WO2023116934A1 - Krasg12d protein hydrolysis regulator, and preparation method therefor and use thereof - Google Patents

Krasg12d protein hydrolysis regulator, and preparation method therefor and use thereof Download PDF

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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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group
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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苏州泽璟生物制药股份有限公司
上海泽璟医药技术有限公司
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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

The present invention relates to a KRASG12D protein hydrolysis regulator, and a preparation method therefor and the use thereof. Specifically, a compound of the present invention has the structure as shown in formula (I). The present invention further discloses a method for preparing the compound and the use of the compound as the KRASG12D protein hydrolysis regulator. The compound of the present invention has a good selective regulatory effect on the hydrolysis of KRASG12D.

Description

KRAS G12D蛋白水解调节剂及其制备方法和应用 KRAS G12D proteolysis regulator and its preparation method and application 技术领域technical field
本发明属于药物领域，具体涉及一种KRAS G12D蛋白水解调节剂及其制备方法和应用。 The invention belongs to the field of medicine, and in particular relates to a KRAS G12D proteolysis regulator, a preparation method and application thereof.
背景技术Background technique
在所有人类肿瘤中约四分之一是由RAS突变引起，每年有近一百万人因此而失去生命。在RAS家族中，KRAS突变占到了所有RAS突变的85％。在近90％的胰腺癌、30-40％的结肠癌中、以及15-20％的肺癌中(主要为非小细胞肺癌)中发现KRAS突变。在KRAS突变中最主要的突变时G12C和G12D突变，其中G12C突变主要发生在HSCLC中，而G12D突变主要发生在胰腺癌中。到目前为止，市场上仍然没有针对KRAS G12D突变的药物被批准上市。 About a quarter of all human tumors are caused by RAS mutations, and nearly one million people lose their lives each year. In RAS families, 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.
目前临床上胰腺癌常规治疗方案包括吉西他滨单药疗法、吉西他滨联合白蛋白紫杉醇、以及FOLFIRINOX方案(奥沙利铂+伊立替康+5-FU/LV)等。其中脂质体伊立替康适用于与氟尿嘧啶和亚叶酸联用治疗经吉西他滨化疗效果不佳的晚期胰腺癌患者(二线疗法)。但是总的来说，目前胰腺癌有效的治疗手段有限，患者总生存时间不超过1年。虽然针对晚期胰腺癌患者的药物探索在持续不断开展，但到现在为止研究进展仍较为缓慢。Currently, conventional clinical treatment options for pancreatic cancer include gemcitabine monotherapy, gemcitabine combined with nab-paclitaxel, and FOLFIRINOX regimen (oxaliplatin+irinotecan+5-FU/LV). Among them, 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). But in general, the current effective treatment methods for pancreatic cancer are limited, and the overall survival time of patients is less than 1 year. Although drug discovery for patients with advanced pancreatic cancer continues, research progress has been slow so far.
由于KRAS G12D靶蛋白在病理学上与多种疾病相关，尤其胰腺癌，因此目前需要新型的KRAS G12D抑制剂用于临床治疗。高选择性高活性的KRAS G12D抑制剂可以对KRAS G12D突变导致的癌症等疾病更有效治疗，以及减少脱靶效应的潜力，因而具有更迫切的临床需求。 Since 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.
蛋白水解在细胞的正常生命活动中是至关重要且被严格调控的，其过程主要是通过泛素化酶系统的参与而完成的。待分解的蛋白质通过E1、E2和E3泛素连接酶系统标记，进而被蛋白酶识别并水解。蛋白水解调节剂类分子是一种双功能活性化合物，分子的一端与靶蛋白紧密结合，另一端与E3泛素连接酶相结合，两端并通过各种连接链连接。这种双功能分子在体内可以同时识别靶蛋白和E3泛素连接酶，将靶蛋白和E3泛素连接酶拉近后使靶蛋白被泛素化，然后通过泛素-蛋白酶体途径水解。靶蛋白水解后，这个双功能性分子又可以被释放出来参与到下一周期的蛋白水解过程，从而具有催化效果，因此在临床上可以通过较少的药物给药剂量就可以实现高效的治疗作用。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. .
由于KRAS G12D靶蛋白在病理学上与多种疾病相关，因此目前还需要新型的KRAS G12D抑制剂用于临床治疗。高选择性高活性的KRAS G12D蛋白水解调节剂可以对KRAS突变导致的癌症等疾病更有效治疗，以及减少脱靶效应的潜力，因而具有更迫切的临床需求。 Since 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.
发明内容Contents of the invention
本发明的目的在于提供一类新型的KRAS G12D蛋白水解调节剂及其制备方法和应用。 The purpose of the present invention is to provide a novel KRAS G12D proteolysis regulator and its preparation method and application.
本发明第一方面，提供了一种具有式(I)结构的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药：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 :
Figure PCTCN2022142077-appb-000001
Figure PCTCN2022142077-appb-000001
式中：In the formula:
ULM代表一个可以和E3连接酶结合的小分子配体部分；ULM represents a small molecule ligand part that can bind to E3 ligase;
PTM代表一个可以和KRAS G12D蛋白结合的小分子配体部分； PTM represents a small molecule ligand part that can bind to KRAS G12D protein;
L可以是键或者是可以连接PTM和ULM的连接基团。L can be a bond or a linking group that can connect the PTM and ULM.
在另一优选例中，PTM具有式(PTM-I)所示结构In another preference, PTM has the structure shown in formula (PTM-I)
Figure PCTCN2022142077-appb-000002
Figure PCTCN2022142077-appb-000002
式中，In the formula,
虚线表示通过任意位置与L的连接；Dashed lines indicate connections to L through arbitrary locations;
Q选自：N、C-CN、C-H、C-F、或C-Cl；Q is selected from: N, C-CN, C-H, C-F, or C-Cl;
R 1选自：H、-CONH 2、或-(C＝NH)NH 2； R 1 is selected from: H, -CONH 2 , or -(C=NH)NH 2 ;
X选自取代或未取代的下组基团：4-14元饱和或不饱和的杂环基、5-14元杂芳基；其中，所述取代是指被一个或多个R 2取代；R 2选自取代或未取代的下组基团：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 3-C 20环烷基、4-20元杂环基、C 6-C 14芳基、5-14元杂芳基、卤素、硝基、羟基、氧代基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基；其中，R 2中所述取代是指被一个或多个R取代； 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 ureido group; wherein, the substitution in R2 means replaced by one or more R;
A选自：C、CH或N；A is selected from: C, CH or N;
Y选自：键、O或NR b；R b选自取代或未取代的下组基团：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、氨基、羟基、4-20元杂环基、C 6-C 14芳基、5-14元杂芳基；其中，所述取代是指被一个或多个R取代； 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选自取代或未取代的下组基团：-(CH 2) nR 7、-(CH 2) nO(CH 2) mR 7、-(CH 2) nSR 7、-(CH 2) nCOR 7、-(CH 2) nC(O)OR 7、-(CH 2) nS(O) qR 7、-(CH 2) nNR 5R 7、-(CH 2) nC(O)NR 5R 7、-(CH 2) nNR 5C(O)R 7、-(CH 2) nNR 5C(O)NR 7R 8、-(CH 2) nS(O) qNR 5R 7、-(CH 2) nNR 5S(O) qR 7、-(CH 2) nNR 5S(O) qNR 7R 8，其中，CH 2中的H可以被取代；R 5、R 7、和R 8相同或不同，且各自独立地选自取代或未取代的下组基团：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、氨 基、羟基、4-20元杂环基、C 6-C 14芳基、5-14元杂芳基；或者R 5和R 7、R 5和R 8或R 7和R 8以及相邻的原子环合形成4-20元杂环基；其中，所述取代是指被一个或多个R取代； 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) q NR 7 R 8 , where H in CH 2 can be substituted ; R 5 , R 7 , and R 8 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 alkane radical, 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 group, amino, hydroxyl, 4-20 membered heterocyclic group, C 6 -C 14 aryl group, 5-14 membered heteroaryl group; or R 5 and R 7 , R 5 and R 8 or R 7 and R 8 and the corresponding Adjacent atoms are ring-joined to form a 4-20-membered heterocyclic group; wherein, the substitution refers to being substituted by one or more R;
R 3和R 6相同或不同，各自独立地选自取代或未取代的下组基团：氢、氘、卤素、氨基、氰基、C 1-C 3烷基、氘代C 1-C 3烷基、卤代C 1-C 3烷基、C 3-C 6环烷基、氘代C 3-C 6环烷基、卤代C 3-C 6环烷基；其中，所述取代是指被一个或多个R取代； 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选自取代或未取代的下组取代或未取代的下组基团：4-14元杂环基、C 6-C 14芳基、5-14元杂芳基；其中，所述取代是指被一个或多个R取代； 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选自：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、(C 3-C 18环烷基)C 1-C 18烷基、(4-20元杂环基)C 1-C 18烷基、(C 1-C 18烷氧基)C 1-C 18烷基、C 3-C 18环烷基氧基、(C 3-C 18环烷基氧基)C 1-C 18烷基、4-20元杂环基氧基、(4-20元杂环基氧基)C 1-C 18烷基、C 6-C 20芳基氧基、(C 6-C 20芳基氧基)C 1-C 18烷基、5-20元杂芳基氧基、(5-20元杂芳基氧基)C 1-C 18烷基、C 1-C 18烷基胺基、(C 1-C 18烷基胺基)C 1-C 18烷基、C 3-C 18环烷基胺基、(C 3-C 18环烷基胺基)C 1-C 18烷基、4-20元杂环基胺基、(4-20元杂环基胺基)C 1-C 18烷基、C 6-C 20芳基胺基、(C 6-C 20芳基胺基)C 1-C 18烷基、5-20元杂芳基胺基、(5-20元杂芳基胺基)C 1-C 18烷基、乙烯基、乙炔基、(C 1-C 6烷基)乙烯基、氘代(C 1-C 6烷基)乙烯基、卤代(C 1-C 6烷基)乙烯基、(C 1-C 6烷基)乙炔基、氘代(C 1-C 6烷基)乙炔基、卤代(C 1-C 6烷基)乙炔基、(C 3-C 14环烷基)乙炔基、(4-14元环杂环基)乙炔基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 3-C 20环烷基、4-20元杂环基、C 6-C 14芳基、5-14元杂芳基、卤素、硝基、羟基、氧代基、氰基、酯基、胺基、酰胺基、砜基、磺酰基或脲基； 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 alkylamino, (C 1 -C 18 alkylamino)C 1 -C 18 alkyl, C 3 -C 18 cycloalkylamino, (C 3 -C 18 cycloalkylamino) C 1 -C 18 alkyl, 4-20 membered heterocyclylamine, (4-20 membered heterocyclylamino) C 1 -C 18 alkyl, C 6 -C 20 arylamino, (C 6 -C 20 arylamino) C 1 -C 18 alkyl, 5-20 membered heteroarylamine, (5-20 membered heteroarylamino) C 1 -C 18 Alkyl, vinyl, ethynyl, (C 1 -C 6 alkyl) vinyl, deuterated (C 1 -C 6 alkyl) vinyl, halogenated (C 1 -C 6 alkyl) vinyl, (C 1 -C 6 alkyl)ethynyl, deuterated (C 1 -C 6 alkyl)ethynyl, halo(C 1 -C 6 alkyl)ethynyl, (C 3 -C 14 cycloalkyl) Ethynyl, (4-14 membered ring heterocyclyl) ethynyl, 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 heterocyclic group, C 6 -C 14 aryl group, 5-14 membered heteroaryl group, halogen, nitro, hydroxyl, oxo, cyano, ester, amine, Amide, sulfone, sulfonyl or ureido groups;
n和m各自独立地选自0、1、2、3、4、5或6；n and m are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
q为1或2。q is 1 or 2.
在另一优选例中，PTM-I中
Figure PCTCN2022142077-appb-000003
部分选自： In another preferred example, in PTM-I
Figure PCTCN2022142077-appb-000003
Some selected from:
Figure PCTCN2022142077-appb-000004
Figure PCTCN2022142077-appb-000004
Figure PCTCN2022142077-appb-000005
Figure PCTCN2022142077-appb-000005
其中，p选自0、1、2、3、4、5或6；R 1和R 2的定义如上所述。 Wherein, p is selected from 0, 1, 2, 3, 4, 5 or 6; R 1 and R 2 are as defined above.
在另一优选例中，
Figure PCTCN2022142077-appb-000006
部分选自：
Figure PCTCN2022142077-appb-000007
优选地为
Figure PCTCN2022142077-appb-000008
更优选地为
Figure PCTCN2022142077-appb-000009
In another preferred example,
Figure PCTCN2022142077-appb-000006
Some selected from:
Figure PCTCN2022142077-appb-000007
preferably
Figure PCTCN2022142077-appb-000008
more preferably
Figure PCTCN2022142077-appb-000009
在另一优选例中，PTM具有式(PTM-2)所示结构：In another preference, PTM has the structure shown in formula (PTM-2):
Figure PCTCN2022142077-appb-000010
Figure PCTCN2022142077-appb-000010
式中，In the formula,
p选自0、1、2、3、4、5或6；p is selected from 0, 1, 2, 3, 4, 5 or 6;
R 2、R 3、R 4、Y和Z的定义如上所述。 R 2 , R 3 , R 4 , Y and Z are as defined above.
在另一优选例中，PTM具有式(PTM-3)所示结构：In another preference, PTM has the structure shown in formula (PTM-3):
Figure PCTCN2022142077-appb-000011
Figure PCTCN2022142077-appb-000011
式中，In the formula,
p选自0、1、2、3、4、5或6；p is selected from 0, 1, 2, 3, 4, 5 or 6;
R 2、R 3、R 4和Z的定义如上所述。 R 2 , R 3 , R 4 and Z are as defined above.
在另一优选例中，R 4选自取代或为取代的下组基团：萘基、喹啉基、异喹啉基、苯并噻吩、苯并噻唑、苯并呋喃、苯基、咪唑基、噻吩基、呋喃基、噻唑基、恶唑基、吡啶基、吡嗪基、苯并吡嗪基；其中，所述取代是指被选自下组的一个或多个基团取代：羟基、炔基、卤素、NH 2、CN、乙烯基、C 1-C 6烷基、C 3-C 6环烷基、4-6元杂环基。 In another preferred embodiment, 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.
在另一优选例中，Z选自取代或未取代的下组基团：
Figure PCTCN2022142077-appb-000012
Figure PCTCN2022142077-appb-000013
Figure PCTCN2022142077-appb-000014
其中，所述取代是指基团中的任意H原子被选自下组的基团取代：卤素、羟基、氰基、NH 2、C 1-C 6烷基、C 3-C 6环烷基、4-6元杂环基、C 1-C 6烷氧基、C3-C6环烷基氧基、4-6元杂环基氧基、C 1-C 6烷胺基、C 3-C 6环烷基胺基、4-6元杂环基胺基、C1-C6烷胺基C1-C6烷基、C 3-C 6环烷基胺基C 1-C 6烷基、4-6元杂环基胺基C1-C6烷基、C 1-C 6酰基、C 1-C 6磺酰基。 In another preferred example, Z is selected from the following groups of substituted or unsubstituted groups:
Figure PCTCN2022142077-appb-000012
Figure PCTCN2022142077-appb-000013
Figure PCTCN2022142077-appb-000014
Wherein, 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.
在另一优选例中，PTM选自：In another preference, PTM is selected from:
Figure PCTCN2022142077-appb-000015
Figure PCTCN2022142077-appb-000015
Figure PCTCN2022142077-appb-000016
Figure PCTCN2022142077-appb-000016
Figure PCTCN2022142077-appb-000017
Figure PCTCN2022142077-appb-000017
在另一优选例中，ULM选自可以和选自下组的E3连接酶结合的小分子配体部分：VHL(Von Rippel-Lindau)、CRBN(Cereblon)、MDM2(Mouse double-minute homolog2)、IAP、Keap1、HSP70、FKBP、DCAF15、DCAF16、RNF4、RNF114和AhR。In another preferred embodiment, 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.
在另一优选例中，ULM优选自可以和VHL(Von Rippel-Lindau)、CRBN(Cereblon)、MDM2(Mouse double-minute homolog2)、或IAP等E3连接酶结合的小分子VLM、CLM、MLM或ILM配体部分。In another preferred example, 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. ILM ligand part.
在另一优选例中，ULM选自可以和VHL(Von Rippel-Lindau)、CRBN(Cereblon)等E3连接酶结合的小分子VLM、或CLM配体部分，更优选地为和CRBN(Cereblon)E3连接酶结合的小分子CLM配体部分。In another preferred embodiment, 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.
在另一优选例中，式(I)化合物选自下组：PTM-VLM、PTM-CLM、PTM-MLM、PTM-ILM、PTM-L-VLM、PTM-L-CLM、PTM-L-MLM或PTM-L-ILM。In another preferred embodiment, 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.
在另一优选例中，ULM为VLM，其具有式(VLM-I)所示的结构：In another preference, ULM is VLM, which has the structure shown in formula (VLM-1):
Figure PCTCN2022142077-appb-000018
Figure PCTCN2022142077-appb-000018
式中，In the formula,
虚线表示通过任意位置与L的连接；Dashed lines indicate connections to L through arbitrary locations;
X a1和X a2各自独立地选自下组：键、O、NR a2、CR a3R a4、C＝O、C＝S、SO和SO 2；其中，R a2、R a3、R a4各自独立地选自取代或未取代的下组基团：C 1-C 18烷基、C 3-C 12环烷基、4-12元杂环基； X a1 and X a2 are each independently selected from the following group: bond, O, NR a2 , CR a3 R a4 , C=O, C=S, SO and SO 2 ; wherein R a2 , R a3 , and R a4 are each independently is selected from the following groups of substituted or unsubstituted groups: C 1 -C 18 alkyl, C 3 -C 12 cycloalkyl, 4-12 membered heterocyclic group;
各R a1相同或者不同，独立地选自：卤素、羟基、NH 2、CN、C 1-C 6烷基、或者(＝O)；或者不同R a1之间环合形成3-4元环； Each R a1 is the same or different, independently selected from: halogen, hydroxyl, NH 2 , CN, C 1 -C 6 alkyl, or (=O); or 3-4 membered rings formed by cyclization between different R a1s ;
n a1选自：0、1、2、3、或4； n a1 is selected from: 0, 1, 2, 3, or 4;
W a1和W a2各自独立地选自取代或未取代的下组基团：-X a3-X a4-或-X a4；其中，X a3、X a4各自独立地选自取代或未取代的下组基团：-(CH 2) m a1R a5、-(CH 2) m a1O(CH 2) m a2R a5、-(CH 2) m a1SR a5、H-(CH 2) m a1COR a5、-(CH 2) m a1C(O)OR a5、-(CH 2) m a1S(O) m a3R a5、-(CH 2) m a1NR a5R a6、 -(CH 2) m a1C(O)NR a5R a6、-(CH 2) m a1NR a5C(O)R a6-、-(CH 2) m a1NR a5C(O)NR a6R a7、-(CH 2) m a1S(O) m a3NR a5R a6、-(CH 2) m a1NR a5S(O) m a3R a6、-(CH 2) m a1NR a5S(O) m a3NR a6R a7，其中，任意位置的H可以任选地被取代；R a5、R a6、R a7各自独立地选自取代或未取代的下组基团：键、氢、C 1-C 18烷基、C 3-C 20环烷基、4-20元杂环基、C 6-C 14芳基、5-20元杂芳基； 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 a5 R a6 , -(CH 2 ) m a1 NR a5 C(O)R a6 -, -(CH 2 ) m a1 NR a5 C(O)NR a6 R a7 , -(CH 2 ) m a1 S(O) m a3 NR a5 R a6 , -(CH 2 ) m a1 NR a5 S(O) m a3 R a6 , -(CH 2 ) m a1 NR a5 S(O) m a3 NR a6 R a7 , wherein, the H at any position can be optionally substituted; R a5 , R a6 , and R a7 are each independently selected from the following group of substituted or unsubstituted groups: bond, hydrogen, C 1 -C 18 alkyl, C 3 -C 20 cycloalkyl, 4-20 membered heterocyclic group, C 6 -C 14 aryl, 5-20 membered heteroaryl;
m a1、 m a2各自独立地选自：0、1、2、3、4、5或6； m a1 , m a2 are each independently selected from: 0, 1, 2, 3, 4, 5 or 6;
m a3选自：0、1或2； m a3 is selected from: 0, 1 or 2;
所述取代是指被选自下组的一个或多个基团取代：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 6-C 14芳基、5-14元杂芳基、4-20元杂环基、卤素、氧代基、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基；或者被L所取代。 The 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.
在另一优选例中，ULM为VLM，其具有式(VLM-IIA-C)所示的结构：In another preferred embodiment, ULM is VLM, which has the structure shown in formula (VLM-IIA-C):
Figure PCTCN2022142077-appb-000019
Figure PCTCN2022142077-appb-000019
虚线表示通过任意位置与L的连接，如通过R a8、R a9、R a10、R a11、R a12、苯环、OH、CH或NH等基团与L的连接； 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和R a10各自独立地选自取代或未取代的下组基团：氢、卤素、氰基、C 1-C 18烷基或亚烷基、C 3-C 12环烷基或亚环烷基、4-12元杂环基或亚杂环基、C 6-C 14芳基或亚芳基、5-20元杂芳基或亚杂芳基、-NR a13R a14；其中R a13、R a14独立地选自取代或未取代的下组基团：氢、C 1-C 6烷基、C 3-C 6环烷基、4-6元杂环基、COC 1-C 6烷基、COC 1-C 6卤代烷基、COC 1-C 6烷胺基、COC 1-C 6烷胺基C 1-C 6烷基、COC 3-C 6环烷基、COC 1-C 6卤代环烷基、COC 4-C 6杂环基、COC 4-C 6卤代杂环基； 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, COC 3 -C 6 cycloalkyl, COC 1 - C 6 halocycloalkyl, COC 4 -C 6 heterocyclyl, COC 4 -C 6 haloheterocyclyl;
R a11各自独立地选自取代或未取代的下组基团：氢、卤素、氰基、C 1-C 6酰基、C 1-C 6烷基、C 3-C 6环烷基、或4-6元杂环基； 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相同或不同，各自独立地选自取代或未取代的下组基团：OH、卤素、C 6-C 14芳基和5-20元杂芳基； 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相同或不同，各自独立地选自取代或未取代的下组基团：OH、卤素、C 6-C 14芳基和5-20元杂芳基； 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;
m a4和 m a5各自独立地选自：1、2、3、4、或5； m a4 and m a5 are each independently selected from: 1, 2, 3, 4, or 5;
所述取代是指被选自下组的一个或多个基团取代：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 6-C 14芳基、5-14元杂芳基、4-20元杂环基、卤素、氧代基、 硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基； The 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;
虚线如上定义。Dashed lines are as defined above.
在另一优选例中，ULM为CLM，其选自下组：In another preference, ULM is CLM, which is selected from the following group:
Figure PCTCN2022142077-appb-000020
Figure PCTCN2022142077-appb-000020
各式中，各基团独立地如下定义：In each formula, each group is independently defined as follows:
虚线表示与L的连接；The dotted line indicates the connection to L;
Q a1、Q a2、Q a3和Q a4各自独立地选自：CH或N； Q a1 , Q a2 , Q a3 and Q a4 are each independently selected from: CH or N;
W b1相同或不同，各自独立地选自：C＝O、SO 2、CR b’3R b’4、NR b5；其中，R b’3和R b’4各自独立地选自取代或未取代的下组基团：氢、卤素、氰基、C 1-C 6烷基、C 3-C 6环烷基和4-6元杂环基；R b5选自取代或未取代的下组基团：氢、C 1-C 6烷基、C 3-C 6环烷基、或4-6元杂环基、C 6-C 14芳基和5-14元杂芳基； W b1 is the same or different, each independently selected from: C=O, SO 2 , CR b'3 R b'4 , NR b5 ; wherein, each of R b'3 and R b'4 is independently selected from substituted or unsubstituted Substituted subgroups: hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl and 4-6 membered heterocyclic groups; R b5 is selected from substituted or unsubstituted subgroups Group: hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or 4-6 membered heterocyclic group, C 6 -C 14 aryl and 5-14 membered heteroaryl;
X b1、X b2和X b3相同或不同，各自独立地选自：CH 2、O或S； X b1 , X b2 and X b3 are the same or different, each independently selected from: CH 2 , O or S;
Z b1和Z b2相同或不同，各自独立地选自：CH 2、O或S； Z b1 and Z b2 are the same or different, each independently selected from: CH 2 , O or S;
Y b1选自：CH 2、O、S或NR b6；R b6选自取代或未取代的下组基团：氢、C 1-C 6烷基、C 3-C 6环烷基、或4-6元杂环基、C 6-C 14芳基和5-14元杂芳基； 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、G b2相同或不同，各自独立地选自取代或未取代的下组基团：氢、C 1-C 6烷基、C 3-C 6环烷基、4-6元杂环基、C 6-C 14芳基和5-14元杂芳基； 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、A b2相同或不同，各自独立地选自取代或未取代的下组基团：氢、卤素、氰基、C 1-C 6烷基、C 3-C 6环烷基、4-6元杂环基、C 6-C 14芳基和5-14元杂芳基； 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和R b3相同或不同，各自独立地选自取代或未取代的下组基团：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 6-C 14芳基、5-14元杂芳基、4-20元杂环基、卤素、氧代基、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基和脲基； 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、n b2相同或不同，各自独立地选自：0、1、2、3或4； n b1 and n b2 are the same or different, each independently selected from: 0, 1, 2, 3 or 4;
所述取代是指被选自下组的一个或多个基团取代：氢、氘、C 1-C 18烷基、氘代C 1-C 18 烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 6-C 14芳基、5-14元杂芳基、4-20元杂环基、卤素、氧代基、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基和脲基。 The 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.
在另一优选例中，ULM为CLM，其选自下组：In another preference, ULM is CLM, which is selected from the following group:
Figure PCTCN2022142077-appb-000021
Figure PCTCN2022142077-appb-000021
虚线、W b1、R b1、R b2、R b3、A b1、A b2、G b2、Y b1、n b1和n b2的定义如上所述。 Dashed lines, 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.
在另一优选例中，ULM为CLM，其选自下组：In another preference, ULM is CLM, which is selected from the following group:
Figure PCTCN2022142077-appb-000022
Figure PCTCN2022142077-appb-000022
虚线、R b1、R b2、R b3、n b1和n b2的定义如上所述。 Dashed lines, R b1 , R b2 , R b3 , n b1 and n b2 are as defined above.
在另一优选例中，ULM为MLM，其选自下组：In another preferred embodiment, ULM is MLM, which is selected from the following group:
Figure PCTCN2022142077-appb-000023
Figure PCTCN2022142077-appb-000023
Figure PCTCN2022142077-appb-000024
Figure PCTCN2022142077-appb-000024
各式中，各基团独立地如下定义：In each formula, each group is independently defined as follows:
虚线表示与L的连接；The dotted line indicates the connection to L;
X c1选自下组：O、S、SO、SO 2、CR c29R c30、NR c31，其中，R c29和R c30相同或不同，且各自独立地选自取代或未取代的下组基团：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 6-C 14芳基、5-14元杂芳基、4-20元杂环基、卤素、氧代基、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基，或者R c29和R c30环合形成3-6元杂环基；R c31选自取代或未取代的下组基团：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 6-C 14芳基、5-14元杂芳基、4-20元杂环基； 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, sulfonamide group or ureido group, or R c29 and R c30 ring to form 3-6 Member heterocyclic group; R c31 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 Base, C 6 -C 14 aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclic group;
Y c1和Z c1各自独立地选自：N或CR c32，其中，R c32选自取代或未取代的下组基团：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 6-C 14芳基、5-14元杂芳基、4-20元杂环基、卤素、氧代基、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基； 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或A c3各自独立地选自：N、O、S或CR c33，或者A c1、A c2和A c3的其中两个环合形成C 3-C 8环烷基、4-8元杂环基、C 6-C 14芳基、5-14元杂芳基；R c33取代或未取代的下组基团：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 6-C 14芳基、5-14元杂芳基、4-20元杂环基、卤素、氧代基、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基； 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 membered heterocyclic group, halogen, oxo, nitro, Hydroxyl, cyano, ester, amine, amide, sulfonamide or urea groups;
Figure PCTCN2022142077-appb-000025
独立地代表单键或者双键；
Figure PCTCN2022142077-appb-000025
independently represent a single bond or a double bond;
R c”选自取代或未取代的下组基团：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 6-C 14芳基、5-14元杂芳基、4-20元杂环基； 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相同或不同，各自独立地选自取代或未取代的下组基团：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 6-C 14芳基、5-14元杂芳基、4-20元杂环基、 卤素、氧代基、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基；或者各自独立地选自取代或未取代的下组基团：-(CH 2) m c1R c34、-(CH 2) m c1O(CH 2) m c2R c34、-(CH 2) m c1SR c34、-(CH 2) m c1COR c34、-(CH 2) m c1C(O)OR c34、-(CH 2) m c1S(O) m c3R c34、-(CH 2) m c1NR c34R c35、-(CH 2) m c1C(O)NR c34R c35、-(CH 2) m c1NR c34C(O)R c35、-(CH 2) m c1NR c34C(O)NR c35R c36、-(CH 2) m c1S(O) m c3NR c34R c35、-(CH 2) m c1NR c34S(O) m c3R c35、-(CH 2) m c1NR c34S(O) m c3NR c35R c36，其中任意位置的H可以任选地被取代；R c34、R c35和R c36各自独立地选自取代或未取代的下组基团：键、氢、C 1-C 18烷基、C 3-C 20环烷基、4-20元杂环基、C 6-C 14芳基、5-20元杂芳基；或者R c34、R c35和R c36中的任意两者环合形成取代或未取代的4-20元杂环基或5-20元杂芳基； 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 , -(CH 2 ) m c1 O(CH 2 ) m c2 R c34 , -(CH 2 ) m c1 SR c34 , -(CH 2 ) m c1 COR c34 , -(CH 2 ) m c1 C(O)OR c34 , -(CH 2 ) m c1 S(O) m c3 R c34 , -(CH 2 ) m c1 NR c34 R c35 , -(CH 2 ) m c1 C(O)NR c34 R c35 , -(CH 2 ) m c1 NR c34 C(O)R c35 , -( CH 2 ) m c1 NR c34 C(O)NR c35 R c36 , -(CH 2 ) m c1 S(O) m c3 NR c34 R c35 , -(CH 2 ) m c1 NR c34 S(O) m c3 R c35 , -(CH 2 ) m c1 NR c34 S(O) m c3 NR c35 R c36 , wherein the H at any position can be optionally substituted; R c34 , R c35 and R c36 are each independently selected from substituted or unsubstituted Substituted groups below: bond, hydrogen, C 1 -C 18 alkyl, C 3 -C 20 cycloalkyl, 4-20 membered heterocyclic group, C 6 -C 14 aryl, 5-20 membered heteroaryl or any two of R c34 , R c35 and R c36 are ring-closed to form a substituted or unsubstituted 4-20 membered heterocyclic group or a 5-20 membered heteroaryl group;
m c1和m c2各自独立地选自：0、1、2、3、4、5或6； m c1 and m c2 are each independently selected from: 0, 1, 2, 3, 4, 5 or 6;
m c3选自：0、1或2； m c3 is selected from: 0, 1 or 2;
所述取代是指被选自下组的一个或多个基团取代：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 6-C 14芳基、5-14元杂芳基、4-20元杂环基、卤素、氧代基、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基；或者被L所取代。 The 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.
在另一优选例中，ULM为MLM，其具有式(MLM-dII)所示的结构：In another preference, ULM is MLM, which has the structure shown in formula (MLM-dII):
Figure PCTCN2022142077-appb-000026
Figure PCTCN2022142077-appb-000026
其中，in,
R c37和R c38相同或不同，且各自独立地选自取代或未取代的下组基团：氢、C 1-C 18烷基、C 3-C 20环烷基、4-20元杂环基、C 6-C 14芳基、5-20元杂芳基；或者R c37、R c38环合形成取代或未取代的4-20元杂环基、或5-20元杂芳基； 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和R c40各自独立地选自取代或未取代的下组基团：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 6-C 14芳基、5-14元杂芳基、4-20元杂环基、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基； 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;
m c4和m c5各自独立地选自：0、1、2、3、4、5或6； m c4 and m c5 are each independently selected from: 0, 1, 2, 3, 4, 5 or 6;
虚线、R c”和R c14如上所述； Dotted line, Rc " and Rc14 as above;
所述取代是指被选自下组的一个或多个基团取代：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 6-C 14芳基、5-14元杂芳基、4-20元杂环基、卤素、氧代基、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基。 The 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.
在另一优选例中，ULM为MLM，其具有式(MLM-dIII)或(MLM-dIV)所示的结构In another preferred embodiment, ULM is MLM, which has the structure shown in formula (MLM-dIII) or (MLM-dIV)
Figure PCTCN2022142077-appb-000027
Figure PCTCN2022142077-appb-000027
在另一优选例中，ULM为ILM，其具有如下所示的结构：In another preferred embodiment, ULM is ILM, which has the following structure:
Figure PCTCN2022142077-appb-000028
Figure PCTCN2022142077-appb-000028
各式中，各基团独立地如下定义：In each formula, each group is independently defined as follows:
虚线表示与L连接；Dotted line indicates connection with L;
R d1-R d6相同或不同，且各自独立地选自取代或未取代的下组基团：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 6-C 14芳基、5-14元杂芳基、4-20元杂环基、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基； 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;
或者R d5和R d6与它们连接的原子共同形成取代或未取代的4-20元杂环基； Or R d5 and R d6 form a substituted or unsubstituted 4-20 membered heterocyclic group together with the atoms they are connected to;
或者R d3和R d6与它们连接的原子共同形成取代或未取代的5-20元杂环基； Or 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选自取代或未取代的下组基团：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 6-C 14芳基、5-14元杂芳基、4-20元杂环基、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基；或者选自取代或未取代的下组基团：-(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’、H-(CH 2) m d1’NR d9’C(O)R d10’、-(CH 2) m d1’NR d9’C(O)NR d10’R d11’、H-(CH 2) m d1’S(O) m d3’NR d9’R d10’、-(CH 2) m d1’NR d9’S(O) m d3’R d10’、-(CH 2) m d1’NR d9’S(O) m d3’NR d10’R d11’，其中，任意位置的的H可以任选地被取代；R d9’、R d10’和R d11’各自独立地选自取代或未取代的下组基团：键、氢、 C 1-C 18烷基、C 3-C 20环烷基、4-20元杂环基、C 6-C 14芳基、5-20元杂芳基；或者R d9’、R d10’和R d11’中的两个可以环合形成取代或未取代的4-20元杂环基或5-20元杂芳基； 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(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' , H-(CH 2 ) m d1' NR d9' C(O )R d10' , -(CH 2 ) m d1' NR d9' C(O)NR d10' R d11' , H-(CH 2 ) m d1' S(O) m d3' NR d9' R d10' , -(CH 2 ) m d1' NR d9' S(O) m d3' R d10' , -(CH 2 ) m d1' NR d9' S(O) m d3' NR d10' R d11' , where any The H in the position can be optionally substituted; R d9' , R d10' and R d11' are each independently selected from the following group of substituted or unsubstituted groups: bond, hydrogen, C 1 -C 18 alkyl, C 3 -C 20 cycloalkyl, 4-20 membered heterocyclyl, C 6 -C 14 aryl, 5-20 membered heteroaryl; or two of R d9' , R d10' and R d11' can be ring Combined to form a substituted or unsubstituted 4-20 membered heterocyclic group or a 5-20 membered heteroaryl group;
m d1’和m d2’各自独立地选自：0、1、2、3、4、5或6； m d1' and m d2' are each independently selected from: 0, 1, 2, 3, 4, 5 or 6;
m d3’选自：0、1、或2； m d3' is selected from: 0, 1, or 2;
W d1选自取代或未取代的下组基团：C 6-C 14芳基和5-20元杂芳基； 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独立地选自取代或未取代的下组基团：-(CH 2) m d1R d9、-(CH 2) m d1O(CH 2) m d2R d9、-(CH 2) m d1SR d9、-(CH 2) m d1COR d9、-(CH 2) m d1C(O)OR d9、-(CH 2) m d1S(O) m d3R d9、-(CH 2) m d1NR d9R d10、-(CH 2) m d1C(O)NR d9R d10、-(CH 2) m d1NR d9C(O)R d10、-(CH 2) m d1NR d9C(O)NR d10R d11、-(CH 2) m d1S(O) m d3NR d9R d10、-(CH 2) m d1NR d9S(O) m d3R d10、-(CH 2) m d1NR d9S(O) m d3NR d10R d11，其中，任意位置的H可以任选地被取代；R d9、R d10和R d11各自独立地选自取代或未取代的下组基团：键、氢、C 1-C 18烷基、C 3-C 20环烷基、4-20元杂环基、C 6-C 14芳基、5-20元杂芳基；或者R d9、R d10和R d11中两个可以环合形成取代或未取代的4-20元杂环基或5-20元杂芳基； 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) NR d10 R d11 , -(CH 2 ) m d1 S(O) m d3 NR d9 R d10 , -(CH 2 ) m d1 NR d9 S(O) m d3 R d10 , -(CH 2 ) m d1 NR d9 S(O) m d3 NR d10 R d11 , wherein, H at any position can be optionally substituted; R d9 , R d10 and R d11 are each independently selected from the following groups of substituted or unsubstituted groups: bond, hydrogen , C 1 -C 18 alkyl, C 3 -C 20 cycloalkyl, 4-20 membered heterocyclyl, C 6 -C 14 aryl, 5-20 membered heteroaryl; or R d9 , R d10 and R Two of d11 can be cyclized to form a substituted or unsubstituted 4-20 membered heterocyclic group or a 5-20 membered heteroaryl group;
nd 1、m d1和m d2各自独立地选自：0、1、2、3、4、5或6； nd 1 , m d1 and m d2 are each independently selected from: 0, 1, 2, 3, 4, 5 or 6;
m d3选自0、1或2； m d3 is selected from 0, 1 or 2;
所述取代是指被选自下组的一个或多个基团取代：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 6-C 14芳基、5-14元杂芳基、4-20元杂环基、卤素、氧代基、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基；或者被L所取代。 The 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.
在另一优选例中，ULM为ILM，其具有如下所示的结构In another preferred embodiment, ULM is ILM, which has the structure shown below
Figure PCTCN2022142077-appb-000029
Figure PCTCN2022142077-appb-000029
各式中，各基团独立地如下定义：In each formula, each group is independently defined as follows:
R d”选自：氢、卤素、氰基、C 1-C 3烷基； R d "is selected from: hydrogen, halogen, cyano, C 1 -C 3 alkyl;
A d1和A d2各自独立地选自取代或未取代的下组基团：C 6-C 14芳基和5-14元杂芳基； 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;
W d1、R d8、nd 1和虚线的定义如上所述。 Definitions of W d1 , R d8 , nd 1 and the dashed lines are as described above.
在另一优选例中，ULM选自下组:In another preference, ULM is selected from the following group:
Figure PCTCN2022142077-appb-000030
Figure PCTCN2022142077-appb-000030
Figure PCTCN2022142077-appb-000031
Figure PCTCN2022142077-appb-000031
Figure PCTCN2022142077-appb-000032
Figure PCTCN2022142077-appb-000032
在另一优选例中，L选自：In another preferred example, L is selected from:
Figure PCTCN2022142077-appb-000033
Figure PCTCN2022142077-appb-000033
Figure PCTCN2022142077-appb-000034
Figure PCTCN2022142077-appb-000034
其中：in:
NH中的H可以独立任选地被氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、C 3-C 20环烷基、C 1-C 18烷基酰基、磺酰基取代； 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;
R L1-R L6相同或不同，且各自独立地选自取代或未取代的下组基团：键、CH 2、C＝O、O、NH、SO、SO 2、P＝O、NHCO、NHSO 2、OCH 2、OCH 2CH 2、CH 2OCH 2、NHCH 2、NMeCH 2、NHCH 2CH 2、NMeCH 2CH 2、CH 2NHCO、NHCOCH 2、 R L1 -R L6 are the same or different, and are independently selected from the following groups of substituted or unsubstituted groups: bond, CH 2 , C=O, O, NH, SO, SO 2 , P=O, NHCO, NHSO 2. OCH 2 , OCH 2 CH 2 , CH 2 OCH 2 , NHCH 2 , NMeCH 2 , NHCH 2 CH 2 , NMeCH 2 CH 2 , CH 2 NHCO, NHCOCH 2 ,
Figure PCTCN2022142077-appb-000035
Figure PCTCN2022142077-appb-000035
Figure PCTCN2022142077-appb-000036
Figure PCTCN2022142077-appb-000036
Figure PCTCN2022142077-appb-000037
Figure PCTCN2022142077-appb-000037
所述取代是指被选自下组的一个或多个基团取代：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 6-C 14芳基、5-14元杂芳基、4-20元杂环基、卤素、氧代基、 硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基； The 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;
各p L1-p L6独立地选自：0、1、2、3、4、5或6。 Each p L1 -p L6 is independently selected from: 0, 1, 2, 3, 4, 5 or 6.
在另一优选例中，L任选地通过R L1端或R L6端和PTM或ULM相连接。 In another preferred example, L is optionally connected to PTM or ULM through RL1 or RL6 .
在另一优选例中，L选自取代或未取代的下组基团：In another preferred example, L is selected from the following groups of substituted or unsubstituted groups:
Figure PCTCN2022142077-appb-000038
Figure PCTCN2022142077-appb-000039
中的
Figure PCTCN2022142077-appb-000040
部分选自取代或非取代的下组基团：
Figure PCTCN2022142077-appb-000038
Figure PCTCN2022142077-appb-000039
middle
Figure PCTCN2022142077-appb-000040
Some are selected from substituted or unsubstituted following groups:
Figure PCTCN2022142077-appb-000041
Figure PCTCN2022142077-appb-000041
Figure PCTCN2022142077-appb-000042
Figure PCTCN2022142077-appb-000042
Figure PCTCN2022142077-appb-000043
Figure PCTCN2022142077-appb-000043
Figure PCTCN2022142077-appb-000044
Figure PCTCN2022142077-appb-000044
Figure PCTCN2022142077-appb-000045
Figure PCTCN2022142077-appb-000045
Figure PCTCN2022142077-appb-000046
Figure PCTCN2022142077-appb-000046
Figure PCTCN2022142077-appb-000047
Figure PCTCN2022142077-appb-000047
Figure PCTCN2022142077-appb-000048
Figure PCTCN2022142077-appb-000048
Figure PCTCN2022142077-appb-000049
Figure PCTCN2022142077-appb-000049
Figure PCTCN2022142077-appb-000050
Figure PCTCN2022142077-appb-000050
Figure PCTCN2022142077-appb-000051
Figure PCTCN2022142077-appb-000051
Figure PCTCN2022142077-appb-000052
Figure PCTCN2022142077-appb-000052
Figure PCTCN2022142077-appb-000053
Figure PCTCN2022142077-appb-000053
Figure PCTCN2022142077-appb-000054
Figure PCTCN2022142077-appb-000054
Figure PCTCN2022142077-appb-000055
Figure PCTCN2022142077-appb-000055
Figure PCTCN2022142077-appb-000056
Figure PCTCN2022142077-appb-000056
Figure PCTCN2022142077-appb-000057
Figure PCTCN2022142077-appb-000057
Figure PCTCN2022142077-appb-000058
Figure PCTCN2022142077-appb-000058
Figure PCTCN2022142077-appb-000059
Figure PCTCN2022142077-appb-000059
Figure PCTCN2022142077-appb-000060
Figure PCTCN2022142077-appb-000060
Figure PCTCN2022142077-appb-000061
Figure PCTCN2022142077-appb-000061
Figure PCTCN2022142077-appb-000062
Figure PCTCN2022142077-appb-000062
Figure PCTCN2022142077-appb-000063
Figure PCTCN2022142077-appb-000063
Figure PCTCN2022142077-appb-000064
Figure PCTCN2022142077-appb-000064
Figure PCTCN2022142077-appb-000065
Figure PCTCN2022142077-appb-000065
Figure PCTCN2022142077-appb-000066
Figure PCTCN2022142077-appb-000066
Figure PCTCN2022142077-appb-000067
Figure PCTCN2022142077-appb-000067
Figure PCTCN2022142077-appb-000068
Figure PCTCN2022142077-appb-000068
Figure PCTCN2022142077-appb-000069
Figure PCTCN2022142077-appb-000069
Figure PCTCN2022142077-appb-000070
Figure PCTCN2022142077-appb-000070
Figure PCTCN2022142077-appb-000071
Figure PCTCN2022142077-appb-000071
Figure PCTCN2022142077-appb-000072
Figure PCTCN2022142077-appb-000072
Figure PCTCN2022142077-appb-000073
Figure PCTCN2022142077-appb-000073
Figure PCTCN2022142077-appb-000074
Figure PCTCN2022142077-appb-000074
Figure PCTCN2022142077-appb-000075
Figure PCTCN2022142077-appb-000075
Figure PCTCN2022142077-appb-000076
Figure PCTCN2022142077-appb-000076
Figure PCTCN2022142077-appb-000077
Figure PCTCN2022142077-appb-000077
Figure PCTCN2022142077-appb-000078
Figure PCTCN2022142077-appb-000078
Figure PCTCN2022142077-appb-000079
Figure PCTCN2022142077-appb-000079
各式中，CH 2、CH中的H可以独立任选地被取代； In each formula, H in CH 2 and CH can be independently and optionally substituted;
其中，所述取代是指被选自下组的一个或多个基团取代：氢、氘、C 1-C 18烷基、氘代 C 1-C 18烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 6-C 14芳基、5-14元杂芳基、4-20元杂环基、卤素、氧代基、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基；NH可以独立任选地被氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、C 3-C 20环烷基、C 1-C 18烷基酰基、磺酰基取代；且 Wherein, the 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, halogenated C 1 - C 18 alkyl hydroxy, C 3 -C 20 cycloalkyl, C 1 -C 18 alkyl acyl, sulfonyl substituted; and
L中，各R L1-R L6基团中相邻的两个基团，可各自独立地通过C、N、O或S原子等彼此连接。 In L, 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.
在另一优选例中，
Figure PCTCN2022142077-appb-000080
选自取代或未取代的选自下组的基团： In another preferred example,
Figure PCTCN2022142077-appb-000080
A substituted or unsubstituted group selected from the group consisting of:
Figure PCTCN2022142077-appb-000081
Figure PCTCN2022142077-appb-000081
Figure PCTCN2022142077-appb-000082
Figure PCTCN2022142077-appb-000082
Figure PCTCN2022142077-appb-000083
Figure PCTCN2022142077-appb-000083
Figure PCTCN2022142077-appb-000084
Figure PCTCN2022142077-appb-000084
Figure PCTCN2022142077-appb-000085
Figure PCTCN2022142077-appb-000085
各式中，CH 2、CH和NH中的H可以独立任选地被取代；且所述取代是指被选自下组的一个或多个基团取代：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 6-C 14芳基、5-14元杂芳基、4-20元杂环基、卤素、氧代基、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基；NH可以独立任选地被氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、C 3-C 20环烷基、C 1-C 18烷基酰基、磺酰基取代。 In each formula, 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 alkyl, halogenated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkylhydroxyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkylacyl, sulfonyl substitution.
在另一优选例中，PTM选自：In another preference, PTM is selected from:
Figure PCTCN2022142077-appb-000086
Figure PCTCN2022142077-appb-000086
Figure PCTCN2022142077-appb-000087
Figure PCTCN2022142077-appb-000087
Figure PCTCN2022142077-appb-000088
Figure PCTCN2022142077-appb-000088
且同时
Figure PCTCN2022142077-appb-000089
选自取代或未取代的选自下组的基团： and at the same time
Figure PCTCN2022142077-appb-000089
A substituted or unsubstituted group selected from the group consisting of:
Figure PCTCN2022142077-appb-000090
Figure PCTCN2022142077-appb-000090
Figure PCTCN2022142077-appb-000091
Figure PCTCN2022142077-appb-000091
Figure PCTCN2022142077-appb-000092
Figure PCTCN2022142077-appb-000092
Figure PCTCN2022142077-appb-000093
Figure PCTCN2022142077-appb-000093
Figure PCTCN2022142077-appb-000094
Figure PCTCN2022142077-appb-000094
各式中，CH 2、CH和NH中的H可以独立任选地被取代；且所述取代是指被选自下组的一个或多个基团取代：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 6-C 14芳基、5-14元杂芳基、4-20元杂环基、卤素、氧代基、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基；NH可以独立任选地被氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、C 3-C 20环烷基、C 1-C 18烷基酰基、磺酰基取代。 In each formula, 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 alkyl, halogenated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkylhydroxyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkylacyl, sulfonyl substitution.
在另一优选例中，ULM、L和PTM为实施例中各具体化合物所对应部分。In another preferred example, ULM, L and PTM are the corresponding parts of each specific compound in the examples.
在另一优选例中，式(I)化合物为实施例中所示的化合物，例如实施例I-1-I-22和实施例II-1-II-6。In another preferred example, 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.
本发明第二方面，提供一种药物组合物，其包含一种或多种如第一方面所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药；和药学上可接受的载体。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.
在另一优选例中，所述药物组合物还包含选自下组的药物：PD-1抑制剂(如nivolumab、pembrolizumab、pidilizumab、cemiplimab、JS-001、SHR-120、BGB-A317、IBI-308、GLS-010、GB-226、STW204、HX008、HLX10,BAT 1306、AK105、LZM 009或上述药物的生物类似药等)、PD-L1抑制剂(如durvalumab、atezolizumab、avelumab、CS1001、KN035、HLX20、SHR-1316、BGB-A333、JS003、CS1003、KL-A167、F 520、GR1405、MSB2311或上述药物的生物类似药等)、CD20抗体(如rituximab、obinutuzumab、ofatumumab、veltuzumab、tositumomab、131I-tositumomab、ibritumomab、90Y-ibritumomab、90In-ibritumomab、ibritumomab tiuxetan等)、CD47抗体(如Hu5F9-G4、CC-90002、TTI-621、TTI-622、OSE-172、SRF-231、ALX-148、NI-1701、SHR-1603、IBI188、IMM01)、ALK抑制剂(如Ceritinib、Alectinib、Brigatinib、Lorlatinib、奥卡替尼)、PI3K抑制剂(如Idelalisib、Duvelisib、Dactolisib、Taselisib、Bimiralisib、Omipalisib、Buparlisib等)、BTK抑制剂(如Ibrutinib、Tirabrutinib、Acalabrutinib、Zanubrutinib、Vecabrutinib等)、EGFR抑制剂(如Afatinib、Gefitinib、Erlotinib、Lapatinib、Dacomitinib、Icotinib、Canertinib、Sapitinib、Naquotinib、Pyrotinib、Rociletinib、Osimertinib等)、VEGFR抑制剂(如Sorafenib、Pazopanib、 Regorafenib、Sitravatinib、Ningetinib、Cabozantinib、Sunitinib、多纳非尼等)、HDAC抑制剂(如Givinostat、Tucidinostat、Vorinostat、Fimepinostat、Droxinostat、Entinostat、Dacinostat、Quisinostat、Tacedinaline等)、CDK抑制剂(如Palbociclib、Ribociclib、Abemaciclib、Milciclib、Trilaciclib、Lerociclib等)、MEK抑制剂(如Selumetinib(AZD6244)、Trametinib(GSK1120212)、PD0325901、U0126、Pimasertib(AS-703026)、PD184352(CI-1040)等)、mTOR抑制剂(如Vistusertib等)、SHP2抑制剂(如RMC-4630、JAB-3068、TNO155等)或其组合。In another preferred example, 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, veltuzumab, tositumomab, 131I- tositumomab, ibritumomab, 90Y-ibritumomab, 90In-ibritumomab, ibritumomab tiuxetan, etc.), CD47 antibody (such as Hu5F9-G4, CC-90002, TTI-621, TTI-622, OSE-172, SRF-231, ALX-148, NI -1701, SHR-1603, IBI188, IMM01), ALK inhibitors (such as Ceritinib, Alectinib, Brigatinib, Lorlatinib, Ocatinib), PI3K inhibitors (such as Idelalisib, Duvelisib, Dactolisib, Taselisib, Bimiralisib, Omipalisib, Buparlisib, etc. ), 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, Quisinostat, Tacedinaline, etc.) , CDK inhibitors (such as PalboCiclib, Ribociclib, ABEMACICLIB, Milciclib, Trilaciclib, Lerociclib, etc.), MEK inhibitors (such as Selumetinib (AZD6244), Trametinib (GSK1112 0212), PD0325901, U0126, PIMASERTIB (AS-703026), PD184352 (CI- 1040), etc.), mTOR inhibitors (such as Vistusertib, etc.), SHP2 inhibitors (such as RMC-4630, JAB-3068, TNO155, etc.) or combinations thereof.
本发明第三方面，提供一种如第一方面所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，或包含其的药物组合物的用途，用于制备预防和/或治疗与KRAS G12D活性或表达量相关的疾病的药物。 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.
在另一优选例中，所述的疾病为肿瘤或失调性疾病。In another preferred example, the disease is a tumor or a disorder.
在另一优选例中，所述疾病选自下组：肺癌、乳腺癌、前列腺癌、食道癌、结直肠癌、骨癌、肾癌、胃癌、肝癌、大肠癌、黑色素瘤、淋巴瘤、血癌、脑瘤、骨髓瘤、软组织肉瘤、胰腺癌、皮肤癌。In another preferred example, 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.
本发明第四方面，提供了一种非诊断性、非治疗性地抑制KRAS G12D的方法，其包括步骤：向所需对象施用有效量的如第一方面所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，或施用如第二方面所述的药物组合物。 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.
在另一优选例中，所述的对象为哺乳动物，较佳地为人。In another preferred example, the subject is a mammal, preferably a human.
本发明第五方面，提供一种体外抑制KRAS G12D活性的方法，包括步骤：将如第一方面所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，或如第二方面所述的药物组合物与蛋白或者细胞接触，从而抑制KRAS G12D的活性。 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 .
在另一优选例中，所述的细胞选自下组：巨噬细胞、肠道细胞(包括肠干细胞、肠上皮细胞)、或其组合。In another preferred embodiment, the cells are selected from the group consisting of macrophages, intestinal cells (including intestinal stem cells, intestinal epithelial cells), or combinations thereof.
在另一优选例中，所述的细胞来自啮齿动物(如小鼠、大鼠)、或灵长动物(如人)。In another preferred example, the cells are from rodents (such as mice, rats), or primates (such as humans).
本发明第五方面，提供了一种预防和/或治疗KRAS G12D活性或表达量相关的疾病的方法，其包括步骤：向有需要的对象施用有效量的如本发明第一方面所述的通式(I)化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，或施用本发明第三方面所述的药物组合物。 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 compound of formula (I), its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, or administer the pharmaceutical combination described in the third aspect of the present invention thing.
在另一优选例中，所述对象为哺乳动物，如人、大鼠或小鼠。In another preferred embodiment, the subject is a mammal, such as a human, a rat or a mouse.
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described in the following (such as embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, we will not repeat them here.
附图说明Description of drawings
图1示出了实施例I-11对KRAS G12D蛋白的降解。 Figure 1 shows the degradation of KRAS G12D protein by Example I-11.
具体实施方式Detailed ways
本发明人经过长期而深入的研究，意外地发现了一类新型的针对KRAS G12D的蛋白水解调节剂。在此基础上，发明人完成了本发明。 After long-term and in-depth research, the inventors unexpectedly discovered a new class of proteolysis regulators targeting KRAS G12D . On this basis, the inventors have completed the present invention.
术语the term
在本发明中，除非特别指出，所用术语具有本领域技术人员公知的一般含义。In the present invention, unless otherwise specified, the terms used have the usual meanings known to those skilled in the art.
术语“烷基”是指本身或作为另一取代基的一部分是指具有指定碳原子数的直链或支链烷烃基，可包含1-20个碳原子，如包括1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17或18个碳原子。典型的“烷基”包括甲基、乙基、丙基、异丙基、正丁基、叔丁基、异丁基、
Figure PCTCN2022142077-appb-000095
正戊基、异戊基、正己基、异己基、正庚基、异庚基4,4–二甲基戊基、辛基、2,2,4-三甲基戊基、壬基、癸基、十一烷基、十二烷基等等。 The term "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,
Figure PCTCN2022142077-appb-000095
n-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl base, undecyl, dodecyl, etc.
术语“取代烷基”是指烷基中的一个或多个位置被取代，尤其是1-4个取代基，可在任何位置上取代。典型的取代包括但不限于一个或多个以下基团：如氢，氘，卤素(例如，单卤素取代基或多卤素取代基，后者如三氟甲基或包含Cl 3的烷基)、腈基、硝基、氧(如＝O)、三氟甲基、三氟甲氧基、环烷基、烯基、环烯基、炔基、杂环、芳环、OR a、SR a、S(＝O)R e、S(＝O) 2R e、P(＝O) 2R e、S(＝O) 2OR e,P(＝O) 2OR e、NR bR c、NR bS(＝O) 2R e、NR bP(＝O) 2R e、S(＝O) 2NR bR c、P(＝O) 2NR bR c、C(＝O)OR d、C(＝O)R a、C(＝O)NR bR c、OC(＝O)R a、OC(＝O)NR bR c、NR bC(＝O)OR e,NR dC(＝O)NR bR c、NR dS(＝O) 2NR bR c、NR dP(＝O) 2NR bR c、NR bC(＝O)R a、或NR bP(＝O) 2R e，其中在此出现的R a可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环，R b、R c和R d可以独立表示氢、氘、烷基、环烷基、杂环或芳环，或者说R b和R c与N原子一起可以形成杂环；R e可以独立表示氢、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环。上述典型的取代基，如烷基、环烷基、烯基、环烯基、炔基、杂环或芳环可以任选取代。 The term "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. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (e.g., monohalogen substituents or polyhalogen substituents, the latter such as trifluoromethyl or Cl3 containing alkyl), Nitrile, nitro, oxygen (eg =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aromatic ring, OR a , SR a , S(=O)R e , S(=O) 2 R e , P(=O) 2 R e , S(=O) 2 OR e , P(=O) 2 OR e , NR b R c , NR b S(=O) 2 R e , NR b P(=O) 2 R e , S(=O) 2 NR b R c , P(=O) 2 NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , NR b C(=O)OR e , NR d C (=O)NR b R c , NR d S(=O) 2 NR b R c , NR d P(=O) 2 NR b R c , NR b C(=O)R a , or NR b P( =O) 2 R e , wherein R a appearing here can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring, R b , R c and R d can independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocyclic or aromatic ring, or R b and R c can form a heterocyclic ring together with N atoms; Re can independently represent hydrogen, alkyl, cycloalkane group, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring. The typical substituents mentioned above, such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic or aromatic rings may be optionally substituted.
术语“亚烷基”本身或作为另一取代基的一部分是指“烷基”再脱掉一个氢原子所形成的基团，亚烷基可包含1-18个碳原子，如包括1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17或18个碳原子。例如，亚甲基、亚乙基、亚丙基、亚异丙基(如
Figure PCTCN2022142077-appb-000096
)、亚丁基(如
Figure PCTCN2022142077-appb-000097
)、亚戊基(如
Figure PCTCN2022142077-appb-000098
)、亚己基(如
Figure PCTCN2022142077-appb-000099
)、 亚庚基(如
Figure PCTCN2022142077-appb-000100
)等。 The term "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. For example, methylene, ethylene, propylene, isopropylidene (such as
Figure PCTCN2022142077-appb-000096
), butylene (such as
Figure PCTCN2022142077-appb-000097
), pentylene (such as
Figure PCTCN2022142077-appb-000098
), hexamethylene (such as
Figure PCTCN2022142077-appb-000099
), Heptylene (such as
Figure PCTCN2022142077-appb-000100
)wait.
术语“环烷基”是指完全饱和的环状烃类化合物基团，包括1-4个环，每个环中含有3-30个碳原子，如包括1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17或18个碳原子。“取代环烷基”是指环烷基中的一个或多个位置被取代，尤其是1-4个取代基，可在任何位置上取代。典型的取代包括但不限于一个或多个以下基团：如氢、氘、卤素(例如，单卤素取代基或多卤素取代基，后者如三氟甲基或包含Cl 3的烷基)、腈基、硝基、氧(如＝O)、三氟甲基、三氟甲氧基、环烷基、烯基、环烯基、炔基、杂环、芳环、OR a、SR a、S(＝O)R e、S(＝O) 2R e、P(＝O) 2R e、S(＝O) 2OR e,P(＝O) 2OR e、NR bR c、NR bS(＝O) 2R e、NR bP(＝O) 2R e、S(＝O) 2NR bR c、P(＝O) 2NR bR c、C(＝O)OR d、C(＝O)R a、C(＝O)NR bR c、OC(＝O)R a、OC(＝O)NR bR c、NR bC(＝O)OR e,NR dC(＝O)NR bR c、NR dS(＝O) 2NR bR c、NR dP(＝O) 2NR bR c、NR bC(＝O)R a、或NR bP(＝O) 2R e，其中在此出现的R a可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环，R b、R c和R d可以独立表示氢、氘、烷基、环烷基、杂环或芳环，或者说R b和R c与N原子一起可以形成杂环；R e可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环。上述典型的取代基可以任选被取代。典型的取代还包括螺环、桥环或稠环取代基，尤其是螺环烷基、螺环烯基、螺环杂环(不包括杂芳环)、桥环烷基、桥环烯基、桥环杂环(不包括杂芳环)、稠环烷基、稠环烯基、稠环杂环基或稠环芳环基，上述环烷基、环烯基、杂环基和杂环芳基可以任选取代。环上的任意两个或两个以上的原子可以与其他环烷基、杂环基、芳基和杂芳基进一步并环连接。 The term "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. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (eg, monohalogen substituents or polyhalogen substituents, the latter such as trifluoromethyl or alkyl containing Cl 3 ), Nitrile, nitro, oxygen (eg =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aromatic ring, OR a , SR a , S(=O)R e , S(=O) 2 R e , P(=O) 2 R e , S(=O) 2 OR e , P(=O) 2 OR e , NR b R c , NR b S(=O) 2 R e , NR b P(=O) 2 R e , S(=O) 2 NR b R c , P(=O) 2 NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , NR b C(=O)OR e , NR d C (=O)NR b R c , NR d S(=O) 2 NR b R c , NR d P(=O) 2 NR b R c , NR b C(=O)R a , or NR b P( =O) 2 R e , wherein R a appearing here can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring, R b , R c and R d can independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocyclic ring or aromatic ring, or R b and R c can form a heterocyclic ring together with N atoms; R e can independently represent hydrogen, deuterium, alkyl, Cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring. 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.
术语“亚环烷基”本身或作为另一取代基的一部分是指上述环烷基脱掉两个氢原子所形成的基团，如：
Figure PCTCN2022142077-appb-000101
Figure PCTCN2022142077-appb-000102
Figure PCTCN2022142077-appb-000103
等。 The term "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:
Figure PCTCN2022142077-appb-000101
Figure PCTCN2022142077-appb-000102
Figure PCTCN2022142077-appb-000103
wait.
术语“亚烷基亚环烷基”是指上述的环烷基烷基或烷基环烷基脱掉两个氢原子所形成的基团，其中，“C1-C18亚烷基C3-C20亚环烷基”或“C3-C20亚环烷基C1-C18亚烷基”具有 相同含义，优选地，C1-C6亚烷基C3-C12亚环烷基，包括但不限于：
Figure PCTCN2022142077-appb-000104
Figure PCTCN2022142077-appb-000105
Figure PCTCN2022142077-appb-000106
等。 The term "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:
Figure PCTCN2022142077-appb-000104
Figure PCTCN2022142077-appb-000105
Figure PCTCN2022142077-appb-000106
wait.
术语“杂环基”是指完全饱和的或部分不饱和的的环状基团，可包括3、4、5、6、7、8、9、10、11、12、13、14、15、16、17或18个环原子(包含但不限于如3-7元单环，6-11元双环，或8-16元三环系统)，其中至少有一个杂原子存在于至少有一个碳原子的环中。每个含有杂原子的杂环可以带有1，2，3或4个杂原子，这些杂原子选自氮原子、氧原子或硫原子，其中氮原子或硫原子可以被氧化，氮原子也可以被季铵化。杂环基团可以连接到环或环系分子的任何杂原子或碳原子的残基上。典型的单环杂环包括但不限于氮杂环丁烷基、吡咯烷基、氧杂环丁烷基、吡唑啉基、咪唑啉基、咪唑烷基、噁唑烷基、异噁唑烷基、噻唑烷基、异噻唑烷基、四氢呋喃基、哌啶基、哌嗪基、2-氧代哌嗪基、2-氧代哌啶基、2-氧代吡咯烷基、六氢吖庚因基、4-哌啶酮基、四氢吡喃基、吗啡啉基、硫代吗啡啉基、硫代吗啡啉亚砜基、硫代吗啡啉砜基、1,3-二噁烷基和四氢-1,1-二氧噻吩等。多环杂环基包括螺环、稠环和桥环的杂环基；其中涉及到的螺环、稠环和桥环的杂环基任选与其他基团通过单键相连接，或者通过环上的任意两个或两个以上的原子与其他环烷基、杂环基、芳基和杂芳基进一步并环连接；杂环基团可以是取代的或者未取代的，当被取代时，取代基优选为一个或多个一下基团，其独立地选自烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、烯基、炔基、烷硫基、烷基氨基、卤素、氨基、硝基、羟基、巯基、氰基、环烷基、杂环基、芳基、杂芳基、环烷硫基、氧代基、羧基和羧酸酯基，其中，环上的任意两个或两个以上的原子可以与其他环烷基、杂环基、芳基和杂芳基进一步并环连接。The term "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, 1,3-dioxanyl and Tetrahydro-1,1-dioxythiophene, etc. 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, the ring Any two or more atoms can be further connected to other cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups.
术语“亚杂环基”是指上述杂环基脱掉两个氢原子所形成的基团，如包括但不限于：The term "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:
Figure PCTCN2022142077-appb-000107
Figure PCTCN2022142077-appb-000108
Figure PCTCN2022142077-appb-000109
等。
Figure PCTCN2022142077-appb-000107
Figure PCTCN2022142077-appb-000108
Figure PCTCN2022142077-appb-000109
wait.
术语“亚杂环烷基亚烷基”是指环烷基烷基或烷基环烷基脱掉两个氢原子所形成的基团，其中，“4-20元亚杂环烷基C1-C18亚烷基”或“C1-C18亚烷基4-20元亚杂环烷基”具有相同含义，优选地为4-12元亚杂环烷基C1-6亚烷基，包括但不限于：
Figure PCTCN2022142077-appb-000110
Figure PCTCN2022142077-appb-000111
Figure PCTCN2022142077-appb-000112
等。 The term "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:
Figure PCTCN2022142077-appb-000110
Figure PCTCN2022142077-appb-000111
Figure PCTCN2022142077-appb-000112
wait.
术语“芳基”是指芳香环状烃类化合物基团，具有1-5个环，尤其指单环和双环基团，如苯基、联苯基或萘基。凡含有两个或两个以上芳香环(双环等)，芳基基团的芳香环可由单键联接(如联苯)，或稠合(如萘、蒽等等)。“取代芳基”是指芳基中的一个或多个位置被取代，尤其是1-3个取代基，可在任何位置上取代。The term "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.
术语“亚芳基”是指上述芳基脱掉两个氢原子所形成的基团。The term "arylene group" refers to a group formed by removing two hydrogen atoms from the above-mentioned aryl group.
术语“杂芳基”指包含1-4(如2或3个)个杂原子、5-14个环原子的杂芳族体系，其中杂原子选自氧、氮和硫，杂环基可包括5、6、7、8、9、10、11、12、13或14个环原子。杂芳基优选5至10元环，更优选为5元或6元，例如吡咯基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、噻二唑基、异噻唑基、呋喃基、吡啶基、吡嗪基、嘧啶基、哒嗪基、三氮嗪基、三氮唑基及四氮唑基等。“杂芳基”可以是取代的或者未取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、烯基、炔基、烷硫基、烷基氨基、卤素、氨基、硝基、羟基、巯基、氰基、环 烷基、杂环基、芳基、杂芳基、环烷硫基、氧代基、羧基和羧酸酯基。The term "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. "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.
术语“亚杂芳基”是指上述杂芳基脱掉两个氢原子所形成的基团。The term "heteroarylene" refers to a group formed by removing two hydrogen atoms from the above-mentioned heteroaryl group.
术语“C1-C18烷氧基”是指具有1至18个碳原子的直链或支链或环状烷基氧基，非限制性地包括甲氧基、乙氧基、丙氧基、异丙氧基和丁氧基等。优选为C1-C8烷氧基，更优选C1-C6烷氧基或C1-C4烷氧基。The term "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.
术语“C1-C18亚烷氧基”是指“C1-C18烷氧基”脱掉一个氢原子所得基团。The term "C1-C18 alkyleneoxy" refers to a group obtained by removing a hydrogen atom from "C1-C18 alkoxy".
术语“卤素”或“卤”是指氯、溴、氟、碘。The term "halogen" or "halo" refers to chlorine, bromine, fluorine, iodine.
术语“卤代”是指被卤素取代。The term "halo" means substituted by halogen.
术语“氘代”是指被氘( 2H)取代。 The term "deuterated" refers to substitution with deuterium ( 2H ).
术语“羟基”是指带有结构OH的基团。The term "hydroxyl" refers to a group bearing the structure OH.
术语“硝基”是指带有结构NO 2的基团。 The term "nitro" refers to a group bearing the structure NO2 .
术语“氰基”是指带有结构CN的基团。The term "cyano" refers to a group bearing the structure CN.
术语“酯基”是指带有结构-COOR的基团，其中R代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环基或取代的杂环基。酯基的实例包括但不限于：-COOCH 3、-COOCH 2CH 3、-COOCH 2CH 2CH 3、-COO(环丙基)、-COOCH 2(环丙基)等。 The term "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. Examples of ester groups include, but are not limited to , -COOCH3 , -COOCH2CH3 , -COOCH2CH2CH3 , -COO( cyclopropyl ), -COOCH2 (cyclopropyl), and the like.
术语“胺基”是指带有结构-NRR'的基团，其中R和R'可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环基或取代的杂环基，如上文所定义。R和R'在二烷基胺片段中可以相同或不同。胺基优选地为C 1-C 18烷基胺基、C 3-C 18环烷基胺基、4-20元杂环基胺基、C 6-C 20芳基胺基、5-20元杂芳基胺基或NH 2，更优选地为C 1-C 6烷基胺基、C 3-C 6环烷基胺基、4-6元杂环基胺基、C 6-C 10芳基胺基、5-10元杂芳基胺基或NH 2。“胺基”的实例包括但不限于：NH 2、-NHCH 3、-N(CH 3) 2、-NH(环丙基)等。 The term "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 . Examples of "amino group" include, but are not limited to: NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -NH(cyclopropyl) and the like.
术语“酰胺基”是指带有结构-CONRR'的基团，其中R和R'可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环基或取代的杂环基，如上文所定义。R和R'在二烷基胺片段中可以相同或不同。“酰胺基”的实例包括但不限于：-CONH 2、-CONHCH 3、-CON(CH 3) 2。 The term "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 .
术语“磺酰胺基”是指带有结构-SO 2NRR'的基团，其中R和R'可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环基或取代的杂环基，如上文所定义。R和R'在二烷基胺片段中可以相同或不同。“磺酰胺基”实例包括但不限于：-SO 2NH 2、-SO 2NHCH 3、-SO 2N(CH 3) 2。 The term "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 .
术语“脲基”是指带有结构-NRCONR'R"的基团，其中R、R'和R"可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环基或取代的杂环基，如上文所定义。R、R'和R"在二烷基胺片段中可以相同或不同。“脲基”实例包括但不限于：-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等。 The term "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. Examples of "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.
术语"烷基胺基烷基"是指带有结构-RNHR'或-RNR'R"的基团，其中R、R'和R"'可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环基或取代的杂环基，如上文所定义。R、R'和R"可以相同或不同。"烷基胺基烷基"优选地为(C 1-C 18烷基胺基)C 1-C 18烷基，更优选地为(C 1-C 6烷基胺基)C 1-C 6烷基，更优选地为(C 1-C 6烷基胺基)C 1-C 3烷基。"烷基胺基烷基"的实例包括但不限于：-CH 2NHCH 3、-CH 2N(CH 3) 2、-CH 2CH 2NHCH 3、-CH 2CH 2CH 2N(CH 3) 2、-CH 2CH 2CH 2NHCH 3、-CH 2CH 2CH 2N(CH 3) 2。(环烷基胺基)烷基、(杂环基胺基)烷基、(芳基胺基)烷基和(杂芳基胺基烷基具有类似含义。例如，
Figure PCTCN2022142077-appb-000113
Figure PCTCN2022142077-appb-000114
Figure PCTCN2022142077-appb-000115
等。 The term "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. Examples of "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,
Figure PCTCN2022142077-appb-000113
Figure PCTCN2022142077-appb-000114
Figure PCTCN2022142077-appb-000115
wait.
术语"杂环基烷基"是指带有结构-RR'的基团，其中R可以独立的代表烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基；R'代表杂环基或取代的杂环基。The term "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.
术语“酰基”是指带有结构R-C＝O-的基团，其中R可以独立的代表烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基；R'代表杂环基或取代的杂环基。优选地“酰基”为C1-C6酰基，即C1-C5烷基-C＝O-。The term "acyl" refers to a group with the structure R-C=O-, wherein 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. Preferably "acyl" is C1-C6 acyl, ie C1-C5 alkyl-C=O-.
在本发明中，术语“取代”指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基，或各实施例中所出现的取代基。除非特别说明，某个取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基，所述的取代基在各个位置上可以是相同或不同的。本领域技术人员应理解，本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。优选地，如无特别说明，取代可为被选自下组的一个或多个取代基取代：例如(但并不限于)：卤素、羟基、氰基、羧基(-COOH)、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 8环烷基、4-12元杂环基、芳基、杂芳基、C 1-C 8醛基、C 1-C 10酰基、C 2-C 10酯基、胺基、C 1-C 6烷氧基、C 1-C 10磺酰基、及C 1-C 6脲基等。 In the present invention, the term "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. Unless otherwise specified, 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. Those skilled in the art will appreciate that combinations of substituents contemplated by this invention are those that are stable or chemically feasible. Preferably, unless otherwise specified, 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.
除非另外说明，假定任何不满价态的杂原子有足够的氢原子补充其价态。Unless otherwise stated, it is assumed that any heteroatom with a dissatisfied valence has sufficient hydrogen atoms to fill its valence.
当取代基为非末端取代基时，其为相应基团的亚基，例如烷基对应于亚烷基、环烷基 对应亚环烷基、杂环基对亚杂环基、烷氧基对应亚烷氧基等。When 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蛋白水解调节剂 KRAS G12D proteolysis regulator
如本文所用，“KRAS G12D蛋白水解调节剂”和“靶向KRAS G12D的蛋白酶降解剂”可互换使用，指靶向KRAS G12D的蛋白酶降解剂(PROTAC),该化合物利用了细胞内的“清洁工”—泛素-蛋白酶体系统来降解KRAS G12D蛋白。 As used herein, "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.
优选地，所述KRAS G12D蛋白水解调节剂为本发明的式I化合物。 Preferably, the KRAS G12D proteolysis regulator is the compound of formula I of the present invention.
靶向配体targeting ligand
靶向配体(或靶蛋白部分或靶蛋白配体或配体)是能够结合目标靶蛋白的小分子。A targeting ligand (or target protein portion or target protein ligand or ligand) is a small molecule capable of binding a target protein of interest.
本发明中，所述靶向配体(PTM部分)由靶向KRAS G12D的小分子化合物形成，优选由如上所述的PTMI化合物形成。 In the present invention, the targeting ligand (PTM part) is formed by a small molecular compound targeting KRAS G12D , preferably a PTMI compound as described above.
E3连接酶配体E3 ligase ligand
在本发明中，E3连接酶配体部分(ULM部分)用于结合E3连接酶。本发明对E3连接酶配体种类没有特别要求，可使用本发明常用的能与E3连接酶结合的分子或结构片段。In the present invention, 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.
典型地，ULM由可以和选自下组的连接酶结合的小分子配体形成(但并不限于)：VHL(Von Rippel-Lindau)、CRBN(Cereblon)、MDM2(Mouse double-minute homolog2)、IAP、Keap1、HSP70、FKBP、DCAF15、DCAF16、RNF4、RNF114和AhR等。Typically, 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.
优选地，所述ULM由选自下组的小分子配体形成：VLM、CLM、MLM或ILM。Preferably, said ULM is formed by a small molecule ligand selected from the group consisting of VLM, CLM, MLM or ILM.
连接基团(如本文中所述的L)Linking group (L as described herein)
本发明的连接基团用于连接靶标分子和E3连接酶配体。The linking groups of the present invention are used to link target molecules and E3 ligase ligands.
优选地，所述靶标分子(部分)或E3连接酶配体(部分)可以通过-O-、-S-、-NH-、-NR-、-(C＝O)-、-(C＝O)O-、-(C＝O)NR-、-SO 2-、-SO 2NR-等基团与连接基团连接。 Preferably, the target molecule (part) or E3 ligase ligand (part) can be passed through -O-, -S-, -NH-, -NR-, -(C=O)-, -(C=O )O-, -(C=O)NR-, -SO 2 -, -SO 2 NR- and other groups are connected to the linking group.
在本发明的连接基团上，还可进一步含有其它各种官能团，例如-OH、-NHR、-SH等官能团。The linking group of the present invention may further contain various other functional groups, such as -OH, -NHR, -SH and other functional groups.
典型地，靶标分子或E3连接酶配体上含有例如-OH、-SH、-NH 2、-NHR、-SOOH或-COOH等可发生取代反应的官能团时，可使用含有对应反应官能团的连接分子与其反应(如OH/SH/NH2与-COOH/-COCl等)，从而实现与靶标分子和/或E3连接酶配体的连接。能够发生上述取代反应的官能团，以及在分子上引入上述官能团的方法对于本领域技术人员而言是已知的。 Typically, when 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.
在本发明中，连接基团L与PTM和ULM部分的连接方向可以是任意的，L基团可以左边与PTM连接而右边与ULM连接，或者L基团右边与PTM连接而左边与ULM连接，例如，当L为-C 1-C 4亚烷基CO-时，包括-C 1-C 4亚烷基CO-和-CO-C 1-C 4亚烷基-。 In the present invention, the 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, For example, when L is -C 1 -C 4 alkylene CO-, it includes -C 1 -C 4 alkylene CO- and -CO-C 1 -C 4 alkylene CO-.
活性成分active ingredient
如本文所用，“本发明化合物”指式I所示的化合物，并且还包括式I化合物的立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药：As used herein, "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. Substances or Prodrugs:
Figure PCTCN2022142077-appb-000116
Figure PCTCN2022142077-appb-000116
式中：In the formula:
ULM代表可以和E3连接酶结合的小分子配体部分；ULM represents the small molecule ligand part that can bind to E3 ligase;
PTM代表可以和KRAS G12D结合的小分子配体部分； PTM represents the small molecule ligand part that can bind to KRAS G12D ;
L可以是键或者是可以连接PTM和ULM的连接基团。L can be a bond or a linking group that can connect the PTM and ULM.
例如：For example:
Figure PCTCN2022142077-appb-000117
可以选自
Figure PCTCN2022142077-appb-000118
Figure PCTCN2022142077-appb-000117
can be selected from
Figure PCTCN2022142077-appb-000118
在另一优选例中，L中，各R L1-R L6基团中相邻的两个基团，可各自独立地通过C、N、O或S原子等彼此连接。 In another preferred example, in L, two adjacent groups in each R L1 -R L6 group can be connected to each other independently via C, N, O or S atoms.
例如：For example:
Figure PCTCN2022142077-appb-000119
可以选自
Figure PCTCN2022142077-appb-000120
Figure PCTCN2022142077-appb-000119
can be selected from
Figure PCTCN2022142077-appb-000120
在另一优选例中，PTM、L和ULM分别独立地为本发明实施例化合物的对应部分。In another preferred example, PTM, L and ULM are independently corresponding parts of the compounds of the examples of the present invention.
在另一优选例中，所述通式(I)结构的化合物选自本发明实施例制备的化合物。In another preferred example, the compound of the general formula (I) is selected from the compounds prepared in the examples of the present invention.
在另一优选例中，所式(I)结构的化合物选自实施例中所示的化合物。In another preferred example, the compound of the formula (I) is selected from the compounds shown in the examples.
本发明中的化合物可能形成的盐也是属于本发明的范围。除非另有说明，本发明中的化合物被理解为包括其盐类。在此使用的术语“盐”，指用无机或有机酸和碱形成酸式或碱式的盐。此外，当本发明中的化合物含一个碱性片段时，它包括但不限于吡啶或咪唑，含一个酸性片段时，包括但不限于羧酸，可能形成的两性离子(“内盐”)包含在术语“盐”的范围内。药学上可接受的(即无毒，生理可接受的)盐是首选，虽然其他盐类也有用，例如可以用在制备过程中的分离或纯化步骤。本发明的化合物可能形成盐，例如，化合物I与一定量如等当量的酸或碱反应，在介质中盐析出来，或在水溶液中冷冻干燥得来。The 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. In addition, when 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.
本发明中的化合物含有的碱性片段，包括但不限于胺或吡啶或咪唑环，可能会和有机或无机酸形成盐。可以成盐的典型的酸包括醋酸盐(如用醋酸或三卤代醋酸，如三氟乙酸)、己二酸盐、藻朊酸盐、抗坏血酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、硼酸 盐、丁酸盐、柠檬酸盐、樟脑盐、樟脑磺酸盐、环戊烷丙酸盐、二甘醇酸盐、十二烷基硫酸盐、乙烷磺酸盐、延胡索酸盐、葡庚糖酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、羟基乙磺酸盐(如，2-羟基乙磺酸盐)、乳酸盐、马来酸盐、甲磺酸盐、萘磺酸盐(如，2-萘磺酸盐)、烟酸盐、硝酸盐、草酸盐、果胶酸盐、过硫酸盐、苯丙酸盐(如3-苯丙酸盐)、磷酸盐、苦味酸盐、新戊酸盐、丙酸盐，水杨酸盐、琥珀酸盐、硫酸盐(如与硫酸形成的)、磺酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐如对甲苯磺酸盐、十二烷酸盐等等Basic moieties contained in the compounds of the present invention, including but not limited to amines or pyridine or imidazole rings, 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, maleate, methanesulfonate, naphthalenesulfonate (eg, 2-naphthalenesulfonate), nicotinate, nitrate, oxalate Salt, pectate, persulfate, phenylpropionate (as 3-phenylpropionate), phosphate, picrate, pivalate, propionate, salicylate, succinate, Sulfates (as formed with sulfuric acid), sulfonates, tartrates, thiocyanates, toluenesulfonates such as p-toluenesulfonate, dodecanoate, etc.
本发明的某些化合物可能含有的酸性片段，包括但不限于羧酸，可能会和各种有机或无机碱形成盐。典型的碱形成的盐包括铵盐、碱金属盐如钠、锂、钾盐，碱土金属盐如钙、镁盐，和有机碱形成的盐(如有机胺)，如苄星、二环已基胺、海巴胺(与N,N-二(去氢枞基)乙二胺形成的盐)、N-甲基-D-葡糖胺、N-甲基-D-葡糖酰胺、叔丁基胺，以及和氨基酸如精氨酸、赖氨酸等等形成的盐。碱性含氮基团可以与卤化物季铵盐，如小分子烷基卤化物(如甲基、乙基、丙基和丁基的氯化物、溴化物及碘化物)，二烷基硫酸盐(如，硫酸二甲酯、二乙酯，二丁酯和二戊酯)，长链卤化物(如癸基、十二烷基、十四烷基和十四烷基的氯化物、溴化物及碘化物)，芳烷基卤化物(如苄基和苯基溴化物)等等。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.
本发明中化合物的前药及溶剂合物也在涵盖的范围之内。此处术语“前药”是指一种化合物，在治疗相关疾病时，经过代谢或化学过程的化学转化而产生本发明中的化合物、盐、或溶剂合物。本发明的化合物包括溶剂合物，如水合物。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.
本发明中的化合物、盐或溶剂合物，可能存在的互变异构形式(例如酰胺和亚胺醚)。所有这些互变异构体都是本发明的一部分。Compounds, salts or solvates of the present invention, possible tautomeric forms (such as amides and imino ethers). All such tautomers are part of the present invention.
所有化合物的立体异构体(例如，那些由于对各种取代可能存在的不对称碳原子)，包括其对映体形式和非对映形式，都属于本发明的设想范围。本发明中的化合物独立的立体异构体可能不与其他异构体同时存在(例如，作为一个纯的或者实质上是纯的光学异构体具有特殊的活性)，或者也可能是混合物，如消旋体，或与所有其他立体异构体或其中的一部分形成的混合物。本发明的手性中心有S或R两种构型，由理论与应用化学国际联合会(IUPAC)1974年建议定义。外消旋形式可通过物理方法解决，例如分步结晶，或通过衍生为非对映异构体分离结晶，或通过手性柱色谱法分离。单个的光学异构体可通过合适的方法由外消旋体得到，包括但不限于传统的方法，例如与光学活性酸成盐后再结晶。All stereoisomers of the compounds (for example, those due to possible asymmetric carbon atoms for various substitutions), including their enantiomeric and diastereomeric forms, 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). The 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.
本发明中的化合物，依次通过制备、分离纯化获得的该化合物其重量含量等于或大于90％，例如，等于或大于95％，等于或大于99％(“非常纯”的化合物)，在正文描述列出。此处这种“非常纯”本发明的化合物也作为本发明的一部分。The compound in the present invention, 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.
本发明的化合物所有的构型异构体都在涵盖的范围之内，无论是混合物、纯的或非常纯的形式。在本发明化合物的定义包含顺式(Z)和返式(E)两种烯烃异构体，以及碳环和杂环的顺式和反式异构体。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.
在整个说明书中，基团和取代基可以被选择以提供稳定的片段和化合物。Throughout the specification, groups and substituents may be selected to provide stable fragments and compounds.
特定官能团和化学术语定义都详细介绍如下。对本发明来说，化学元素与Periodic Table of the Elements,CAS version,Handbook of Chemistry and Physics,75 th Ed.中定义的一致。特定官能团的定义也在其中描述。此外，有机化学的基本原则以及特定官能团和反应性在“Organic Chemistry”,Thomas Sorrell,University Science Books,Sausalito:1999,也有说明，其全部内容纳入参考文献之列。 Definitions of specific functional groups and chemical terms are detailed below. For the purposes of the present invention, the chemical elements are as defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Ed. Definitions of specific functional groups are also described therein. In addition, the basic principles of organic chemistry as well as specific functional groups and reactivity are also described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, the entire contents of which are incorporated by reference.
本发明的某些化合物可能存在于特定的几何或立体异构体形式。本发明涵盖所有的化合物，包括其顺式和反式异构体、R和S对映异构体、非对映体、(D)型异构体、(L)型异构体、外消旋混合物和其它混合物。另外不对称碳原子可表示取代基，如烷基。所有异构体以及它们的混合物，都包涵在本发明中。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. Alternatively 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.
按照本发明，同分异构体的混合物含有异构体的比率可以是多样的。例如，在只有两个异构体的混合物可以有以下组合：50:50，60:40，70:30，80:20，90:10，95:5，96:4，97:3，98:2，99:1，或100:0，异构体的所有比率都在本发明范围之内。本专业内一般技术人员容易理解的类似的比率，及为更复杂的异构体的混合物的比率也在本发明范围之内。According to the present invention, the mixture of isomers may contain various 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.
本发明还包括同位素标记的化合物，等同于原始化合物在此公开。不过实际上对一个或更多的原子被与其原子量或质量序数不同的原子取代通常会出现。可以列为本发明的化合物同位素的例子包括氢，碳，氮，氧，磷，硫，氟和氯同位素，分别如 2H、 3H、 13C、 11C、 14C、 15N、 18O、 17O、 31P、 32P、 35S、 18F和 36Cl。本发明中的化合物，或对映体，非对映体，异构体，或药学上可接受的盐或溶剂化物，其中含有上述化合物的同位素或其他同位素原子都在本发明的范围之内。本发明中某些同位素标记化合物，例如 3H和 14C的放射性同位素也在其中，在药物和底物的组织分布实验中是有用的。氚，即 3H和碳-14，即 14C，它们的制备和检测比较容易。是同位素中的首选。此外，较重同位素取代如氘，即 2H，由于其很好的代谢稳定性在某些疗法中有优势，例如在体内增加半衰期或减少用量，因此，在某些情况下可以优先考虑。同位素标记的化合物可以用一般的方法，通过用易得的同位素标记试剂替换为非同位素的试剂，用批露在示例中的方案可以制备。 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. Examples of 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. In addition, substitution of heavier isotopes such as deuterium, ie 2 H, may be preferred in some cases due to its good metabolic stability, which has advantages in certain therapies, such as increased half-life in vivo or reduced dosage. 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.
如果要设计一个本发明的化合物特定的对映体的合成，它可以不对称合成制备，或用手性辅剂衍生化，将所产生的非对映混合物分离，再除去手性辅剂而得到纯的对映体。另外，如果分子中含有一个碱性官能团，如氨基酸，或酸性官能团，如羧基，可以用合适的光学活性的酸或碱的与之形成非对映异构体盐，再通过分离结晶或色谱等常规手段分离，然后就得到了纯的对映体。If the synthesis of a specific enantiomer of a compound of the present invention is to be designed, it 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. In addition, if 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.
如本文所述，本发明中的化合物可与任何数量取代基或官能团取而扩大其包涵范围。通常，术语“取代”不论在术语“可选”前面或后面出现，在本发明配方中包括取代基的通式，是指用指定结构取代基，代替氢自由基。当特定结构中的多个在位置被多个特定的取代基取代时，取代基每一个位置可以是相同或不同。本文中所使用的术语“取代”包括所有允许有机化合物取代。从广义上讲，允许的取代基包括非环状的、环 状的、支链的非支链的、碳环的和杂环的，芳环的和非芳环的有机化合物。在本发明中，如杂原子氮可以有氢取代基或任何允许的上文所述的有机化合物来补充其价态。此外，本发明是无意以任何方式限制允许取代有机化合物。本发明认为取代基和可变基团的组合在以稳定化合物形式在疾病的治疗上是很好的，例如传染病或增生性疾病。此处术语“稳定”是指具有稳定的化合物，在足够长的时间内检测足以维持化合物结构的完整性，最好是在足够长的时间内都在效，本文在此用于上述目的。As described herein, the compounds of the present invention may be substituted with any number of substituents or functional groups to broaden their scope. Generally, whether the term "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. When multiple positions in a specific structure are substituted with multiple specific substituents, the substituents may be the same or different for each position. The term "substitution" as used herein 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. In the present invention eg heteroatom nitrogen may have hydrogen substituents or any permissible organic compound as described above to complement its valence. Furthermore, 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. The term "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.
本申请所涉及的化合物及其药学可接受的盐的代谢产物，以及可以在体内转变为本申请所涉及的化合物及其药学可接受的盐的结构的前药，也包含在本申请的权利要求中。The metabolites of the compounds involved in the application and their pharmaceutically acceptable salts, and the prodrugs that can be transformed into the structures of the compounds involved in the application and the pharmaceutically acceptable salts thereof in vivo are also included in the claims of the application middle.
制备方法Preparation
下面更具体地描述本发明式(I)结构化合物的制备方法，但这些具体方法不对本发明构成任何限制。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便地制得，这样的组合可由本发明所属领域的技术人员容易地进行。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.
典型地，本发明化合物的制备工艺流程如下，其中所用原料和试剂如无特殊说明，均可通过商业途径购买。Typically, 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.
Figure PCTCN2022142077-appb-000121
Figure PCTCN2022142077-appb-000121
(i)式(PG 1-PTM-I-LG 1)化合物与式(LG 2-L-ULM)在碱(如DIPEA、TEA、Py、或DMAP)、缩合剂(如DCC、EDCI、PyBOP、HATU、或BOP)或者在催化剂(如Pd(OAc) 2、Pd 2(dba) 3、Pd(PPh 3) 4、PdCl 2(dppf)、CuI、或Cu(OAc) 2等)作用下反应分别得到式(PG 1-PTM-I-L-ULM)化合物； (i) compound of formula (PG 1 -PTM-I-LG 1 ) and formula (LG 2 -L-ULM) in base (such as DIPEA, TEA, Py, or DMAP), condensation agent (such as DCC, EDCI, PyBOP, HATU, or BOP) or under the action of a catalyst (such as Pd(OAc) 2 , Pd 2 (dba) 3 , Pd(PPh 3 ) 4 , PdCl 2 (dppf), CuI, or Cu(OAc) 2 , etc.) A compound of formula (PG 1 -PTM-IL-ULM) is obtained;
(ii)(PG 1-PTM-I-L-ULM)化合物在酸(如TFA、HCl、TsOH、MsOH等)、或者碱(如哌啶、吗啡啉等)或者氢化、或者氧化(如CAN)或其他条件(如氯甲酸-1-氯乙酯，Pd(PPh 3) 4等)下脱去保护基得到式(PTM-I-L-ULM)化合物； (ii) (PG 1 -PTM-IL-ULM) compound in acid (such as TFA, HCl, TsOH, MsOH, etc.), or base (such as piperidine, morpholine, etc.) or hydrogenation, or oxidation (such as CAN) or 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为一个或多个保护基团，各自独立地选自：Ac、Bn、PMB、MOM、TBS、TBDPS、SEM、Boc、Fmoc、allyl等； 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、LG 2相同或不同，为离去基团，各自独立地选自：氢、OH、卤素、OTs、OMs、OTf、或B(OH) 2等；两个分子的离去基团可形成至少一个小分子(如H 2O、HCl、TsOH、MsOH、TfOH等)。 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、Z的定义如上所述。 R 1 , R 3 , R 4 , R 6 , A, X, Y, and Z are as defined above.
药物组合物、用途和施用方法Pharmaceutical compositions, uses and methods of administration
本发明的药物组合物包括上述活性成分及药学上可接受的载体。The pharmaceutical composition of the present invention includes the above-mentioned active ingredients and a pharmaceutically acceptable carrier.
本发明的化合物可以降低KRAS G12D的活性、表达量、促进KRAS G12D蛋白降解和/或降低KRAS G12D水平，从而可以用于预防和/或治疗KRAS G12D活性或表达量相关的疾病。本发明所述的药物组合物可用于预防和/或治疗以下疾病：炎症、癌症、心血管疾病、感染、免疫性疾病、代谢性疾病。 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.
在另一优选例中，所述癌症为KRAS突变导致的癌症。In another preferred example, the cancer is a cancer caused by KRAS mutation.
在另一优选例中，所述癌症包括(但并不限于)：肺癌(小细胞肺癌(SCLC)、非小细胞肺癌(NSCLC))、乳腺癌、前列腺癌、食道癌、结直肠癌、骨癌、肾癌、胃癌、肝癌、大肠癌、黑色素瘤、淋巴瘤、血癌、脑瘤、骨髓瘤、软组织肉瘤、胰腺癌、皮肤癌。In another preferred example, 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.
通式(I)所述化合物可以与已知的治疗或改进相似病状的其他药物联用。联合给药时，原来药物的给药方式和剂量可以保持不变，而同时或随后服用式I的化合物。当式I化合物与其它一种或几种药物同时服用时，可以优选使用同时含有一种或几种已知药物和式I化合物的药用组合物。药物联用也包括在重叠的时间段服用式I化合物与其它一种或几种已知药物。当式I化合物与其它一种或几种药物进行药物联用时，式I化合物或已知药物的剂量可能比它们单独用药的剂量低。The compound of general formula (I) can be used in combination with other known drugs for treating or improving similar diseases. In the case of combined administration, 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. When the compound of formula I is taken together with one or several other drugs, 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. When the compound of formula I is used in combination with one or several other drugs, the dosage of the compound of formula I or known drugs may be lower than that of their single administration.
可以与通式(I)所述化合物进行药物联用的药物或活性成分包括但不局限为：PD-1抑制剂(如nivolumab、pembrolizumab、pidilizumab、cemiplimab、JS-001、SHR-120、BGB-A317、IBI-308、GLS-010、GB-226、STW204、HX008、HLX10、BAT 1306、AK105、LZM 009或上述药物的生物类似药等)、PD-L1抑制剂(如durvalumab、atezolizumab、avelumab、CS1001、KN035、HLX20、SHR-1316、BGB-A333、JS003、CS1003,KL-A167、F 520、GR1405、MSB2311或上述药物的生物类似药等)、CD20抗体(如rituximab、obinutuzumab、ofatumumab、veltuzumab、tositumomab、131I-tositumomab、ibritumomab、90Y-ibritumomab、90In-ibritumomab、ibritumomab tiuxetan等)、CD47抗体(如Hu5F9-G4、CC-90002、TTI-621、TTI-622、OSE-172、SRF-231、ALX-148、NI-1701、SHR-1603、IBI188、IMM01)、ALK抑制剂(如Ceritinib、Alectinib、Brigatinib、Lorlatinib、奥卡替尼)、PI3K抑制剂(如Idelalisib、Duvelisib、Dactolisib、Taselisib、Bimiralisib、Omipalisib、Buparlisib等)、BTK抑制剂(如Ibrutinib、Tirabrutinib、Acalabrutinib、Zanubrutinib、Vecabrutinib等)、EGFR抑制剂(如Afatinib、Gefitinib、Erlotinib、Lapatinib、Dacomitinib、Icotinib、Canertinib、Sapitinib、Naquotinib、Pyrotinib、Rociletinib、Osimertinib等)、VEGFR抑制剂(如Sorafenib、Pazopanib、Regorafenib、Sitravatinib、Ningetinib、Cabozantinib、Sunitinib、多纳非尼等)、HDAC抑制剂(如Givinostat、Tucidinostat、Vorinostat、Fimepinostat、Droxinostat、Entinostat、Dacinostat、Quisinostat、Tacedinaline等)、CDK抑制剂(如Palbociclib、Ribociclib、Abemaciclib、Milciclib、Trilaciclib、Lerociclib等)、MEK抑制剂(如Selumetinib(AZD6244)、Trametinib(GSK1120212)、PD0325901、U0126、Pimasertib(AS-703026)、PD184352(CI-1040)等)、mTOR抑制剂(如Vistusertib等)、SHP2抑制剂(如RMC-4630、JAB-3068、TNO155 等)或其组合。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, veltuzumab, tositumomab, 131I-tositumomab, ibritumomab, 90Y-ibritumomab, 90In-ibritumomab, ibritumomab tiuxetan, etc.), CD47 antibody (such as Hu5F9-G4, CC-90002, TTI-621, TTI-622, OSE-172, SRF-231, ALX -148, NI-1701, SHR-1603, IBI188, IMM01), ALK inhibitors (such as Ceritinib, Alectinib, Brigatinib, Lorlatinib, Ocatinib), PI3K inhibitors (such as Idelalisib, Duvelisib, Dactolisib, Taselisib, Bimiralisib, Omipalisib, Buparlisib, etc.), 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, Quisinostat , Tacedinaline, etc.), CDK inhibitors (such as Palbociclib, Ribociclib, Abemaciclib, Milciclib, Trilaciclib, Lerociclib, etc.), MEK inhibitors (such as Selumetinib (AZD6244), Trametinib (GSK1120212), PD0325901, U0126, Pimasertib (AS-703026), PD184352 (CI-1040, etc.), mTOR inhibitors (such as Vistusertib, etc.), SHP2 inhibitors (such as RMC-4630, JAB-3068, TNO155, etc.) or combinations thereof.
本发明所述药物组合物的剂型包括(但并不限于)：注射剂、片剂、胶囊剂、气雾剂、栓剂、膜剂、滴丸剂、外用擦剂、控释型或缓释型或纳米制剂。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.
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有10-1000mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。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. Wherein, "safe and effective dose" refers to: the amount of the compound is sufficient to obviously improve the condition without causing severe side effects. Usually, 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. Preferably, the "one dose" is a capsule or tablet.
“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如
Figure PCTCN2022142077-appb-000122
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。 "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
Figure PCTCN2022142077-appb-000122
), wetting agent (such as sodium lauryl sulfate), coloring agent, flavoring agent, stabilizer, antioxidant, preservative, pyrogen-free water, etc.
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。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 .
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, 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 monostearate; (h) adsorbents such as kaolin; and (i) lubricants such as talc, hard Calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。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. 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.
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁 二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, 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.
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。Besides such inert diluents, the compositions can also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。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.
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。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.
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。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.
本发明治疗方法可以单独施用，或者与其它治疗手段或者治疗药物联用。The treatment method of the present invention can be used alone or in combination with other treatment methods or drugs.
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选50～1000mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。When using a pharmaceutical composition, 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. Of course, 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.
本发明还提供了一种药物组合物的制备方法，包括步骤：将药学上可接受的载体与本发明所述通式(I)化合物或其晶型、药学上可接受的盐、水合物或溶剂合物进行混合，从而形成药物组合物。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.
本发明还提供了一种治疗方法，它包括步骤：给需要治疗的对象施用本发明中所述通式(I)化合物，或其晶型、药学上可接受的盐、水合物或溶剂合物，或施用本发明所述的药物组合物，用于选择性地抑制KRAS G12D。 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 .
与现有技术相比，本发明具有以下主要优点：Compared with the prior art, the present invention has the following main advantages:
(1)所述化合物能够选择性的促进KRAS G12D蛋白水解，从而预防和/或治疗KRAS G12D活性或表达量相关的疾病(尤其对肿瘤细胞选择性高)，活性高，安全性好； (1) 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;
(2)本发明的化合物可以催化量发挥抑制细胞增殖的效果。细胞内能够循环发挥降解靶蛋白的作用，实现减少给药剂量，延长给药周期，达到安全有效的抗肿瘤效果；(2) 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;
(3)所述化合物具有更好的体内外药效学、药代动力学性能和/或更低的毒副作用。(3) The compound has better in vivo and in vitro pharmacodynamics, pharmacokinetic properties and/or lower toxic and side effects.
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件如Sambrook等人，分子克隆：实验室手册(New York:Cold Spring Harbor Laboratory Press,1989)中所述的条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。Below in conjunction with specific embodiment, further illustrate the present invention. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental method that does not indicate specific conditions in the following examples, usually according to conventional conditions such as Sambrook et al., molecular cloning: the conditions described in the laboratory manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the manufacturer suggested conditions. Percentages and parts are by weight unless otherwise indicated.
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。Unless otherwise defined, all professional and scientific terms used herein have the same meanings as commonly understood by those skilled in the art. In addition, any methods and materials similar or equivalent to those described can be applied to the method of the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only.
本发明的化合物结构是通过核磁共振(NMR)和液质联用色谱(LC-MS)来确定的。The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and liquid chromatography-mass chromatography (LC-MS).
NMR是使用Bruker AVANCE-400核磁仪检测的，测定溶剂包含氘代二甲亚砜(DMSO-d 6)、氘代丙酮(CD 3COCD 3)、氘代氯仿(CDCl 3)及氘代甲醇(CD 3OD)等，内标采用四甲基硅烷(TMS)，化学位移以百万分之一(ppm)的单位计量。 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).
液质联用色谱(LC-MS)是使用Waters SQD2质谱仪检测的。HPLC的测定使用Agilent 1100高压色谱仪(Microsorb 5 micron C18 100 x 3.0mm色谱柱)。Liquid chromatography-mass chromatography (LC-MS) was detected using a Waters SQD2 mass spectrometer. The determination of HPLC uses Agilent 1100 high pressure chromatograph (Microsorb 5 micron C18 100 x 3.0mm chromatographic column).
薄层层析硅胶板使用青岛GF254硅胶板，TLC采用的是0.15-0.20mm，制备薄层色谱采用的是0.4mm-0.5mm。柱层析一般使用青岛硅胶200-300目硅胶作为载体。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.
本发明实施例中的起始原料都是已知并有市售的，或者可以采用或按照本领域已报道的文献资料合成的。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.
除特殊说明外，本发明所有反应均在干燥的惰性气体(如氮气或氩气)保护下通过连续磁力搅拌进行，反应温度均为摄氏度。Unless otherwise specified, all the reactions of the present invention are carried out under the protection of dry inert gas (such as nitrogen or argon) by continuous magnetic stirring, and the reaction temperatures are all in degrees Celsius.
实施例Example
中间体A(1R,5S)-3-(2,7-二氯-8-氟吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯的制备Intermediate A(1R,5S)-3-(2,7-dichloro-8-fluoropyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1] Preparation of tert-butyl octane-8-carboxylate
Figure PCTCN2022142077-appb-000123
Figure PCTCN2022142077-appb-000123
步骤一：2,4,7-三氯-8-氟吡啶[4,3-d]嘧啶的制备Step 1: Preparation of 2,4,7-trichloro-8-fluoropyridino[4,3-d]pyrimidine
在0℃下，7-氯-8-氟吡啶[4,3-d]嘧啶-2,4-二醇(3.00g,13.9mmol,1.00eq)的POCl 3(49.5g,323mmol,30.0mL,23.2eq)溶液中加入DIEA(5.40g,41.8mmol,7.27mL,3.00eq)。得到的反应液在110℃反应2h，然后减压浓缩出去POCl 3。残余物中加入冰(150g)然后用EtOAc(100mL*3)萃取。合并的有机相用饱和食盐水(100mL)洗涤，经无水Na 2SO 4干燥后过滤。滤液减压浓缩，残余物用硅胶柱层析分离得到目标产物(2.66g,10.5mmol,产率：75.7％)。 At 0°C, 7-chloro-8-fluoropyridino[4,3-d]pyrimidine-2,4-diol (3.00g, 13.9mmol, 1.00eq) in POCl 3 (49.5g, 323mmol, 30.0mL, 23.2eq) solution was added DIEA (5.40g, 41.8mmol, 7.27mL, 3.00eq). The obtained reaction liquid was reacted at 110° C. for 2 h, and then concentrated under reduced pressure to remove POCl 3 . Ice (150 g) was added to the residue followed by extraction with EtOAc (100 mL*3). 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, and the residue was separated by silica gel column chromatography to obtain the target product (2.66 g, 10.5 mmol, yield: 75.7%).
LC-MS：m/z 252(M+H) +。 LC-MS: m/z 252 (M+H) + .
步骤二：(1R,5S)-3-(2,7-二氯-8-氟吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯的制备Step 2: (1R,5S)-3-(2,7-dichloro-8-fluoropyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1] Preparation of tert-butyl octane-8-carboxylate
2,4,7-三氯-8-氟吡啶[4,3-d]嘧啶(2.50g,9.90mmol,1.00eq)和(1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(2.10g,9.90mmol,1.00eq)的DCM(50.0mL)溶液冷却到-40℃，随后滴加DIEA(3.84g,29.7mmol,5.17mL,3.00eq)。得到的反应液在-40℃反应0.5h， 然后用H 2O(50mL)淬灭再用DCM(100mL*2)萃取。合并的有机相用饱和食盐水(100mL)洗涤，经无水Na 2SO 4干燥后过滤。滤液减压浓缩得到目标产物(4.10g,粗产品)。无需纯化直接用于下一步反应。 2,4,7-Trichloro-8-fluoropyridino[4,3-d]pyrimidine (2.50g, 9.90mmol, 1.00eq) and (1R,5S)-3,8-diazabicyclo[3.2.1 A solution of tert-butyl octane-8-carboxylate (2.10 g, 9.90 mmol, 1.00 eq) in DCM (50.0 mL) was cooled to -40 °C, followed by dropwise addition of DIEA (3.84 g, 29.7 mmol, 5.17 mL, 3.00 eq) . 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.
LC-MS：m/z 428(M+H) +。 LC-MS: m/z 428 (M+H) + .
中间体B-1和B-2Intermediates B-1 and B-2
Figure PCTCN2022142077-appb-000124
Figure PCTCN2022142077-appb-000124
步骤一：1-苄基2-甲基2-(丁-3-烯-1-基)吡咯啉-1,2-二甲酸酯的制备Step 1: Preparation of 1-benzyl 2-methyl 2-(but-3-en-1-yl)pyrroline-1,2-dicarboxylate
氮气保护下，在-70℃将1-苄基2-甲基(S)-吡咯啉-1,2-二甲酸酯(50.0g,190mmol,1.00eq)的THF(100mL)溶液滴加到LiHMDS(1.00M,285mL,1.50eq)中，得到的反应液在-70℃反应2h，随后在此温度下滴加4-溴丁-1-烯(51.2g,380mmol,38.6mL,2.00eq)。得到的反应液升温至25℃并反应16h。得到的反应液用NH 4Cl(200mL)淬灭再用EtOAc(100mL*3)萃取。合并的有机相用饱和食盐水(100mL)洗涤，经无水Na 2SO 4干燥后过滤。滤液减压浓缩，残余物用硅胶柱层析分离得到目标产物(38.0g,120mmol,产率：63.1％)。 Under nitrogen protection, a THF (100 mL) solution of 1-benzyl 2-methyl (S)-pyrroline-1,2-dicarboxylate (50.0 g, 190 mmol, 1.00 eq) was added dropwise to In LiHMDS (1.00M, 285mL, 1.50eq), the resulting reaction solution was reacted at -70°C for 2h, and then 4-bromobut-1-ene (51.2g, 380mmol, 38.6mL, 2.00eq) was added dropwise at this temperature . The obtained reaction solution was warmed up to 25°C and reacted for 16h. The resulting reaction solution was quenched with NH 4 Cl (200 mL) and extracted with EtOAc (100 mL*3). 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, and the residue was separated by silica gel column chromatography to obtain the target product (38.0 g, 120 mmol, yield: 63.1%).
1H NMR(400MHz，CDCl 3)δ7.33(m,5H)5.77(m,1H)5.07(m,4H)3.72(m,3H)3.48(m,2H)2.01(m,8H). 1 H NMR (400MHz, CDCl 3 )δ7.33(m,5H)5.77(m,1H)5.07(m,4H)3.72(m,3H)3.48(m,2H)2.01(m,8H).
步骤二：1-苄基2-甲基2-(2-(环氧乙烷-2-基)乙基)吡咯啉-1,2-二甲酸酯的制备Step 2: Preparation of 1-benzyl 2-methyl 2-(2-(oxiran-2-yl)ethyl)pyrroline-1,2-dicarboxylate
在0℃，1-苄基2-甲基2-(丁-3-烯-1-基)吡咯啉-1,2-二甲酸酯(37.5g,118mmol,1.00eq)的DCM(650mL)溶液中分批加入m-CPBA(60.0g,295mmol,纯度：85.0％,2.50eq)。得到的反应液在25℃反应16h，然后用Sat.aq.Na 2SO 3(300mL*3)洗涤。有机相分离后经无水Na 2SO 4干燥后过滤。滤液减压浓缩，残余物用硅胶柱层析分离得到目标产物(29.0g,87.0mmol,产率：73.6％)。 1-Benzyl 2-methyl 2-(but-3-en-1-yl)pyrroline-1,2-dicarboxylate (37.5 g, 118 mmol, 1.00 eq) in DCM (650 mL) at 0 °C m-CPBA (60.0 g, 295 mmol, purity: 85.0%, 2.50 eq) was added in portions to the solution. The obtained reaction solution was reacted at 25°C for 16 h, and then washed with Sat.aq.Na 2 SO 3 (300 mL*3). The organic phase was separated and dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the target product (29.0 g, 87.0 mmol, yield: 73.6%).
1H NMR(400MHz，CDCl 3)δ7.33(br d,J＝7.88Hz,5H)5.11(m,2H)3.70(m,3H)3.48(m,2H)2.73(m,2H)2.36(m,2H)1.98(m,5H)1.50(m,2H) 1 H NMR (400MHz, CDCl 3 ) δ7.33 (br d, J = 7.88Hz, 5H) 5.11 (m, 2H) 3.70 (m, 3H) 3.48 (m, 2H) 2.73 (m, 2H) 2.36 (m ,2H)1.98(m,5H)1.50(m,2H)
步骤三：3-(羟甲基)四氢-1H-双稠吡咯啶-7a(5H)-甲酸甲酯的制备Step 3: Preparation of 3-(hydroxymethyl)tetrahydro-1H-biscondensed pyrrolidine-7a(5H)-methyl carboxylate
氮气保护下，1-苄基2-甲基2-(2-(环氧乙烷-2-基)乙基)吡咯啉-1,2-二甲酸酯(28.0g,84.0mmol,1.00eq)的MeOH(600mL)溶液中加入Pd/C(6.00g,纯度10.0％)。得到的混合物在氢气氛围(15psi)下在25℃反应16h。得到的反应液过滤，滤液减压浓缩得到目标产物(16.8g,crude)。Under nitrogen protection, 1-benzyl 2-methyl 2-(2-(oxiran-2-yl)ethyl)pyrroline-1,2-dicarboxylate (28.0g, 84.0mmol, 1.00eq ) in MeOH (600 mL) was added Pd/C (6.00 g, purity 10.0%). The resulting mixture was reacted at 25° C. for 16 h under hydrogen atmosphere (15 psi). The obtained reaction liquid was filtered, and the filtrate was concentrated under reduced pressure to obtain the target product (16.8 g, crude).
LC-MS：m/z 200(M+H) +。 LC-MS: m/z 200 (M+H) + .
步骤四：(顺式)-3-(((叔丁基二苯基硅基)氧基)甲基)四氢-1H-双稠吡咯啶-7a(5H)-甲酸甲酯及(反式)-3-(((叔丁基二苯基硅基)氧基)甲基)四氢-1H-双稠吡咯啶-7a(5H)-甲酸甲酯的 制备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
3-(羟甲基)四氢-1H-双稠吡咯啶-7a(5H)-甲酸甲酯(13.0g,65.3mmol,1.00eq)的DMF(300mL)溶液中加入咪唑(8.88g,130mmol,2.00eq)和TBDPSCl(26.9g,97.9mmol,25.1mL,1.50eq)。得到的反应液在25℃反应16h，然后减压浓缩。残余物用硅胶柱层析分离得到(顺式)-3-(((叔丁基二苯基硅基)氧基)甲基)四氢-1H-双稠吡咯啶-7a(5H)-甲酸甲酯(6.21g,14.2mmol,产率：21.8％)和(反式)-3-(((叔丁基二苯基硅基)氧基)甲基)四氢-1H-双稠吡咯啶-7a(5H)-甲酸甲酯(7.39g,16.9mmol,产率：25.9％)。Add imidazole (8.88g, 130mmol, 2.00eq) and TBDPSCl (26.9g, 97.9mmol, 25.1 mL, 1.50eq). The obtained reaction liquid was reacted at 25° C. for 16 h, and then concentrated under reduced pressure. The residue was separated by silica gel column chromatography to obtain (cis)-3-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-1H-biscondensed pyrrolidine-7a(5H)-carboxylic acid Methyl ester (6.21 g, 14.2 mmol, yield: 21.8%) and (trans)-3-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-1H-biscondensed pyrrolidine -7a(5H)-Methyl formate (7.39 g, 16.9 mmol, yield: 25.9%).
(顺式)-3-(((叔丁基二苯基硅基)氧基)甲基)四氢-1H-双稠吡咯啶-7a(5H)-甲酸甲酯(cis)-3-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-1H-biscondensed pyrrolidine-7a(5H)-methyl carboxylate
LC-MS：m/z 438(M+H) +。 1H NMR(400MHz，CDCl 3)δ7.70(td,J＝7.94,1.50Hz,4H)7.39(m,6H)3.76(m,1H)3.64(s,3H)3.55(dd,J＝9.88,7.25Hz,1H)3.04(m,1H)2.87(m,1H)2.70(dt,J＝10.82,5.60Hz,1H)2.38(ddd,J＝12.26,6.38,2.38Hz,1H)2.19(m,1H)2.05(m,1H)1.72(m,5H)1.07(s,9H). LC-MS: m/z 438 (M+H) + . 1 H NMR (400MHz, CDCl 3 ) δ7.70(td, J=7.94, 1.50Hz, 4H) 7.39(m, 6H) 3.76(m, 1H) 3.64(s, 3H) 3.55(dd, J=9.88, 7.25Hz,1H)3.04(m,1H)2.87(m,1H)2.70(dt,J＝10.82,5.60Hz,1H)2.38(ddd,J＝12.26,6.38,2.38Hz,1H)2.19(m,1H) )2.05(m,1H)1.72(m,5H)1.07(s,9H).
(反式)-3-(((叔丁基二苯基硅基)氧基)甲基)四氢-1H-双稠吡咯啶-7a(5H)-甲酸甲酯(trans)-3-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-1H-biscondensed pyrrolidine-7a(5H)-methyl carboxylate
LC-MS：m/z 438(M+H) +。 1H NMR(400MHz，CDCl 3)δ7.67(m,4H)7.41(m,6H)3.98(dd,J＝10.39,4.40Hz,1H)3.81(dd,J＝10.39,6.48Hz,1H)3.72(s,3H)3.38(m,1H)2.91(m,1H)2.82(m,1H)2.46(m,1H)2.21(m,1H)1.95(m,1H)1.80(m,4H)1.60(m,1H)1.06(s,9H)。 LC-MS: m/z 438 (M+H) + . 1 H NMR (400MHz, CDCl 3 ) δ7.67 (m, 4H) 7.41 (m, 6H) 3.98 (dd, J = 10.39, 4.40Hz, 1H) 3.81 (dd, J = 10.39, 6.48Hz, 1H) 3.72 (s,3H)3.38(m,1H)2.91(m,1H)2.82(m,1H)2.46(m,1H)2.21(m,1H)1.95(m,1H)1.80(m,4H)1.60(m ,1H) 1.06(s,9H).
中间体C-1(1R,5S)-3-(7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(((反式)-3-(羟甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯的制备Intermediate C-1(1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-( ((trans)-3-(hydroxymethyl)tetrahydro-1H-biscondensed pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-4-yl)-3 , Preparation of tert-butyl 8-diazabicyclo[3.2.1]octane-8-carboxylate
Figure PCTCN2022142077-appb-000125
Figure PCTCN2022142077-appb-000125
第一步：((反式)-3-(((叔丁基二苯基硅基)氧基)甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲醇的制备Step 1: Preparation of ((trans)-3-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-1H-biscondensed pyrrolidin-7a(5H)-yl)methanol
氮气保护下，在-20℃将LiAlH 4(520mg,13.7mmol,2.00eq)加入到(反式)-3-(((叔丁 基二苯基硅基)氧基)甲基)四氢-1H-双稠吡咯啶-7a(5H)-甲酸甲酯(3.00g,6.85mmol,1.00eq)的THF(30.0mL)溶液中。得到的反应液在-20℃反应1h，然后在0℃依次加入H 2O(700uL)、5％NaOH(700uL)和H 2O(2100uL)淬灭，然后用无水Mg 2SO 4干燥后过滤。滤液减压浓缩，残余物用硅胶柱层析分离得到目标产物(2.72g,6.64mmol,产率：96.9％)。 Under nitrogen protection, LiAlH 4 (520mg, 13.7mmol, 2.00eq) was added to (trans)-3-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro- 1H-Dicondensed pyrrolidine-7a(5H)-methyl carboxylate (3.00g, 6.85mmol, 1.00eq) in THF (30.0mL). The resulting reaction solution was reacted at -20°C for 1 h, then quenched by sequentially adding H 2 O (700uL), 5% NaOH (700uL) and H 2 O (2100uL) at 0°C, and then dried with anhydrous Mg 2 SO 4 filter. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the target product (2.72 g, 6.64 mmol, yield: 96.9%).
1H NMR(400MHz，CDCl 3)δ7.68(dt,J＝7.78,1.63Hz,4H)7.42(m,6H)3.92(dd,J＝10.54,6.27Hz,1H)3.77(m,1H)3.28(m,2H)3.17(m,1H)2.95(br s,1H)2.83(m,1H)2.70(td,J＝9.47,6.65Hz,1H)1.96(m,1H)1.66(m,7H)1.07(s,9H). 1 H NMR (400MHz, CDCl 3 ) δ7.68 (dt, J = 7.78, 1.63Hz, 4H) 7.42 (m, 6H) 3.92 (dd, J = 10.54, 6.27Hz, 1H) 3.77 (m, 1H) 3.28 (m,2H)3.17(m,1H)2.95(br s,1H)2.83(m,1H)2.70(td,J＝9.47,6.65Hz,1H)1.96(m,1H)1.66(m,7H)1.07 (s,9H).
第二步：(1R,5S)-3-(2-(((反式)-3-(((叔丁基二苯基硅基)氧基)甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)-7-氯-8-氟吡啶[4,3-d]嘧啶-4-基)-3,8二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯的制备The second step: (1R,5S)-3-(2-(((trans)-3-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-1H-biscondensed pyrrole Pyridin-7a(5H)-yl)methoxy)-7-chloro-8-fluoropyridin[4,3-d]pyrimidin-4-yl)-3,8diazabicyclo[3.2.1]octane - Preparation of tert-butyl 8-formate
在0℃下，(1R,5S)-3-(2,7-二氯-8-氟吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(2.00g,4.16mmol,纯度89.0％,1.00eq)和((反式)-3-(((叔丁基二苯基硅基)氧基)甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲醇(2.21g,5.40mmol,1.30eq)的THF(50.0mL)溶液中加入t-BuONa(519mg,5.40mmol,1.30eq)。得到的混合物在25℃反应3h，然后加入DCM(400mL)稀释，然后用H 2O(40mL)洗涤。有机相分离后用无水Mg 2SO 4干燥后过滤。滤液减压浓缩，残余物用硅胶柱层析分离得到目标产物(2.20g,2.74mmol,产率：66.1％)。 At 0°C, (1R,5S)-3-(2,7-dichloro-8-fluoropyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2. 1] tert-butyl octane-8-carboxylate (2.00g, 4.16mmol, purity 89.0%, 1.00eq) and ((trans)-3-(((tert-butyldiphenylsilyl)oxy)methyl t-BuONa (519mg, 5.40mmol, 1.30eq) in THF (50.0mL) solution of tetrahydro-1H-biscondensed pyrrolidin-7a(5H)-yl)methanol (2.21g, 5.40mmol, 1.30eq) ). 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%).
1H NMR(400MHz，CDCl 3)δ8.72(s,1H)7.68(m,4H)7.41(m,6H)4.41(m,4H)4.24(m,1H)4.15(d,J＝10.22Hz,1H)3.99(dd,J＝10.38,4.58Hz,1H)3.78(m,3H)3.29(br s,1H)2.82(m,2H)2.19(dt,J＝12.70,4.25Hz,1H)1.87(m,8H)1.69(m,3H)1.52(s,9H)1.06(s,9H) 1 H NMR (400MHz, CDCl 3 )δ8.72(s,1H)7.68(m,4H)7.41(m,6H)4.41(m,4H)4.24(m,1H)4.15(d,J=10.22Hz, 1H)3.99(dd, J＝10.38,4.58Hz,1H)3.78(m,3H)3.29(br s,1H)2.82(m,2H)2.19(dt,J＝12.70,4.25Hz,1H)1.87(m ,8H)1.69(m,3H)1.52(s,9H)1.06(s,9H)
第三步:(1R,5S)-3-(2-(((反式)-3-(((叔丁基二苯基硅基)氧基)甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基硅基)乙炔基)萘-1-基)吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯的制备The third step: (1R,5S)-3-(2-(((trans)-3-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-1H-biscondensed pyrrole Pyridine-7a(5H)-yl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl) Preparation of tert-butyl naphthalene-1-yl)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
氮气保护下，(1R,5S)-3-(2-(((反式)-3-(((叔丁基二苯基硅基)氧基)甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)-7-氯-8-氟吡啶[4,3-d]嘧啶-4-基)-3,8二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(2.10g,2.62mmol,1.00eq)和((2-氟-6-(甲氧基甲氧)-8-(4,4,5,5-四甲基-1,3,2-二氧环戊硼烷-2-基)萘-1-基)乙炔基)三异丙基硅烷(1.61g,3.14mmol,1.20eq)的二恶烷(25.2mL)和H 2O(6.30mL)的混合物中加入Cs 2CO 3(2.56g,7.86mmol,3.00eq)和CataCXium Pd G2(175mg,262umol,0.100eq)。反应混合物在100℃反应1h，然后用EtOAc(200mL*2)萃取。有机相分离后用无水Mg 2SO 4干燥后过滤。滤液减压浓缩，残余物用硅胶柱层析分离得到目标产物(2.60g,2.26mmol,产率：86.2％)。 Under nitrogen protection, (1R,5S)-3-(2-(((trans)-3-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-1H-biscondensed pyrrole Pyridin-7a(5H)-yl)methoxy)-7-chloro-8-fluoropyridin[4,3-d]pyrimidin-4-yl)-3,8diazabicyclo[3.2.1]octane -tert-butyl 8-carboxylate (2.10g, 2.62mmol, 1.00eq) and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1 , 3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (1.61 g, 3.14 mmol, 1.20 eq) in dioxane (25.2 mL) and H To a mixture of 2 O (6.30 mL) was added Cs 2 CO 3 (2.56 g, 7.86 mmol, 3.00 eq) and CataCXium Pd G2 (175 mg, 262 umol, 0.100 eq). 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%).
1H NMR(400MHz，CDCl 3)δ9.04(s,1H)7.78(dd,J＝9.05,5.62Hz,1H)7.68(m,4H)7.51(d,J＝2.57Hz,1H)7.41(m,6H)7.31(m,2H)7.31(m,1H)5.30(m,2H)4.17(m,3H)4.00(dd,J＝10.27,4.65Hz,1H)3.82(ddd,J＝10.21,6.60,3.48Hz,2H)3.51(m,4H)3.31(m,1H)2.83(m,2H)2.23(m,1H)1.86(m,15H)1.53(s,9H)1.53(m,1H)1.06(d,J＝1.59Hz, 9H)0.87(m,18H) 1 H NMR (400MHz, CDCl 3 ) δ9.04(s,1H)7.78(dd,J=9.05,5.62Hz,1H)7.68(m,4H)7.51(d,J=2.57Hz,1H)7.41(m ,6H)7.31(m,2H)7.31(m,1H)5.30(m,2H)4.17(m,3H)4.00(dd,J=10.27,4.65Hz,1H)3.82(ddd,J=10.21,6.60, 3.48Hz,2H)3.51(m,4H)3.31(m,1H)2.83(m,2H)2.23(m,1H)1.86(m,15H)1.53(s,9H)1.53(m,1H)1.06(d ,J＝1.59Hz, 9H)0.87(m,18H)
第四步:(1R,5S)-3-(7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(((反式)-3-(羟甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯的制备The fourth step: (1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(( (trans)-3-(hydroxymethyl)tetrahydro-1H-biscondensed pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-4-yl)-3, Preparation of tert-butyl 8-diazabicyclo[3.2.1]octane-8-carboxylate
(1R,5S)-3-(2-(((反式)-3-(((叔丁基二苯基硅基)氧基)甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基硅基)乙炔基)萘-1-基)吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(2.50g,2.17mmol,1.00eq)的THF(25.0mL)溶液中加入TBAF(1.00M,6.51mL,3.00eq)。得到的反应液在25℃反应16h，然后加入EtOAc(100mL)稀释后，再依次用H 2O(50mL)和盐水(50mL)洗涤。有机相分离后用无水Mg 2SO 4干燥后过滤。滤液减压浓缩得到目标产物。无需纯化直接用于下一步反应。 (1R,5S)-3-(2-(((trans)-3-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-1H-biscondensed pyrrolidine-7a( 5H)-yl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1- Base) pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (2.50g, 2.17mmol, 1.00eq) To THF (25.0 mL) solution was added TBAF (1.00 M, 6.51 mL, 3.00 eq). The resulting reaction solution was reacted at 25° C. for 16 h, then diluted with EtOAc (100 mL), and washed with H 2 O (50 mL) and brine (50 mL) successively. The organic phase was separated and dried over anhydrous Mg2SO4 and filtered. The filtrate was concentrated under reduced pressure to obtain the target product. It was directly used in the next reaction without purification.
LC-MS：m/z 757(M+H) +。 LC-MS: m/z 757 (M+H) + .
第五步:(1R,5S)-3-(2-(((反式)-3-((1,3-二氧异吲哚-2-基)甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)-7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯的制备The fifth step: (1R,5S)-3-(2-(((trans)-3-((1,3-dioxoisoindol-2-yl)methyl)tetrahydro-1H-double Pyrrolidine-7a(5H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoropyridin[4 Preparation of ,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester
氮气保护下，(1R,5S)-3-(7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(((反式)-3-(羟甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯、异吲哚啉-1,3-二酮(29.2mg,198umol,1.50eq)和PPh 3(65.9mg,251umol,1.90eq)的THF(3.00mL)的溶液中滴加入DIAD(50.8mg,251umol,48.8uL,1.90eq)。得到的反应液在25℃反应3h，然后用H 2O(6mL)淬灭后用EtOAc(10mL*2)萃取。有机相合并后用无水Mg 2SO 4干燥后过滤。滤液减压浓缩，残余物用硅胶柱层析分离得到目标产物(85.0mg,95.9umol,产率：72.6％)。 Under nitrogen protection, (1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(( (trans)-3-(hydroxymethyl)tetrahydro-1H-biscondensed pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-4-yl)-3, 8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester, isoindoline-1,3-dione (29.2mg, 198umol, 1.50eq) and PPh 3 (65.9mg, 251umol, DIAD (50.8mg, 251umol, 48.8uL, 1.90eq) was added dropwise to a solution of 1.90eq) in THF (3.00mL). The resulting reaction solution was reacted at 25° C. for 3 h, then quenched with H 2 O (6 mL) and extracted with EtOAc (10 mL*2). The combined organic phases were 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 (85.0mg, 95.9umol, yield: 72.6%).
LC-MS：m/z 885(M+H) +。 LC-MS: m/z 885 (M+H) + .
第六步:(1R,5S)-3-(2-(((反式)-3-(氨甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)-7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯的制备The sixth step: (1R,5S)-3-(2-(((trans)-3-(aminomethyl)tetrahydro-1H-biscondensed pyrrolidine-7a(5H)-yl)methoxy) -7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-4-yl)-3, Preparation of tert-butyl 8-diazabicyclo[3.2.1]octane-8-carboxylate
(1R,5S)-3-(2-(((反式)-3-((1,3-二氧异吲哚-2-基)甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)-7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(100mg,90umol,1.00eq)的EtOH(2mL)溶液中加入NH 2NH 2.H 2O(103mg,纯度：85.0％,7.75eq)。得到的反应液在25℃反应2h，然后用制备液相分离得到目标产物(22mg,29umol,产率：33％)。 (1R,5S)-3-(2-(((trans)-3-((1,3-dioxindol-2-yl)methyl)tetrahydro-1H-biscondensed pyrrolidine-7a (5H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoropyridin[4,3-d ]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (100mg, 90umol, 1.00eq) in EtOH (2mL) was added NH 2 NH 2 .H 2 O (103 mg, purity: 85.0%, 7.75 eq). The obtained reaction solution was reacted at 25° C. for 2 h, and then separated by preparative liquid phase to obtain the target product (22 mg, 29 umol, yield: 33%).
LC-MS：m/z 756(M+H) +。 1H NMR(400MHz，DMSO-d 6)δ9.09(s,1H)8.34(s,1H)8.10(dd,J＝9.13,5.88Hz,1H)7.74(d,J＝2.38Hz,1H)7.55(t,J＝9.01Hz,1H)7.38(s,1H)5.37(s,2H)4.55(br d,J＝11.76Hz,1H)4.39(br s,1H)4.31(br s,2H)4.10(m,4H)3.99(br s,2H)3.65(m,1H)3.44(s,3H)3.16(br s,1H)3.06(br d,J＝12.01Hz,1H)2.96(br s,1H)2.86(br s,1H)2.57(br s,1H)2.09(br dd,J＝11.76,5.75Hz,1H)1.71(m,11H)1.46(s,9H). LC-MS: m/z 756 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 )δ9.09(s,1H)8.34(s,1H)8.10(dd,J＝9.13,5.88Hz,1H)7.74(d,J＝2.38Hz,1H)7.55 (t,J=9.01Hz,1H)7.38(s,1H)5.37(s,2H)4.55(br d,J=11.76Hz,1H)4.39(br s,1H)4.31(br s,2H)4.10( m,4H)3.99(br s,2H)3.65(m,1H)3.44(s,3H)3.16(br s,1H)3.06(br d,J＝12.01Hz,1H)2.96(br s,1H)2.86 (br s,1H)2.57(br s,1H)2.09(br dd,J=11.76,5.75Hz,1H)1.71(m,11H)1.46(s,9H).
中间体C-2(1R,5S)-3-(2-(((顺式)-3-(氨甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)-7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯的制备Intermediate C-2(1R,5S)-3-(2-(((cis)-3-(aminomethyl)tetrahydro-1H-biscondensed pyrrolidin-7a(5H)-yl)methoxy )-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-4-yl)-3 , Preparation of tert-butyl 8-diazabicyclo[3.2.1]octane-8-carboxylate
Figure PCTCN2022142077-appb-000126
Figure PCTCN2022142077-appb-000126
LC-MS：m/z 756(M+H) +。 1H NMR(400MHz，DMSO-d 6)δ9.09(d,J＝2.81Hz,1H)8.10(dd,J＝9.05,5.99Hz,1H)7.75(d,J＝2.45Hz,1H)7.55(t,J＝8.99Hz,1H)7.38(s,1H)5.37(s,2H)4.55(m,1H)4.38(br s,1H)4.31(br s,2H)4.11(m,2H)4.00(m,1H)3.61(m,1H)3.44(s,3H)3.15(br d,J＝10.76Hz,2H)2.94(m,4H)2.69(m,2H)1.99(m,1H)1.74(m,11H)1.46(s,9H). LC-MS: m/z 756 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 ) δ9.09 (d, J=2.81Hz, 1H) 8.10 (dd, J=9.05, 5.99Hz, 1H) 7.75 (d, J=2.45Hz, 1H) 7.55( t,J＝8.99Hz,1H)7.38(s,1H)5.37(s,2H)4.55(m,1H)4.38(br s,1H)4.31(br s,2H)4.11(m,2H)4.00(m ,1H)3.61(m,1H)3.44(s,3H)3.15(br d,J=10.76Hz,2H)2.94(m,4H)2.69(m,2H)1.99(m,1H)1.74(m,11H )1.46(s,9H).
中间体C-3(1R,5S)-3-(2-(((反式)-3-(N-甲基胺基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)-7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯的制备Intermediate C-3(1R,5S)-3-(2-(((trans)-3-(N-methylaminomethyl)tetrahydro-1H-biscondensed pyrrolidine-7a(5H)- Base)methoxy)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoropyridin[4,3-d]pyrimidine-4 Preparation of -yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester
Figure PCTCN2022142077-appb-000127
Figure PCTCN2022142077-appb-000127
LC-MS：m/z 770(M+H) +。 1H NMR(400MHz，DMSO-d 6)δ9.08(s,1H)8.10(dd,J＝9.19,5.94Hz,1H)7.75(d,J＝2.50Hz,1H)7.55(t,J＝9.01Hz,1H)7.38(s,1H)5.37(s,2H)4.55(br d,J＝12.76Hz,1H)4.33(m,3H)4.12(m,1H)4.02(m,2H)3.64(br t,J＝13.95Hz,2H)3.44(s,3H)3.07(br dd,J＝6.69,3.56Hz,1H)2.74(br d,J＝6.63Hz,2H)2.58(br dd,J＝11.63,6.75Hz,2H)2.30(d,J＝1.63Hz,3H)2.04(m,1H)1.86(m,2H)1.71(m,7H)1.52(m,2H)1.46(s,9H)。 LC-MS: m/z 770 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 ) δ9.08(s,1H)8.10(dd,J=9.19,5.94Hz,1H)7.75(d,J=2.50Hz,1H)7.55(t,J=9.01 Hz,1H)7.38(s,1H)5.37(s,2H)4.55(br d,J=12.76Hz,1H)4.33(m,3H)4.12(m,1H)4.02(m,2H)3.64(br t , J = 13.95Hz, 2H) 3.44 (s, 3H) 3.07 (br dd, J = 6.69, 3.56Hz, 1H) 2.74 (br d, J = 6.63Hz, 2H) 2.58 (br dd, J = 11.63, 6.75 Hz, 2H) 2.30 (d, J = 1.63 Hz, 3H) 2.04 (m, 1H) 1.86 (m, 2H) 1.71 (m, 7H) 1.52 (m, 2H) 1.46 (s, 9H).
中间体C-4(1R,5S)-3-(2-(((顺式)-3-(N-甲基胺基甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)-7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯的制备Intermediate C-4(1R,5S)-3-(2-(((cis)-3-(N-methylaminomethyl)tetrahydro-1H-biscondensed pyrrolidine-7a(5H)- Base)methoxy)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoropyridin[4,3-d]pyrimidine-4 Preparation of -yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester
Figure PCTCN2022142077-appb-000128
Figure PCTCN2022142077-appb-000128
LC-MS：m/z 770(M+H) +。 1H NMR(400MHz，DMSO-d 6)δ9.09(s,1H)8.10(dd,J＝9.13,5.88Hz,1H)7.75(d,J＝2.50Hz,1H)7.56(t,J＝9.01Hz,1H)7.38(m,1H)5.38(s,2H)4.55 (br d,J＝12.01Hz,1H)4.30(br s,3H)4.04(m,3H)3.64(br t,J＝13.88Hz,2H)3.44(s,3H)2.92(m,1H)2.78(br s,1H)2.64(m,1H)2.45(m,2H)2.30(d,J＝4.75Hz,3H)2.00(br dd,J＝11.69,6.44Hz,1H)1.92(br d,J＝6.75Hz,1H)1.77(m,7H)1.57(m,3H)1.46(s,9H). LC-MS: m/z 770 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 ) δ9.09(s,1H)8.10(dd,J=9.13,5.88Hz,1H)7.75(d,J=2.50Hz,1H)7.56(t,J=9.01 Hz,1H)7.38(m,1H)5.38(s,2H)4.55 (br d,J=12.01Hz,1H)4.30(br s,3H)4.04(m,3H)3.64(br t,J=13.88Hz ,2H)3.44(s,3H)2.92(m,1H)2.78(br s,1H)2.64(m,1H)2.45(m,2H)2.30(d,J＝4.75Hz,3H)2.00(br dd, J=11.69,6.44Hz,1H)1.92(br d,J=6.75Hz,1H)1.77(m,7H)1.57(m,3H)1.46(s,9H).
中间体D(1R,5S)-3-(7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(((R)-吡咯啉-2-基)甲氧基)吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂环[3.2.1]辛烷-8-甲酸叔丁酯的制备Intermediate D(1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-((( R)-pyrroline-2-yl)methoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylic acid tert-butyl Preparation of esters
Figure PCTCN2022142077-appb-000129
Figure PCTCN2022142077-appb-000129
第一步:2-(三甲基硅基)乙基(R)-2-(羟甲基)吡咯啉-1-甲酸酯的制备The first step: the preparation of 2-(trimethylsilyl)ethyl (R)-2-(hydroxymethyl)pyrroline-1-carboxylate
(R)-吡咯啉-2-基甲醇(1.80g,17.8mmol,1.73mL,1.00eq)的ACN(20.0mL)溶液中加入Teoc-OSu(6.00g,23.1mmol,1.30eq)和TEA(5.40g,53.4mmol,7.43mL,3.00eq)。反应物在25℃反应16h，然后加入EtOAc(30mL)和H 2O(20mL)分层。有机相分离后用饱和食盐水(15mL*2)洗涤，经无水MgSO 4干燥后过滤。滤液减压浓缩得到目标产物(3.60g,14.7mmol,产率：82.4％)。无需纯化直接用于下一步反应。 (R)-Pyrrolin-2-ylmethanol (1.80g, 17.8mmol, 1.73mL, 1.00eq) in ACN (20.0mL) was added Teoc-OSu (6.00g, 23.1mmol, 1.30eq) and TEA (5.40 g, 53.4mmol, 7.43mL, 3.00eq). The reactant was reacted at 25° C. for 16 h, then EtOAc (30 mL) and H 2 O (20 mL) were added to separate the layers. The organic phase was separated and washed with saturated brine (15 mL*2), dried over anhydrous MgSO 4 and filtered. The filtrate was concentrated under reduced pressure to obtain the target product (3.60 g, 14.7 mmol, yield: 82.4%). It was directly used in the next reaction without purification.
LC-MS：m/z 246(M+H) +。 1H NMR(400MHz，CDCl 3)δ4.59(br d,J＝5.75Hz,1H)4.21(td,J＝8.38,1.83Hz,2H)4.00(br d,J＝6.48Hz,1H)3.57-3.70(m,2H)3.46-3.56(m,1H)3.28-3.43(m,1H)1.75-1.95(m,3H)1.58(dq,J＝12.72,6.44Hz,1H)1.00-1.06(m,2H)0.06(s,9H). LC-MS: m/z 246 (M+H) + . 1 H NMR (400MHz, CDCl 3 ) δ4.59 (br d, J = 5.75Hz, 1H) 4.21 (td, J = 8.38, 1.83Hz, 2H) 4.00 (br d, J = 6.48Hz, 1H) 3.57- 3.70(m,2H)3.46-3.56(m,1H)3.28-3.43(m,1H)1.75-1.95(m,3H)1.58(dq,J＝12.72,6.44Hz,1H)1.00-1.06(m,2H) )0.06(s,9H).
第二步：(1R,5S)-3-(7-氯-8-氟-2-(((R)-1-((2-(三甲基硅基)乙氧基)甲酰)吡咯啉-2-基)甲氧基)吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂环[3.2.1]辛烷-8-甲酸叔丁酯的制备The second step: (1R,5S)-3-(7-chloro-8-fluoro-2-(((R)-1-((2-(trimethylsilyl)ethoxy)formyl)pyrrole Preparation of tert-butyl oxetane-2-yl)methoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylate
(1R,5S)-3-(2,7-氯-8-氟啶[4,3-d]嘧啶-4-基)-3,8-二氮杂环[3.2.1]辛烷-8-甲酸叔丁酯(700mg,1.63mmol,1.00eq)和2-(三甲基硅基)乙基(R)-2-(羟甲基)吡咯啉-1-甲酸酯(314mg,3.27mmol,2.00eq)的THF(7.00mL)溶液中加入t-BuONa(314mg,3.27mmol,2.00eq)。反应物在25℃反应16h，然后加入EtOAc(30mL)和H 2O(20mL)分层。有机相分离后用饱和食盐水(40mL)洗涤，经无水MgSO 4干燥后过滤。滤液减压浓缩。残余物用硅胶柱层析分离得到目标产物(0.78g,1.16mmol,产率：71.2％,纯度：95.0％)。 (1R,5S)-3-(2,7-Chloro-8-fluoropyridin[4,3-d]pyrimidin-4-yl)-3,8-diazacyclo[3.2.1]octane-8 - tert-butyl formate (700mg, 1.63mmol, 1.00eq) and 2-(trimethylsilyl)ethyl (R)-2-(hydroxymethyl)pyrroline-1-carboxylate (314mg, 3.27mmol , 2.00eq) in THF (7.00mL) was added t-BuONa (314mg, 3.27mmol, 2.00eq). The reactant was reacted at 25° C. for 16 h, then EtOAc (30 mL) and H 2 O (20 mL) were added to separate the layers. The organic phase was separated and washed with brine (40 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 (0.78 g, 1.16 mmol, yield: 71.2%, purity: 95.0%).
LC-MS：m/z 637(M+H) +。 1H NMR(400MHz，DMSO-d 6)δ8.92(s,1H)4.28-4.61(m, 4H)3.96-4.23(m,5H)3.62(br d,J＝12.30Hz,2H)1.70-1.97(m,6H)1.62(br d,J＝7.28Hz,2H)1.46(s,9H)0.85(br d,J＝6.27Hz,2H)-0.04-0.03(m,9H) LC-MS: m/z 637 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.92 (s, 1H) 4.28-4.61 (m, 4H) 3.96-4.23 (m, 5H) 3.62 (br d, J = 12.30Hz, 2H) 1.70-1.97 (m,6H)1.62(br d,J=7.28Hz,2H)1.46(s,9H)0.85(br d,J=6.27Hz,2H)-0.04-0.03(m,9H)
第三步:(1R,5S)-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基硅基)乙炔基)萘-1-基)-2-(((R)-1-((2-(三甲基硅基)乙氧基)甲酰)吡咯啉-2-基)甲氧基)吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂环[3.2.1]辛烷-8-甲酸叔丁酯的制备The third step: (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene -1-yl)-2-(((R)-1-((2-(trimethylsilyl)ethoxy)formyl)pyrroline-2-yl)methoxy)pyridine[4,3 Preparation of -d]pyrimidin-4-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester
氮气保护下，(1R,5S)-3-(7-氯-8-氟-2-(((R)-1-((2-(三甲基硅基)乙氧基)甲酰)吡咯啉-2-基)甲氧基)吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂环[3.2.1]辛烷-8-甲酸叔丁酯(0.75g,1.18mmol,1.00eq)和((2-氟-6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)萘-1-基)乙炔基)三异丙基硅烷(664mg,1.29mmol,1.10eq)的二恶烷(7.00mL)和H 2O(2.00mL)的混合溶液中依次加入Cs 2CO 3(767mg,2.35mmol,2.00eq)和CataCXium Pd G2(39.4mg,58.9umol,0.05eq)。反应物在100℃反应1h，然后用H 2O(5mL)淬灭，再加入EtOAc(10mL*3)萃取。有机相分离后用饱和食盐水(30mL)洗涤，经无水MgSO 4干燥后过滤。滤液减压浓缩。残余物用硅胶柱层析分离得到目标产物(0.73g,702umol,产率：59.7％,纯度：95.0％)。 Under nitrogen protection, (1R,5S)-3-(7-chloro-8-fluoro-2-(((R)-1-((2-(trimethylsilyl)ethoxy)formyl)pyrrole Lin-2-yl)methoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.75g , 1.18mmol, 1.00eq) and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborin Mixed solution of cyclopentan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (664mg, 1.29mmol, 1.10eq) in dioxane (7.00mL) and H 2 O (2.00mL) Cs 2 CO 3 (767mg, 2.35mmol, 2.00eq) and CataCXium Pd G2 (39.4mg, 58.9umol, 0.05eq) were added in sequence. 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%).
LC-MS：m/z 987(M+H) +。 1H NMR(400MHz，DMSO-d 6)δ9.18(s,1H)8.11(dd,J＝9.11,5.93Hz,1H)7.75(d,J＝2.57Hz,1H)7.57(t,J＝8.99Hz,1H)7.34(s,1H)5.30-5.44(m,2H)4.78(br d,J＝12.23Hz,1H)4.00-4.55(m,9H)3.94(s,1H)3.78(br d,J＝11.25Hz,1H)3.43(s,2H)3.43-3.48(m,1H)1.80-2.06(m,8H)1.47(s,9H)0.90-0.99(m,2H)0.81(t,J＝7.27Hz,18H)0.38-0.54(m,3H)-0.06-0.06(m,9H) LC-MS: m/z 987 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 ) δ9.18(s, 1H) 8.11(dd, J=9.11, 5.93Hz, 1H) 7.75(d, J=2.57Hz, 1H) 7.57(t, J=8.99 Hz,1H)7.34(s,1H)5.30-5.44(m,2H)4.78(br d,J=12.23Hz,1H)4.00-4.55(m,9H)3.94(s,1H)3.78(br d,J =11.25Hz,1H)3.43(s,2H)3.43-3.48(m,1H)1.80-2.06(m,8H)1.47(s,9H)0.90-0.99(m,2H)0.81(t,J＝7.27Hz ,18H)0.38-0.54(m,3H)-0.06-0.06(m,9H)
第四步：(1R,5S)-3-(7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(((R)-吡咯啉-2-基)甲氧基)吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂环[3.2.1]辛烷-8-甲酸叔丁酯的制备The fourth step: (1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(( (R)-pyrrolin-2-yl)methoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylic acid tert Preparation of butyl ester
(1R,5S)-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基硅基)乙炔基)萘-1-基)-2-(((R)-1-((2-(三甲基硅基)乙氧基)甲酰)吡咯啉-2-基)甲氧基)吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂环[3.2.1]辛烷-8-甲酸叔丁酯(0.72g,729umol,1.00eq)的THF(7.00mL)溶液中加入TBAF(1.00M,18.2mL,25.0eq)。反应物在25℃反应16h，然后用H 2O(20mL)淬灭，再加入EtOAc(20mL*3)萃取。有机相分离后经无水MgSO 4干燥后过滤。滤液减压浓缩。残余物用硅胶柱层析分离得到目标产物(364mg,530umol,产率：72.7％)。 (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl )-2-(((R)-1-((2-(trimethylsilyl)ethoxy)formyl)pyrroline-2-yl)methoxy)pyridin[4,3-d]pyrimidine TBAF (1.00M , 18.2mL, 25.0eq). The reactant was reacted at 25° C. for 16 h, then quenched with H 2 O (20 mL), and then extracted with EtOAc (20 mL*3). The organic phase was separated, dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography to obtain the target product (364mg, 530umol, yield: 72.7%).
LC-MS：m/z 687(M+H) +。 1H NMR(400MHz，DMSO-d 6)δ8.78-8.87(m,1H)8.09(dd,J＝9.16,5.90Hz,1H)7.72(s,1H)7.54(t,J＝9.03Hz,1H)7.28-7.40(m,1H)5.76(s,1H)5.37(s,2H)5.20-5.31(m,0.5H)4.82(q,J＝5.44Hz,0.5H)4.38-4.60(m,1H)4.38-4.60(m,1H)4.13-4.37(m,4H)4.04(d,J＝4.52Hz,1H)3.50-3.82(m,5H)3.44(s,3H)1.68-2.10(m,8H)1.47(s,9H). LC-MS: m/z 687 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.78-8.87(m,1H)8.09(dd,J=9.16,5.90Hz,1H)7.72(s,1H)7.54(t,J=9.03Hz,1H )7.28-7.40(m,1H)5.76(s,1H)5.37(s,2H)5.20-5.31(m,0.5H)4.82(q,J＝5.44Hz,0.5H)4.38-4.60(m,1H) 4.38-4.60(m,1H)4.13-4.37(m,4H)4.04(d,J＝4.52Hz,1H)3.50-3.82(m,5H)3.44(s,3H)1.68-2.10(m,8H)1.47 (s,9H).
按照中间体D同样方法，以不同起始原料合成中间体EAccording to the same method as intermediate D, intermediate E was synthesized with different starting materials
中间体E(1R,5S)-3-(7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(((S)-吡咯啉-2-基)甲氧基)吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂环[3.2.1]辛烷-8-甲酸叔丁酯的制备Intermediate E(1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-((( S)-pyrroline-2-yl)methoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylic acid tert-butyl Preparation of esters
Figure PCTCN2022142077-appb-000130
Figure PCTCN2022142077-appb-000130
LC-MS：m/z 687(M+H) +。 1H NMR(400MHz，DMSO-d 6)δ8.85-8.82(m,1H),8.11-8.07(m,1H),7.72(d,J＝1.6Hz,1H),7.54(t,J＝9.2Hz,1H),7.37-7.33(m,1H),5.38(s,2H),5.24-4.79(m,1H),4.60-4.20(m,5H),4.04-4.03(m,1H),3.78-3.47(m,5H),3.45(s,3H),2.08-1.77(m,8H),1.47(s,9H). LC-MS: m/z 687 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.85-8.82(m, 1H), 8.11-8.07(m, 1H), 7.72(d, J=1.6Hz, 1H), 7.54(t, J=9.2 Hz,1H),7.37-7.33(m,1H),5.38(s,2H),5.24-4.79(m,1H),4.60-4.20(m,5H),4.04-4.03(m,1H),3.78- 3.47(m,5H),3.45(s,3H),2.08-1.77(m,8H),1.47(s,9H).
实施例I-1 N-(((反式)-7a-(((4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟吡啶[4,3-d]嘧啶-2-基)氧基)甲基)六氢-1H-双稠吡咯啶-3-基)甲基)-3-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚啉-4-基)氨基)丙酰胺的制备Example I-1 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 Fused pyrrolidin-3-yl)methyl)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino) Preparation of propionamide
Figure PCTCN2022142077-appb-000131
Figure PCTCN2022142077-appb-000131
第一步：(1R,5S)-3-(2-(((反式)-3-((3-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚啉-4-基)氨基)丙酰胺)甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)-7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯的制备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
(1R,5S)-3-(2-(((反式)-3-(氨甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)-7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(22mg，0.029mmol)、3-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)氧基)丙酸(9.4mg，0.029mmol,1eq)、吡啶(7mg，0.087mmol,3eq)和N,N-二甲基甲酰胺(0.3mL)，搅拌溶解，随后分批加入EDCI(12mg，0.058mmol,2eq)。加完后反应液在25℃反应1小时，然后用制备液相分离得到目标化合物(11.9mg，0.011mmol，产率：37.9％)。(1R,5S)-3-(2-(((trans)-3-(aminomethyl)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-diaze Heterobicyclo[3.2.1]octane-8-carboxylate tert-butyl ester (22mg, 0.029mmol), 3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo Isoindol-4-yl)oxy)propionic acid (9.4mg, 0.029mmol, 1eq), pyridine (7mg, 0.087mmol, 3eq) and N,N-dimethylformamide (0.3mL), stirred and dissolved, Then EDCI (12mg, 0.058mmol, 2eq) was added in portions. After the addition, the reaction solution was reacted at 25° C. for 1 hour, and then separated by preparative liquid phase to obtain the target compound (11.9 mg, 0.011 mmol, yield: 37.9%).
LC-MS：m/z 1083(M+H) +。 LC-MS: m/z 1083 (M+H) + .
第二步：N-(((反式)-7a-(((4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟吡啶[4,3-d]嘧啶-2-基)氧基)甲基)六氢-1H-双稠吡咯啶-3-基)甲基)-3-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚啉-4-基)氨基)丙酰胺的制备The second step: 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-double Pyrrolidin-3-yl)methyl)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)propane Preparation of amides
在0℃下，(1R,5S)-3-(2-(((反式)-3-((3-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚啉-4-基) 氨基)丙酰胺)甲基)四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)-7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(11.9mg，0.011mmol)的DCM(0.5mL)溶液中加入TFA(50μL)。反应液在25℃反应2hr,然后补加入TFA(50μL)。得到的反应液在rt继续反应2hr后用饱和NaHCO 3(20mL)淬灭后再用EtOAc(3 x 15mL)萃取。合并的有机相经无水硫酸钠干燥后过滤。滤液减压浓缩，残余物用制备液相分离得到目标产物(4.2mg,0.0045mmol，产率：41％)。 At 0°C, (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] To a solution of tert-butyl octane-8-carboxylate (11.9 mg, 0.011 mmol) in DCM (0.5 mL) was added TFA (50 μL). The reaction solution was reacted at 25°C for 2hr, and then added TFA (50μL). 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%).
LC-MS：m/z 939(M+H) +。 1H NMR(400MHz，DMSO-d 6)δ11.09(s,1H),10.16(s,1H),9.04(s,1H),8.08–8.03(m,1H),7.98(dd,J＝9.2,5.9Hz,1H),7.63–7.54(m,1H),7.47(t,J＝9.0Hz,1H),7.39(d,J＝2.6Hz,1H),7.18(d,J＝2.5Hz,1H),7.14(d,J＝8.6Hz,1H),7.02(d,J＝7.0Hz,1H),6.71(t,J＝6.1Hz,1H),5.04(dd,J＝12.9,5.4Hz,1H),4.47(d,J＝12.3Hz,1H),4.31(d,J＝12.0Hz,1H),4.15–3.97(m,2H),3.93(s,1H),3.69–3.48(m,4H),3.27–3.14(m,2H),3.09–2.96(m,1H),2.94–2.80(m,1H),2.80–2.72(m,1H),2.70–2.52(m,4H),2.47–2.42(m,2H),2.13–1.94(m,3H),1.78–1.59(m,9H),1.58–1.41(m,3H). LC-MS: m/z 939 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 ) δ11.09(s,1H), 10.16(s,1H), 9.04(s,1H), 8.08–8.03(m,1H), 7.98(dd,J=9.2 ,5.9Hz,1H),7.63–7.54(m,1H),7.47(t,J=9.0Hz,1H),7.39(d,J=2.6Hz,1H),7.18(d,J=2.5Hz,1H ), 7.14(d, J=8.6Hz, 1H), 7.02(d, J=7.0Hz, 1H), 6.71(t, J=6.1Hz, 1H), 5.04(dd, J=12.9, 5.4Hz, 1H ),4.47(d,J=12.3Hz,1H),4.31(d,J=12.0Hz,1H),4.15–3.97(m,2H),3.93(s,1H),3.69–3.48(m,4H) ,3.27–3.14(m,2H),3.09–2.96(m,1H),2.94–2.80(m,1H),2.80–2.72(m,1H),2.70–2.52(m,4H),2.47–2.42( m,2H),2.13–1.94(m,3H),1.78–1.59(m,9H),1.58–1.41(m,3H).
按照实施例I-1的方法以不同的起始原料合成了以下化合物：Synthesized the following compounds with different starting materials according to the method of Example I-1:
实施例I-2 N-(((反式)-7a-(((4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟吡啶[4,3-d]嘧啶-2-基)氧基)甲基)六氢-1H-双稠吡咯啶-3-基)甲基)-4-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚啉-4-基)氨基)丁酰胺的制备Example I-2 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)-4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino) Preparation of butanamide
Figure PCTCN2022142077-appb-000132
Figure PCTCN2022142077-appb-000132
LC-MS：m/z 953(M+H) +。 1H NMR(400MHz，DMSO-d 6)δ11.10(s,1H),10.17(s,1H),9.03(s,1H),7.98(dd,J＝9.2,5.9Hz,1H),7.92(q,J＝5.3Hz,1H),7.57(dd,J＝8.6,7.1Hz,1H),7.47(t,J＝9.0Hz,1H),7.39(d,J＝2.6Hz,1H),7.18(d,J＝2.5Hz,1H),7.11(d,J＝8.7Hz,1H),7.00(dd,J＝7.0,1.5Hz,1H),6.61(t,J＝6.1Hz,1H),5.05(dd,J＝12.9,5.4Hz,1H),4.47(d,J＝12.2Hz,1H),4.30(d,J＝12.1Hz,1H),4.17–3.98(m,2H),3.93(s,1H),3.68–3.53(m,4H),3.30–3.17(m,2H),3.13–2.99(m,1H),2.95–2.81(m,1H),2.82–2.74(m,1H),2.71–2.52(m,4H),2.19(t,J＝7.1Hz,2H),2.10–1.95(m,3H),1.83–1.74(m,2H),1.73–1.64(m,9H),1.61–1.42(m,3H). LC-MS: m/z 953 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 ) δ11.10(s, 1H), 10.17(s, 1H), 9.03(s, 1H), 7.98(dd, J=9.2, 5.9Hz, 1H), 7.92( q,J=5.3Hz,1H),7.57(dd,J=8.6,7.1Hz,1H),7.47(t,J=9.0Hz,1H),7.39(d,J=2.6Hz,1H),7.18( d,J=2.5Hz,1H),7.11(d,J=8.7Hz,1H),7.00(dd,J=7.0,1.5Hz,1H),6.61(t,J=6.1Hz,1H),5.05( dd,J=12.9,5.4Hz,1H),4.47(d,J=12.2Hz,1H),4.30(d,J=12.1Hz,1H),4.17–3.98(m,2H),3.93(s,1H ),3.68–3.53(m,4H),3.30–3.17(m,2H),3.13–2.99(m,1H),2.95–2.81(m,1H),2.82–2.74(m,1H),2.71–2.52 (m,4H),2.19(t,J＝7.1Hz,2H),2.10–1.95(m,3H),1.83–1.74(m,2H),1.73–1.64(m,9H),1.61–1.42(m ,3H).
实施例I-3 N-(((反式)-7a-(((4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟吡啶[4,3-d]嘧啶-2-基)氧基)甲基)六氢-1H-双稠吡咯啶-3-基)甲基)-5-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚啉-4-基)氨基)戊酰胺的制备Example I-3 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 Fused pyrrolidin-3-yl)methyl)-5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino) Preparation of valeramide
Figure PCTCN2022142077-appb-000133
Figure PCTCN2022142077-appb-000133
LC-MS：m/z 967(M+H) +。 1H NMR(400MHz，DMSO-d 6)δ11.09(s,1H),10.17(s,1H), 9.04(s,1H),7.98(dd,J＝9.2,5.9Hz,1H),7.87(q,J＝5.4Hz,1H),7.56(dd,J＝8.6,7.1Hz,1H),7.47(t,J＝9.0Hz,1H),7.39(d,J＝2.6Hz,1H),7.18(d,J＝2.5Hz,1H),7.08(d,J＝8.6Hz,1H),7.00(d,J＝7.0Hz,1H),6.55(t,J＝6.0Hz,1H),5.04(dd,J＝12.9,5.4Hz,1H),4.49(d,J＝12.2Hz,1H),4.33(d,J＝12.0Hz,1H),4.08(dd,J＝32.5,9.8Hz,2H),3.93(s,1H),3.74–3.54(m,4H),3.28–3.15(m,2H),3.14–3.01(m,1H),2.94–2.76(m,2H),2.73–2.50(m,4H),2.20–2.10(m,2H),2.09–1.94(m,3H),1.81–1.64(m,9H),1.64–1.42(m,7H). LC-MS: m/z 967 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 ) δ11.09(s, 1H), 10.17(s, 1H), 9.04(s, 1H), 7.98(dd, J=9.2, 5.9Hz, 1H), 7.87( q,J=5.4Hz,1H),7.56(dd,J=8.6,7.1Hz,1H),7.47(t,J=9.0Hz,1H),7.39(d,J=2.6Hz,1H),7.18( d,J=2.5Hz,1H),7.08(d,J=8.6Hz,1H),7.00(d,J=7.0Hz,1H),6.55(t,J=6.0Hz,1H),5.04(dd, J=12.9,5.4Hz,1H), 4.49(d,J=12.2Hz,1H),4.33(d,J=12.0Hz,1H),4.08(dd,J=32.5,9.8Hz,2H),3.93( s,1H),3.74–3.54(m,4H),3.28–3.15(m,2H),3.14–3.01(m,1H),2.94–2.76(m,2H),2.73–2.50(m,4H), 2.20–2.10(m,2H),2.09–1.94(m,3H),1.81–1.64(m,9H),1.64–1.42(m,7H).
实施例I-4 N-(((反式)-7a-(((4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟吡啶[4,3-d]嘧啶-2-基)氧基)甲基)六氢-1H-双稠吡咯啶-3-基)甲基)-6-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚啉-4-基)氨基)己酰胺的制备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
Figure PCTCN2022142077-appb-000134
Figure PCTCN2022142077-appb-000134
LC-MS：m/z 981(M+H) +。 1H NMR(400MHz，DMSO-d 6)δ11.10(s,1H),10.15(s,1H),9.03(s,1H),7.98(dd,J＝9.2,5.9Hz,1H),7.82(q,J＝5.4Hz,1H),7.56(dd,J＝8.6,7.1Hz,1H),7.46(t,J＝9.0Hz,1H),7.39(d,J＝2.6Hz,1H),7.18(d,J＝2.5Hz,1H),7.07(d,J＝8.6Hz,1H),7.00(d,J＝7.0Hz,1H),6.51(t,J＝6.0Hz,1H),5.04(dd,J＝12.9,5.4Hz,1H),4.47(d,J＝12.2Hz,1H),4.30(d,J＝11.9Hz,1H),4.06(dd,J＝35.8,10.6Hz,2H),3.93(s,1H),3.70–3.51(m,4H),3.31–3.18(m,2H),3.09–2.98(m,1H),2.95–2.81(m,1H),2.82–2.74(m,1H),2.71–2.51(m,4H),2.17–1.94(m,5H),1.80–1.63(m,9H),1.63–1.46(m,7H),1.38–1.26(m,2H). LC-MS: m/z 981 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 ) δ11.10(s, 1H), 10.15(s, 1H), 9.03(s, 1H), 7.98(dd, J=9.2, 5.9Hz, 1H), 7.82( q,J=5.4Hz,1H),7.56(dd,J=8.6,7.1Hz,1H),7.46(t,J=9.0Hz,1H),7.39(d,J=2.6Hz,1H),7.18( d,J=2.5Hz,1H),7.07(d,J=8.6Hz,1H),7.00(d,J=7.0Hz,1H),6.51(t,J=6.0Hz,1H),5.04(dd, J=12.9,5.4Hz,1H), 4.47(d,J=12.2Hz,1H),4.30(d,J=11.9Hz,1H),4.06(dd,J=35.8,10.6Hz,2H),3.93( s,1H),3.70–3.51(m,4H),3.31–3.18(m,2H),3.09–2.98(m,1H),2.95–2.81(m,1H),2.82–2.74(m,1H), 2.71–2.51(m,4H),2.17–1.94(m,5H),1.80–1.63(m,9H),1.63–1.46(m,7H),1.38–1.26(m,2H).
实施例I-5 N-(((反式)-7a-(((4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟吡啶[4,3-d]嘧啶-2-基)氧基)甲基)六氢-1H-双稠吡咯啶-3-基)甲基)-7-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚啉-4-基)氨基)庚酰胺的制备Example I-5 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)-7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino) Preparation of Heptanamide
Figure PCTCN2022142077-appb-000135
Figure PCTCN2022142077-appb-000135
LC-MS：m/z 995(M+H) +。 1H NMR(400MHz，DMSO-d 6)δ11.11(s,1H),10.17(s,1H),9.03(s,1H),7.98(dd,J＝9.2,5.9Hz,1H),7.82(d,J＝5.4Hz,1H),7.56(dd,J＝8.5,7.1Hz,1H),7.46(t,J＝9.0Hz,1H),7.39(d,J＝2.6Hz,1H),7.18(d,J＝2.5Hz,1H),7.07(d,J＝8.6Hz,1H),7.00(d,J＝7.0Hz,1H),6.52(t,J＝6.0Hz,1H),5.05(dd,J＝12.9,5.4Hz,1H),4.47(d,J＝12.2Hz,1H),4.31(d,J＝11.8Hz,1H),4.06(m,2H),3.94(s,1H),3.64(d,J＝12.3Hz,1H),3.61–3.52(m,3H),3.30–3.22(m,2H),3.11–2.97(m,1H),2.95–2.81(m,1H),2.82–2.74(m,1H),2.70–2.46(m,4H),2.14–1.94(m,5H),1.80–1.62(m,9H),1.60–1.46(m,7H),1.40–1.19(m,5H). LC-MS: m/z 995 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 ) δ11.11(s, 1H), 10.17(s, 1H), 9.03(s, 1H), 7.98(dd, J=9.2, 5.9Hz, 1H), 7.82( d,J=5.4Hz,1H),7.56(dd,J=8.5,7.1Hz,1H),7.46(t,J=9.0Hz,1H),7.39(d,J=2.6Hz,1H),7.18( d,J=2.5Hz,1H),7.07(d,J=8.6Hz,1H),7.00(d,J=7.0Hz,1H),6.52(t,J=6.0Hz,1H),5.05(dd, J=12.9,5.4Hz,1H),4.47(d,J=12.2Hz,1H),4.31(d,J=11.8Hz,1H),4.06(m,2H),3.94(s,1H),3.64( d,J＝12.3Hz,1H),3.61–3.52(m,3H),3.30–3.22(m,2H),3.11–2.97(m,1H),2.95–2.81(m,1H),2.82–2.74( m,1H),2.70–2.46(m,4H),2.14–1.94(m,5H),1.80–1.62(m,9H),1.60–1.46(m,7H),1.40–1.19(m,5H).
实施例I-6 N-(((顺式)-7a-(((4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-7-(8-乙炔基 -7-氟-3-羟基萘-1-基)-8-氟吡啶[4,3-d]嘧啶-2-基)氧基)甲基)六氢-1H-双稠吡咯啶-3-基)甲基)-7-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚啉-4-基)氨基)-N-甲基丙酰胺的制备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
Figure PCTCN2022142077-appb-000136
Figure PCTCN2022142077-appb-000136
LC-MS：m/z 953(M+H) +。 1H NMR(400MHz，DMSO-d 6)δ11.07(s,1H),10.18(s,1H),9.04(d,J＝8.8Hz,1H),8.02–7.92(m,1H),7.58–7.43(m,2H),7.40(d,J＝2.4Hz,1H),7.19(s,1H),7.13–6.94(m,2H),6.72(s,1H),5.06–4.99(m,1H),4.51–4.21(m,4H),4.07–3.80(m,4H),3.57(d,J＝23.2Hz,4H),2.99(s,2H),2.84(s,4H),2.60(s,2H),1.95(d,J＝36.0Hz,5H),1.70(d,J＝39.2Hz,9H),1.52(s,4H). LC-MS: m/z 953 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 )δ11.07(s,1H),10.18(s,1H),9.04(d,J=8.8Hz,1H),8.02–7.92(m,1H),7.58– 7.43(m,2H),7.40(d,J=2.4Hz,1H),7.19(s,1H),7.13–6.94(m,2H),6.72(s,1H),5.06–4.99(m,1H) ,4.51–4.21(m,4H),4.07–3.80(m,4H),3.57(d,J＝23.2Hz,4H),2.99(s,2H),2.84(s,4H),2.60(s,2H ),1.95(d,J=36.0Hz,5H),1.70(d,J=39.2Hz,9H),1.52(s,4H).
实施例I-7 N-(((顺式)-7a-(((4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟吡啶[4,3-d]嘧啶-2-基)氧基)甲基)六氢-1H-双稠吡咯啶-3-基)甲基)-7-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚啉-4-基)氨基)-N-甲基丁酰胺的制备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
Figure PCTCN2022142077-appb-000137
Figure PCTCN2022142077-appb-000137
LC-MS：m/z 967(M+H) +。 1H NMR(400MHz，DMSO-d 6)δ11.07(s,1H),10.19(s,1H),9.02(d,J＝5.8Hz,1H),7.98(dd,J＝9.1,5.9Hz,1H),7.48(ddd,J＝28.6,18.4,5.0Hz,3H),7.22–7.07(m,2H),6.98(dd,J＝21.0,7.0Hz,1H),6.60(d,J＝27.7Hz,1H),5.03(dd,J＝12.8,5.4Hz,1H),4.46(s,1H),4.30(d,J＝11.5Hz,1H),4.16–3.91(m,4H),3.58(d,J＝35.3Hz,4H),3.26–3.13(m,4H),2.99(s,2H),2.91–2.76(m,6H),2.38–2.33(m,1H),2.01(s,2H),1.93(s,1H),1.77(s,6H),1.63(d,J＝17.8Hz,6H),1.54–1.41(m,2H). LC-MS: m/z 967 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 ) δ11.07(s, 1H), 10.19(s, 1H), 9.02(d, J=5.8Hz, 1H), 7.98(dd, J=9.1, 5.9Hz, 1H), 7.48(ddd, J＝28.6, 18.4, 5.0Hz, 3H), 7.22–7.07(m, 2H), 6.98(dd, J＝21.0, 7.0Hz, 1H), 6.60(d, J＝27.7Hz ,1H),5.03(dd,J=12.8,5.4Hz,1H),4.46(s,1H),4.30(d,J=11.5Hz,1H),4.16–3.91(m,4H),3.58(d, J＝35.3Hz,4H),3.26–3.13(m,4H),2.99(s,2H),2.91–2.76(m,6H),2.38–2.33(m,1H),2.01(s,2H),1.93 (s,1H),1.77(s,6H),1.63(d,J＝17.8Hz,6H),1.54–1.41(m,2H).
实施例I-8 N-(((顺式)-7a-(((4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟吡啶[4,3-d]嘧啶-2-基)氧基)甲基)六氢-1H-双稠吡咯啶-3-基)甲基)-7-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚啉-4-基)氨基)-N-甲基戊酰胺的制备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
Figure PCTCN2022142077-appb-000138
Figure PCTCN2022142077-appb-000138
LC-MS：m/z 981(M+H) +。 1H NMR(400MHz，DMSO-d 6)δ11.12(s,2H),10.17(s,2H),9.07–8.96(m,4H),7.98(dd,J＝9.3,6.0Hz,5H),7.49(dd,J＝27.9,19.6Hz,10H),7.39(d,J＝2.4Hz,5H),7.18(s,5H),7.11–6.93(m,11H),6.51(d,J＝22.4Hz,6H),5.07–5.01(m,6H),4.48(d,J＝11.1Hz,6H),4.30(d,J＝11.4Hz,6H),4.10(d,J＝6.2Hz,5H),4.01(d,J＝7.8Hz,6H),3.95–3.91(m,6H),3.58(d,J＝31.8Hz,20H),3.23(s,14H),2.99(s,11H),2.84 (d,J＝23.0Hz,39H),2.60(s,10H),2.02(s,19H),1.77(s,20H),1.66(s,19H),1.57(s,30H). LC-MS: m/z 981 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 )δ11.12(s,2H),10.17(s,2H),9.07–8.96(m,4H),7.98(dd,J=9.3,6.0Hz,5H), 7.49(dd, J=27.9, 19.6Hz, 10H), 7.39(d, J=2.4Hz, 5H), 7.18(s, 5H), 7.11–6.93(m, 11H), 6.51(d, J=22.4Hz ,6H),5.07–5.01(m,6H),4.48(d,J=11.1Hz,6H),4.30(d,J=11.4Hz,6H),4.10(d,J=6.2Hz,5H),4.01 (d,J=7.8Hz,6H),3.95–3.91(m,6H),3.58(d,J=31.8Hz,20H),3.23(s,14H),2.99(s,11H),2.84(d, J＝23.0Hz,39H),2.60(s,10H),2.02(s,19H),1.77(s,20H),1.66(s,19H),1.57(s,30H).
实施例I-9 N-(((顺式)-7a-(((4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟吡啶[4,3-d]嘧啶-2-基)氧基)甲基)六氢-1H-双稠吡咯啶-3-基)甲基)-7-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚啉-4-基)氨基)-N-甲基己酰胺的制备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
Figure PCTCN2022142077-appb-000139
Figure PCTCN2022142077-appb-000139
LC-MS：m/z 995(M+H) +。 1H NMR(400MHz，DMSO-d 6)δ11.09(s,1H),10.15(s,1H),9.02(d,J＝6.1Hz,2H),7.96(s,2H),7.58–7.37(m,7H),7.20(d,J＝13.7Hz,5H),6.99(dd,J＝21.1,7.8Hz,5H),6.67(s,3H),6.43(s,3H),5.33(t,J＝4.7Hz,5H),5.04(s,3H),4.46(s,3H),4.29(s,5H),4.11(s,5H),4.04–3.91(m,7H),3.54(s,10H),3.22(s,16H),2.99(s,6H),2.84(d,J＝29.3Hz,17H),2.27(s,5H),2.01(dd,J＝14.7,7.0Hz,30H),1.77(s,12H),1.66(s,11H),1.54–1.42(m,22H),1.27(d,J＝22.3Hz,90H),0.86(t,J＝6.7Hz,12H). LC-MS: m/z 995 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 ) δ11.09(s, 1H), 10.15(s, 1H), 9.02(d, J=6.1Hz, 2H), 7.96(s, 2H), 7.58–7.37( m,7H),7.20(d,J=13.7Hz,5H),6.99(dd,J=21.1,7.8Hz,5H),6.67(s,3H),6.43(s,3H),5.33(t,J =4.7Hz,5H),5.04(s,3H),4.46(s,3H),4.29(s,5H),4.11(s,5H),4.04–3.91(m,7H),3.54(s,10H) ,3.22(s,16H),2.99(s,6H),2.84(d,J=29.3Hz,17H),2.27(s,5H),2.01(dd,J=14.7,7.0Hz,30H),1.77( s,12H),1.66(s,11H),1.54–1.42(m,22H),1.27(d,J=22.3Hz,90H),0.86(t,J=6.7Hz,12H).
实施例I-10 N-(((顺式)-7a-(((4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟吡啶[4,3-d]嘧啶-2-基)氧基)甲基)六氢-1H-双稠吡咯啶-3-基)甲基)-7-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚啉-4-基)氨基)-N-甲基庚酰胺的制备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
Figure PCTCN2022142077-appb-000140
Figure PCTCN2022142077-appb-000140
LC-MS：m/z 1009(M+H) +。 1H NMR(400MHz，DMSO-d 6)δ11.11(s,1H),10.18(s,1H),9.08–8.97(m,1H),7.99–7.93(m,1H),7.61–7.45(m,2H),7.39(t,J＝2.5Hz,1H),7.18(s,1H),7.08–6.91(m,2H),6.48(d,J＝28.8Hz,1H),5.05(dd,J＝12.7,5.3Hz,1H),4.48(d,J＝10.9Hz,1H),4.30(d,J＝11.0Hz,1H),4.10(d,J＝7.6Hz,1H),4.01(d,J＝11.1Hz,1H),3.94–3.90(m,1H),3.65(s,1H),3.54(s,3H),3.17(s,3H),2.98(d,J＝4.4Hz,2H),2.87(d,J＝11.3Hz,3H),2.80(s,3H),2.59(d,J＝17.1Hz,2H),2.25(s,1H),2.02(s,3H),1.77(s,4H),1.65(s,6H),1.48(s,5H),1.28(d,J＝29.1Hz,5H). LC-MS: m/z 1009 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 ) δ11.11(s,1H),10.18(s,1H),9.08–8.97(m,1H),7.99–7.93(m,1H),7.61–7.45(m ,2H),7.39(t,J=2.5Hz,1H),7.18(s,1H),7.08–6.91(m,2H),6.48(d,J=28.8Hz,1H),5.05(dd,J= 12.7, 5.3Hz, 1H), 4.48(d, J=10.9Hz, 1H), 4.30(d, J=11.0Hz, 1H), 4.10(d, J=7.6Hz, 1H), 4.01(d, J= 11.1Hz, 1H), 3.94–3.90(m, 1H), 3.65(s, 1H), 3.54(s, 3H), 3.17(s, 3H), 2.98(d, J＝4.4Hz, 2H), 2.87( d,J=11.3Hz,3H),2.80(s,3H),2.59(d,J=17.1Hz,2H),2.25(s,1H),2.02(s,3H),1.77(s,4H), 1.65(s,6H),1.48(s,5H),1.28(d,J=29.1Hz,5H).
实施例I-11 N-(((顺式)-7a-(((4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟吡啶[4,3-d]嘧啶-2-基)氧基)甲基)六氢-1H-双稠吡咯啶-3-基)甲基)-7-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚啉-4-基)氨基)-N-甲基癸酰胺的制备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
Figure PCTCN2022142077-appb-000141
Figure PCTCN2022142077-appb-000141
LC-MS：m/z 1051(M+H) +。 1H NMR(400MHz，DMSO-d 6)δ11.11(s,1H),10.17(s,1H),9.03(d,J＝3.3Hz,1H),8.01–7.92(m,1H),7.57(dd,J＝16.1,8.5Hz,1H),7.46(td,J＝8.8,4.3Hz,1H),7.39(s,1H),7.17(s,1H),7.11–6.97(m,2H),6.56–6.43(m,1H),5.05(dd,J＝ 12.9,5.3Hz,1H),4.48(d,J＝11.5Hz,1H),4.27(d,J＝11.7Hz,1H),4.15–3.99(m,2H),3.93(dd,J＝7.9,2.3Hz,1H),3.68–3.52(m,4H),3.27–3.13(m,4H),3.02–2.74(m,7H),2.59(d,J＝16.8Hz,2H),2.34–2.19(m,2H),2.03(d,J＝8.3Hz,3H),1.77(s,3H),1.70–1.41(m,11H),1.30–1.11(m,11H). LC-MS: m/z 1051 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 ) δ11.11(s, 1H), 10.17(s, 1H), 9.03(d, J=3.3Hz, 1H), 8.01–7.92(m, 1H), 7.57( dd,J=16.1,8.5Hz,1H),7.46(td,J=8.8,4.3Hz,1H),7.39(s,1H),7.17(s,1H),7.11–6.97(m,2H),6.56 –6.43(m,1H),5.05(dd,J=12.9,5.3Hz,1H),4.48(d,J=11.5Hz,1H),4.27(d,J=11.7Hz,1H),4.15–3.99( m,2H),3.93(dd,J＝7.9,2.3Hz,1H),3.68–3.52(m,4H),3.27–3.13(m,4H),3.02–2.74(m,7H),2.59(d, J＝16.8Hz, 2H), 2.34–2.19(m, 2H), 2.03(d, J＝8.3Hz, 3H), 1.77(s, 3H), 1.70–1.41(m, 11H), 1.30–1.11(m ,11H).
实施例I-12 N-(((顺式)-7a-(((4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟吡啶[4,3-d]嘧啶-2-基)氧基)甲基)六氢-1H-双稠吡咯啶-3-基)甲基)-2-(4-(1-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚啉-5-基)哌啶-4-基)哌嗪-1-基)-N-甲基乙酰胺的制备Example I-12 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 Fused pyrrolidin-3-yl)methyl)-2-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5 Preparation of -yl)piperidin-4-yl)piperazin-1-yl)-N-methylacetamide
Figure PCTCN2022142077-appb-000142
Figure PCTCN2022142077-appb-000142
LC-MS：m/z 1091(M+H) +。 LC-MS: m/z 1091 (M+H) + .
实施例I-13 N 1-(((顺式)-7a-(((4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟吡啶[4,3-d]嘧啶-2-基)氧基)甲基)六氢-1H-双稠吡咯啶-3-基)甲基)-N 3-((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑基-5-基)苄基)氨基甲酰基)吡咯啶-1-基)-3,3-二甲基-1-氧丁基-2-基)-N 1-甲基丙二酰胺 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
Figure PCTCN2022142077-appb-000143
Figure PCTCN2022142077-appb-000143
LC-MS：m/z 1124(M+H) +。 LC-MS: m/z 1124 (M+H) + .
实施例I-14 N 1-(((顺式)-7a-(((4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟吡啶[4,3-d]嘧啶-2-基)氧基)甲基)六氢-1H-双稠吡咯啶-3-基)甲基)-N 3-((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑基-5-基)苄基)氨基甲酰基)吡咯啶-1-基)-3,3-二甲基-1-氧丁基-2-基)-N 1-甲基丁二酰胺 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
Figure PCTCN2022142077-appb-000144
Figure PCTCN2022142077-appb-000144
LC-MS：m/z 1138(M+H) +。 LC-MS: m/z 1138 (M+H) + .
实施例I-15 N 1-(((顺式)-7a-(((4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟吡啶[4,3-d]嘧啶-2-基)氧基)甲基)六氢-1H-双稠吡咯啶-3-基)甲基)-N 3-((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑基-5-基)苄基)氨基甲酰基)吡咯啶-1-基)-3,3-二甲基-1-氧丁基-2-基)-N 1-甲基戊二酰胺 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
Figure PCTCN2022142077-appb-000145
Figure PCTCN2022142077-appb-000145
LC-MS：m/z 1152(M+H) +。 LC-MS: m/z 1152 (M+H) + .
实施例I-16 N 1-(((顺式)-7a-(((4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟吡啶[4,3-d]嘧啶-2-基)氧基)甲基)六氢-1H-双稠吡咯啶-3-基)甲基)-N 3-((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑基-5-基)苄基)氨基甲酰基)吡咯啶-1-基)-3,3-二甲基-1-氧丁基-2-基)-N 1-甲基己二酰胺 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
Figure PCTCN2022142077-appb-000146
Figure PCTCN2022142077-appb-000146
LC-MS：m/z 1166(M+H) +。 LC-MS: m/z 1166 (M+H) + .
实施例I-17 N 1-(((顺式)-7a-(((4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟吡啶[4,3-d]嘧啶-2-基)氧基)甲基)六氢-1H-双稠吡咯啶-3-基)甲基)-N 3-((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑基-5-基)苄基)氨基甲酰基)吡咯啶-1-基)-3,3-二甲基-1-氧丁基-2-基)-N 1-甲基庚二酰胺 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
Figure PCTCN2022142077-appb-000147
Figure PCTCN2022142077-appb-000147
LC-MS：m/z 1180(M+H) +。 1H NMR(400MHz，DMSO-d 6)δ10.19–10.07(m,1H),9.03(s,1H),8.98(s,1H),8.56(d,J＝5.9Hz,1H),8.00–7.93(m,1H),7.87–7.79(m,1H),7.42(dt,J＝16.0,8.6Hz,6H),7.17(s,1H),5.14(s,1H),4.48(ddd,J＝24.3,12.3,6.4Hz,4H),4.37–4.17(m,4H),4.15–3.91(m,4H),3.61(d,J＝30.3Hz,5H),3.17(d,J＝9.9Hz,3H),2.98(s,2H),2.80(s,5H),2.44(s,3H),2.22(s,2H),2.02(s,2H),1.76(d,J＝6.3Hz,3H),1.63(d,J＝26.7Hz,5H),1.46(s,6H),1.22(d,J＝9.2Hz,4H),0.91(d,J＝9.7Hz,9H). LC-MS: m/z 1180 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 )δ10.19–10.07(m,1H),9.03(s,1H),8.98(s,1H),8.56(d,J＝5.9Hz,1H),8.00– 7.93(m,1H),7.87–7.79(m,1H),7.42(dt,J=16.0,8.6Hz,6H),7.17(s,1H),5.14(s,1H),4.48(ddd,J= 24.3,12.3,6.4Hz,4H),4.37–4.17(m,4H),4.15–3.91(m,4H),3.61(d,J＝30.3Hz,5H),3.17(d,J＝9.9Hz,3H ),2.98(s,2H),2.80(s,5H),2.44(s,3H),2.22(s,2H),2.02(s,2H),1.76(d,J＝6.3Hz,3H),1.63 (d,J=26.7Hz,5H),1.46(s,6H),1.22(d,J=9.2Hz,4H),0.91(d,J=9.7Hz,9H).
实施例I-18 N 1-(((顺式)-7a-(((4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟吡啶[4,3-d]嘧啶-2-基)氧基)甲基)六氢-1H-双稠吡咯啶-3-基)甲基)-N 3-((S)-1-((2S,4R)-4-羟基-2-(((S)-4-(4-甲基噻唑基-5-基)苯基)乙基)氨基甲酰基)吡咯啶-1-基)-3,3-二甲基-1-氧丁基-2-基)-N 1-甲基庚二酰胺 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
Figure PCTCN2022142077-appb-000148
Figure PCTCN2022142077-appb-000148
LC-MS：m/z 1194(M+H) +。 1H NMR(400MHz，DMSO-d 6)δ10.16(s,1H),9.02(d,J＝26.1Hz,2H),8.37(d,J＝7.7Hz,1H),7.97(dd,J＝9.1,6.0Hz,1H),7.77(t,J＝10.1Hz,1H),7.42(dq,J＝10.2,8.7Hz,7H),7.18(s,1H),5.11(s,1H),4.91(t,J＝7.3Hz,1H),4.59–4.21(m,5H),4.18–3.89(m,3H),3.81–3.55(m,6H),2.97(d,J＝10.4Hz,2H),2.81(s,3H),2.42(d,J＝23.5Hz,4H),2.22(d,J＝5.2Hz,2H),2.09–1.96(m,4H),1.85–1.70(m,8H),1.45(dd,J＝66.8,32.6Hz,12H),1.23(s,4H),0.88(dd,J＝26.4,8.7Hz,10H). LC-MS: m/z 1194 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 ) δ10.16(s, 1H), 9.02(d, J=26.1Hz, 2H), 8.37(d, J=7.7Hz, 1H), 7.97(dd, J= 9.1,6.0Hz,1H),7.77(t,J=10.1Hz,1H),7.42(dq,J=10.2,8.7Hz,7H),7.18(s,1H),5.11(s,1H),4.91( t,J=7.3Hz,1H),4.59–4.21(m,5H),4.18–3.89(m,3H),3.81–3.55(m,6H),2.97(d,J=10.4Hz,2H),2.81 (s,3H),2.42(d,J=23.5Hz,4H),2.22(d,J=5.2Hz,2H),2.09–1.96(m,4H),1.85–1.70(m,8H),1.45( dd,J=66.8,32.6Hz,12H),1.23(s,4H),0.88(dd,J=26.4,8.7Hz,10H).
实施例I-19(2S,4R)-1-((S)-2-(2-(2-((((顺式)-7a-(((4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟吡啶[4,3-d]嘧啶-2-基)氧基)甲基)六氢-1H-双稠吡咯啶-3-基)甲基)六氢-1H-双稠吡咯啶-3-基)甲基)(甲基)氨基)-2-氧乙氧基)乙酰氨基)-3,3-二甲基丁氧基)-4-羟基-N-(4-(4-甲基噻唑基-5-基)苄基)吡咯啶-2-甲酰胺Embodiment I-19(2S, 4R)-1-((S)-2-(2-(2-((((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-biscondensed pyrrolidin-3-yl)methyl)hexahydro-1H-biscondensed pyrrolidin-3-yl)methyl)(form Base)amino)-2-oxyethoxy)acetamido)-3,3-dimethylbutoxy)-4-hydroxy-N-(4-(4-methylthiazolyl-5-yl)benzyl base) pyrrolidine-2-carboxamide
Figure PCTCN2022142077-appb-000149
Figure PCTCN2022142077-appb-000149
LC-MS：m/z 1154(M+H) +。 1H NMR(400MHz，DMSO-d 6)δ10.18(s,1H),9.05(s,1H),8.97(s,1H),8.59(s,1H),7.97(dd,J＝9.1,6.0Hz,1H),7.81(dd,J＝17.4,9.4Hz,1H),7.50–7.35(m,6H),7.18(s,1H),4.54(d,J＝4.9Hz,2H),4.38(ddd,J＝41.5,25.1,18.1Hz,7H),4.17–3.88(m,6H),3.81–3.60(m,6H),3.25–3.20(m,1H),2.88(d,J＝27.4Hz,6H),2.43(s,3H),2.08–1.86(m,5H),1.75(s,7H),1.61(s,4H),0.98–0.78(m,9H). LC-MS: m/z 1154 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 ) δ10.18(s, 1H), 9.05(s, 1H), 8.97(s, 1H), 8.59(s, 1H), 7.97(dd, J=9.1, 6.0 Hz,1H),7.81(dd,J=17.4,9.4Hz,1H),7.50–7.35(m,6H),7.18(s,1H),4.54(d,J=4.9Hz,2H),4.38(ddd ,J＝41.5,25.1,18.1Hz,7H),4.17–3.88(m,6H),3.81–3.60(m,6H),3.25–3.20(m,1H),2.88(d,J＝27.4Hz,6H ),2.43(s,3H),2.08–1.86(m,5H),1.75(s,7H),1.61(s,4H),0.98–0.78(m,9H).
实施例I-20(2S,4R)-1-((S)-2-(2-(2-((((顺式)-7a-(((4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟吡啶[4,3-d]嘧啶-2-基)氧基)甲基)六氢-1H-双稠吡咯啶-3-基)甲基)六氢-1H-双稠吡咯啶-3-基)甲基)(甲基)氨基)-3-氧丙氧基)乙酰氨基)-3,3-二甲基丁氧基)-4-羟基-N-(4-(4-甲基噻唑基-5-基)苄基)吡咯啶-2-甲酰胺Embodiment I-20(2S, 4R)-1-((S)-2-(2-(2-((((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-biscondensed pyrrolidin-3-yl)methyl)hexahydro-1H-biscondensed pyrrolidin-3-yl)methyl)(form Base)amino)-3-oxopropoxy)acetamido)-3,3-dimethylbutoxy)-4-hydroxy-N-(4-(4-methylthiazolyl-5-yl)benzyl base) pyrrolidine-2-carboxamide
Figure PCTCN2022142077-appb-000150
Figure PCTCN2022142077-appb-000150
LC-MS：m/z 1168(M+H) +。 1H NMR(400MHz，DMSO-d 6)δ9.02(s,1H),8.97(s,1H),8.59(s,1H),7.97(dd,J＝9.1,5.9Hz,1H),7.66(d,J＝9.2Hz,1H),7.46(t,J＝9.0Hz,1H),7.41(d,J＝19.6Hz,5H),7.17(s,1H),5.14(s,1H),4.40(ddd,J＝57.1,34.0,11.2Hz,9H),4.00(s,3H),3.91(d,J＝12.6Hz,3H),3.67(d,J＝15.8Hz,5H),3.53(s,3H),3.20–3.18(m,1H),3.01(s,3H),2.83(s,3H),2.43(s,3H),2.08–2.00(m,3H),1.90(s,2H),1.75(s,3H),1.64(s,4H),1.59(s,2H),1.53–1.43(m,2H),1.00–0.88(m,9H). LC-MS: m/z 1168 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 ) δ9.02(s, 1H), 8.97(s, 1H), 8.59(s, 1H), 7.97(dd, J=9.1, 5.9Hz, 1H), 7.66( d,J=9.2Hz,1H),7.46(t,J=9.0Hz,1H),7.41(d,J=19.6Hz,5H),7.17(s,1H),5.14(s,1H),4.40( ddd, J＝57.1, 34.0, 11.2Hz, 9H), 4.00(s, 3H), 3.91(d, J＝12.6Hz, 3H), 3.67(d, J＝15.8Hz, 5H), 3.53(s, 3H ),3.20–3.18(m,1H),3.01(s,3H),2.83(s,3H),2.43(s,3H),2.08–2.00(m,3H),1.90(s,2H),1.75( s,3H),1.64(s,4H),1.59(s,2H),1.53–1.43(m,2H),1.00–0.88(m,9H).
实施例I-21(2S,4R)-1-((S)-2-(2-(2-((((顺式)-7a-(((4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟吡啶[4,3-d]嘧啶-2-基)氧基)甲基)六氢-1H-双稠吡咯啶-3-基)甲基)六氢-1H-双稠吡咯啶-3-基)甲基)(甲基)氨基)-3-氧丙氧基)丙酰氨基)-3,3-二甲基丁氧基)-4-羟基-N-(4-(4-甲基噻唑基-5-基)苄基)吡咯啶-2-甲酰胺Embodiment I-21(2S, 4R)-1-((S)-2-(2-(2-((((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-biscondensed pyrrolidin-3-yl)methyl)hexahydro-1H-biscondensed pyrrolidin-3-yl)methyl)(form Base)amino)-3-oxopropoxy)propionylamino)-3,3-dimethylbutoxy)-4-hydroxy-N-(4-(4-methylthiazolyl-5-yl) Benzyl)pyrrolidine-2-carboxamide
Figure PCTCN2022142077-appb-000151
Figure PCTCN2022142077-appb-000151
LC-MS：m/z 1182(M+H) +。 1H NMR(400MHz，DMSO-d 6)δ10.17(s,1H),9.02(d,J＝24.2Hz,2H),8.58(s,1H),8.04–7.83(m,2H),7.52–7.32(m,6H),7.19(s,1H),6.67(s,1H),5.15(s,1H),4.31(dddd,J＝104.2,66.0,23.7,15.2Hz,9H),3.72–3.50(m,8H),2.99(s,1H),2.82(s,3H),2.65(d,J＝28.1Hz,2H),2.45(s,3H),2.34(s,2H),1.99(dd,J＝27.6,20.1Hz,4H),1.64(dd,J＝76.2,36.1Hz,11H),1.25(s,6H),0.97–0.85(m,9H). LC-MS: m/z 1182 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 )δ10.17(s, 1H), 9.02(d, J=24.2Hz, 2H), 8.58(s, 1H), 8.04–7.83(m, 2H), 7.52– 7.32(m,6H),7.19(s,1H),6.67(s,1H),5.15(s,1H),4.31(dddd,J=104.2,66.0,23.7,15.2Hz,9H),3.72–3.50( m,8H),2.99(s,1H),2.82(s,3H),2.65(d,J＝28.1Hz,2H),2.45(s,3H),2.34(s,2H),1.99(dd,J =27.6,20.1Hz,4H),1.64(dd,J=76.2,36.1Hz,11H),1.25(s,6H),0.97–0.85(m,9H).
实施例I-22(2S,4R)-1-((S)-1-((顺式)-7a-(((4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟吡啶[4,3-d]嘧啶-2-基)氧基)甲基)六氢-1H-双稠吡咯啶-3-基)-14-(叔丁基)-2-甲基-3,12-二氧代-6,9-二氧杂-2,13-二氮杂十五烷-15-氧代)-4-羟基-N-(4-(4-甲基噻唑基-5-基)苄基)吡咯啶-2-甲酰胺Embodiment I-22(2S, 4R)-1-((S)-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)-14-(tert-butyl)-2-methyl-3,12-dioxo-6,9-dioxa- 2,13-diazapentadecane-15-oxo)-4-hydroxy-N-(4-(4-methylthiazolyl-5-yl)benzyl)pyrrolidine-2-carboxamide
Figure PCTCN2022142077-appb-000152
Figure PCTCN2022142077-appb-000152
LC-MS：m/z 1226(M+H) +。 1H NMR(400MHz，DMSO-d 6)δ10.24(s,1H),9.08(d,J＝26.2Hz,2H),8.64(t,J＝5.7Hz,1H),8.12–7.93(m,2H),7.64–7.37(m,8H),7.25(s,1H),5.21(s,1H),4.65–4.35(m,8H),4.28(dd,J＝15.8,5.1Hz,2H),4.10(ddd,J＝38.1,23.3,5.7Hz,4H),3.67(dd,J＝28.2,20.3Hz,13H),3.08(d,J＝14.7Hz,2H),2.88(s,4H),2.45–2.31(m,2H),2.20–2.06(m,4H),1.95–1.52(m,15H),1.09–0.91(m,12H). LC-MS: m/z 1226 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 ) δ10.24(s, 1H), 9.08(d, J=26.2Hz, 2H), 8.64(t, J=5.7Hz, 1H), 8.12–7.93(m, 2H),7.64–7.37(m,8H),7.25(s,1H),5.21(s,1H),4.65–4.35(m,8H),4.28(dd,J＝15.8,5.1Hz,2H),4.10 (ddd, J=38.1, 23.3, 5.7Hz, 4H), 3.67(dd, J=28.2, 20.3Hz, 13H), 3.08(d, J=14.7Hz, 2H), 2.88(s, 4H), 2.45– 2.31(m,2H),2.20–2.06(m,4H),1.95–1.52(m,15H),1.09–0.91(m,12H).
实施例II-1 4-((3-((R)-2-(((4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟吡啶[4,3-d]嘧啶-2-基)氧基)甲基)吡咯啉-1-基)-3-氧丙基)氨基)-2-(2,6-二氧哌啶-3-基)异吲哚-1,3-二酮的制备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 Preparation of -yl)-3-oxopropyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione
Figure PCTCN2022142077-appb-000153
Figure PCTCN2022142077-appb-000153
LC-MS：m/z 870(M+H) +。 1H NMR(400MHz，DMSO-d 6)δ11.09(s,1H),10.12(s,1H),8.80(d,J＝4.5Hz,1H),7.96(dd,J＝9.2,6.0Hz,1H),7.66–7.52(m,1H),7.45(t,J＝9.0Hz,1H),7.37(d,J＝2.6Hz,1H),7.25–6.97(m,3H),6.76–6.60(m,1H),5.12–5.00(m,1H),4.64–3.91(m,7H),3.69–3.46(m,9H),2.95–2.81(m,1H),2.78–2.68(m,2H),2.67–2.53(m,3H),2.12–1.82(m,5H),1.80–1.59(m,4H). LC-MS: m/z 870 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 ) δ11.09(s, 1H), 10.12(s, 1H), 8.80(d, J=4.5Hz, 1H), 7.96(dd, J=9.2, 6.0Hz, 1H),7.66–7.52(m,1H),7.45(t,J=9.0Hz,1H),7.37(d,J=2.6Hz,1H),7.25–6.97(m,3H),6.76–6.60(m ,1H),5.12–5.00(m,1H),4.64–3.91(m,7H),3.69–3.46(m,9H),2.95–2.81(m,1H),2.78–2.68(m,2H),2.67 –2.53(m,3H),2.12–1.82(m,5H),1.80–1.59(m,4H).
实施例II-2 4-((4-((R)-2-(((4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟吡啶[4,3-d]嘧啶-2-基)氧基)甲基)吡咯啉-1-基)-4-氧丁基)氨基)-2-(2,6-二氧哌啶-3-基)异吲哚-1,3-二酮的制备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 Preparation of -yl)-4-oxobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione
Figure PCTCN2022142077-appb-000154
Figure PCTCN2022142077-appb-000154
LC-MS：m/z 884(M+H) +。 1H NMR(400MHz，DMSO-d 6)δ11.10(s,1H),10.44(s,1H),9.98(s,1H),9.59(s,1H),8.97(d,J＝9.2Hz,1H),8.03(dd,J＝9.2,5.9Hz,1H),7.66–7.42(m,3H),7.41–7.19(m,3H),7.18–6.96(m,2H),6.68(s,2H),5.15–4.98(m,1H),4.78–4.38(m,4H),4.37–4.27(m,1H),4.25–4.10(m,4H),4.10–3.82(m,3H),3.43–3.24(m,2H),2.97–2.81(m,1H),2.66–2.54(m,2H),2.50–2.34(m,2H),2.17–1.87(m,9H),1.88–1.71(m,2H). LC-MS: m/z 884 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 )δ11.10(s,1H),10.44(s,1H),9.98(s,1H),9.59(s,1H),8.97(d,J=9.2Hz, 1H), 8.03(dd, J＝9.2, 5.9Hz, 1H), 7.66–7.42(m, 3H), 7.41–7.19(m, 3H), 7.18–6.96(m, 2H), 6.68(s, 2H) ,5.15–4.98(m,1H),4.78–4.38(m,4H),4.37–4.27(m,1H),4.25–4.10(m,4H),4.10–3.82(m,3H),3.43–3.24( m,2H),2.97–2.81(m,1H),2.66–2.54(m,2H),2.50–2.34(m,2H),2.17–1.87(m,9H),1.88–1.71(m,2H).
实施例II-3 4-((5-((R)-2-(((4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟吡啶[4,3-d]嘧啶-2-基)氧基)甲基)吡咯啉-1-基)-5-氧戊基)氨基)-2-(2,6-二氧哌啶-3-基)异吲哚-1,3-二酮的制备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 Preparation of -yl)-5-oxopentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione
Figure PCTCN2022142077-appb-000155
Figure PCTCN2022142077-appb-000155
LC-MS：m/z 898(M+H) +。 1H NMR(400MHz，DMSO-d 6)δ11.10(s,1H),10.44(s,1H),10.02(s,1H),9.64(s,1H),8.96(d,J＝8.3Hz,1H),8.02(dd,J＝9.2,5.9Hz,1H),7.66–7.44(m,3H),7.43–7.18(m,3H),7.15–6.97(m,2H),6.86–6.39(m,2H),5.10–5.02(m,1H),4.77–4.38(m,4H),4.37–4.23(m,1H),4.23–4.11(m,4H),4.11–3.91(m,3H),3.37–3.20(m,2H),2.97–2.81(m,1H),2.63–2.54(m,2H),2.46–2.30(m,2H),2.13–1.86(m,9H),1.68–1.48(m,4H). LC-MS: m/z 898 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 )δ11.10(s,1H),10.44(s,1H),10.02(s,1H),9.64(s,1H),8.96(d,J=8.3Hz, 1H),8.02(dd,J＝9.2,5.9Hz,1H),7.66–7.44(m,3H),7.43–7.18(m,3H),7.15–6.97(m,2H),6.86–6.39(m, 2H),5.10–5.02(m,1H),4.77–4.38(m,4H),4.37–4.23(m,1H),4.23–4.11(m,4H),4.11–3.91(m,3H),3.37– 3.20(m,2H),2.97–2.81(m,1H),2.63–2.54(m,2H),2.46–2.30(m,2H),2.13–1.86(m,9H),1.68–1.48(m,4H ).
实施例II-4 4-((6-((R)-2-(((4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟吡啶[4,3-d]嘧啶-2-基)氧基)甲基)吡咯啉-1-基)-6-氧己基)氨 基)-2-(2,6-二氧哌啶-3-基)异吲哚-1,3-二酮的制备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 Preparation of -yl)-6-oxohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione
Figure PCTCN2022142077-appb-000156
Figure PCTCN2022142077-appb-000156
LC-MS：m/z 912(M+H) +。 1H NMR(400MHz，DMSO-d 6)δ11.10(s,1H),10.44(s,1H),10.00(s,1H),9.63(s,1H),8.97(d,J＝5.7Hz,1H),8.06–7.98(m,1H),7.67–7.43(m,3H),7.41–7.20(m,2H),7.15–6.96(m,2H),6.83–6.34(m,2H),5.05(dd,J＝12.7,5.2Hz,1H),4.78–4.38(m,4H),4.35–4.24(m,1H),4.24–4.11(m,4H),4.10–3.84(m,3H),3.33–3.16(m,2H),2.95–2.83(m,1H),2.65–2.54(m,2H),2.42–2.25(m,2H),2.14–1.85(m,9H),1.69–1.44(m,4H),1.42–1.22(m,2H). LC-MS: m/z 912 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 )δ11.10(s,1H),10.44(s,1H),10.00(s,1H),9.63(s,1H),8.97(d,J=5.7Hz, 1H),8.06–7.98(m,1H),7.67–7.43(m,3H),7.41–7.20(m,2H),7.15–6.96(m,2H),6.83–6.34(m,2H),5.05( dd,J＝12.7,5.2Hz,1H),4.78–4.38(m,4H),4.35–4.24(m,1H),4.24–4.11(m,4H),4.10–3.84(m,3H),3.33– 3.16(m,2H),2.95–2.83(m,1H),2.65–2.54(m,2H),2.42–2.25(m,2H),2.14–1.85(m,9H),1.69–1.44(m,4H ),1.42–1.22(m,2H).
实施例II-5 4-((7-((R)-2-(((4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟吡啶[4,3-d]嘧啶-2-基)氧基)甲基)吡咯啉-1-基)-7-氧庚基)氨基)-2-(2,6-二氧哌啶-3-基)异吲哚-1,3-二酮的制备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 Preparation of -yl)-7-oxoheptyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione
Figure PCTCN2022142077-appb-000157
Figure PCTCN2022142077-appb-000157
LC-MS：m/z 926(M+H) +。 1H NMR(400MHz，DMSO-d 6)δ11.10(s,1H),10.44(s,1H),10.01(s,1H),9.65(s,1H),8.96(d,J＝6.0Hz,1H),8.02(dd,J＝9.3,6.0Hz,1H),7.62–7.46(m,3H),7.41–7.21(m,2H),7.17–6.96(m,2H),6.81–6.35(m,2H),5.05(dd,J＝12.8,5.4Hz,1H),4.77–4.38(m,4H),4.37–4.26(m,1H),4.23–4.10(m,4H),4.10–3.85(m,3H),3.31–3.18(m,2H),2.96–2.82(m,1H),2.63–2.52(m,2H),2.42–2.23(m,2H),2.15–1.84(m,9H),1.64–1.42(m,4H),1.41–1.16(m,4H). LC-MS: m/z 926 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 )δ11.10(s,1H),10.44(s,1H),10.01(s,1H),9.65(s,1H),8.96(d,J=6.0Hz, 1H),8.02(dd,J＝9.3,6.0Hz,1H),7.62–7.46(m,3H),7.41–7.21(m,2H),7.17–6.96(m,2H),6.81–6.35(m, 2H), 5.05(dd, J＝12.8, 5.4Hz, 1H), 4.77–4.38(m, 4H), 4.37–4.26(m, 1H), 4.23–4.10(m, 4H), 4.10–3.85(m, 3H),3.31–3.18(m,2H),2.96–2.82(m,1H),2.63–2.52(m,2H),2.42–2.23(m,2H),2.15–1.84(m,9H),1.64– 1.42(m,4H),1.41–1.16(m,4H).
实施例II-6 4-((10-((R)-2-(((4-((1R,5S)-3,8-3,8-二氮杂双环[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟吡啶并[4,3-d]嘧啶-2-基)氧基)甲基)吡咯烷-1-基)-10-氧代癸基)氨基)-2-(2,6-二氧哌啶-3-基)异吲哚-1,3-二酮的制备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
Figure PCTCN2022142077-appb-000158
Figure PCTCN2022142077-appb-000158
LC-MS:m/z 968(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ11.12(s,1H),10.47(s,1H),10.09(s,1H),9.71(s,1H),8.99(s,1H),8.04(dd,J＝9.3,6.0Hz,1H),7.63–7.49(m,3H),7.44–7.22(m,2H),7.20–6.99(m,2H),6.84–6.33(m,2H),5.07(dd,J＝12.8,5.4Hz,1H),4.77–4.40(m,4H),4.39–4.26(m,1H),4.26–4.12(m,4H),4.12–3.93(m,3H),3.38–3.19(m,2H),2.97–2.84(m,1H),2.65–2.54(m,2H),2.41–2.23(m,2H),2.16–1.87(m,9H),1.65–1.41(m,4H),1.40–1.04(m,10H). LC-MS: m/z 968 (M+H) + . 1 H NMR (400MHz,DMSO-d 6 )δ11.12(s,1H),10.47(s,1H),10.09(s,1H),9.71(s,1H),8.99(s,1H),8.04( dd,J＝9.3,6.0Hz,1H),7.63–7.49(m,3H),7.44–7.22(m,2H),7.20–6.99(m,2H),6.84–6.33(m,2H),5.07( dd,J＝12.8,5.4Hz,1H),4.77–4.40(m,4H),4.39–4.26(m,1H),4.26–4.12(m,4H),4.12–3.93(m,3H),3.38– 3.19(m,2H),2.97–2.84(m,1H),2.65–2.54(m,2H),2.41–2.23(m,2H),2.16–1.87(m,9H),1.65–1.41(m,4H ),1.40–1.04(m,10H).
实验例 生物学测试评价Experimental example Biological test evaluation
以下生物学测试例进一步描述解释本发明，但这些实例并非意味着限制本发明的范围。The following biological test examples are further described to explain the present invention, but these examples are not meant to limit the scope of the present invention.
化合物对KRAS G12D和SOS1结合的抑制实验。 Inhibition experiments of compounds on the binding of KRAS G12D and SOS1.
实验步骤Experimental procedure
a.使用DMSO对待测化合物进行3倍的梯度稀释，10个浓度梯度，第11个浓度为无化合物的DMSO对照。a. Use DMSO to carry out 3-fold serial dilution of the test compound, 10 concentration gradients, and the eleventh concentration is the DMSO control without compound.
b.梯度稀释后的化合物使用ECHO加入到384反应板(6008260,PerkinElmer)中，100nL/孔，每个浓度梯度2个重复。b. Compounds after gradient dilution were added to a 384 reaction plate (6008260, PerkinElmer) using ECHO, 100 nL/well, and each concentration gradient was replicated twice.
c.向含化合物的384反应板中加入5μL Tag2-KRASG12D和GTP的混合液，1000rpm离心1min。c. Add 5 μL of the mixture of Tag2-KRASG12D and GTP to the 384 reaction plate containing the compound, and centrifuge at 1000 rpm for 1 min.
d.再加入5μL Tag1-SOS1溶液，1000rpm离心1min，25℃孵育15min。d. Add 5 μL of Tag1-SOS1 solution, centrifuge at 1000 rpm for 1 min, and incubate at 25°C for 15 min.
e.孵育结束后每孔加入10μL anti-Tag1-Tb3+和anti-Tag2-XL665混合液，1000rpm离心1min。e. After incubation, add 10 μL of anti-Tag1-Tb3+ and anti-Tag2-XL665 mixture to each well, and centrifuge at 1000 rpm for 1 min.
f.4℃孵育3h。f. Incubate at 4°C for 3h.
g.使用Envision多功能读板机读取665/615nm比值。g. Use the Envision multifunctional plate reader to read the ratio of 665/615nm.
h.使用GraphPad Prism软件的四参数logistic回归模型(4PL)计算和分析测试化合物的IC50水平。h. Use the four parameter logistic regression model (4PL) of GraphPad Prism software to calculate and analyze the IC50 level of the test compound.
参照化合物结构如下：The reference compound structure is as follows:
Figure PCTCN2022142077-appb-000159
Figure PCTCN2022142077-appb-000159
表1本发明中实施例化合物抑制活性Example compound inhibitory activity in the present invention in table 1
IC 50 IC50 (nM)(nM)
实施例I-1Example I-1 12.912.9
实施例I-2Example I-2 12.412.4
实施例I-3Example I-3 14.214.2
实施例I-4Example I-4 12.512.5
实施例I-5Example I-5 //
实施例II-5Example II-5 36643664
实施例II-6Example II-6 21002100
MRTX1133MRTX1133 17.717.7
ERK磷酸化抑制实验ERK phosphorylation inhibition assay
实验步骤Experimental procedure
在384孔板中种入GP2D细胞，37℃,5％CO2培养箱中培养过夜。GP2D cells were seeded into 384-well plates and cultured overnight in a 37°C, 5% CO2 incubator.
用Echo 500加入200nL稀释好的化合物，DMSO终浓度为0.5％，在37℃，5％CO2培养箱中培养1小时。加入hEGF作用10分钟。Add 200nL of the diluted compound with Echo 500, the final concentration of DMSO is 0.5%, and incubate at 37°C, 5% CO2 incubator for 1 hour. Add hEGF for 10 minutes.
移去培养基，加入细胞固定液，固定细胞Remove medium, add cell fixative, fix cells
PBS洗1次，冷的100％甲醇孵育，Wash once with PBS, incubate in cold 100% methanol,
移去甲醇，加入PBS洗1次。Remove methanol, add PBS to wash once.
移去PBS,每孔加入Li-Cor封闭缓冲液，室温封闭1hr。Remove PBS, add Li-Cor blocking buffer to each well, and block at room temperature for 1 hr.
移去封闭液，每孔加入一抗混合液，4℃室温孵育过夜。Remove the blocking solution, add the primary antibody mixture to each well, and incubate overnight at room temperature at 4°C.
移去一抗混合液，加入PBST洗3次。Remove the primary antibody mixture, add PBST and wash 3 times.
加入二抗混合液，室温避光孵育45min。Add the secondary antibody mixture and incubate at room temperature for 45 min in the dark.
移去二抗混合液，加入PBST洗3次,最后吸出PBST,倒扣离心，1000rpm离心1min。Remove the secondary antibody mixture, add PBST to wash 3 times, finally suck out the PBST, centrifuge upside down, and centrifuge at 1000rpm for 1min.
Odyssey CLx读数。实验结果如表2所示Odyssey CLx readout. The experimental results are shown in Table 2
表2ERK磷酸化抑制实验结果Table 2 ERK phosphorylation inhibition experiment results
实施例Example IC 50(nM) IC 50 (nM)
实施例I-4Example I-4 525525
实施例I-6Example I-6 325325
实施例I-7Example I-7 178178
实施例I-8Example I-8 119119
实施例I-9Example I-9 9999
实施例I-10Example I-10 6666
实施例I-11Example I-11 2828
实施例I-12Example I-12 8787
实施例I-13Example I-13 150150
实施例I-14Example I-14 305305
实施例I-15Example I-15 234234
实施例I-16Example I-16 428428
实施例I-17Example I-17 227227
实施例I-18Example I-18 264264
实施例I-19Example I-19 171171
实施例I-20Example I-20 601601
实施例I-21Example I-21 10521052
实施例I-22Example I-22 373373
结果表明，本发明实施例化合物对于KRAS G12D显示出了很好的抑制活性。 The results show that the compounds of the examples of the present invention have good inhibitory activity on KRAS G12D .
化合物对SNU-61(KRAS G12D突变)细胞、GP2D(KRAS G12D突变)、GP5D(KRAS G12D突变)、LS-513(KRAS G12D突变)细胞的抗增殖活性的细胞实验。 Cell experiments on the anti-proliferative activity of compounds on SNU-61 (KRAS G12D mutation) cells, GP2D (KRAS G12D mutation), GP5D (KRAS G12D mutation), LS-513 (KRAS G12D mutation) cells.
实验步骤Experimental procedure
向384微孔板的外围孔中加入40μL磷酸盐缓冲液，随后向其他孔中加入40μL待测细胞悬浮液，然后将微孔板置于二氧化碳培养箱中培养过夜。Add 40 μL of phosphate buffer to the peripheral wells of the 384 microwell plate, then add 40 μL of the cell suspension to be tested to the other wells, and then place the microplate in a carbon dioxide incubator for overnight culture.
对待测化合物进行梯度稀释，将每个化合物稀释10个浓度梯度(从50μM稀释到0.003μM)并分别加100nL到微孔板的对应孔中。加药以后，在A、P行及1、24列每孔加 入40μL磷酸盐缓冲液，然后将微孔板置于二氧化碳培养箱中培养5天。The compounds to be tested were serially diluted, and each compound was diluted in 10 concentration gradients (from 50 μM to 0.003 μM) and 100 nL was added to the corresponding wells of the microwell plate. After dosing, add 40 μL 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.
向微孔板每孔中加入20μL的Promega CellTiter-Glo试剂，随后在室温震荡10min使发光信号稳定，然后采用PekinElmer Envision多标记分析仪读数。Add 20 μL of Promega CellTiter-Glo reagent to each well of the microplate, then shake at room temperature for 10 minutes to stabilize the luminescent signal, and then use the PekinElmer Envision multi-label analyzer to read.
最后应用GraphPad Prism软件计算化合物的IC 50值，并绘出拟合曲线。 Finally, the GraphPad Prism software was used to calculate the IC50 values of the compounds and draw the fitting curve.
化合物对KRAS G12D蛋白水解的调节实验 Modulation experiments of compounds on KRAS G12D proteolysis
实验步骤Experimental procedure
(1)接种肿瘤细胞(例如SNU-61、GP2D，5x10 5～1x10 6)在培养皿(2D，P100 mm dish)培养2-4天，至70-80％饱和； (1) 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;
(2)更换10ml新鲜培养液后，继续培养箱内温孵过夜，然后加入相同浓度的本发明的PROTAC候选物以及对照pair的G12Di，轻微摇动混匀。(2) After replacing 10ml of fresh culture medium, continue to incubate overnight in the incubator, then add the same concentration of the PROTAC candidate of the present invention and the G12Di of the control pair, and shake slightly to mix.
(3)细胞继续培养1～48小时，做同浓度下(0.1或者1μM)时间曲线(1，2，4，6，8，24，48)或者6、24或48小时下剂量曲线。(3) The cells were cultured for 1-48 hours, and the time curve (1, 2, 4, 6, 8, 24, 48) or the dose curve of 6, 24 or 48 hours was made at the same concentration (0.1 or 1 μM).
(4)在所设计的时间或者浓度终点，弃去培养液，把培养皿转移到冰上，用50毫升冰冷PBS清洗3次，尽量吸干剩余液体，然后加入冰冷裂解液(含detergent例如triton,NP40等)以及蛋白水解酶抑制剂。(4) At the end of the designed time or concentration, discard the culture medium, transfer the culture dish to ice, wash with 50 ml of ice-cold PBS for 3 times, try to absorb the remaining liquid, and then add ice-cold lysate (containing detergent such as triton , NP40, etc.) and proteolytic enzyme inhibitors.
(5)用细胞刮刀在冰上把细胞刮下，然后转移到1.5毫升离心管内，4度高速离心20分钟，取上清液液，并转移到新的管内。测定蛋白含量后，蛋白上清液用4X上胶液混合，加热(100度，5-10分钟)，冷却后加入10X抗氧剂成最终上胶样品，并于-20度保存。(5) Scrape the cells on ice with a cell scraper, then transfer to a 1.5 ml centrifuge tube, centrifuge at 4°C for 20 minutes at high speed, take the supernatant, and transfer it to a new tube. After measuring the protein content, the protein supernatant was mixed with 4X sizing solution, heated (100 degrees, 5-10 minutes), cooled and then added with 10X antioxidant to form the final sizing sample, and stored at -20 degrees.
(6)样品做Western-blot，用SDS-PAGE胶跑电泳，样品可上样10-50微克总蛋白，电转硝酸纤维膜后，切好条带和各自抗体温孵。然后用标记2抗温孵后，做自发光显色，拍照。(6) Western-blot the sample, run electrophoresis with SDS-PAGE gel, the sample can be loaded with 10-50 micrograms of total protein, and after electrotransfer to the nitrocellulose membrane, cut the strips and incubate with the respective antibodies. Then, after incubating with Marker 2, do self-luminescence color development, and take pictures.
(7)最后应用GraphPad Prism软件计算化合物的IC 50值，并绘出拟合曲线，结果如图1所示。 (7) Finally, the GraphPad Prism software was used to calculate the IC50 values of the compounds, and a fitting curve was drawn. The results are shown in Figure 1.
实验结果表明，本发明的化合物具有靶向降解KRAS G12D蛋白的作用。 Experimental results show that the compound of the present invention has the effect of targeting and degrading KRAS G12D protein.
药代动力学测试评价Pharmacokinetic test evaluation
雄性SD大鼠，体重220g左右，禁食过夜后，SC或者IP给予本发明化合物的溶液[DMSO/PEG/生理盐水为载体]。分别在给于本发明化合物后0.5，1.0，2.0，4.0，6.0，8.0，12，和24h采血，用LC/MS/MS测定血浆中本发明化合物的浓度。Male SD rats with a body weight of about 220 g were given SC or IP with a solution of the compound of the present invention [DMSO/PEG/normal saline as a carrier] after overnight fasting. Blood was collected at 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12, and 24 hours after administration of the compound of the present invention, and the concentration of the compound of the present invention in plasma was determined by LC/MS/MS.
实验结果表明，本发明化合物通过SC或者IP注射给药都具有良好的药代动力学特性，且毒副作用小。Experimental results show that the compound of the present invention has good pharmacokinetic properties and less toxic and side effects when administered by SC or IP injection.
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。All documents mentioned in this application are incorporated by reference in this application as if each were individually incorporated by reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims (13)

  1. 具有式(I)结构的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药：Compounds with the structure of formula (I), their stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs:
    Figure PCTCN2022142077-appb-100001
    Figure PCTCN2022142077-appb-100001
    式中：In the formula:
    ULM代表一个可以和E3连接酶结合的小分子配体部分；ULM represents a small molecule ligand part that can bind to E3 ligase;
    PTM代表一个可以和KRAS G12D蛋白结合的小分子配体部分； PTM represents a small molecule ligand part that can bind to KRAS G12D protein;
    L可以是键或者是可以连接PTM和ULM的连接基团。L can be a bond or a linking group that can connect the PTM and ULM.
  2. 如权利要求1所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，PTM具有式(PTM-I)所示结构The compound as claimed in claim 1, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, is characterized in that, PTM has formula (PTM -I) the structure shown
    Figure PCTCN2022142077-appb-100002
    Figure PCTCN2022142077-appb-100002
    式中，In the formula,
    虚线表示通过任意位置与L的连接；Dashed lines indicate connections to L through arbitrary locations;
    Q选自：N、C-CN、C-H、C-F、或C-Cl；Q is selected from: N, C-CN, C-H, C-F, or C-Cl;
    R 1选自：H、-CONH 2、或-(C＝NH)NH 2； R 1 is selected from: H, -CONH 2 , or -(C=NH)NH 2 ;
    X选自取代或未取代的下组基团：4-14元饱和或不饱和的杂环基、5-14元杂芳基；其中，所述取代是指被一个或多个R 2取代；R 2选自取代或未取代的下组基团：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 3-C 20环烷基、4-20元杂环基、C 6-C 14芳基、5-14元杂芳基、卤素、硝基、羟基、氧代基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基；其中，R 2中所述取代是指被一个或多个R取代； 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 ureido group; wherein, the substitution in R2 means replaced by one or more R;
    A选自：C、CH或N；A is selected from: C, CH or N;
    Y选自：键、O或NR b；R b选自取代或未取代的下组基团：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、氨基、羟基、4-20元杂环基、C 6-C 14芳基、5-14元杂芳基；其中，所述取代是指被一个或多个R取代； 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选自取代或未取代的下组基团：-(CH 2) nR 7、-(CH 2) nO(CH 2) mR 7、-(CH 2) nSR 7、-(CH 2) nCOR 7、-(CH 2) nC(O)OR 7、-(CH 2) nS(O) qR 7、-(CH 2) nNR 5R 7、-(CH 2) nC(O)NR 5R 7、-(CH 2) nNR 5C(O)R 7、-(CH 2) nNR 5C(O)NR 7R 8、-(CH 2) nS(O) qNR 5R 7、-(CH 2) nNR 5S(O) qR 7、 -(CH 2) nNR 5S(O) qNR 7R 8，其中，CH 2中的H可以被取代；R 5、R 7、和R 8相同或不同，且各自独立地选自取代或未取代的下组基团：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、氨基、羟基、4-20元杂环基、C 6-C 14芳基、5-14元杂芳基；或者R 5和R 7、R 5和R 8或R 7和R 8以及相邻的原子环合形成4-20元杂环基；其中，所述取代是指被一个或多个R取代； 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) q NR 7 R 8 , where H in CH 2 can be substituted ; R 5 , R 7 , and R 8 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 alkane radical, 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 group, amino, hydroxyl, 4-20 membered heterocyclic group, C 6 -C 14 aryl group, 5-14 membered heteroaryl group; or R 5 and R 7 , R 5 and R 8 or R 7 and R 8 and the corresponding Adjacent atoms are ring-joined to form a 4-20-membered heterocyclic group; wherein, the substitution refers to being substituted by one or more R;
    R 3和R 6相同或不同，各自独立地选自取代或未取代的下组基团：氢、氘、卤素、氨基、氰基、C 1-C 3烷基、氘代C 1-C 3烷基、卤代C 1-C 3烷基、C 3-C 6环烷基、氘代C 3-C 6环烷基、卤代C 3-C 6环烷基；其中，所述取代是指被一个或多个R取代； 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选自取代或未取代的下组取代或未取代的下组基团：4-14元杂环基、C 6-C 14芳基、5-14元杂芳基；其中，所述取代是指被一个或多个R取代； 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选自：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、(C 3-C 18环烷基)C 1-C 18烷基、(4-20元杂环基)C 1-C 18烷基、(C 1-C 18烷氧基)C 1-C 18烷基、C 3-C 18环烷基氧基、(C 3-C 18环烷基氧基)C 1-C 18烷基、4-20元杂环基氧基、(4-20元杂环基氧基)C 1-C 18烷基、C 6-C 20芳基氧基、(C 6-C 20芳基氧基)C 1-C 18烷基、5-20元杂芳基氧基、(5-20元杂芳基氧基)C 1-C 18烷基、C 1-C 18烷基胺基、(C 1-C 18烷基胺基)C 1-C 18烷基、C 3-C 18环烷基胺基、(C 3-C 18环烷基胺基)C 1-C 18烷基、4-20元杂环基胺基、(4-20元杂环基胺基)C 1-C 18烷基、C 6-C 20芳基胺基、(C 6-C 20芳基胺基)C 1-C 18烷基、5-20元杂芳基胺基、(5-20元杂芳基胺基)C 1-C 18烷基、乙烯基、乙炔基、(C 1-C 6烷基)乙烯基、氘代(C 1-C 6烷基)乙烯基、卤代(C 1-C 6烷基)乙烯基、(C 1-C 6烷基)乙炔基、氘代(C 1-C 6烷基)乙炔基、卤代(C 1-C 6烷基)乙炔基、(C 3-C 14环烷基)乙炔基、(4-14元环杂环基)乙炔基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 3-C 20环烷基、4-20元杂环基、C 6-C 14芳基、5-14元杂芳基、卤素、硝基、羟基、氧代基、氰基、酯基、胺基、酰胺基、砜基、磺酰基或脲基； 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 alkylamino, (C 1 -C 18 alkylamino)C 1 -C 18 alkyl, C 3 -C 18 cycloalkylamino, (C 3 -C 18 cycloalkylamino) C 1 -C 18 alkyl, 4-20 membered heterocyclylamine, (4-20 membered heterocyclylamino) C 1 -C 18 alkyl, C 6 -C 20 arylamino, (C 6 -C 20 arylamino) C 1 -C 18 alkyl, 5-20 membered heteroarylamine, (5-20 membered heteroarylamino) C 1 -C 18 Alkyl, vinyl, ethynyl, (C 1 -C 6 alkyl) vinyl, deuterated (C 1 -C 6 alkyl) vinyl, halogenated (C 1 -C 6 alkyl) vinyl, (C 1 -C 6 alkyl)ethynyl, deuterated (C 1 -C 6 alkyl)ethynyl, halo(C 1 -C 6 alkyl)ethynyl, (C 3 -C 14 cycloalkyl) Ethynyl, (4-14 membered ring heterocyclyl) ethynyl, 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 heterocyclic group, C 6 -C 14 aryl group, 5-14 membered heteroaryl group, halogen, nitro, hydroxyl, oxo, cyano, ester, amine, Amide, sulfone, sulfonyl or ureido groups;
    n和m各自独立地选自0、1、2、3、4、5或6；n and m are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
    q为1或2。q is 1 or 2.
  3. 如权利要求2所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，PTM-I中
    Figure PCTCN2022142077-appb-100003
    部分选自：     The compound as claimed in claim 2, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, is characterized in that, in PTM-I
    Figure PCTCN2022142077-appb-100003
    Some selected from:
    Figure PCTCN2022142077-appb-100004
    Figure PCTCN2022142077-appb-100004
    其中，p选自0、1、2、3、4、5或6；R 1和R 2的定义如权利要求2所述。 Wherein, p is selected from 0, 1, 2, 3, 4, 5 or 6; R 1 and R 2 are as defined in claim 2.
  4. 如权利要求1-3中任一项所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，PTM具有式(PTM-2)所示结构：The compound according to any one of claims 1-3, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, characterized in that , PTM has the structure shown in formula (PTM-2):
    Figure PCTCN2022142077-appb-100005
    Figure PCTCN2022142077-appb-100005
    式中，In the formula,
    p选自0、1、2、3、4、5或6；p is selected from 0, 1, 2, 3, 4, 5 or 6;
    R 2、R 3、R 4、Y和Z的定义如权利要求2所述。 The definitions of R 2 , R 3 , R 4 , Y and Z are as described in claim 2.
  5. 如权利要求1-4中任一项所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，PTM具有式(PTM-3)所示结构：The compound according to any one of claims 1-4, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, characterized in that , PTM has the structure shown in formula (PTM-3):
    Figure PCTCN2022142077-appb-100006
    Figure PCTCN2022142077-appb-100006
    式中，In the formula,
    p选自0、1、2、3、4、5或6；p is selected from 0, 1, 2, 3, 4, 5 or 6;
    R 2、R 3、R 4和Z的定义如权利要求2所述。 The definitions of R 2 , R 3 , R 4 and Z are as described in claim 2.
  6. 如权利要求1-5中任一项所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，PTM选自：The compound according to any one of claims 1-5, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, characterized in that , PTM selected from:
    Figure PCTCN2022142077-appb-100007
    Figure PCTCN2022142077-appb-100007
    Figure PCTCN2022142077-appb-100008
    Figure PCTCN2022142077-appb-100008
  7. 如权利要求1所述的式(I)结构的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，The compound of formula (I) structure as claimed in claim 1, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, it is characterized in that ,
    ULM选自可以和选自下组的E3连接酶结合的小分子配体部分：VHL(Von Rippel-Lindau)、CRBN(Cereblon)、MDM2(Mouse double-minute homolog2)、IAP、Keap1、HSP70、FKBP、DCAF15、DCAF16、RNF4、RNF114和AhR。ULM is selected from the small molecule ligand part that can be combined with the E3 ligase selected from the following group: VHL (Von Rippel-Lindau), CRBN (Cereblon), MDM2 (Mouse double-minute homolog2), IAP, Keap1, HSP70, FKBP , DCAF15, DCAF16, RNF4, RNF114 and AhR.
  8. 如权利要求1所述的式(I)结构的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，L选自：The compound of formula (I) structure as claimed in claim 1, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, it is characterized in that , L is selected from:
    Figure PCTCN2022142077-appb-100009
    Figure PCTCN2022142077-appb-100009
    其中：in:
    NH中的H可以独立任选地被氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、C 3-C 20环烷基、C 1-C 18烷基酰基、磺酰基取代； 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;
    R L1-R L6相同或不同，且各自独立地选自取代或未取代的下组基团：键、CH 2、C＝O、O、NH、SO、SO 2、P＝O、NHCO、NHSO 2、OCH 2、OCH 2CH 2、CH 2OCH 2、NHCH 2、NMeCH 2、NHCH 2CH 2、NMeCH 2CH 2、CH 2NHCO、NHCOCH 2、 R L1 -R L6 are the same or different, and are independently selected from the following groups of substituted or unsubstituted groups: bond, CH 2 , C=O, O, NH, SO, SO 2 , P=O, NHCO, NHSO 2. OCH 2 , OCH 2 CH 2 , CH 2 OCH 2 , NHCH 2 , NMeCH 2 , NHCH 2 CH 2 , NMeCH 2 CH 2 , CH 2 NHCO, NHCOCH 2 ,
    Figure PCTCN2022142077-appb-100010
    Figure PCTCN2022142077-appb-100010
    Figure PCTCN2022142077-appb-100011
    Figure PCTCN2022142077-appb-100011
    Figure PCTCN2022142077-appb-100012
    Figure PCTCN2022142077-appb-100012
    所述取代是指被选自下组的一个或多个基团取代：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 6-C 14芳基、5-14元杂芳基、4-20元杂环基、卤素、氧代基、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基； The 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;
    各p L1-p L6独立地选自：0、1、2、3、4、5或6。 Each p L1 -p L6 is independently selected from: 0, 1, 2, 3, 4, 5 or 6.
  9. 如权利要求1所述式(I)结构的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，The compound of formula (I) structure as claimed in claim 1, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, it is characterized in that,
    L选自取代或未取代的下组基团：
    Figure PCTCN2022142077-appb-100013
    Figure PCTCN2022142077-appb-100014
    L is selected from the following substituted or unsubstituted groups:
    Figure PCTCN2022142077-appb-100013
    Figure PCTCN2022142077-appb-100014
    且
    Figure PCTCN2022142077-appb-100015
    Figure PCTCN2022142077-appb-100016
    Figure PCTCN2022142077-appb-100017
    中的
    Figure PCTCN2022142077-appb-100018
    部分选自取代或非取代的下组基团：     and
    Figure PCTCN2022142077-appb-100015
    Figure PCTCN2022142077-appb-100016
    Figure PCTCN2022142077-appb-100017
    middle
    Figure PCTCN2022142077-appb-100018
    Some are selected from substituted or unsubstituted following groups:
    Figure PCTCN2022142077-appb-100019
    Figure PCTCN2022142077-appb-100019
    Figure PCTCN2022142077-appb-100020
    Figure PCTCN2022142077-appb-100020
    Figure PCTCN2022142077-appb-100021
    Figure PCTCN2022142077-appb-100021
    Figure PCTCN2022142077-appb-100022
    Figure PCTCN2022142077-appb-100022
    Figure PCTCN2022142077-appb-100023
    Figure PCTCN2022142077-appb-100023
    Figure PCTCN2022142077-appb-100024
    Figure PCTCN2022142077-appb-100024
    Figure PCTCN2022142077-appb-100025
    Figure PCTCN2022142077-appb-100025
    Figure PCTCN2022142077-appb-100026
    Figure PCTCN2022142077-appb-100026
    Figure PCTCN2022142077-appb-100027
    Figure PCTCN2022142077-appb-100027
    Figure PCTCN2022142077-appb-100028
    Figure PCTCN2022142077-appb-100028
    Figure PCTCN2022142077-appb-100029
    Figure PCTCN2022142077-appb-100029
    Figure PCTCN2022142077-appb-100030
    Figure PCTCN2022142077-appb-100030
    Figure PCTCN2022142077-appb-100031
    Figure PCTCN2022142077-appb-100031
    Figure PCTCN2022142077-appb-100032
    Figure PCTCN2022142077-appb-100032
    Figure PCTCN2022142077-appb-100033
    Figure PCTCN2022142077-appb-100033
    Figure PCTCN2022142077-appb-100034
    Figure PCTCN2022142077-appb-100034
    Figure PCTCN2022142077-appb-100035
    Figure PCTCN2022142077-appb-100035
    Figure PCTCN2022142077-appb-100036
    Figure PCTCN2022142077-appb-100036
    Figure PCTCN2022142077-appb-100037
    Figure PCTCN2022142077-appb-100037
    Figure PCTCN2022142077-appb-100038
    Figure PCTCN2022142077-appb-100038
    Figure PCTCN2022142077-appb-100039
    Figure PCTCN2022142077-appb-100039
    Figure PCTCN2022142077-appb-100040
    Figure PCTCN2022142077-appb-100040
    Figure PCTCN2022142077-appb-100041
    Figure PCTCN2022142077-appb-100041
    Figure PCTCN2022142077-appb-100042
    Figure PCTCN2022142077-appb-100042
    Figure PCTCN2022142077-appb-100043
    Figure PCTCN2022142077-appb-100043
    Figure PCTCN2022142077-appb-100044
    Figure PCTCN2022142077-appb-100044
    Figure PCTCN2022142077-appb-100045
    Figure PCTCN2022142077-appb-100045
    Figure PCTCN2022142077-appb-100046
    Figure PCTCN2022142077-appb-100046
    Figure PCTCN2022142077-appb-100047
    Figure PCTCN2022142077-appb-100047
    Figure PCTCN2022142077-appb-100048
    Figure PCTCN2022142077-appb-100048
    Figure PCTCN2022142077-appb-100049
    Figure PCTCN2022142077-appb-100049
    Figure PCTCN2022142077-appb-100050
    Figure PCTCN2022142077-appb-100050
    Figure PCTCN2022142077-appb-100051
    Figure PCTCN2022142077-appb-100051
    Figure PCTCN2022142077-appb-100052
    Figure PCTCN2022142077-appb-100052
    Figure PCTCN2022142077-appb-100053
    Figure PCTCN2022142077-appb-100053
    Figure PCTCN2022142077-appb-100054
    Figure PCTCN2022142077-appb-100054
    Figure PCTCN2022142077-appb-100055
    Figure PCTCN2022142077-appb-100055
    Figure PCTCN2022142077-appb-100056
    Figure PCTCN2022142077-appb-100056
    Figure PCTCN2022142077-appb-100057
    Figure PCTCN2022142077-appb-100057
    各p L1-p L6独立地选自：0、1、2、3、4、5或6； each p L1 -p L6 is independently selected from: 0, 1, 2, 3, 4, 5 or 6;
    各式中，CH 2、CH中的H可以独立任选地被取代； In each formula, H in CH 2 and CH can be independently and optionally substituted;
    其中，所述取代是指被选自下组的一个或多个基团取代：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 6-C 14芳基、5-14元杂芳基、4-20元杂环基、卤素、氧代基、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基；NH可以独立任选地被氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、C 3-C 20环烷基、C 1-C 18烷基酰基、磺酰基取代；且 Wherein, the 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, halogenated C 1 - C 18 alkyl hydroxy, C 3 -C 20 cycloalkyl, C 1 -C 18 alkyl acyl, sulfonyl substituted; and
    L中，各R L1-R L6基团中相邻的两个基团，可各自独立地通过C、N、O或S原子等彼此连接。 In L, 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.
  10. 如权利要求1所述的式(I)结构的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，
    Figure PCTCN2022142077-appb-100058
    选自取代或未取代的选自下组的基团：     The compound of formula (I) structure as claimed in claim 1, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, it is characterized in that ,
    Figure PCTCN2022142077-appb-100058
    A substituted or unsubstituted group selected from the group consisting of:
    Figure PCTCN2022142077-appb-100059
    Figure PCTCN2022142077-appb-100059
    Figure PCTCN2022142077-appb-100060
    Figure PCTCN2022142077-appb-100060
    Figure PCTCN2022142077-appb-100061
    Figure PCTCN2022142077-appb-100061
    Figure PCTCN2022142077-appb-100062
    Figure PCTCN2022142077-appb-100062
    Figure PCTCN2022142077-appb-100063
    Figure PCTCN2022142077-appb-100063
    各式中，CH 2、CH和NH中的H可以独立任选地被取代；且所述取代是指被选自下组的一个或多个基团取代：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 6-C 14芳基、5-14元杂芳基、4-20元杂环基、卤素、氧代基、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基；NH可以独立任选地被氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、C 3-C 20环烷基、C 1-C 18烷基酰基、磺酰基取代。 In each formula, 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 alkyl, halogenated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkylhydroxyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkylacyl, sulfonyl substitution.
  11. 如权利要求1所述的式(I)结构的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，PTM选自：The compound of formula (I) structure as claimed in claim 1, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, it is characterized in that , PTM selected from:
    Figure PCTCN2022142077-appb-100064
    Figure PCTCN2022142077-appb-100064
    Figure PCTCN2022142077-appb-100065
    Figure PCTCN2022142077-appb-100065
    Figure PCTCN2022142077-appb-100066
    Figure PCTCN2022142077-appb-100066
    且同时
    Figure PCTCN2022142077-appb-100067
    选自取代或未取代的选自下组的基团：     and at the same time
    Figure PCTCN2022142077-appb-100067
    A substituted or unsubstituted group selected from the group consisting of:
    Figure PCTCN2022142077-appb-100068
    Figure PCTCN2022142077-appb-100068
    Figure PCTCN2022142077-appb-100069
    Figure PCTCN2022142077-appb-100069
    Figure PCTCN2022142077-appb-100070
    Figure PCTCN2022142077-appb-100070
    Figure PCTCN2022142077-appb-100071
    Figure PCTCN2022142077-appb-100071
    Figure PCTCN2022142077-appb-100072
    Figure PCTCN2022142077-appb-100072
    各式中，CH 2、CH和NH中的H可以独立任选地被取代；且所述取代是指被选自下组的一个或多个基团取代：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 6-C 14芳基、5-14元杂芳基、4-20元杂环基、卤素、氧代基、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基；NH可以独立任选地被氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、C 3-C 20环烷基、C 1-C 18烷基酰基、磺酰基取代。 In each formula, 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 alkyl, halogenated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkylhydroxyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkylacyl, sulfonyl substitution.
  12. 一种药物组合物，其特征在于，包含一种或多种如权利要求1-11中任一项所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药；和药学上可接受的载体。A pharmaceutical composition, characterized in that it comprises one or more compounds according to any one of claims 1-11, stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs; and pharmaceutically acceptable carriers.
  13. 一种如权利要求1-11任一项所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，或包含其的药物组合物的用途，其特征在于，用于制备预防和/或治疗与KRAS G12D活性或表达量相关的疾病的药物组合物。 A compound as claimed in any one of claims 1-11, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, or comprising The use of its pharmaceutical composition is characterized in that it is used to prepare a pharmaceutical composition for preventing and/or treating diseases related to KRAS G12D activity or expression.
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