
halogenated
deuterated
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吕彬华
崔大为
庞旭东
张青
梁辉
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Suzhou Zelgen Biopharmaceutical Co Ltd
Shanghai Zelgen Pharmatech Co Ltd
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Suzhou Zelgen Biopharmaceutical Co Ltd
Shanghai Zelgen Pharmatech Co Ltd
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    • 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
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • 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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention belongs to the field of medicine, and in particular relates to a KRAS G12D proteolysis regulator, a preparation method and application thereof.
  • KRAS mutations account for 85% of all RAS mutations. KRAS mutations are found in nearly 90% of pancreatic cancers, 30-40% of colon cancers, and 15-20% of lung cancers (mainly non-small cell lung cancers).
  • the most important mutations in KRAS mutations are G12C and G12D mutations, among which G12C mutations mainly occur in HSCLC, while G12D mutations mainly occur in pancreatic cancer. So far, there are still no approved drugs for the KRAS G12D mutation on the market.
  • pancreatic cancer conventional clinical treatment options for pancreatic cancer include gemcitabine monotherapy, gemcitabine combined with nab-paclitaxel, and FOLFIRINOX regimen (oxaliplatin+irinotecan+5-FU/LV).
  • gemcitabine monotherapy gemcitabine combined with nab-paclitaxel
  • FOLFIRINOX regimen oxaliplatin+irinotecan+5-FU/LV.
  • liposomal irinotecan is suitable for the treatment of patients with advanced pancreatic cancer who have not responded well to gemcitabine chemotherapy in combination with fluorouracil and leucovorin (second-line therapy).
  • second-line therapy fluorouracil and leucovorin
  • KRAS G12D target proteins are pathologically associated with various diseases, especially pancreatic cancer
  • novel KRAS G12D inhibitors are currently needed for clinical treatment.
  • Highly selective and highly active KRAS G12D inhibitors can more effectively treat diseases such as cancer caused by KRAS G12D mutations, and reduce the potential for off-target effects, so there is a more urgent clinical need.
  • Proteolysis is crucial and strictly regulated in the normal life activities of cells, and its process is mainly completed through the participation of ubiquitinase system.
  • the protein to be decomposed is marked by the E1, E2 and E3 ubiquitin ligase system, and then recognized and hydrolyzed by proteases.
  • Proteolysis regulator molecules are bifunctional active compounds, one end of the molecule is tightly bound to the target protein, the other end is bound to E3 ubiquitin ligase, and the two ends are connected by various connecting chains.
  • This bifunctional molecule can simultaneously recognize the target protein and E3 ubiquitin ligase in vivo, bring the target protein and E3 ubiquitin ligase closer to make the target protein be ubiquitinated, and then hydrolyze through the ubiquitin-proteasome pathway. After the target protein is hydrolyzed, this bifunctional molecule can be released to participate in the next cycle of proteolysis, thus having a catalytic effect. Therefore, it can achieve high-efficiency therapeutic effect with less drug dosage in clinical practice. .
  • KRAS G12D target proteins are pathologically associated with various diseases, novel KRAS G12D inhibitors are still needed for clinical treatment.
  • Highly selective and highly active KRAS G12D proteolysis regulators can be more effective in treating diseases such as cancer caused by KRAS mutations, and reduce the potential for off-target effects, so there is a more urgent clinical need.
  • the purpose of the present invention is to provide a novel KRAS G12D proteolysis regulator and its preparation method and application.
  • the first aspect of the present invention provides a compound having the structure of formula (I), its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug :
  • ULM represents a small molecule ligand part that can bind to E3 ligase
  • PTM represents a small molecule ligand part that can bind to KRAS G12D protein
  • L can be a bond or a linking group that can connect the PTM and ULM.
  • PTM has the structure shown in formula (PTM-I)
  • Dashed lines indicate connections to L through arbitrary locations
  • Q is selected from: N, C-CN, C-H, C-F, or C-Cl;
  • X is selected from the following groups of substituted or unsubstituted groups: 4-14 membered saturated or unsaturated heterocyclic groups, 5-14 membered heteroaryl groups; wherein, the substitution refers to being substituted by one or more R 2 ;
  • R 2 is selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 alkoxy, C 3 -C 20 cycloalkyl, 4-20 membered heterocyclyl, C 6 -C 14 aromatic group, 5-14 membered heteroaryl group, halogen, nitro group, hydroxyl group, oxo group, cyano group, ester group, amine group, amido group, sulfonamide group or
  • A is selected from: C, CH or N;
  • Y is selected from: bond, O or NR b ;
  • R b is selected from substituted or unsubstituted following groups: hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 alkoxy, amino, hydroxyl , 4-20 membered heterocyclic group, C 6 -C 14 aryl group, 5-14 membered heteroaryl group; wherein, the substitution refers to being substituted by one or more R;
  • Z is selected from the group of substituted or unsubstituted groups: -(CH 2 ) n R 7 , -(CH 2 ) n O(CH 2 ) m R 7 , -(CH 2 ) n SR 7 , -(CH 2 ) n COR 7 , -(CH 2 ) n C(O)OR 7 , -(CH 2 ) n S(O) q R 7 , -(CH 2 ) n NR 5 R 7 , -(CH 2 ) n C (O)NR 5 R 7 , -(CH 2 ) n NR 5 C(O)R 7 , -(CH 2 ) n NR 5 C(O)NR 7 R 8 , -(CH 2 ) n S(O) q NR 5 R 7 , -(CH 2 ) n NR 5 S(O) q R 7 , -(CH 2 ) n NR 5 S(O)
  • R 3 and R 6 are the same or different, each independently selected from substituted or unsubstituted following groups: hydrogen, deuterium, halogen, amino, cyano, C 1 -C 3 alkyl, deuterated C 1 -C 3 Alkyl, halogenated C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, deuterated C 3 -C 6 cycloalkyl, halogenated C 3 -C 6 cycloalkyl; wherein, the substitution is means replaced by one or more R;
  • R 4 is selected from the following group of substituted or unsubstituted substituted or unsubstituted groups: 4-14 membered heterocyclic group, C 6 -C 14 aryl group, 5-14 membered heteroaryl group; wherein, the substituted means substituted by one or more R;
  • R is selected from: hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkyl, (C 3 -C 18 cycloalkyl)C 1 -C 18 alkyl, (4-20 membered heterocyclic group) C 1 -C 18 alkyl, (C 1 -C 18 alkoxy) C 1 -C 18 alkyl, C 3 -C 18 cycloalkyloxy, (C 3 -C 18 cycloalkyloxy) C 1 -C 18 alkyl, 4-20 membered heterocyclyloxy, (4-20 membered heterocyclyloxy) C 1 -C 18 alkyl, C 6 -C 20 aryloxy, (C 6 -C 20 aryloxy) C 1 -C 18 alkyl, 5-20 membered heteroaryloxy, (5-20 membered heteroaryloxy) C 1 -C 18 alkyl, C 1 -C 18 al
  • n and m are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
  • q 1 or 2.
  • p is selected from 0, 1, 2, 3, 4, 5 or 6; R 1 and R 2 are as defined above.
  • PTM has the structure shown in formula (PTM-2):
  • p is selected from 0, 1, 2, 3, 4, 5 or 6;
  • R 2 , R 3 , R 4 , Y and Z are as defined above.
  • PTM has the structure shown in formula (PTM-3):
  • p is selected from 0, 1, 2, 3, 4, 5 or 6;
  • R 2 , R 3 , R 4 and Z are as defined above.
  • R is selected from substituted or substituted groups: naphthyl, quinolinyl, isoquinolyl, benzothiophene, benzothiazole, benzofuran, phenyl, imidazolyl , thienyl, furyl, thiazolyl, oxazolyl, pyridyl, pyrazinyl, benzopyrazinyl; wherein, the substitution refers to being substituted by one or more groups selected from the following group: hydroxyl, Alkynyl, halogen, NH 2 , CN, vinyl, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclic group.
  • Z is selected from the following groups of substituted or unsubstituted groups:
  • the substitution means that any H atom in the group is replaced by a group selected from the following group: halogen, hydroxyl, cyano, NH 2 , C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl , 4-6 membered heterocyclyl, C 1 -C 6 alkoxy, C3-C6 cycloalkyloxy, 4-6 membered heterocyclyloxy, C 1 -C 6 alkylamino, C 3 -C 6 cycloalkylamino, 4-6 membered heterocyclic amino, C1-C6 alkylamino C1-C6 alkyl, C 3 -C 6 cycloalkylamino C 1 -C 6 alkyl, 4-6 C1-C6 alkyl group, C1 - C6 acyl group, C1 - C6 sulfonyl group.
  • PTM is selected from:
  • the ULM is selected from the small molecule ligand part that can be combined with the E3 ligase selected from the group: VHL (Von Rippel-Lindau), CRBN (Cereblon), MDM2 (Mouse double-minute homolog2), IAP, Keap1, HSP70, FKBP, DCAF15, DCAF16, RNF4, RNF114, and AhR.
  • the ULM is preferably selected from small molecule VLM, CLM, MLM or VLM that can be combined with E3 ligases such as VHL (Von Rippel-Lindau), CRBN (Cereblon), MDM2 (Mouse double-minute homolog2), or IAP.
  • VHL Volon Rippel-Lindau
  • CRBN Cyereblon
  • MDM2 Me double-minute homolog2
  • IAP ILM ligand part.
  • the ULM is selected from small molecule VLMs that can be combined with E3 ligases such as VHL (Von Rippel-Lindau), CRBN (Cereblon), or CLM ligands, more preferably with CRBN (Cereblon) E3 Ligase-bound small molecule CLM ligand moiety.
  • E3 ligases such as VHL (Von Rippel-Lindau), CRBN (Cereblon), or CLM ligands, more preferably with CRBN (Cereblon) E3 Ligase-bound small molecule CLM ligand moiety.
  • the compound of formula (I) is selected from the following group: PTM-VLM, PTM-CLM, PTM-MLM, PTM-ILM, PTM-L-VLM, PTM-L-CLM, PTM-L-MLM or PTM-L-ILM.
  • ULM is VLM, which has the structure shown in formula (VLM-1):
  • Dashed lines indicate connections to L through arbitrary locations
  • n a1 is selected from: 0, 1, 2, 3, or 4;
  • W a1 and W a2 are each independently selected from the following groups of substituted or unsubstituted groups: -X a3 -X a4 -or-X a4 ; wherein, X a3 and X a4 are each independently selected from the following substituted or unsubstituted groups Group: -(CH 2 ) m a1 R a5 , -(CH 2 ) m a1 O(CH 2 ) m a2 R a5 , -(CH 2 ) m a1 SR a5 , H-(CH 2 ) m a1 COR a5 ⁇ -(CH 2 ) m a1 C(O)OR a5 ⁇ -(CH 2 ) m a1 S(O) m a3 R a5 ⁇ -(CH 2 ) m a1 NR a5 R a6 ⁇ -(CH 2 ) m a1 C(O)NR
  • n a1 , m a2 are each independently selected from: 0, 1, 2, 3, 4, 5 or 6;
  • m a3 is selected from: 0, 1 or 2;
  • substitution refers to being substituted by one or more groups selected from the group consisting of hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkyl , halogenated C 1 -C 18 alkylhydroxyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 alkoxy group, C 6 -C 14 aryl group, 5-14 membered heteroaryl group, 4-20 membered heterocyclic group, halogen, oxo group, nitro group, hydroxyl group, cyano group, ester group, amine group, amido group, sulfonate group Amide or ureido; or substituted by L.
  • groups selected from the group consisting of hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18
  • ULM is VLM, which has the structure shown in formula (VLM-IIA-C):
  • the dotted line indicates the connection with L through any position, such as the connection with L through groups such as R a8 , R a9 , R a10 , R a11 , R a12 , benzene ring, OH, CH or NH;
  • R a8 , R a9 and R a10 are each independently selected from the following group of substituted or unsubstituted groups: hydrogen, halogen, cyano, C 1 -C 18 alkyl or alkylene, C 3 -C 12 cycloalkyl Or cycloalkylene, 4-12 membered heterocyclyl or heterocyclylene, C 6 -C 14 aryl or arylene, 5-20 membered heteroaryl or heteroarylene, -NR a13 R a14 ; wherein R a13 and R a14 are independently selected from substituted or unsubstituted groups: hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclic group, COC 1 - C 6 alkyl, COC 1 -C 6 haloalkyl, COC 1 -C 6 alkylamino, COC 1 -C 6 alkylamino C 1 -C 6 alkyl,
  • Each R a11 is independently selected from the following groups of substituted or unsubstituted groups: hydrogen, halogen, cyano, C 1 -C 6 acyl, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or 4 -6 membered heterocyclyl;
  • R a12 is the same or different, each independently selected from the following groups of substituted or unsubstituted groups: OH, halogen, C 6 -C 14 aryl and 5-20 membered heteroaryl;
  • R a15 is the same or different, each independently selected from the following groups of substituted or unsubstituted groups: OH, halogen, C 6 -C 14 aryl and 5-20 membered heteroaryl;
  • n a4 and m a5 are each independently selected from: 1, 2, 3, 4, or 5;
  • substitution refers to being substituted by one or more groups selected from the group consisting of hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkyl , halogenated C 1 -C 18 alkylhydroxyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 alkoxy group, C 6 -C 14 aryl group, 5-14 membered heteroaryl group, 4-20 membered heterocyclic group, halogen, oxo group, nitro group, hydroxyl group, cyano group, ester group, amine group, amido group, sulfo group Amide or urea groups;
  • ULM is CLM, which is selected from the following group:
  • each group is independently defined as follows:
  • the dotted line indicates the connection to L
  • Q a1 , Q a2 , Q a3 and Q a4 are each independently selected from: CH or N;
  • X b1 , X b2 and X b3 are the same or different, each independently selected from: CH 2 , O or S;
  • Z b1 and Z b2 are the same or different, each independently selected from: CH 2 , O or S;
  • Y b1 is selected from: CH 2 , O, S or NR b6 ;
  • R b6 is selected from substituted or unsubstituted following groups: hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or 4 -6 membered heterocyclic group, C 6 -C 14 aryl group and 5-14 membered heteroaryl group;
  • G b1 and G b2 are the same or different, each independently selected from the following groups of substituted or unsubstituted groups: hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclic group , C 6 -C 14 aryl and 5-14 membered heteroaryl;
  • a b1 and A b2 are the same or different, each independently selected from the following groups of substituted or unsubstituted groups: hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 4- 6-membered heterocyclic group, C 6 -C 14 aryl group and 5-14 membered heteroaryl group;
  • R b1 , R b2 and R b3 are the same or different, each independently selected from the following group of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halogen Substituted C 1 -C 18 alkyl, halogenated C 1 -C 18 alkylhydroxyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halo C 1 -C 18 alkoxy, C 6 -C 14 aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclic, halogen, oxo, nitro, hydroxyl, cyano, ester , amine group, amido group, sulfonamide group and urea group;
  • n b1 and n b2 are the same or different, each independently selected from: 0, 1, 2, 3 or 4;
  • substitution refers to being substituted by one or more groups selected from the group consisting of hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkyl , halogenated C 1 -C 18 alkylhydroxyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 alkoxy group, C 6 -C 14 aryl group, 5-14 membered heteroaryl group, 4-20 membered heterocyclic group, halogen, oxo group, nitro group, hydroxyl group, cyano group, ester group, amine group, amido group, sulfonate group amido and urea groups.
  • ULM is CLM, which is selected from the following group:
  • W b1 , R b1 , R b2 , R b3 , A b1 , A b2 , G b2 , Y b1 , n b1 , and n b2 are as defined above.
  • ULM is CLM, which is selected from the following group:
  • R b1 , R b2 , R b3 , n b1 and n b2 are as defined above.
  • ULM is MLM, which is selected from the following group:
  • each group is independently defined as follows:
  • the dotted line indicates the connection to L
  • X c1 is selected from the following group: O, S, SO, SO 2 , CR c29 R c30 , NR c31 , wherein R c29 and R c30 are the same or different, and each independently selected from the group of substituted or unsubstituted groups : hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkylhydroxyl, C 3 -C 20 ring Alkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 alkoxy, C 6 -C 14 aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclic group, halogen, oxo group, nitro group, hydroxyl group, cyano group, ester group, amine group, amido group, sulf
  • Y c1 and Z c1 are each independently selected from: N or CR c32 , wherein, R c32 is selected from the following group of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkylhydroxyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 Alkoxy, halogenated C 1 -C 18 alkoxy, C 6 -C 14 aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclic, halogen, oxo, nitro, hydroxyl, cyano, ester, amine, amide, sulfonamide or urea groups;
  • a c1 , A c2 or A c3 are each independently selected from: N, O, S or CR c33 , or two of A c1 , A c2 and A c3 are ring-closed to form a C 3 -C 8 cycloalkyl, 4- 8-membered heterocyclic group, C 6 -C 14 aryl group, 5-14 membered heteroaryl group; R c33 substituted or unsubstituted following groups: hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkylhydroxyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 - C 18 alkoxy, halogenated C 1 -C 18 alkoxy, C 6 -C 14 aryl, 5-14 membered heteroaryl, 4-20 member
  • R c is selected from the following group of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkylhydroxyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 alkoxy, C 6 -C 14 aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclic group;
  • R c1 -R c28 are the same or different, each independently selected from the following group of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkylhydroxyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 alkoxy, C 6 -C 14 aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclic, halogen, oxo, nitro, hydroxyl, cyano, ester, amino , amide group, sulfonamide group or ureido group; or each independently selected from the following groups of substituted or unsubstituted groups: -(CH 2 ) m c1 R c34
  • n c1 and m c2 are each independently selected from: 0, 1, 2, 3, 4, 5 or 6;
  • m c3 is selected from: 0, 1 or 2;
  • substitution refers to being substituted by one or more groups selected from the group consisting of hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkyl , halogenated C 1 -C 18 alkylhydroxyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 alkoxy group, C 6 -C 14 aryl group, 5-14 membered heteroaryl group, 4-20 membered heterocyclic group, halogen, oxo group, nitro group, hydroxyl group, cyano group, ester group, amine group, amido group, sulfonate group Amide or ureido; or substituted by L.
  • groups selected from the group consisting of hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18
  • ULM is MLM, which has the structure shown in formula (MLM-dII):
  • R c37 and R c38 are the same or different, and are independently selected from the following groups of substituted or unsubstituted groups: hydrogen, C 1 -C 18 alkyl, C 3 -C 20 cycloalkyl, 4-20 membered heterocycle group, C 6 -C 14 aryl group, 5-20 membered heteroaryl group; or R c37 , R c38 ring-closed to form a substituted or unsubstituted 4-20 membered heterocyclic group, or 5-20 membered heteroaryl group;
  • R c39 and R c40 are each independently selected from the group consisting of substituted or unsubstituted: hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkane radical, halogenated C 1 -C 18 alkylhydroxyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 alkane Oxygen, C 6 -C 14 aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclic, halogen, nitro, hydroxyl, cyano, ester, amine, amido, sulfonamide or Urea group;
  • n c4 and m c5 are each independently selected from: 0, 1, 2, 3, 4, 5 or 6;
  • substitution refers to being substituted by one or more groups selected from the group consisting of hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkyl , halogenated C 1 -C 18 alkylhydroxyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 alkoxy group, C 6 -C 14 aryl group, 5-14 membered heteroaryl group, 4-20 membered heterocyclic group, halogen, oxo group, nitro group, hydroxyl group, cyano group, ester group, amine group, amido group, sulfonate group Amide or urea groups.
  • ULM is MLM, which has the structure shown in formula (MLM-dIII) or (MLM-dIV)
  • ULM is ILM, which has the following structure:
  • each group is independently defined as follows:
  • R d1 -R d6 are the same or different, and are each independently selected from the following groups of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkylhydroxyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 alkoxy, C 6 -C 14 aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclic, halogen, nitro, hydroxyl, cyano, ester, amine, amido , sulfonamide group or urea group;
  • R d5 and R d6 form a substituted or unsubstituted 4-20 membered heterocyclic group together with the atoms they are connected to;
  • R d3 and R d6 form a substituted or unsubstituted 5-20 membered heterocyclic group together with the atoms they are connected to;
  • R d7 is selected from the following groups of substituted or unsubstituted: hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkylhydroxyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 alkoxy, C 6 - C 14 aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclic group, halogen, nitro, hydroxyl, cyano, ester group, amine group, amido group, sulfonamide group or ureido group; or selected from Substituted or unsubstituted following groups: -(CH 2 ) m d1' R d9' , -(CH 2 ) m d1' O(
  • n d1' and m d2' are each independently selected from: 0, 1, 2, 3, 4, 5 or 6;
  • m d3' is selected from: 0, 1, or 2;
  • W d1 is selected from the following groups of substituted or unsubstituted groups: C 6 -C 14 aryl and 5-20 membered heteroaryl;
  • R d8 is independently selected from the following substituted or unsubstituted groups: -(CH 2 ) m d1 R d9 , -(CH 2 ) m d1 O(CH 2 ) m d2 R d9 , -(CH 2 ) m d1 SR d9 , -(CH 2 ) m d1 COR d9 , -(CH 2 ) m d1 C(O)OR d9 , -(CH 2 ) m d1 S(O) m d3 R d9 , -(CH 2 ) m d1 NR d9 R d10 , -(CH 2 ) m d1 C(O)NR d9 R d10 , -(CH 2 ) m d1 NR d9 C(O)R d10 , -(CH 2 ) m d1 NR d9 C(O)R
  • nd 1 , m d1 and m d2 are each independently selected from: 0, 1, 2, 3, 4, 5 or 6;
  • m d3 is selected from 0, 1 or 2;
  • substitution refers to being substituted by one or more groups selected from the group consisting of hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkyl , halogenated C 1 -C 18 alkylhydroxyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 alkoxy group, C 6 -C 14 aryl group, 5-14 membered heteroaryl group, 4-20 membered heterocyclic group, halogen, oxo group, nitro group, hydroxyl group, cyano group, ester group, amine group, amido group, sulfonate group Amide or ureido; or substituted by L.
  • groups selected from the group consisting of hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18
  • ULM is ILM, which has the structure shown below
  • each group is independently defined as follows:
  • R d is selected from: hydrogen, halogen, cyano, C 1 -C 3 alkyl;
  • a d1 and A d2 are each independently selected from the following groups of substituted or unsubstituted groups: C 6 -C 14 aryl and 5-14 membered heteroaryl;
  • ULM is selected from the following group:
  • L is selected from:
  • H in NH can be independently optionally replaced by deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkylhydroxyl , C 3 -C 20 cycloalkyl, C 1 -C 18 alkyl acyl, sulfonyl substitution;
  • substitution refers to being substituted by one or more groups selected from the group consisting of hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkyl , halogenated C 1 -C 18 alkylhydroxyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 alkoxy group, C 6 -C 14 aryl group, 5-14 membered heteroaryl group, 4-20 membered heterocyclic group, halogen, oxo group, nitro group, hydroxyl group, cyano group, ester group, amine group, amido group, sulfo group Amide or urea groups;
  • Each p L1 -p L6 is independently selected from: 0, 1, 2, 3, 4, 5 or 6.
  • L is optionally connected to PTM or ULM through RL1 or RL6 .
  • L is selected from the following groups of substituted or unsubstituted groups:
  • H in CH 2 and CH can be independently and optionally substituted
  • substitution refers to being substituted by one or more groups selected from the group consisting of hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halogenated C 1 -C 18 Alkyl, halogenated C 1 -C 18 alkylhydroxyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 Alkoxy, C 6 -C 14 aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclic, halogen, oxo, nitro, hydroxyl, cyano, ester, amine, amido , sulfonamide or ureido; NH can be independently optionally replaced by deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkyl, hal
  • two adjacent groups in each R L1 -R L6 group can be connected to each other independently via a C, N, O or S atom or the like.
  • a substituted or unsubstituted group selected from the group consisting of:
  • H in CH 2 , CH and NH can be independently and optionally substituted; and the substitution refers to being substituted by one or more groups selected from the following group: hydrogen, deuterium, C 1 -C 18 Alkyl, deuterated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkylhydroxyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy group, deuterated C 1 -C 18 alkoxyl group, halogenated C 1 -C 18 alkoxyl group, C 6 -C 14 aryl group, 5-14 membered heteroaryl group, 4-20 membered heterocyclic group, halogen, Oxo, nitro, hydroxyl, cyano, ester, amine, amido, sulfonamide or ureido; NH can be independently optionally deuterized, C 1 -C 18 alkyl, deuterated C 1 -C 18
  • PTM is selected from:
  • a substituted or unsubstituted group selected from the group consisting of:
  • H in CH 2 , CH and NH can be independently and optionally substituted; and the substitution refers to being substituted by one or more groups selected from the following group: hydrogen, deuterium, C 1 -C 18 Alkyl, deuterated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkylhydroxyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy group, deuterated C 1 -C 18 alkoxyl group, halogenated C 1 -C 18 alkoxyl group, C 6 -C 14 aryl group, 5-14 membered heteroaryl group, 4-20 membered heterocyclic group, halogen, Oxo, nitro, hydroxyl, cyano, ester, amine, amido, sulfonamide or ureido; NH can be independently optionally deuterized, C 1 -C 18 alkyl, deuterated C 1 -C 18
  • ULM, L and PTM are the corresponding parts of each specific compound in the examples.
  • the compound of formula (I) is the compound shown in the Examples, such as Example I-1-I-22 and Example II-1-II-6.
  • the second aspect of the present invention provides a pharmaceutical composition, which comprises one or more compounds as described in the first aspect, their stereoisomers, tautomers, crystal forms, and pharmaceutically acceptable salts , hydrate, solvate or prodrug; and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition further comprises a drug selected from the group consisting of PD-1 inhibitors (such as nivolumab, pembrolizumab, pidilizumab, cemiplimab, JS-001, SHR-120, BGB-A317, IBI- 308, GLS-010, GB-226, STW204, HX008, HLX10, BAT 1306, AK105, LZM 009 or biosimilars of the above drugs, etc.), PD-L1 inhibitors (such as durvalumab, atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F 520, GR1405, MSB2311 or biosimilars of the above drugs, etc.), CD20 antibodies (such as rituximab, obinutuzumab, ofatumumab, veltuzum
  • BTK inhibitors such as Ibrutinib, Tirabrutinib, Acalabrutinib, Zanubrutinib, Vecabrutinib, etc.
  • EGFR inhibitors such as Afatinib, Gefitinib, Erlotinib, Lapatinib, Dacomitinib, Icotinib, Canertinib, Sapitinib, Naquottinib, Pyrotinib, Rociletinib, Osimertinib, etc.
  • VEGFR inhibitors such as Sorafenib, Pazopanib, Regorafenib, Sitravatinib, Ningetinib, Cabozantinib, Sunitinib, Donafenib, etc.
  • HDAC inhibitors such as Givinostat, Tucidinostat, Vorinostat, Fimepinostat, Droxinostat, Entinostat, Dacinostat, Quisin
  • the third aspect of the present invention provides a compound as described in the first aspect, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, Or the use of the pharmaceutical composition comprising it, for the preparation of medicines for preventing and/or treating diseases related to KRAS G12D activity or expression.
  • the disease is a tumor or a disorder.
  • the disease is selected from the group consisting of lung cancer, breast cancer, prostate cancer, esophagus cancer, colorectal cancer, bone cancer, kidney cancer, stomach cancer, liver cancer, colorectal cancer, melanoma, lymphoma, blood cancer , brain tumor, myeloma, soft tissue sarcoma, pancreatic cancer, skin cancer.
  • the fourth aspect of the present invention provides a method for non-diagnostic and non-therapeutic inhibition of KRAS G12D , which includes the step of: administering an effective amount of the compound or its stereoisomer as described in the first aspect to the subject in need , tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, or administering the pharmaceutical composition as described in the second aspect.
  • the subject is a mammal, preferably a human.
  • the fifth aspect of the present invention provides a method for inhibiting the activity of KRAS G12D in vitro, comprising the steps of: preparing the compound as described in the first aspect, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable The salt, hydrate, solvate or prodrug, or the pharmaceutical composition according to the second aspect is contacted with the protein or the cell, thereby inhibiting the activity of KRAS G12D .
  • the cells are selected from the group consisting of macrophages, intestinal cells (including intestinal stem cells, intestinal epithelial cells), or combinations thereof.
  • the cells are from rodents (such as mice, rats), or primates (such as humans).
  • the fifth aspect of the present invention provides a method for preventing and/or treating diseases related to KRAS G12D activity or expression, which includes the step of: administering an effective amount of the general medicine as described in the first aspect of the present invention to a subject in need
  • the subject is a mammal, such as a human, a rat or a mouse.
  • Figure 1 shows the degradation of KRAS G12D protein by Example I-11.
  • alkyl means by itself or as part of another substituent means a straight or branched chain alkane radical having the indicated number of carbon atoms, which may contain from 1 to 20 carbon atoms, such as including 1, 2, 3, 4 , 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 carbon atoms.
  • Typical "alkyl” groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, n-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl base, undecyl, dodecyl, etc.
  • substituted alkyl means that one or more positions in the alkyl group are substituted, especially 1-4 substituents, which can be substituted at any position.
  • alkylene by itself or as part of another substituent refers to a group formed by removing a hydrogen atom from “alkyl”.
  • the alkylene group can contain 1-18 carbon atoms, such as including 1, 2 , 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 carbon atoms.
  • cycloalkyl refers to a fully saturated cyclic hydrocarbon group, including 1-4 rings, each ring contains 3-30 carbon atoms, such as including 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 carbon atoms. "Substituted cycloalkyl” means that one or more positions in the cycloalkyl group are substituted, especially 1-4 substituents, which can be substituted at any position.
  • the typical substituents mentioned above may be optionally substituted.
  • Typical substitutions also include spiro, bridged or fused ring substituents, especially spirocycloalkyl, spirocycloalkenyl, spiroheterocycle (excluding heteroaryl rings), bridged cycloalkyl, bridged cycloalkenyl, Bridged ring heterocycle (excluding heteroaryl ring), fused ring alkyl group, fused ring alkenyl group, condensed ring heterocyclic group or condensed ring aromatic ring group, the above-mentioned cycloalkyl group, cycloalkenyl group, heterocyclic group and heterocyclic aromatic ring group
  • the groups can be optionally substituted. Any two or more atoms on the ring can be further linked with other cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups.
  • cycloalkylene by itself or as part of another substituent refers to the group formed by the removal of two hydrogen atoms from the above cycloalkyl group, such as: wait.
  • alkylenecycloalkylene refers to a group formed by removing two hydrogen atoms from the above-mentioned cycloalkylalkyl or alkylcycloalkyl, wherein, "C1-C18alkylene C3-C20alkylene Cycloalkyl” or "C3-C20 cycloalkylene C1-C18 alkylene” have the same meaning, preferably, C1-C6 alkylene C3-C12 cycloalkylene, including but not limited to: wait.
  • heterocyclyl refers to a fully saturated or partially unsaturated cyclic group, which may include 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 ring atoms (including but not limited to such as 3-7 membered monocyclic rings, 6-11 membered bicyclic rings, or 8-16 membered tricyclic ring systems), in which at least one heteroatom is present on at least one carbon atom in the ring.
  • Each heterocyclic ring containing heteroatoms can have 1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen or sulfur atoms, wherein the nitrogen or sulfur atoms can be oxidized, and the nitrogen atoms can also be is quaternized.
  • a heterocyclic group may be attached to the residue of any heteroatom or carbon atom of a ring or ring system molecule.
  • Typical monocyclic heterocycles include, but are not limited to, azetidinyl, pyrrolidinyl, oxetanyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidine base, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, hexahydroazepine Gene group, 4-piperidinonyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone
  • Polycyclic heterocyclic groups include spiro rings, fused rings and bridged ring heterocyclic groups; the spiro rings, condensed rings and bridged ring heterocyclic groups involved are optionally connected to other groups through single bonds, or through rings Any two or more atoms on the ring are further linked with other cycloalkyl, heterocyclic, aryl and heteroaryl groups; the heterocyclic group can be substituted or unsubstituted, when substituted,
  • the substituent is preferably one or more of the following groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, Halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylthio, oxo, carboxyl and carboxylate, wherein
  • heterocyclic group refers to a group formed by removing two hydrogen atoms from the above-mentioned heterocyclic group, such as including but not limited to:
  • heterocycloalkylene refers to a group formed by removing two hydrogen atoms from cycloalkylalkyl or alkylcycloalkyl, wherein, "4-20 membered heterocycloalkylene C1-C18 "Alkylene” or "C1-C18 alkylene 4-20 membered heterocycloalkylene” have the same meaning, preferably 4-12 membered heterocycloalkylene C1-6 alkylene, including but not limited to: wait.
  • aryl refers to an aromatic cyclic hydrocarbon compound group with 1-5 rings, especially monocyclic and bicyclic groups, such as phenyl, biphenyl or naphthyl. Where there are two or more aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group can be connected by a single bond (such as biphenyl), or fused (such as naphthalene, anthracene, etc.). "Substituted aryl” means that one or more positions in the aryl group are substituted, especially 1-3 substituents, which can be substituted at any position.
  • arylene group refers to a group formed by removing two hydrogen atoms from the above-mentioned aryl group.
  • heteroaryl refers to a heteroaromatic system containing 1-4 (such as 2 or 3) heteroatoms, 5-14 ring atoms, wherein the heteroatoms are selected from oxygen, nitrogen and sulfur, and the heterocyclic group may include 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms.
  • Heteroaryl is preferably a 5- to 10-membered ring, more preferably 5- or 6-membered, such as pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl , furyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazazinyl, triazolyl and tetrazolyl, etc.
  • pyrrolyl pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl , furyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazazinyl, triazolyl and tetrazolyl, etc.
  • Heteroaryl may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy , haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkane Thio, oxo, carboxyl and carboxylate groups.
  • heteroarylene refers to a group formed by removing two hydrogen atoms from the above-mentioned heteroaryl group.
  • C1-C18 alkoxy refers to a linear or branched or cyclic alkyloxy group having 1 to 18 carbon atoms, including without limitation methoxy, ethoxy, propoxy, iso Propoxy and Butoxy, etc. It is preferably C1-C8 alkoxy, more preferably C1-C6 alkoxy or C1-C4 alkoxy.
  • C1-C18 alkyleneoxy refers to a group obtained by removing a hydrogen atom from "C1-C18 alkoxy”.
  • halogen refers to chlorine, bromine, fluorine, iodine.
  • halo means substituted by halogen.
  • deuterated refers to substitution with deuterium ( 2H ).
  • hydroxyl refers to a group bearing the structure OH.
  • nitro refers to a group bearing the structure NO2 .
  • cyano refers to a group bearing the structure CN.
  • ester group refers to a group with the structure -COOR, wherein R represents hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl radical or substituted aryl, heterocyclyl or substituted heterocyclyl.
  • ester groups include, but are not limited to , -COOCH3 , -COOCH2CH3 , -COOCH2CH2CH3 , -COO( cyclopropyl ), -COOCH2 (cyclopropyl), and the like.
  • amino refers to a group with the structure -NRR', wherein R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or Substituted cycloalkenyl, aryl or substituted aryl, heterocyclyl or substituted heterocyclyl, as defined above. R and R' can be the same or different in the dialkylamine moiety.
  • the amine group is preferably a C 1 -C 18 alkylamine group, a C 3 -C 18 cycloalkylamine group, a 4-20 membered heterocyclylamine group, a C 6 -C 20 arylamine group, a 5-20 membered Heteroarylamine or NH 2 , more preferably C 1 -C 6 alkylamine, C 3 -C 6 cycloalkylamine, 4-6 membered heterocyclylamine, C 6 -C 10 aromatic Base amino group, 5-10 membered heteroaryl amino group or NH 2 .
  • amino group include, but are not limited to: NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -NH(cyclopropyl) and the like.
  • amido refers to a group with the structure -CONRR', wherein R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or Substituted cycloalkenyl, aryl or substituted aryl, heterocyclyl or substituted heterocyclyl, as defined above. R and R' can be the same or different in the dialkylamine moiety. Examples of “amido” include, but are not limited to: -CONH 2 , -CONHCH 3 , -CON(CH 3 ) 2 .
  • sulfonamido refers to a group with the structure -SO 2 NRR', wherein R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, ring Alkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocyclyl or substituted heterocyclyl, as defined above. R and R' can be the same or different in the dialkylamine moiety. Examples of “sulfonamido” include, but are not limited to: -SO 2 NH 2 , -SO 2 NHCH 3 , -SO 2 N(CH 3 ) 2 .
  • ureido refers to a group with the structure -NRCONR'R", wherein R, R' and R" can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl , cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocyclyl or substituted heterocyclyl, as defined above. R, R' and R" may be the same or different in the dialkylamine moiety.
  • ureido groups include, but are not limited to: -NHCONH 2 , -NHCONHCH 3 , -NHCON(CH 3 ) 2 , -N(CH 3 )CONH 2 , -N(CH 3 )CONHCH 3 , -N(CH 3 )CON(CH 3 ) 2 and the like.
  • alkylaminoalkyl refers to a group with the structure -RNHR' or -RNR'R", wherein R, R' and R"' can independently represent hydrogen, alkyl or substituted alkyl, Cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocyclyl or substituted heterocyclyl, as defined above. R, R' and R" may be the same or different.
  • Alkylaminoalkyl is preferably (C 1 -C 18 alkylamino)C 1 -C 18 alkyl, more preferably (C 1 - C 6 alkylamino)C 1 -C 6 alkyl, more preferably (C 1 -C 6 alkylamino)C 1 -C 3 alkyl.
  • alkylaminoalkyl include but Not limited to: -CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2 , -CH 2 CH 2 NHCH 3 , -CH 2 CH 2 CH 2 N (CH 3 ) 2 , -CH 2 CH 2 CH 2 NHCH 3 , -CH 2 CH 2 CH 2 N(CH 3 ) 2 .
  • (cycloalkylamino)alkyl, (heterocyclylamino)alkyl, (arylamino)alkyl and (heteroarylamino) Alkyl has a similar meaning. For example, wait.
  • heterocyclylalkyl refers to a group with the structure -RR', where R can independently represent alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted Cycloalkenyl, aryl or substituted aryl; R' represents heterocyclyl or substituted heterocyclyl.
  • R can independently represent alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl , aryl or substituted aryl; R'represents heterocyclic or substituted heterocyclic.
  • substituted means that one or more hydrogen atoms on a specific group are replaced by a specific substituent.
  • the specific substituents are the corresponding substituents described above, or the substituents appearing in each embodiment.
  • a substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituents may be the same or different at each position.
  • substituents contemplated by this invention are those that are stable or chemically feasible.
  • the substitution may be substituted by one or more substituents selected from the following group: for example (but not limited to): halogen, hydroxyl, cyano, carboxyl (-COOH), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, 4-12 membered heterocyclyl, aryl, heteroaryl, C 1 -C 8 aldehyde group, C 1 -C 10 acyl group, C 2 -C 10 ester group, amine group, C 1 -C 6 alkoxy group, C 1 -C 10 sulfonyl group, and C 1 -C 6 ureido group, etc.
  • substituents selected from the following group: for example (but not limited to): halogen, hydroxyl, cyano, carboxyl (-COOH), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C
  • a substituent is a non-terminal substituent, it is the subunit of the corresponding group, for example, alkyl corresponds to alkylene, cycloalkyl corresponds to cycloalkylene, heterocyclyl corresponds to heterocyclylene, alkoxy corresponds to Alkyleneoxy, etc.
  • KRAS G12D proteolytic modulator and “KRAS G12D -targeting protease degrader” are used interchangeably to refer to KRAS G12D -targeting protease degraders (PROTACs), which utilize intracellular "cleaning""work”-ubiquitin-proteasome system to degrade KRAS G12D protein.
  • PROTACs KRAS G12D -targeting protease degraders
  • the KRAS G12D proteolysis regulator is the compound of formula I of the present invention.
  • a targeting ligand is a small molecule capable of binding a target protein of interest.
  • the targeting ligand is formed by a small molecular compound targeting KRAS G12D , preferably a PTMI compound as described above.
  • the E3 ligase ligand moiety (ULM moiety) is used to bind E3 ligase.
  • the present invention has no special requirements on the type of E3 ligase ligand, and commonly used molecules or structural fragments that can bind to E3 ligase can be used.
  • the ULM is formed by a small molecule ligand that can bind to a ligase selected from (but not limited to): VHL (Von Rippel-Lindau), CRBN (Cereblon), MDM2 (Mouse double-minute homolog2), IAP, Keap1, HSP70, FKBP, DCAF15, DCAF16, RNF4, RNF114 and AhR etc.
  • said ULM is formed by a small molecule ligand selected from the group consisting of VLM, CLM, MLM or ILM.
  • the linking groups of the present invention are used to link target molecules and E3 ligase ligands.
  • the linking group of the present invention may further contain various other functional groups, such as -OH, -NHR, -SH and other functional groups.
  • the target molecule or E3 ligase ligand contains a functional group that can undergo a substitution reaction such as -OH, -SH, -NH 2 , -NHR, -SOOH or -COOH
  • a linker molecule containing the corresponding reactive functional group can be used React with it (such as OH/SH/NH2 and -COOH/-COCl, etc.), so as to realize the connection with the target molecule and/or E3 ligase ligand.
  • Functional groups capable of undergoing the above-mentioned substitution reactions, and methods for introducing the above-mentioned functional groups into molecules are known to those skilled in the art.
  • connection direction of the linking group L and the PTM and ULM parts can be arbitrary, the L group can be connected with the PTM on the left and the ULM on the right, or the L group can be connected with the PTM on the right and the ULM on the left,
  • L is -C 1 -C 4 alkylene CO-
  • it includes -C 1 -C 4 alkylene CO- and -CO-C 1 -C 4 alkylene CO-.
  • the compound of the present invention refers to the compound shown in Formula I, and also includes stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, and solvates of the compound of Formula I.
  • ULM represents the small molecule ligand part that can bind to E3 ligase
  • PTM represents the small molecule ligand part that can bind to KRAS G12D ;
  • L can be a bond or a linking group that can connect the PTM and ULM.
  • two adjacent groups in each R L1 -R L6 group can be connected to each other independently via C, N, O or S atoms.
  • PTM, L and ULM are independently corresponding parts of the compounds of the examples of the present invention.
  • the compound of the general formula (I) is selected from the compounds prepared in the examples of the present invention.
  • the compound of the formula (I) is selected from the compounds shown in the examples.
  • salts that may be formed by the compounds of the present invention also belong to the scope of the present invention. Unless otherwise stated, the compounds of the present invention are understood to include their salts.
  • the term "salt” as used herein refers to an acidic or basic salt formed with an inorganic or organic acid and a base.
  • a compound of the present invention contains a basic moiety, which includes but is not limited to pyridine or imidazole, and an acidic moiety, including but not limited to carboxylic acid, zwitterions ("inner salts”) that may be formed are contained in within the term "salt".
  • Pharmaceutically acceptable (ie, non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, for example, in isolation or purification steps during preparation.
  • the compound of the present invention may form a salt, for example, compound I reacts with a certain amount, such as an equivalent amount of acid or base, and salts it out in a medium, or freeze-dries it in an aqueous solution.
  • Basic moieties contained in the compounds of the present invention may form salts with organic or inorganic acids.
  • Typical acids from which salts can be formed include acetate (e.g. with acetic acid or a trihaloacetic acid such as trifluoroacetic acid), adipate, alginate, ascorbate, aspartate, benzoate , Benzenesulfonate, Bisulfate, Borate, Butyrate, Citrate, Camphor Salt, Camphorsulfonate, Cyclopentane Propionate, Diglycolate, Lauryl Sulfate, Ethanesulfonate, Fumarate, Glucoheptonate, Glycerophosphate, Hemisulfate, Heptanoate, Hexanoate, Hydrochloride, Hydrobromide, Hydroiodide, Isethionate (eg, 2-hydroxyethanesulfonate), lactate, male
  • Certain compounds of the present invention may contain acidic moieties, including but not limited to carboxylic acids, which may form salts with various organic or inorganic bases.
  • Typical salts formed with bases include ammonium salts, alkali metal salts such as sodium, lithium, potassium salts, alkaline earth metal salts such as calcium, magnesium salts, and salts formed with organic bases (such as organic amines), such as benzathine, dicyclohexyl Amine, Hypamine (salt with N,N-di(dehydroabietyl)ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glucamide, tert-butyl Base amines, and salts with amino acids such as arginine, lysine, etc.
  • Basic nitrogen-containing groups can be combined with halide quaternary ammonium salts, such as small molecule alkyl halides (such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and dipentyl sulfates), long-chain halides (e.g., decyl, dodecyl, tetradecyl, and tetradecyl chlorides, bromides and iodides), aralkyl halides (such as benzyl and phenyl bromides) and the like.
  • alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides
  • dialkyl sulfates e.g., dimethyl, diethyl, dibutyl, and dipenty
  • Prodrugs and solvates of the compounds of the present invention are also contemplated.
  • the term "prodrug” here refers to a compound that undergoes metabolic or chemical transformation during the treatment of related diseases to produce the compound, salt, or solvate of the present invention.
  • the compounds of the present invention include solvates, such as hydrates.
  • All stereoisomers of the compounds are contemplated by the present invention.
  • the individual stereoisomers of the compounds of the present invention may not exist simultaneously with other isomers (for example, as a pure or substantially pure optical isomer having a specific activity), or may be a mixture, such as Racemates, or mixtures with all other stereoisomers or parts thereof.
  • the chiral center of the present invention has two configurations of S or R, which are defined by the 1974 proposal of the International Union of Theoretical and Applied Chemistry (IUPAC).
  • racemic forms can be resolved by physical methods such as fractional crystallization, or by derivatization into diastereoisomers, or by separation by chiral column chromatography.
  • Individual optical isomers can be obtained from racemates by suitable methods, including but not limited to conventional methods such as salt formation with optically active acids followed by crystallization.
  • the weight content of the compound obtained by preparation, separation and purification in sequence is equal to or greater than 90%, for example, equal to or greater than 95%, equal to or greater than 99% ("very pure” compound), described in the main text listed. Such "very pure” compounds of the invention are also included herein as part of the invention.
  • All configurational isomers of the compounds of the invention are contemplated, whether in admixture, pure or very pure form.
  • the definition of the compounds of the present invention includes both cis (Z) and retro (E) olefinic isomers, as well as carbocyclic and heterocyclic cis and trans isomers.
  • Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms.
  • the present invention covers all compounds, including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, racemic spin mixtures and other mixtures.
  • an asymmetric carbon atom may represent a substituent, such as an alkyl group. All isomers, as well as mixtures thereof, are included in the present invention.
  • the mixture of isomers may contain various ratios of isomers.
  • ratios of isomers For example, in a mixture of only two isomers you can have the following combinations: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98: 2, 99:1, or 100:0, all ratios of isomers are within the scope of the present invention. Similar ratios, as well as ratios that are mixtures of more complex isomers, readily understood by one of ordinary skill in the art, are also within the scope of the invention.
  • the invention also includes isotopically labeled compounds equivalent to the original compounds disclosed herein. In practice, however, substitution of one or more atoms by an atom with a different atomic mass or mass number usually occurs.
  • isotopes that may be included in compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, respectively , 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl.
  • the compounds of the present invention or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates, which contain isotopes or other isotopic atoms of the above compounds are within the scope of the present invention.
  • Certain isotopically labeled compounds of the present invention such as 3 H and 14 C radioactive isotopes, are useful in tissue distribution assays for drugs and substrates. Tritium, namely 3 H, and carbon-14, namely 14 C, are relatively easy to prepare and detect. is the first choice among isotopes.
  • isotopically-labeled compounds can be prepared in general manner by substituting a readily available isotopically-labeled reagent for a non-isotopically-labeled reagent, using the protocols disclosed in the Examples.
  • a specific enantiomer of a compound of the present invention can be prepared by asymmetric synthesis, or derivatized with a chiral auxiliary, the resulting diastereomeric mixture is separated, and the chiral auxiliary is removed to obtain pure enantiomers.
  • the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, it can be formed with a suitable optically active acid or base to form a diastereomeric salt, and then separated by crystallization or chromatography. Separation by conventional means then gives the pure enantiomers.
  • the compounds of the present invention may be substituted with any number of substituents or functional groups to broaden their scope.
  • substitution appears before or after the term “optional”
  • the general formula including the substituent in the formula of the present invention means that the hydrogen radical is replaced by the specified structural substituent.
  • substituents may be the same or different for each position.
  • substitution includes all permissible organic compound substitutions. Broadly speaking, the permissible substituents include acyclic, cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic organic compounds.
  • heteroatom nitrogen may have hydrogen substituents or any permissible organic compound as described above to complement its valence.
  • this invention is not intended to be limiting in any way to the organic compounds permissible to be substituted.
  • Combinations of substituents and variables are contemplated by the present invention to be beneficial in the treatment of diseases, such as infectious or proliferative diseases, in the form of stable compounds.
  • stable herein means having a compound that is stable, detectable for a sufficient period of time to maintain the structural integrity of the compound, preferably active for a sufficient period of time, and is used herein for the above purposes.
  • the preparation method of the compound of formula (I) of the present invention is described in more detail below, but these specific methods do not constitute any limitation to the present invention.
  • the compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in the specification or known in the art, and such combinations can be easily performed by those skilled in the art to which the present invention belongs.
  • the preparation process of the compound of the present invention is as follows, wherein the raw materials and reagents used can be purchased through commercial channels unless otherwise specified.
  • (ii) (PG 1 -PTM-IL-ULM) compound in acid such as TFA, HCl, TsOH, MsOH, etc.
  • base such as piperidine, morpholine, etc.
  • hydrogenation such as CAN
  • oxidation such as CAN
  • other Conditions such as chloroformic acid-1-chloroethyl ester, Pd(PPh 3 ) 4 , etc. remove the protecting group to obtain the compound of formula (PTM-IL-ULM);
  • PG 1 is one or more protecting groups, each independently selected from: Ac, Bn, PMB, MOM, TBS, TBDPS, SEM, Boc, Fmoc, allyl, etc.;
  • LG 1 and LG 2 are the same or different, and are leaving groups independently selected from: hydrogen, OH, halogen, OTs, OMs, OTf, or B(OH) 2 , etc.; the leaving groups of the two molecules can be At least one small molecule (such as H2O , HCl, TsOH, MsOH, TfOH, etc.) is formed.
  • R 1 , R 3 , R 4 , R 6 , A, X, Y, and Z are as defined above.
  • compositions Use and methods of administration
  • the pharmaceutical composition of the present invention includes the above-mentioned active ingredients and a pharmaceutically acceptable carrier.
  • the compound of the present invention can reduce the activity and expression of KRAS G12D , promote the degradation of KRAS G12D protein and/or reduce the level of KRAS G12D , so that it can be used to prevent and/or treat diseases related to KRAS G12D activity or expression.
  • the pharmaceutical composition of the present invention can be used to prevent and/or treat the following diseases: inflammation, cancer, cardiovascular disease, infection, immune disease, metabolic disease.
  • the cancer is a cancer caused by KRAS mutation.
  • the cancers include (but are not limited to): lung cancer (small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC)), breast cancer, prostate cancer, esophageal cancer, colorectal cancer, bone cancer, Cancer, kidney cancer, stomach cancer, liver cancer, colorectal cancer, melanoma, lymphoma, blood cancer, brain tumor, myeloma, soft tissue sarcoma, pancreatic cancer, skin cancer.
  • SCLC small cell lung cancer
  • NSCLC non-small cell lung cancer
  • breast cancer breast cancer
  • SCLC small cell lung cancer
  • NSCLC non-small cell lung cancer
  • esophageal cancer colorectal cancer
  • bone cancer Cancer
  • kidney cancer kidney cancer
  • stomach cancer liver cancer
  • colorectal cancer melanoma
  • lymphoma lymphoma
  • blood cancer brain tumor
  • myeloma myeloma
  • soft tissue sarcoma pancreatic cancer
  • the compound of general formula (I) can be used in combination with other known drugs for treating or improving similar diseases.
  • the administration method and dose of the original drug can be kept unchanged, and the compound of formula I can be administered simultaneously or subsequently.
  • the pharmaceutical composition containing one or several known drugs and the compound of formula I can be preferably used.
  • Drug combinations also include administration of a compound of formula I and one or more other known drugs for overlapping periods of time.
  • the dosage of the compound of formula I or known drugs may be lower than that of their single administration.
  • Drugs or active ingredients that can be combined with the compound described in general formula (I) include but are not limited to: PD-1 inhibitors (such as nivolumab, pembrolizumab, pidilizumab, cemiplimab, JS-001, SHR-120, BGB-1 A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT 1306, AK105, LZM 009 or biosimilars of the above drugs, etc.), PD-L1 inhibitors (such as durvalumab, atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F 520, GR1405, MSB2311 or biosimilars of the above drugs, etc.), CD20 antibodies (such as rituximab, obinutuzumab, ofatumumab
  • the dosage form of the pharmaceutical composition of the present invention includes (but not limited to): injection, tablet, capsule, aerosol, suppository, film, drop pill, external liniment, controlled-release or sustained-release or nanometer preparation.
  • the pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof within a safe and effective amount range and a pharmaceutically acceptable excipient or carrier.
  • safe and effective dose refers to: the amount of the compound is sufficient to obviously improve the condition without causing severe side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 10-1000 mg of the compound of the present invention per dose.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and low enough toxicity. "Compatibility” herein means that the components of the composition can be blended with the compound of the present invention and with each other without significantly reducing the efficacy of the compound.
  • Examples of pharmaceutically acceptable carrier parts include cellulose and derivatives thereof (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid , magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agent (such as sodium lauryl sulfate), coloring agent, flavoring agent, stabilizer, antioxidant, preservative, pyrogen-free water, etc.
  • cellulose and derivatives thereof such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
  • gelatin such as talc
  • solid lubricants such as stearic acid , magnesium stearate
  • calcium sulfate such
  • the mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration .
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or extenders, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow agents, such as paraffin; (f) Absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostea, or
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shell materials, such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner.
  • coatings and shell materials such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner.
  • Examples of usable embedding components are polymeric substances and waxy substances.
  • the active compounds can also be in microencapsulated form, if desired, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc.
  • inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and
  • compositions can also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • suspending agents for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • Dosage forms for topical administration of a compound of this invention include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required, if necessary.
  • the treatment method of the present invention can be used alone or in combination with other treatment methods or drugs.
  • a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage when administered, for a person with a body weight of 60kg, the daily
  • the dosage is usually 1-2000 mg, preferably 50-1000 mg.
  • factors such as the route of administration and the health status of the patient should also be considered for the specific dosage, which are within the skill of skilled physicians.
  • the present invention also provides a preparation method of a pharmaceutical composition, comprising the steps of: mixing a pharmaceutically acceptable carrier with the compound of general formula (I) or its crystal form, pharmaceutically acceptable salt, hydrate or The solvates are mixed to form a pharmaceutical composition.
  • the present invention also provides a treatment method, which includes the steps of: administering the compound of general formula (I) described in the present invention, or its crystal form, pharmaceutically acceptable salt, hydrate or solvate to the subject in need of treatment , or administering the pharmaceutical composition of the present invention for selectively inhibiting KRAS G12D .
  • the present invention has the following main advantages:
  • the compound can selectively promote the proteolysis of KRAS G12D , thereby preventing and/or treating diseases related to KRAS G12D activity or expression (especially highly selective for tumor cells), with high activity and good safety;
  • the compound of the present invention can exhibit the effect of inhibiting cell growth in a catalytic amount.
  • the cells can circulate to degrade the target protein, reduce the dosage, prolong the cycle of administration, and achieve safe and effective anti-tumor effect;
  • the compound has better in vivo and in vitro pharmacodynamics, pharmacokinetic properties and/or lower toxic and side effects.
  • the structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and liquid chromatography-mass chromatography (LC-MS).
  • NMR was detected using a Bruker AVANCE-400 nuclear magnetic instrument, and the determination solvent included deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated acetone (CD 3 COCD 3 ), deuterated chloroform (CDCl 3 ) and deuterated methanol ( CD 3 OD), etc., the internal standard adopts tetramethylsilane (TMS), and the chemical shift is measured in parts per million (ppm).
  • DMSO-d 6 deuterated dimethyl sulfoxide
  • CD 3 COCD 3 deuterated acetone
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS tetramethylsilane
  • LC-MS Liquid chromatography-mass chromatography
  • Qingdao GF254 silica gel plates were used for thin-layer chromatography, 0.15-0.20mm for TLC, and 0.4mm-0.5mm for preparative thin-layer chromatography.
  • Column chromatography generally uses Qingdao silica gel 200-300 mesh silica gel as a carrier.
  • the starting materials in the examples of the present invention are all known and commercially available, or can be adopted or synthesized according to literatures reported in the art.
  • the resulting reaction solution was reacted at -40°C for 0.5 h, then quenched with H 2 O (50 mL) and extracted with DCM (100 mL*2). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure to obtain the target product (4.10 g, crude product). It was directly used in the next reaction without purification.
  • Step 4 (cis)-3-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-1H-biscondensed pyrrolidine-7a(5H)-methyl carboxylate and (trans Preparation of )-3-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-1H-biscondensed pyrrolidine-7a(5H)-methyl carboxylate
  • reaction liquid was reacted at 25° C. for 16 h, and then concentrated under reduced pressure.
  • Step 1 Preparation of ((trans)-3-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-1H-biscondensed pyrrolidin-7a(5H)-yl)methanol
  • the resulting mixture was reacted at 25° C. for 3 h, then diluted with DCM (400 mL), and washed with H 2 O (40 mL). The organic phase was separated and dried over anhydrous Mg2SO4 and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the target product (2.20 g, 2.74 mmol, yield: 66.1%).
  • the reaction mixture was reacted at 100 °C for 1 h, then extracted with EtOAc (200 mL*2). The organic phase was separated and dried over anhydrous Mg2SO4 and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the target product (2.60 g, 2.26 mmol, yield: 86.2%).
  • the first step the preparation of 2-(trimethylsilyl)ethyl (R)-2-(hydroxymethyl)pyrroline-1-carboxylate
  • the reactant was reacted at 100°C for 1 h, then quenched with H 2 O (5 mL), and then extracted with EtOAc (10 mL*3). The organic phase was separated and washed with brine (30 mL), dried over anhydrous MgSO 4 and filtered. The filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography to obtain the target product (0.73g, 702umol, yield: 59.7%, purity: 95.0%).
  • intermediate E was synthesized with different starting materials
  • the first step (1R,5S)-3-(2-(((trans)-3-((3-((2-(2,6-dioxopiperidin-3-yl)-1,3 -Dioxoisoindoline-4-yl)amino)propionamide)methyl)tetrahydro-1H-biscondensed pyrrolidin-7a(5H)-yl)methoxy)-7-(8-ethynyl- 7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2. 1] Preparation of tert-butyl octane-8-carboxylate
  • reaction solution was reacted at 25°C for 2hr, and then added TFA (50 ⁇ L).
  • TFA 50 ⁇ L
  • the resulting reaction was quenched with saturated NaHCO 3 (20 mL) and extracted with EtOAc (3 x 15 mL) after continuing to react for 2 hr at rt.
  • the combined organic phases were dried over anhydrous sodium sulfate and filtered.
  • the filtrate was concentrated under reduced pressure, and the residue was separated by preparative liquid phase to obtain the target product (4.2 mg, 0.0045 mmol, yield: 41%).
  • Embodiment I-4 N-(((trans)-7a-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7 -(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-bis Condensed pyrrolidin-3-yl)methyl)-6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino) Preparation of caproamide
  • Embodiment I-6 N-(((cis)-7a-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7 -(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-bis Condensed pyrrolidin-3-yl)methyl)-7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino) Preparation of -N-methylpropanamide
  • Example I-7 N-(((cis)-7a-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7 -(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-bis Condensed pyrrolidin-3-yl)methyl)-7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino) Preparation of -N-methylbutyramide
  • Example I-8 N-(((cis)-7a-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7 -(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-bis Condensed pyrrolidin-3-yl)methyl)-7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino) Preparation of -N-methylpentanamide
  • Example I-9 N-(((cis)-7a-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7 -(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-bis Condensed pyrrolidin-3-yl)methyl)-7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino) Preparation of -N-methylhexanamide
  • Embodiment I-10 N-(((cis)-7a-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7 -(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-bis Condensed pyrrolidin-3-yl)methyl)-7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino) Preparation of -N-methylheptanamide
  • Example I-11 N-(((cis)-7a-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7 -(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-bis Condensed pyrrolidin-3-yl)methyl)-7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino) Preparation of -N-methyldecylamide
  • Example I-13 N 1 -(((cis)-7a-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)- 7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H- Dicondensed pyrrolidin-3-yl)methyl)-N 3 -((S)-1-((2S,4R)-4-hydroxyl-2-((4-(4-methylthiazolyl-5- Base) benzyl) carbamoyl) pyrrolidin-1-yl)-3,3-dimethyl-1 - oxobutyl-2-yl)-N 1 -methylmalonamide
  • Example I-14 N 1 -(((cis)-7a-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)- 7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H- Dicondensed pyrrolidin-3-yl)methyl)-N 3 -((S)-1-((2S,4R)-4-hydroxyl-2-((4-(4-methylthiazolyl-5- Base ) benzyl) carbamoyl) pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutyl-2-yl)-N 1 -methylsuccinamide
  • Example I-15 N 1 -(((cis)-7a-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)- 7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H- Dicondensed pyrrolidin-3-yl)methyl)-N 3 -((S)-1-((2S,4R)-4-hydroxyl-2-((4-(4-methylthiazolyl-5- Base) benzyl) carbamoyl) pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutyl-2-yl)-N 1 -methylglutaramide
  • Example I-16 N 1 -(((cis)-7a-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)- 7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H- Dicondensed pyrrolidin-3-yl)methyl)-N 3 -((S)-1-((2S,4R)-4-hydroxyl-2-((4-(4-methylthiazolyl-5- Base) benzyl) carbamoyl) pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutyl-2-yl)-N 1 -methyl adipamide
  • Example I-17 N 1 -(((cis)-7a-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)- 7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H- Dicondensed pyrrolidin-3-yl)methyl)-N 3 -((S)-1-((2S,4R)-4-hydroxyl-2-((4-(4-methylthiazolyl-5- Base) benzyl) carbamoyl) pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutyl-2-yl)-N 1 -methylpimelic acid
  • Example I-18 N 1 -(((cis)-7a-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)- 7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H- Dicondensed pyrrolidin-3-yl)methyl)-N 3 -((S)-1-((2S,4R)-4-hydroxyl-2-(((S)-4-(4-methylthiazole Base-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutyl- 2 -yl)-N 1 -methylheptane Amide
  • Example II-1 4-((3-((R)-2-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl) -7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)pyrroline-1
  • Example II-2 4-((4-((R)-2-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl) -7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)pyrroline-1
  • Example II-3 4-((5-((R)-2-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl) -7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)pyrroline-1
  • Example II-4 4-((6-((R)-2-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl) -7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)pyrroline-1
  • Example II-5 4-((7-((R)-2-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl) -7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)pyrroline-1
  • Example II-6 4-((10-((R)-2-(((4-((1R,5S)-3,8-3,8-diazabicyclo[3.2.1]octane- 3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl )pyrrolidin-1-yl)-10-oxodecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione
  • the reference compound structure is as follows:
  • Example I-1 12.9
  • Example I-2 12.4
  • Example I-3 14.2
  • Example I-4 12.5
  • Example II-6 2100 MRTX1133 17.7
  • GP2D cells were seeded into 384-well plates and cultured overnight in a 37°C, 5% CO2 incubator.
  • Example IC 50 (nM) Example I-4 525 Example I-6 325 Example I-7 178 Example I-8 119 Example I-9 99 Example I-10 66 Example I-11 28 Example I-12 87 Example I-13 150 Example I-14 305 Example I-15 234 Example I-16 428 Example I-17 227 Example I-18 264 Example I-19 171 Example I-20 601 Example I-21 1052 Example I-22 373
  • the compounds to be tested were serially diluted, and each compound was diluted in 10 concentration gradients (from 50 ⁇ M to 0.003 ⁇ M) and 100 nL was added to the corresponding wells of the microwell plate. After dosing, add 40 ⁇ L of phosphate buffer solution to each well in rows A, P and columns 1 and 24, and then place the microwell plate in a carbon dioxide incubator for 5 days.
  • Inoculate tumor cells such as SNU-61, GP2D, 5x10 5 ⁇ 1x10 6 ) in a culture dish (2D, P100 mm dish) and culture for 2-4 days until 70-80% saturation;

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Abstract

La présente invention concerne un régulateur d'hydrolyse de protéine KRASG12D, son procédé de préparation et son utilisation. Plus particulièrement, un composé selon la présente invention a une structure telle que représentée dans la formule (I). La présente invention concerne en outre un procédé de préparation du composé et l'utilisation du composé en tant que régulateur d'hydrolyse de protéine KRASG12D. Le composé selon la présente invention a un bon effet régulateur sélectif sur l'hydrolyse de KRASG12D.
PCT/CN2022/142077 2021-12-24 2022-12-26 Régulateur d'hydrolyse de protéine krasg12d, son procédé de préparation et son utilisation Ceased WO2023116934A1 (fr)

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Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11912723B2 (en) 2022-02-09 2024-02-27 Quanta Therapeutics, Inc. KRAS modulators and uses thereof
WO2024044334A3 (fr) * 2022-08-24 2024-05-10 Ranok Therapeutics (Hangzhou) Co. Ltd. Procédés et compositions de modulation de kras(g12d)
WO2024206858A1 (fr) 2023-03-30 2024-10-03 Revolution Medicines, Inc. Compositions pour induire une hydrolyse de ras gtp et leurs utilisations
US12110291B2 (en) 2022-11-30 2024-10-08 Tiger Biotherapeutics Inc. Glutarimide-containing pan-KRAS-mutant degrader compounds and uses thereof
WO2024229406A1 (fr) 2023-05-04 2024-11-07 Revolution Medicines, Inc. Polythérapie pour une maladie ou un trouble lié à ras
US12145947B2 (en) 2022-05-25 2024-11-19 Quanta Therapeutics, Inc. Pyrimidine based modulators and uses thereof
US12168058B2 (en) 2022-11-30 2024-12-17 Tiger Biotherapeutics, Inc. Glutarimide-containing KRAS-mutant degrader compounds and uses thereof
WO2024263586A1 (fr) * 2023-06-20 2024-12-26 PAQ Therapeutics Inc. Chimères ciblant la protéolyse kras
WO2025006753A2 (fr) 2023-06-30 2025-01-02 Merck Patent Gmbh Composés hétérobifonctionnels pour la dégradation de la protéine kras
WO2025006783A2 (fr) 2023-06-30 2025-01-02 Merck Patent Gmbh Composés hétérobifonctionnels pour la dégradation de kras
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
WO2025076044A1 (fr) * 2023-10-03 2025-04-10 PAQ Therapeutics Inc. Chimères ciblant la protéolyse kras
WO2025080946A2 (fr) 2023-10-12 2025-04-17 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025085815A1 (fr) * 2023-10-20 2025-04-24 Seed Therapeutics Us, Inc. Composés protac se liant à l'ubiquitine ligase keap1 pour la dégradation ciblée de protéines
WO2025083472A3 (fr) * 2023-10-20 2025-06-05 Seed Therapeutics Us, Inc. Composés protac se liant à l'ubiquitine ligase keap1 pour la dégradation ciblée de protéines
WO2025171296A1 (fr) 2024-02-09 2025-08-14 Revolution Medicines, Inc. Inhibiteurs de ras
US12421254B2 (en) 2023-03-15 2025-09-23 Quanta Therapeutics, Inc. KRAS modulators and uses thereof
US12448399B2 (en) 2023-01-26 2025-10-21 Arvinas Operations, Inc. Cereblon-based KRAS degrading PROTACs and uses related thereto
US12448400B2 (en) 2023-09-08 2025-10-21 Gilead Sciences, Inc. KRAS G12D modulating compounds
WO2025240847A1 (fr) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025255438A1 (fr) 2024-06-07 2025-12-11 Revolution Medicines, Inc. Procédés de traitement d'une maladie ou d'un trouble lié à la protéine ras

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025039676A1 (fr) * 2023-08-18 2025-02-27 贝达药业股份有限公司 Composé de dégradation ciblé de protéine pan-kras et son utilisation
TW202515886A (zh) * 2023-09-22 2025-04-16 大陸商杭州中美華東製藥有限公司 Kras-protac嵌合化合物及其用途

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112218859A (zh) * 2018-04-04 2021-01-12 阿尔维纳斯运营股份有限公司 蛋白水解调节剂及相关使用方法
WO2021041671A1 (fr) * 2019-08-29 2021-03-04 Mirati Therapeutics, Inc. Inhibiteurs de kras g12d
WO2021222138A1 (fr) * 2020-04-27 2021-11-04 Development Center For Biotechnology Composés pour la dégradation de la protéine ras mutante
WO2022105857A1 (fr) * 2020-11-20 2022-05-27 Jacobio Pharmaceuticals Co., Ltd. Inhibiteurs de kras g12d
WO2022105859A1 (fr) * 2020-11-20 2022-05-27 Jacobio Pharmaceuticals Co., Ltd. Inhibiteurs de kras g12d
WO2022266206A1 (fr) * 2021-06-16 2022-12-22 Erasca, Inc. Conjugués d'inhibiteurs de kras

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112218859A (zh) * 2018-04-04 2021-01-12 阿尔维纳斯运营股份有限公司 蛋白水解调节剂及相关使用方法
WO2021041671A1 (fr) * 2019-08-29 2021-03-04 Mirati Therapeutics, Inc. Inhibiteurs de kras g12d
WO2021222138A1 (fr) * 2020-04-27 2021-11-04 Development Center For Biotechnology Composés pour la dégradation de la protéine ras mutante
WO2022105857A1 (fr) * 2020-11-20 2022-05-27 Jacobio Pharmaceuticals Co., Ltd. Inhibiteurs de kras g12d
WO2022105859A1 (fr) * 2020-11-20 2022-05-27 Jacobio Pharmaceuticals Co., Ltd. Inhibiteurs de kras g12d
WO2022266206A1 (fr) * 2021-06-16 2022-12-22 Erasca, Inc. Conjugués d'inhibiteurs de kras

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11912723B2 (en) 2022-02-09 2024-02-27 Quanta Therapeutics, Inc. KRAS modulators and uses thereof
US12145947B2 (en) 2022-05-25 2024-11-19 Quanta Therapeutics, Inc. Pyrimidine based modulators and uses thereof
WO2024044334A3 (fr) * 2022-08-24 2024-05-10 Ranok Therapeutics (Hangzhou) Co. Ltd. Procédés et compositions de modulation de kras(g12d)
US12110291B2 (en) 2022-11-30 2024-10-08 Tiger Biotherapeutics Inc. Glutarimide-containing pan-KRAS-mutant degrader compounds and uses thereof
US12168058B2 (en) 2022-11-30 2024-12-17 Tiger Biotherapeutics, Inc. Glutarimide-containing KRAS-mutant degrader compounds and uses thereof
US12195459B2 (en) 2022-11-30 2025-01-14 Tiger Biotherapeutics Inc. Glutarimide-containing pan-KRAS-mutant degrader compounds and uses thereof
US12448399B2 (en) 2023-01-26 2025-10-21 Arvinas Operations, Inc. Cereblon-based KRAS degrading PROTACs and uses related thereto
US12421254B2 (en) 2023-03-15 2025-09-23 Quanta Therapeutics, Inc. KRAS modulators and uses thereof
WO2024206858A1 (fr) 2023-03-30 2024-10-03 Revolution Medicines, Inc. Compositions pour induire une hydrolyse de ras gtp et leurs utilisations
WO2024229406A1 (fr) 2023-05-04 2024-11-07 Revolution Medicines, Inc. Polythérapie pour une maladie ou un trouble lié à ras
WO2024263586A1 (fr) * 2023-06-20 2024-12-26 PAQ Therapeutics Inc. Chimères ciblant la protéolyse kras
WO2025006783A3 (fr) * 2023-06-30 2025-02-20 Merck Patent Gmbh Composés hétérobifonctionnels pour la dégradation de kras
WO2025006783A2 (fr) 2023-06-30 2025-01-02 Merck Patent Gmbh Composés hétérobifonctionnels pour la dégradation de kras
WO2025006753A2 (fr) 2023-06-30 2025-01-02 Merck Patent Gmbh Composés hétérobifonctionnels pour la dégradation de la protéine kras
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
US12448400B2 (en) 2023-09-08 2025-10-21 Gilead Sciences, Inc. KRAS G12D modulating compounds
WO2025076044A1 (fr) * 2023-10-03 2025-04-10 PAQ Therapeutics Inc. Chimères ciblant la protéolyse kras
US20250144225A1 (en) * 2023-10-03 2025-05-08 PAQ Therapeutics Inc. KRAS Proteolysis Targeting Chimeras
WO2025080946A2 (fr) 2023-10-12 2025-04-17 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025085815A1 (fr) * 2023-10-20 2025-04-24 Seed Therapeutics Us, Inc. Composés protac se liant à l'ubiquitine ligase keap1 pour la dégradation ciblée de protéines
WO2025083472A3 (fr) * 2023-10-20 2025-06-05 Seed Therapeutics Us, Inc. Composés protac se liant à l'ubiquitine ligase keap1 pour la dégradation ciblée de protéines
WO2025171296A1 (fr) 2024-02-09 2025-08-14 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025240847A1 (fr) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025255438A1 (fr) 2024-06-07 2025-12-11 Revolution Medicines, Inc. Procédés de traitement d'une maladie ou d'un trouble lié à la protéine ras

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