Preparation and use of positron emission tomography probe targeting kras g12d mutation

Abstract

The present disclosure relates to the field of pharmaceuticals, and in particular to a compound represented by formula I or a pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated compound, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite, or prodrug thereof. The present disclosure further relates to a compound represented by formula II, a pharmaceutical composition, and pharmaceutical uses. The compounds of the present disclosure can be used for diagnosing and / or treating tumors.

Description

Preparation and Applications of Positron Emission Tomography Probes Targeting KRAS G12D Mutations

[0001] This disclosure is based on and claims priority to Chinese Patent Application No. 2025103822453, filed on March 28, 2025, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0002] This disclosure pertains to the pharmaceutical field, specifically relating to a positron emission tomography probe targeting KRAS G12D mutations, as well as the preparation method and pharmaceutical applications of the probe. Background Technology

[0003] RAS is one of the most common oncogenes in cancer patients. Tumor cells rely on mutations in the Kirsten rat sarcoma viral oncogene homolog (KRAS) to maintain the activation of downstream signaling pathways, promoting tumor development and progression. Compared to wild-type patients, KRAS-mutant patients have shorter survival rates. For conventional chemotherapy, KRAS mutations negatively impact overall survival, progression-free survival, and disease control rates. Moreover, compared to wild-type patients, these patients are more prone to liver and brain metastases. KRAS mutations can significantly reduce or even completely eliminate the response of lung cancer patients to EGFR-TKI treatment; therefore, KRAS mutation itself is an important biomarker for predicting treatment efficacy and poor prognosis. KRAS mutations are the most frequent, with the most common KRASG12D accounting for the following proportions of KRAS mutations in various major cancers: non-small cell lung cancer (17%), pancreatic ductal adenocarcinoma (46%), and colorectal cancer (46%). Because tumor KRAS mutant proteins exhibit high spatial and temporal heterogeneity, invasive biopsy, limited by the puncture site, cannot accurately reflect the heterogeneity of KRAS mutations. Circulating tumor DNA testing suffers from excessively low sensitivity; neither method fully meets the goals of precision medicine. Therefore, a non-invasive method is urgently needed to detect the types and expression levels of KRAS mutations.

[0004] Positron emission tomography (PET) can non-invasively determine the type and expression level of KRAS mutations. PET imaging with specific KRAS G12D probes allows for precise grouping in clinical trials of these anticancer drugs. As an important aspect of precision medicine, specific KRAS G12D PET probes introduce molecular imaging probes into traditional imaging modalities, enabling non-invasive, real-time, and dynamic quantitative analysis of KRAS mutant protein expression levels in tumor sites. This provides accurate diagnosis, staging, classification, personalized treatment guidance, and efficacy monitoring for KRAS G12D mutant tumors. Summary of the Invention

[0005] One of the purposes of this disclosure is to provide a compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated compound, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, which can be used for the diagnosis and / or treatment of tumors, particularly for the diagnosis and / or treatment of KRAS G12D mutant tumors.

[0006] Another object of this disclosure is to provide a pharmaceutical composition comprising the above-described compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated compound, polymorph, solvate, N-oxide, isotope-labeled compound or prodrug thereof, which may be used for the diagnosis and / or treatment of tumors, particularly for the diagnosis and / or treatment of KRAS G12D mutant tumors.

[0007] Another object of this disclosure is to provide the pharmaceutical use of the above-described compounds or their pharmaceutically acceptable salts, stereoisomers, tautomers, deuterated compounds, polymorphs, solvates, N-oxides, isotopically labeled compounds or prodrugs or pharmaceutical compositions thereof.

[0008] To achieve the above objectives, the first aspect of this disclosure provides a compound of Formula I or a pharmaceutically acceptable salt thereof, a stereoisomer, a tautomer, a deuterated compound, a polymorph, a solvate, an N-oxide, an isotope-labeled compound, a metabolite, or a prodrug.

[0009] Where A is selected from

[0010] R 4 Selected from halogens, C1-C6 alkyl groups, halo-C1-C6 alkyl groups, C2-C6 alkenyl groups, C2-C6 alkynyl groups, and -(CH2). m1 -5-10 heteroaryl-(CH2) m2 R a and -(CH2) m3 -5-10 aryl-O-(CH2) m4 R a ;

[0011] R 2 Selected from H and -(CH2) m5 R a ;

[0012] The R 4 and the R 2 At least one of them includes R a ;

[0013] The -(CH2)m1 -5-10 heteroaryl-(CH2) m2 R a The -(CH2) m3 -5-10 aryl-O-(CH2) m4 R a and the aforementioned -(CH2) m5 R a R in a Each group is independently selected from a radionuclide or a group formed by chelating a radionuclide with a chelating agent;

[0014] R 1 Selected from halogens, C1-C6 alkyl groups, halo-C1-C6 alkyl groups, C2-C6 alkenyl groups, and C2-C6 alkynyl groups;

[0015] R 3 Selected from 5-10 membered heterocyclic groups that are unsubstituted or substituted with one or more C1-C6 alkyl groups;

[0016] X1 and X2 are each independently selected from halogens;

[0017] n is independently selected from 0, 1, 2, 3, 4, 5, and 6;

[0018] m1, m2, m3, m4 and m5 are each independently selected from 0, 1, 2, 3, 4, 5 and 6.

[0019] In any embodiment of the first aspect, the types of chelating agents that chelate with radionuclides are well known to those skilled in the art, including but not limited to HYNIC, DOTA, and NOTA.

[0020] In some embodiments of the first aspect, the chelating agent generally chelates with the radionuclide through coordinating atoms (e.g., O, S, etc.).

[0021] In some embodiments of the first aspect, the group formed by chelating a radionuclide with a chelating agent is a group formed by the loss of one or more atoms after the radionuclide is chelated with the chelating agent.

[0022] In any embodiment of the first aspect, the compound of formula I includes any one of the following:

[0023] (1)R 4 Selected from halogens, C1-C4 alkyl groups, halo-C1-C4 alkyl groups, C2-C4 alkenyl groups, C2-C4 alkynyl groups, and -(CH2). m1 -5-8 quinone heteroaryl-(CH2) m2 R a and -(CH2) m3 -5-8-aryl-O-(CH2) m4 Ra m1, m2, m3, and m4 are each independently selected from 1, 2, 3, and 4;

[0024] (2)R 4 Selected from halogens and -(CH2) m1 -5-8 quinone heteroaryl-(CH2) m2 R a m1 and m2 are each independently selected from 1, 2, and 3;

[0025] (3)R 4 Selected from halogens and -(CH2) m1 -5-6 nucleotide heteroaryl-(CH2) m2 R a Among them, the 5-6 member heteroaryl group is selected from m1 and m2 are each independently selected from 1 and 2;

[0026] (4)R 4 Selected from F and n is 1;

[0027] (5) A is selected from

[0028] In any embodiment of the first aspect, the compound of formula I includes any one of the following:

[0029] (1)R 2 Selected from H and -(CH2) m5 R a m5 is selected from 1, 2, 3, and 4;

[0030] (2)R 2 Selected from H and -(CH2)2R a .

[0031] In any embodiment of the first aspect, the compound of formula I includes any one of the following:

[0032] (1) The radionuclides are selected from 18 F, 19 F, 51 Cr 59 Fe、 67 Ga、 68 Ga、 81m Kr、 111 In、 123 I, 124 I, 125 I, 131 I, 133 Xe, 201 Tl、 11 C 13 N、 15O、 61 Cu、 62 Cu、 64 Cu、 67 Cu、 82 Rb、 89 Zr、 211 At、 212 Pd, 212 Bi、 213 Bi、 223 Ra、 224 Ra、 225 Ac、 227 Th、 32 P, 89 Sr、 86 Y、 90 Y、 153 Sm、 161 Tb, 166 Ho、 186 Re、 188 Re、 212 Pb, 43 Sc、 44 Sc、 52 Mn, 152 Tb and 155 Tb;

[0033] (2) The radionuclides are independently selected from 18 F and 19 F.

[0034] In any embodiment of the first aspect, the compound of formula I includes any one of the following:

[0035] (1)R 3 Selected from 5-8 membered heterocyclic groups that are unsubstituted or substituted with one or more C1-C6 alkyl groups;

[0036] (2)R 3 Selected from 5-8 membered heterocyclic groups that are unsubstituted or substituted with one or more C1-C4 alkyl groups; optionally, the 5-8 membered heterocyclic group is selected from...

[0037] (3)R 3 Selected from in, It is either unsubstituted or substituted independently by one or more of the following groups: methyl, ethyl, n-propyl, isopropyl;

[0038] (4)R 3 Selected from

[0039] (5)R3 Selected from

[0040] In any embodiment of the first aspect, the compound of formula I includes any one of the following:

[0041] (1)R 1 Selected from halogens, C1-C4 alkyl groups, halo-C1-C4 alkyl groups, and C2-C4 alkynyl groups;

[0042] (2)R 1 Selected from F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl,

[0043] (3)R 1 Selected from C1-C4 alkyl and C2-C4 alkynyl groups;

[0044] (4)R 1 Selected from ethyl,

[0045] (5)R 1 Selected from ethyl and

[0046] In any embodiment of the first aspect, the compound of formula I comprises one or both of the following:

[0047] 1) X1 and X2 are each independently selected from F, Cl, Br and I; optionally, X1 and X2 are F;

[0048] 2) n is selected from 1 and 2; alternatively, n is 1.

[0049] In any embodiment of the first aspect, the structure of the compound is as shown in Formula I-1.

[0050] Among them, R 4 Selected from halogens, C1-C6 alkyl groups, halo-C1-C6 alkyl groups, C2-C6 alkenyl groups, and C2-C6 alkynyl groups;

[0051] R 2 Selected from -(CH2) m5 R a ;

[0052] R a R 1 R 3 The definitions of X1, X2, n, and m5 are as described above.

[0053] In any embodiment of the first aspect, the compound of formula I-1 includes any one of the following:

[0054] (1)R 4 Selected from halogens, C1-C4 alkyl groups, halo-C1-C4 alkyl groups, and C2-C4 alkynyl groups; R 2 Selected from -(CH2) m5 R a m5 is selected from 1, 2, 3, and 4;

[0055] (2)R 4 Selected from halogens; R 2 Selected from -(CH2) m5 R a m5 is selected from 1, 2, and 3;

[0056] (3)R 4 Selected from F, Cl, Br and I; R 2 Selected from -(CH2)2R a .

[0057] In any embodiment of the first aspect, the structure of the compound is as shown in Formula I-2.

[0058] Among them, R 4 Selected from -(CH2) m1 -5-10 heteroaryl-(CH2) m2 R a and -(CH2) m3 -5-10 aryl-O-(CH2) m4 R a ;

[0059] R 2 For H;

[0060] R a R 1 R 3 The definitions of X1, X2, m1, m2, m3, m4 and n are as described above.

[0061] In any embodiment of the first aspect, the compound of formula I-2 includes any one of the following:

[0062] (1)R 4 Selected from -(CH2) m1 -5-8 quinone heteroaryl-(CH2) m2 R a and -(CH2) m3 -5-8-aryl-O-(CH2) m4 R a m1, m2, m3, and m4 are each independently selected from 1, 2, 3, and 4;

[0063] (2)R 4Selected from -(CH2) m1 -5-8 quinone heteroaryl-(CH2) m2 R a m1 and m2 are each independently selected from 1, 2, and 3;

[0064] (3)R 4 Selected from -(CH2) m1 -5-6 nucleotide heteroaryl-(CH2) m2 R a Among them, the 5-6 member heteroaryl group is selected from m1 and m2 are each independently selected from 1 and 2;

[0065] (4)R 4 Selected from

[0066] In any embodiment of the first aspect, the compound is selected from:

[0067] The second aspect of this disclosure provides compounds of Formula II or pharmaceutically acceptable salts thereof, stereoisomers, tautomers, deuterated compounds, polymorphs, solvates, N-oxides, or isotope-labeled compounds.

[0068] Where A' is selected from

[0069] R 6 Selected from halogens and C2-C6 alkynyl groups;

[0070] R 5 Selected from H and -(CH2) m6 -p-Toluenesulfonyloxy;

[0071] Each 's' is independently selected from 0, 1, 2, 3, 4, 5, and 6;

[0072] m6 is selected from 0, 1, 2, 3, 4, 5, and 6;

[0073] X 1 X 2 R 1 and R 3 As described in the first aspect of this disclosure.

[0074] In any embodiment of the second aspect, the compound of formula II comprises any one of the following:

[0075] 1)R 6 Selected from halogens, F and R are optional. 5 Selected from -(CH2) m6 -p-Toluenesulfonyloxy; m6 is selected from 1, 2, 3 and 4, and can be 1 or 2;

[0076] 2)R 6 Selected from C2-C4 alkynyl groups, which can be chosen as... R 5 For H.

[0077] In any embodiment of the second aspect, the compound of formula II is selected from:

[0078] A third aspect of this disclosure provides a pharmaceutical composition comprising a compound of the first aspect of this disclosure or a pharmaceutically acceptable salt thereof, a stereoisomer, a tautomer, a deuterated compound, a polymorph, a solvate, an N-oxide, an isotope-labeled compound, a metabolite or a prodrug, and a pharmaceutical excipient.

[0079] In any embodiment of the third aspect, the pharmaceutical composition further includes a pharmaceutically active ingredient for treating tumors.

[0080] In any embodiment of the third aspect, the pharmaceutical composition is a pharmaceutical composition for diagnosing and / or treating tumors;

[0081] Optionally, the tumor is a KRAS G12D mutant tumor; more preferably, the KRAS G12D mutant tumor includes one or more of the following: lung cancer, pancreatic cancer, colon cancer, rectal cancer, melanoma, multiple myeloma, urothelial carcinoma of the bladder, gastric cancer, breast cancer, bladder cancer, cervical cancer, ovarian cancer, uterine cancer, non-small cell lung cancer, brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal carcinoma, pharyngeal cancer, oral cancer, salivary gland cancer, esophageal cancer, liver cancer, kidney cancer, pancreatic cancer, gallbladder cancer, bile duct cancer, small bowel cancer, gastrointestinal stromal tumor, urothelial carcinoma, urethral cancer, vaginal cancer, fallopian tube cancer, testicular cancer, prostate cancer, hemangioma, leukemia, lymphoma, myeloma, skin cancer, lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma, and glioblastoma.

[0082] Optionally, the pharmaceutical composition is an imaging agent, and more preferably a PET imaging agent or a SPECT imaging agent.

[0083] The fourth aspect of this disclosure provides a kit for diagnosing and / or treating tumors, comprising a compound of the first aspect of this disclosure or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, deuterated compound, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug, or a pharmaceutical composition of the third aspect of this disclosure, and adjuvants.

[0084] Optionally, the tumor is a KRAS G12D mutant tumor; more preferably, the KRAS G12D mutant tumor includes one or more of the following: lung cancer, pancreatic cancer, colon cancer, rectal cancer, melanoma, multiple myeloma, urothelial carcinoma of the bladder, gastric cancer, breast cancer, bladder cancer, cervical cancer, ovarian cancer, uterine cancer, non-small cell lung cancer, brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal carcinoma, pharyngeal cancer, oral cancer, salivary gland cancer, esophageal cancer, liver cancer, kidney cancer, pancreatic cancer, gallbladder cancer, bile duct cancer, small bowel cancer, gastrointestinal stromal tumor, urothelial carcinoma, urethral cancer, vaginal cancer, fallopian tube cancer, testicular cancer, prostate cancer, hemangioma, leukemia, lymphoma, myeloma, skin cancer, lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma, and glioblastoma.

[0085] Optionally, the diagnosis is made by imaging, and more preferably by PET or SPECT imaging.

[0086] The fifth aspect of this disclosure provides a method for diagnosing and / or treating tumors, comprising the step of administering to a subject in need an effective amount of a compound of the first aspect of this disclosure or a pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated compound, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug or an effective amount of a pharmaceutical composition of the third aspect of this disclosure;

[0087] Optionally, the tumor is a KRAS G12D mutant tumor; more preferably, the KRAS G12D mutant tumor includes one or more of the following: lung cancer, pancreatic cancer, colon cancer, rectal cancer, melanoma, multiple myeloma, urothelial carcinoma of the bladder, gastric cancer, breast cancer, bladder cancer, cervical cancer, ovarian cancer, uterine cancer, non-small cell lung cancer, brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal carcinoma, pharyngeal cancer, oral cancer, salivary gland cancer, esophageal cancer, liver cancer, kidney cancer, pancreatic cancer, gallbladder cancer, bile duct cancer, small bowel cancer, gastrointestinal stromal tumor, urothelial carcinoma, urethral cancer, vaginal cancer, fallopian tube cancer, testicular cancer, prostate cancer, hemangioma, leukemia, lymphoma, myeloma, skin cancer, lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma, and glioblastoma.

[0088] Optionally, the diagnosis is made by imaging, and more preferably by PET or SPECT imaging.

[0089] The sixth aspect of this disclosure provides the use of the compound of the first aspect of this disclosure or a pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated compound, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug, or pharmaceutical composition of the third aspect of this disclosure in the preparation of a medicament for the diagnosis and / or treatment of tumors.

[0090] Optionally, the tumor is a KRAS G12D mutant tumor; more preferably, the KRAS G12D mutant tumor includes one or more of the following: lung cancer, pancreatic cancer, colon cancer, rectal cancer, melanoma, multiple myeloma, urothelial carcinoma of the bladder, gastric cancer, breast cancer, bladder cancer, cervical cancer, ovarian cancer, uterine cancer, non-small cell lung cancer, brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal carcinoma, pharyngeal cancer, oral cancer, salivary gland cancer, esophageal cancer, liver cancer, kidney cancer, pancreatic cancer, gallbladder cancer, bile duct cancer, small bowel cancer, gastrointestinal stromal tumor, urothelial carcinoma, urethral cancer, vaginal cancer, fallopian tube cancer, testicular cancer, prostate cancer, hemangioma, leukemia, lymphoma, myeloma, skin cancer, lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma, and glioblastoma.

[0091] Optionally, the diagnosis is made by imaging, and more preferably by PET or SPECT imaging.

[0092] The seventh aspect of this disclosure provides a compound of the first aspect of this disclosure or a pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated compound, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug, or a pharmaceutical composition of the third aspect of this disclosure for the diagnosis and / or treatment of tumors.

[0093] Optionally, the tumor is a KRAS G12D mutant tumor; more preferably, the KRAS G12D mutant tumor includes one or more of the following: lung cancer, pancreatic cancer, colon cancer, rectal cancer, melanoma, multiple myeloma, urothelial carcinoma of the bladder, gastric cancer, breast cancer, bladder cancer, cervical cancer, ovarian cancer, uterine cancer, non-small cell lung cancer, brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal carcinoma, pharyngeal cancer, oral cancer, salivary gland cancer, esophageal cancer, liver cancer, kidney cancer, pancreatic cancer, gallbladder cancer, bile duct cancer, small bowel cancer, gastrointestinal stromal tumor, urothelial carcinoma, urethral cancer, vaginal cancer, fallopian tube cancer, testicular cancer, prostate cancer, hemangioma, leukemia, lymphoma, myeloma, skin cancer, lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma, and glioblastoma.

[0094] Optionally, the diagnosis is made by imaging, and more preferably by PET or SPECT imaging.

[0095] The eighth aspect of this disclosure provides the use of the compound of Formula III or a pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated compound, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug in the preparation of a radiopharmaceutical.

[0096] Where M is selected from

[0097] R 7 and R 11 Each is independently selected from H, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxy-C1-C6 alkyl, hydroxy-halo-C1-C6 alkyl, methanesulfonyl-C1-C6 alkylene, C2-C6 alkynyl, 5-10 aryl-C1-C6 alkylene, 5-10 heteroaryl-C1-C6 alkylene, and C3-C6 cycloalkyl-C1-C6 alkylene; wherein, the 5-10 aryl-C1-C6 alkylene contains 5-10 members... The aryl group, the 5-10 heteroaryl group in the 5-10 heteroaryl C1-C6 alkylene group, and the C3-C6 cycloalkyl group in the C3-C6 cycloalkyl C1-C6 alkylene group are each optionally substituted independently by one or more of the following substituents: halogen, amino, cyano, hydroxyl, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C1-C6 alkoxy-C1-C6 alkylene group;

[0098] R 8 Selected from H, C1-C6 alkyl, and halo-C1-C6 alkyl;

[0099] R 9 Selected from 5-10 membered heterocyclic groups, wherein the 5-10 membered heterocyclic group is optionally substituted by one or more of the following substituents: C1-C6 alkyl, hydroxyl, hydroxyC1-C6 alkyl, haloC1-C6 alkyl, oxo group;

[0100] R 10 Selected from H, halogens, C1-C6 alkyl groups and halogenated C1-C6 alkyl groups;

[0101] R 12 and R 13 Each is independently selected from H, halogen, hydroxyl, C1-C6 alkyl, and C1-C6 alkylsulfonyl;

[0102] X 3 and X 4 Each is independently selected from H and halogens;

[0103] t is independently selected from 0, 1, 2, 3, 4, 5 and 6.

[0104] In any embodiment of aspect eight, the compound of formula III comprises any one of the following:

[0105] 1)R 7 and R 11Each is independently selected from H, halogen, C1-C4 alkyl, halo-C1-C4 alkyl, hydroxy-C1-C4 alkyl, hydroxy-halo-C1-C4 alkyl, methanesulfonyl-C1-C4 alkylene, C2-C4 alkynyl, 5-8 aryl-C1-C4 alkylene, 5-8 heteroaryl-C1-C4 alkylene, and C3-C5 cycloalkyl-C1-C4 alkylene; wherein, the 5-8 aryl-C1-C4 alkylene is selected from H, halogen, C1-C4 alkylene, 5-8 heteroaryl-C1-C4 alkylene. The 5-8-membered heteroaryl group in the 5-8-membered heteroaryl C1-C4 alkylene group and the C3-C5 cycloalkyl group in the C3-C5 cycloalkyl C1-C4 alkylene group are each independently optionally substituted by one or more of the following substituents: halogen, amino, cyano, hydroxyl, C1-C4 alkyl, halo-C1-C4 alkyl, C1-C4 alkoxy, halo-C1-C4 alkoxy, C1-C4 alkoxy-C1-C4 alkylene group;

[0106] 2)R 7 and R 11 Each is independently selected from halogens, C1-C4 alkyl groups, halo-C1-C4 alkyl groups, C2-C4 alkynyl groups, 5-8-membered aryl C1-C4 alkylene groups, and 5-8-membered heteroaryl C1-C4 alkylene groups; wherein the 5-8-membered aryl group in the 5-8-membered aryl C1-C4 alkylene group and the 5-8-membered heteroaryl group in the 5-8-membered heteroaryl C1-C4 alkylene group are each independently optionally substituted by one or more of the following substituents: halogens, C1-C4 alkyl groups, halo-C1-C4 alkyl groups, C1-C4 alkoxy groups, and halo-C1-C4 alkoxy groups; optionally, the 5-8-membered aryl group is phenyl; optionally, the 5-8-membered heteroaryl group is selected from...

[0107] 3)R 7 and R 11 Each is independently selected from halogens, methyl, ethyl, n-propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl. Acetyl, propargyl, benzyl, phenethyl and Among them, benzyl, phenylethyl and Each can be independently substituted by one or more of the following substituents: halogen, halo-C1-C4 alkyl, halo-C1-C4 alkoxy;

[0108] 4)R 7 and R 11 Each is independently selected from F, Cl, Br, I, At, methyl, ethyl, n-propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl. Acetylene group,

[0109] 5)R 7 and R 11 Each is independently selected from F and ethyl.

[0110] In any embodiment of aspect eight, the compound of formula III comprises any one of the following:

[0111] 1)R 8 Selected from H, C1-C4 alkyl, and halo-C1-C4 alkyl;

[0112] 2)R 8 Selected from H, C1-C4 alkyl groups and C1-C4 alkyl groups substituted with one or more F groups;

[0113] 3)R 8 Selected from H, monofluoromethyl, difluoromethyl, trifluoromethyl,

[0114] 4)R 8 Selected from H and

[0115] In any embodiment of aspect eight, the compound of formula III comprises any one of the following:

[0116] 1)R 9 The group is selected from 5-8 membered heterocyclic groups, wherein the 5-8 membered heterocyclic group is optionally substituted by one or more of the following substituents: C1-C4 alkyl, hydroxyl, hydroxyC1-C4 alkyl, haloC1-C4 alkyl, oxoyl; optionally, the 5-8 membered heterocyclic group is selected from

[0117] 2)R 9 Selected from 5-8 membered heterocyclic groups, wherein the 5-8 membered heterocyclic group is optionally substituted by one or more of the following substituents: C1-C4 alkyl, halo-C1-C4 alkyl; optionally, the 5-8 membered heterocyclic group is selected from...

[0118] 3)R 9 Selected from in, It is either unsubstituted or substituted independently by one or more of the following groups: methyl, ethyl, n-propyl, isopropyl;

[0119] 4)R 9 Selected from

[0120] In any embodiment of aspect eight, the compound of formula III comprises any one of the following:

[0121] 1)R 10 Selected from H, halogens, C1-C4 alkyl groups and halo-C1-C4 alkyl groups;

[0122] 2)R 10 Selected from H, halogens, and C1-C4 alkyl groups;

[0123] 3)R 10 For H.

[0124] In any embodiment of aspect eight, the compound of formula III comprises any one of the following:

[0125] 1)R 12 and R 13 Each is independently selected from H, halogen, hydroxyl, C1-C4 alkyl, and C1-C4 alkylsulfonyl groups;

[0126] 2)R 12 and R 13 Each is independently selected from H, halogens, and C1-C4 alkyl groups;

[0127] 3)R 12 and R 13 For H.

[0128] In any embodiment of aspect eight, the compound of formula III comprises any one or two of the following:

[0129] 1)X 3 and X 4 Each is independently selected from H, F, Cl, Br, and I; optionally, X 3 and X 4 For F;

[0130] 2) t is independently selected from 1, 2, 3 and 4; optionally, t is 1.

[0131] In any embodiment of aspect eight, the compound of formula III is selected from:

[0132] In any embodiment of the eighth aspect, the radiopharmaceutical is a PET imaging agent or a SPECT imaging agent.

[0133] Unless otherwise specifically defined or explained, the terms used herein shall be interpreted as follows:

[0134] The term "halogen" includes F, Cl, Br, I, At, etc.

[0135] The term "alkyl" is defined as a linear or branched saturated aliphatic hydrocarbon. In some embodiments, the alkyl group has, for example, 1 to 6 carbon atoms or 1 to 4 carbon atoms. As used herein, the term "C1-C6 alkyl" refers to a linear or branched group having 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or n-hexyl), and the term "C1-C4 alkyl" refers to a linear or branched aliphatic hydrocarbon chain having 1 to 4 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl).

[0136] The term "halogenated alkyl" is an alkyl group that is optionally substituted with one or more (such as 1 to 3) halogens, as defined above; for example, halo-C1-C6 alkyl, halo-C1-C4 alkyl, specific examples include CH2F, CHF2, CF3, CCl3, C2F5, C2Cl5, CH2CF3, CH2Cl or -CH2CH2CF3, etc.

[0137] The term "hydroxyalkyl" means that an alkyl group is optionally replaced by one or more hydroxyl groups, and the definition of alkyl is as described above; for example, hydroxyC1-C6 alkyl, hydroxyC1-C4 alkyl; specific examples include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, etc.

[0138] The term "hydroxy-haloalkyl" means that a haloalkyl group is optionally replaced by one or more hydroxyl groups, as defined above; for example, hydroxy-haloC1-C6 alkyl, hydroxy-haloC1-C4 alkyl; specific examples include monohydroxy-fluoromethyl, monohydroxy-chloromethyl, 1-hydroxy-1-fluoroethyl, 2-hydroxy-1-chloroethyl, etc.

[0139] The term "alkylene" refers to a straight or branched divalent hydrocarbon chain obtained by removing a hydrogen atom from an alkyl group, as defined above. In some embodiments, the alkylene is -CH2-, -CH2CH2-, -CH2CH2CH2-, or -CH2CH(CH3)CH2-.

[0140] The term "methanesulfonyl alkylene" is CH3SO2-alkylene-, where alkylene is defined as described above. Examples include methanesulfonyl C1-C6 alkylene (CH3SO2-C1-C6 alkylene-), methanesulfonyl C1-C4 alkylene (CH3SO2-C1-C4 alkylene-), methanesulfonyl C1-C2 alkylene (CH3SO2-C1-C2 alkylene-), etc.

[0141] The term "alkylsulfonyl" is alkyl-SO2-, where alkyl is defined as described above. Examples include C1-C6 alkylsulfonyl, C1-C4 alkylsulfonyl, C1-C3 alkylsulfonyl, and C1-C2 alkylsulfonyl. Specific examples include methanesulfonyl, ethanesulfonyl, etc.

[0142] The term "alkenyl" refers to a straight-chain or branched aliphatic hydrocarbon group having one or more carbon-carbon double bonds. For example, the term "C2-C6 alkenyl" as used herein refers to an alkenyl group having 2-6 carbon atoms and one, two, or three carbon-carbon double bonds. Other examples include C2-C4 alkenyl, C2-C3 alkenyl, etc. Specific examples include vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, etc.

[0143] The term "alkynyl" refers to a straight-chain or branched aliphatic hydrocarbon group having one or more carbon-carbon triple bonds. For example, the term "C2-C6 alkynyl" as used herein refers to an alkynyl group having 2-6 carbon atoms and one, two, or three carbon-carbon triple bonds. Other examples include C2-C4 alkynyl, C2-C3 alkynyl, etc. Specific examples include ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, 3-butynyl, etc.

[0144] The term "aryl" refers to a monocyclic aromatic group consisting of a single carbon atom or a fused polycyclic aromatic group having conjugated π electrons. As used herein, "5-10 aryl" means an aryl group containing 5 to 10 carbon atoms, and "5-8 aryl" means an aryl group containing 5 to 8 carbon atoms, including phenyl, naphthyl, etc.

[0145] The term "arylene" refers to a divalent group formed by removing one hydrogen atom from an aryl group, where the definition of "aryl" is as described above. Examples include 5-10-membered arylene groups and 5-8-membered arylene groups, with specific examples including 1,4-phenylene, 1,3-phenylene, and 1,6-naphthylene.

[0146] The term "arylalkylene" refers to aryl-alkylene-, where "aryl" and "alkylene" are defined as described above. Examples include 5-10-membered aryl C1-C6 alkylene, 5-8-membered aryl C1-C6 alkylene, 5-8-membered aryl C1-C4 alkylene, 5-6-membered aryl C1-C4 alkylene, and 5-6-membered aryl C1-C2 alkylene; specific examples include phenylmethylene, 1-phenyl-1,2-ethylene, 2-phenyl-1,1-ethylene, 1-phenyl-1,3-propylene, and 2-phenyl-1,3-propylene.

[0147] The term "heteroaryl" refers to a monocyclic or polycyclic aromatic monovalent group containing one or more identical or different heteroatoms. As used herein, "5-10-membered heteroaryl" means a heteroaryl containing 5-10 ring atoms, such as 5-6, 7, 8, 9, or 10 ring atoms, e.g., 5-8-membered heteroaryl, 6-8-membered heteroaryl, 6-10-membered heteroaryl, 5-6-membered heteroaryl, etc., where the heteroatoms can be oxygen, nitrogen, or sulfur. It can also be a benzofused heteroaryl. Heteroaryl can include "nitrogen-containing heteroaryl," "oxygen-containing heteroaryl," and "sulfur-containing heteroaryl," and can also include heteroaryl groups containing multiple heteroatoms selected from oxygen, nitrogen, and sulfur. Examples of the aforementioned heteroaryl groups include, but are not limited to, thiophene, furanyl, pyrrole, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, etc., or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., as well as 5-10 membered cyclic groups composed of these groups or benzo[a] derivatives of these groups.

[0148] The term "heteroaryl" refers to a divalent group formed by removing a hydrogen atom from a heteroaryl group, where the definition of "heteroaryl" is as described above. Examples include 5-8-membered heteroaryl, 6-8-membered heteroaryl, 6-10-membered heteroaryl, and 5-6-membered heteroaryl. Examples include, but are not limited to, thienylylene, furanyl, etc. Isooxazolyl, Isothiazolyl, Isooxazolyl, Isothiazolyl wait.

[0149] The term "heteroaryl alkylene" refers to heteroaryl-alkylene-, where "heteroaryl" and "alkylene" are defined as described above. Examples include 5-10-membered heteroaryl-C1-C6 alkylene-, 5-8-membered heteroaryl-C1-C6 alkylene-, 5-8-membered heteroaryl-C1-C4 alkylene-, 5-6-membered heteroaryl-C1-C4 alkylene-, and 5-6-membered heteroaryl-C1-C2 alkylene-. Specific examples include...

[0150] The term "heterocyclic group" refers to an aliphatic monocyclic or polycyclic (e.g., fused, spirocyclic, or bridged heterocyclic) group having two or more (e.g., 3, 4, 5, 6, 7, 8, or 9) carbon atoms and one or more (e.g., 1, 2, 3, or 4) heteroatoms, wherein the heteroatoms include, but are not limited to, oxygen, nitrogen, and sulfur atoms, such as 5-10 membered heterocyclic groups and 5-8 membered heterocyclic groups. Heterocyclic groups include saturated heterocyclic groups and partially saturated heterocyclic groups. "Saturated heterocyclic groups" refer to fully saturated heterocyclic groups, such as 5-10 member saturated heterocyclic groups and 5-8 member saturated heterocyclic groups. Specific examples include tetrahydrofuranyl, piperidinyl, morpholinyl, tetrahydropyranyl, and piperazineyl. "Partially saturated heterocyclic groups" refer to heterocyclic groups that contain both saturated single bonds and unsaturated double bonds, such as 5-10 member partially saturated heterocyclic groups and 5-8 member partially saturated heterocyclic groups. Specific examples include 3,4-dihydro-2H-pyranyl, 1,2,3,4-tetrahydropyridinyl, 4,5-dihydroisoxazolyl, 4,5-dihydrooxazolyl, 2,5-dihydrooxazolyl, and 2,3-dihydrooxazolyl. As used herein, "heterocyclic group" includes, but is not limited to, 5-10 member heterocyclic groups, 6-10 member heterocyclic groups, 5-6 member heterocyclic groups, 5-10 member nitrogen-containing heterocyclic groups, 5-10 member oxygen-containing heterocyclic groups, 5-10 member sulfur-containing heterocyclic groups, 5-8 member nitrogen-containing heterocyclic groups, 5-8 member oxygen-containing heterocyclic groups, and 5-8 member sulfur-containing heterocyclic groups.

[0151] The term "cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon cycloyl group. The term "C3-C6 cycloalkyl" refers to a cycloalkyl group having 3 to 6 cyclic carbon atoms, which can be a monocyclic alkyl group, such as cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, or a bicyclic alkyl group, such as C5-C6 spirocycloalkyl, C5-C6 bridged cycloalkyl, or C5-C6 fused cycloalkyl. Examples include C3-C5 cycloalkyl, C3-C4 cycloalkyl, etc. Specific examples include, but are not limited to, monocyclic alkyl groups (such as cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, etc.) and bicyclic alkyl groups, including spirocycloalkyl, fused cycloalkyl, or bridged cycloalkyl.

[0152] The term "cycloalkyl C1-C6 alkylene" is cycloalkyl-alkylene-, where "cycloalkyl" and "alkylene" are defined as described above. Examples include C3-C6 cycloalkyl C1-C6 alkylene, C3-C5 cycloalkyl C1-C6 alkylene, C3-C6 cycloalkyl C1-C4 alkylene, C3-C5 cycloalkyl C1-C4 alkylene, C5-C6 cycloalkyl C1-C2 alkylene, etc.

[0153] The term "alkoxy" refers to an -O-alkyl group, where alkyl is defined as described above, such as C1-C6 alkoxy, C1-C4 alkoxy, C1-C3 alkoxy, or C1-C2 alkoxy. Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, n-hexoxy, etc. The term "haloalkoxy" refers to an alkoxy group in which the hydrogen atom is replaced by one or more (such as 1 to 3) identical or different halogen atoms.

[0154] The term "alkoxyalkylene" is alkoxy-alkylene-, where "alkoxy" and "alkylene" are defined as described above. Examples include C1-C6 alkoxy-C1-C6 alkylene, C1-C4 alkoxy-C1-C4 alkylene, C1-C2 alkoxy-C1-C2 alkylene, etc.

[0155] The structural formula of the term "p-toluenesulfonyloxy" is:

[0156] The term "cyano" is -CN.

[0157] The term "oxo group" is Group.

[0158] The term “substitution” refers to the selective replacement of one or more (e.g., one, two, three, or four) hydrogen atoms on a specified group by a substituent.

[0159] The term "PET Imaging Agent" is a radioactive tracer used in positron emission tomography (PET).

[0160] The term "SPECT imaging agent" refers to a radioactive tracer used in single-photon emission computed tomography (SPECT).

[0161] The term "optionally substituted with one or more of the following substituents" means that the group may be (1) unsubstituted or (2) substituted. When substituted, one or more hydrogen atoms in the group may be independently replaced by the substituent.

[0162] The term "selected independently" means that each group can be selected independently from the given options, without any interdependence or restriction between them.

[0163] The term "one or more" refers to one or more, such as two, three, four, five, or ten, etc.

[0164] The term "stereoisomer" refers to an isomer formed due to at least one asymmetric center. In compounds having one or more (e.g., one, two, three, or four) asymmetric centers, racemic mixtures, single enantiomers, diastereomer mixtures, and individual diastereomers can be produced. Specific individual molecules can also exist as geometric isomers (cis / trans). Similarly, the compounds of this disclosure can exist in mixtures of two or more different structures in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, etc.

[0165] Pharmaceutically acceptable salts of the compounds disclosed herein include their acid addition salts and base addition salts.

[0166] The compounds disclosed herein may exist in the form of solvates (preferably hydrates).

[0167] Those skilled in the art will understand that not all nitrogen-containing heterocycles can form N-oxides because nitrogen requires available lone pairs of electrons to be oxidized. Those skilled in the art will identify nitrogen-containing heterocycles capable of forming N-oxides. Methods for synthesizing N-oxides are well known to those skilled in the art.

[0168] Metabolites of the compounds disclosed herein are substances formed in the body upon administration of the compounds of the present disclosure. These include substances produced by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc., of the administered compounds. Metabolites of the compounds of the present disclosure include compounds obtained by exposing the compounds of the present disclosure to mammals (including humans) for a sufficient period to produce their metabolites.

[0169] The prodrugs of the disclosed compounds are certain derivatives of the disclosed compounds that may have little or no pharmacological activity, and can be converted into the active compounds of the disclosed compounds when administered to the body. The prodrugs of the disclosed compounds can be prepared by replacing certain groups in the disclosed compounds with suitable functional groups that are present.

[0170] The isotope-labeled compounds of this disclosure are those in which one or more atoms are replaced with atoms having the same atomic number but different atomic masses or mass numbers. Examples of isotopes included in the compounds of this disclosure include, but are not limited to, isotopes of hydrogen (e.g., deuterium). 2 H), tritium ( 3 H); carbon isotopes (e.g., ... 11 C 13 C and 14 C); isotopes of chlorine (e.g.) 36 Cl); isotopes of fluorine (e.g., Cl); 18 F, 19 F); isotopes of iodine (e.g., F);123 I and 125 I); nitrogen isotopes (e.g.) 13 N and 15 N); isotopes of oxygen (e.g., N); 15 O、 17 O and 18 O); isotopes of phosphorus (e.g., O); phosphorus isotopes ... 32 P); and isotopes of sulfur (e.g. 35 S). Isotope-labeled compounds of this disclosure can be prepared by similar methods as described in the examples, using a suitable isotopically labeled reagent instead of the previously used unlabeled reagent. Solvents of this disclosure include those in which the crystallization solvent can be isotopically substituted, for example, D2O, acetone-d6, or DMSO-d6.

[0171] The terms “comprising,” “including,” “containing,” and their other variations herein are inclusive or open-ended and do not exclude other unlisted elements or method steps (these terms also cover the terms “consistently composed of” and “comprises of”).

[0172] This disclosure has achieved one or more of the following beneficial effects:

[0173] The disclosed compound or its pharmaceutically acceptable salts, stereoisomers, tautomers, deuterated compounds, polymorphs, solvates, N-oxides, isotope-labeled compounds, metabolites, or prodrugs are highly specific for KRAS G12D mutant tumors and can be taken up in large quantities by KRAS G12D mutant tumors, thereby enabling specific diagnosis and / or treatment of KRAS G12D mutant tumors. Attached Figure Description

[0174] Figure 1 is 18 Chromatogram of F-LQ-1-41 by high performance liquid chromatography.

[0175] Figure 2 is 18 Micro-PET images of F-LQ-1-41 in wild-type tumor and KRASG 12D mutant tumor model mice.

[0176] Figure 3 is 18 Micro-PET images of F-FDG in mice with wild-type tumors and KRASG 12D mutant tumors.

[0177] Figure 4 shows the MRTX1133 pair 18 PET images of the F-LQ-1-41 blocking experiment.

[0178] Figure 5 is 18Biodistribution of F-LQ-1-41 in KRAS G12D mutant and KRAS wild-type tumor-bearing mice.

[0179] Specific implementation methods

[0180] In all examples, the starting chemicals were purchased from Bidex Pharmaceuticals and used directly without purification. Solvents were purchased from Innovent.

[0181] Example 1: KRAS G12D ligand (GT-2-44), its synthetic route is as follows:

[0182] Step 1: 2,4,7-Trichloro-8-fluoropyrido[4,3-d]pyrimidine (2.5 g, 10.0 mmol, 1.0 eq.) and N,N-diisopropylethylamine (DIPEA) (3.9 g, 30.0 mmol, 3.0 eq.) were dissolved in anhydrous acetonitrile (20 mL) and cooled to -40 °C to obtain a cooled solution. 1,4-oxazacycloheptane (1.2 g, 12.0 mmol, 1.2 eq.) was dissolved in anhydrous acetonitrile (5 mL), and the resulting solution was added dropwise to the cooled solution. After the addition was complete, the reaction system was gradually heated to 0 °C and maintained at this temperature for 2 h. Then, a saturated NaHCO3 aqueous solution was added dropwise to the reaction system to quench the reaction. The reaction product was diluted with 20 mL of water, and the diluted product was extracted three times with ethyl acetate (30 mL × 3). The organic phases obtained from the extraction were combined. The organic phase was first dried with anhydrous sodium sulfate, and then the solvent was removed by rotary evaporation. The remaining crude product was purified by column chromatography to obtain the target product GT-2-37, 2.8 g, with a yield of 89%.

[0183] Step 2: Dissolve ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (970 mg, 6.0 mmol, 1.2 eq.) in anhydrous tetrahydrofuran (20 mL) and cool to 0 °C to obtain a cooled solution. Add NaH (365 mg, 15.0 mmol, 3.0 eq.) to the cooled solution and stir at 0 °C for 1 h to obtain a mixture. Dissolve GT-2-37 (1.6 g, 5.0 mmol, 1.0 eq.) in 10 mL of anhydrous tetrahydrofuran, and add the resulting solution dropwise to the aforementioned mixture. After the addition is complete, gradually raise the reaction system to room temperature and maintain the reaction at room temperature for 6 h, then add water to quench the reaction. Dilute the reaction product with 20 mL of water, remove the tetrahydrofuran from the dilution by rotary evaporation, and extract the remaining substance three times with ethyl acetate (30 mL × 3), combining the organic phases obtained from the extraction. The organic phase was first dried with anhydrous sodium sulfate, and then the solvent was removed by rotary evaporation. The remaining crude product was purified by column chromatography to obtain the target product 4-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane (GT-2-38), 1.6 g, yield 71%.

[0184] Step 3: Dissolve GT-2-38 (1.1 g, 2.5 mmol, 1.0 eq.), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (1.4 g, 3.8 mmol, 1.5 eq.), Pd(PPh3)4 (58.0 mg, 0.05 mmol, 0.02 eq.), and cesium carbonate (2.0 g, 6.3 mmol, 2.5 eq.) in 1,4-epoxyhexane (20 mL) and water (15 mL). Bubble the resulting solution under nitrogen for 10 minutes. After bubbling, heat the reaction system to 95°C and maintain the reaction at 95°C for 6 hours. Cool the reaction product to room temperature and dilute with 15 mL of water. The organic and aqueous phases of the diluted product were separated. The aqueous phase was extracted three times with ethyl acetate (15 mL × 3). The organic phases and the extracted organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The remaining crude product was purified by column chromatography to obtain the target product GT-2-39, 1.3 g, with a yield of 68%.

[0185] Step 4: Dissolve GT-2-39 (320 mg, 0.5 mmol, 1.0 eq.) in dichloromethane (10 mL) and cool to 0 °C to obtain a cooled solution. At 0 °C, slowly add 0.5 mL of 4N HCl in 1,4-dioxane to the cooled solution. After the addition is complete, maintain the reaction system at 0 °C and continue stirring for 1 h. Remove most of the hydrochloric acid from the reaction product by bubbling with nitrogen, then remove the solvent by rotary evaporation. The remaining crude product (GT-2-39') is dried under high vacuum for 1 h and used directly in the next reaction step.

[0186] Step 5: Add anhydrous acetonitrile (10 mL) to the crude product obtained in Step 4, and add triethylamine (0.5 mL) dropwise to the resulting mixture under stirring. After the addition is complete, stir the reaction system at room temperature for 20 minutes, then add 1-fluoro-2-iodoethane (350 mg, 2.0 mmol, 4.0 eq.) and cesium carbonate (650 mg, 2.0 mmol, 4.0 eq.) to the reaction system, and then heat the reaction system to 50 °C and continue the reaction for 5 hours. Filter the reaction product to remove the solid, then remove the solvent by rotary evaporation. The remaining crude product is purified by column chromatography to obtain the target product GT-2-44, 128 mg, with a yield of 40% for Steps 4-5.

[0187] GT-2-44: 1 H NMR(600MHz, CDCl3)δ9.06(s,1H),7.65(dd,J=9.0,5.7Hz,1H),7.30–7.22(m,3H),7.19(t,J=3.9 Hz,1H),5.30(d,J=53.4Hz,1H),4.83(t,J=3.4Hz,1H),4.75(t,J=3.5Hz,1H),4.46–4.22(m,4H), 4.22-4.12(m,4H),4.05-3.99(m,2H),3.90-3.84(m,2H),3.42–3.20(m,3H),3.02-2.98m,1H),2. 56-2.50(m,1H),2.32-2.24(m,2H),2.23-2.16(m,4H),2.05-1.86(m,3H),0.84(t,J=7.5Hz,3H); 13C NMR (151MHz, CDCl3) δ164.2, 163.8, 158.7 (d, J = 240.4Hz), 154.1, 150.8, 149.8 (d, J = 6.5Hz), 149.1, 147.8 (d, J = 14 .0Hz),143.9(d,J=6.5Hz),133.6,127.9(d,J=9.9Hz),126.6(d,J=4.7Hz),125.5–125.3(m),123.4,116.9(d,J=28. 4Hz),111.1,110.5(d,J=8.2Hz),97.5(d,J=176.2Hz),81.9(d,J=171.0Hz),73.2,70.4,67.5(d,J=20.6Hz),60.5( dd,J=19.6,5.6Hz),57.3,53.8,50.7,42.8,36.2(d,J=6.4Hz),30.4,25.6,22.5,19.4(d,J=6.7Hz),14.6.MS:[M+1] + 640.3.

[0188] Example 2: KRAS G12D ligand (GT-2-43), its synthetic route is as follows:

[0189] Step 1: Dissolve GT-2-38 (440 mg, 1.0 mmol, 1.0 eq.), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)naphth-1-yl)ethynyl)triisopropylsilane (768 mg, 1.5 mmol, 1.5 eq.), Pd(PPh3)4 (23.0 mg, 0.02 mmol, 0.02 eq.), and cesium carbonate (2.0 g, 6.3 mmol, 2.5 eq.) in 1,4-epoxyhexane (10 mL) and water (8 mL). Bubble the resulting solution under nitrogen for 10 minutes. After bubbling, heat the reaction system to 95°C and maintain the reaction at 95°C for 6 hours. Cool the reaction product to room temperature and dilute with 15 mL of water. The organic and aqueous phases of the diluted product were separated. The aqueous phase was extracted three times with ethyl acetate (15 mL × 3). The organic phases and the extracted organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The remaining crude product was purified by column chromatography to obtain the target product GT-2-40, 570 mg, with a yield of 72%.

[0190] Step 2: Dissolve GT-2-40 (395 mg, 0.5 mmol, 1.0 eq.) in anhydrous DMF (5 mL). Add cesium fluoride (302 mg, 2.0 mmol, 4.0 eq.) to the solution. Heat the reaction system to 50 °C and react at 50 °C for 2 h. Then, add water dropwise to quench the reaction. Extract the reaction product three times with ethyl acetate (20 mL × 3), and combine the extracted organic phases. Dry the organic phase with anhydrous sodium sulfate, then remove the solvent by rotary evaporation. The remaining crude product is dried under high vacuum for 0.5 h and used directly in the next step of the reaction.

[0191] Step 3: Dissolve the crude product obtained in Step 2 in dichloromethane (10 mL) and cool to 0°C to obtain a cooled solution. At 0°C, slowly add 0.5 mL of 4N HCl in a 1,4-dioxane solution. After the addition is complete, maintain the reaction system at 0°C and continue stirring for 1 hour. Remove most of the hydrochloric acid from the reaction product by bubbling with nitrogen, then remove the solvent by rotary evaporation. The remaining crude product is dried under high vacuum for 1 hour and then used directly in the next reaction step.

[0192] Step 4: Add anhydrous acetonitrile (10 mL) to the crude product obtained in Step 3, and add triethylamine (0.5 mL) dropwise to the resulting mixture under stirring. After the addition is complete, stir the reaction system at room temperature for 20 minutes, then add 1-fluoro-2-iodoethane (350 mg, 2.0 mmol, 4.0 eq.) and cesium carbonate (650 mg, 2.0 mmol, 4.0 eq.) to the reaction system, and then heat the reaction system to 50 °C and continue the reaction for 5 h. Filter the reaction product to remove the solid, then remove the solvent by rotary evaporation. The remaining crude product is purified by column chromatography to obtain the target compound GT-2-43, 83 mg, with a yield of 26% for Steps 2-4.

[0193] GT-2-43: 1H NMR(600MHz, CDCl3)δ9.05(s,1H),7.80(dd,J=9.1,5.6Hz,1H),7.34(d,J=2.6Hz,1H),7.32–7.2 4(m,2H),5.32(d,J=2.3Hz,1H),4.87–4.83(m,1H),4.79–4.75(m,1H),4.38(dd,J=5.3,3.1Hz,1 H),4.34(dd,J=5.3,3.2Hz,1H),4.31–4.09(m,6H),4.01(t,J=4.8Hz,2H),3.90-3.83(m,2H),3. 28–3.12(m,3H),2.99-2.96(m,1H),2.83(d,J=2.9Hz,1H),2.36–2.12(m,5H),1.96–1.82(m,3H); 13 C NMR (151MHz, CDCl3) δ164.2, 163.9, 163.6 (d, J = 250.8Hz), 155.2 (d, J = 2.5Hz), 151.4 (d, J = 260.5Hz), 149.4 (d, J = 12.0H z), 145.6 (d, J = 14.7Hz), 143.4 (d, J = 6.6Hz), 134.5, 132.5, 130.7 (d, J = 9.3Hz), 127.5, 123.4, 116.4 (d, J = 26.0Hz), 111. 3,109.9,104.8(d,J=16.4Hz),98.7(d,J=5.7Hz),97.6(d,J=5.8Hz),87.9(d,J=6.3Hz),81.9(d,J=171.2Hz),75.5,73.3 (d,J=187.7Hz),70.5,69.8,67.5(d,J=20.8Hz),60.6(d,J=19.6Hz),57.3,53.8,50.7,42.9,36.3,30.5,25.8.MS:[M+1] + 636.3.

[0194] Example 3: KRAS G12D ligand (GT-2-59), its synthetic route is as follows:

[0195] Step 1: 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (2.5 g, 10.0 mmol, 1.0 eq.) and DIPEA (3.9 g, 30.0 mmol, 3.0 eq.) were dissolved in anhydrous acetonitrile (20 mL) and cooled to -40 °C to obtain a cooled solution. (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (2.5 g, 12.0 mmol, 1.2 eq.) was dissolved in anhydrous acetonitrile (10 mL), and the resulting solution was added dropwise to the cooled solution. After the addition was complete, the reaction system was gradually heated to 0 °C and maintained at this temperature for 2 h. Then, a saturated NaHCO3 aqueous solution was added dropwise to quench the reaction. The reaction product was diluted with 20 mL of water, and the diluted product was extracted three times with ethyl acetate (30 mL × 3). The organic phases obtained from the extraction were combined. The organic phase was first dried with anhydrous sodium sulfate, and then the solvent was removed by rotary evaporation. The remaining crude product was purified by column chromatography to obtain 3.8 g of the target product, with a yield of 90%.

[0196] Step 2: Dissolve ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (970 mg, 6.0 mmol, 1.2 eq.) in anhydrous tetrahydrofuran (20 mL) and cool to 0 °C to obtain a cooled solution. Add NaH (365 mg, 15.0 mmol, 3.0 eq.) to the cooled solution and stir at 0 °C for 1 h to obtain a mixture. Dissolve the product obtained in Step 1 (2.1 g, 5.0 mmol, 1.0 eq.) in 10 mL of anhydrous tetrahydrofuran and add it dropwise to the reaction system. Add the resulting solution dropwise to the aforementioned mixture. After the addition is complete, gradually raise the reaction system to room temperature and maintain the reaction at room temperature for 6 h. Then add water to quench the reaction. Dilute the reaction product with 20 mL of water, remove the tetrahydrofuran from the dilution by rotary evaporation, and extract the remaining substance three times with ethyl acetate (30 mL × 3). Combine the organic phases obtained from the extraction. The organic phase was first dried with anhydrous sodium sulfate, and then the solvent was removed by rotary evaporation. The remaining crude product was purified by column chromatography to obtain the target product GT-2-58, 2.1 g, with a yield of 78%.

[0197] Step 3: Dissolve GT-2-58 (1.4 g, 2.5 mmol, 1.0 eq.), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (1.4 g, 3.8 mmol, 1.5 eq.), Pd(PPh3)4 (58.0 mg, 0.05 mmol, 0.02 eq.), and cesium carbonate (2.0 g, 6.3 mmol, 2.5 eq.) in 1,4-epoxyhexane (20 mL) and water (15 mL). Bubble the resulting solution under nitrogen for 10 minutes. After bubbling, heat the reaction system to 95°C and maintain the reaction at 95°C for 6 hours. Cool the reaction product to room temperature and dilute with 15 mL of water. The organic and aqueous phases of the diluted product were separated. The aqueous phase was extracted three times with ethyl acetate (15 mL × 3). The organic phases and the extracted organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The remaining crude product was purified by column chromatography to obtain the target product GT-2-59-1, 1.3 g, with a yield of 70%.

[0198] Step 4: Dissolve GT-2-59-1 (374 mg, 0.5 mmol, 1.0 eq.) in dichloromethane (10 mL) and cool to 0 °C to obtain a cooled solution. At 0 °C, slowly add 0.5 mL of 4N HCl in 1,4-dioxane to the cooled solution. After the addition is complete, maintain the reaction system at 0 °C and continue stirring for 1 h. Remove most of the hydrochloric acid from the reaction product by bubbling with nitrogen, then remove the solvent by rotary evaporation. The remaining crude product is dried under high vacuum for 1 h and then used directly in the next reaction step.

[0199] Step 5: Add anhydrous acetonitrile (10 mL) to the crude product obtained in Step 4, and add triethylamine (0.5 mL) dropwise to the resulting mixture under stirring. After the addition is complete, stir the reaction system at room temperature for 20 minutes, then add 1-fluoro-2-iodoethane (350 mg, 2.0 mmol, 4.0 eq.) and cesium carbonate (650 mg, 2.0 mmol, 4.0 eq.) to the reaction system. Then, heat the reaction system to 50 °C and continue the reaction for 5 hours. Filter the reaction product to remove the solid, then remove the solvent by rotary evaporation. The remaining crude product is dried under high vacuum for 1 hour and then used directly in the next step of the reaction.

[0200] Step 6: Dissolve the crude product obtained in Step 5 in dichloromethane (5 mL) and cool to 0°C to obtain a cooled solution. At 0°C, slowly add 3 mL of 4N HCl in a 1,4-dioxane solution to the cooled solution. After the addition is complete, slowly raise the temperature of the reaction system to room temperature and maintain the reaction at room temperature for 10 h. Dilute the reaction system with 10 mL of dichloromethane, cool to 0°C, quench the reaction with a 7N ammonia-methanol solution, and neutralize to pH 7. Remove the solvent from the reaction product by rotary evaporation. The remaining crude product is purified by column chromatography to obtain the target compound GT-2-59, 58 mg, with a yield of 19% for steps 4-6.

[0201] GT-2-59: 1 H NMR(600MHz, CDCl3)δ8.98(s,1H),7.65(dd,J=9.0,5.6Hz,1H),7.28–7.22(m,2H),7.17(t,J=1.9Hz,1H),5.33– 5.20(m,1H),4.83(t,J=4.8Hz,1H),4.75(t,J=4.8Hz,1H),4.59-4.50(m,2H),4.36(t,J=4.5Hz,1H),4.31(t,J=4 .5Hz,1H),4.27(dd,J=10.5,6.6Hz,1H),4.14(d,J=10.3Hz,2H),3.68-3.60(m,4H),3.26(t,J=7.9Hz,1H),3.22– 3.12(m,2H),2.99-2.95(m,1H),2.55-2.48(m,1H),2.31-2.15(m,4H),1.96-1.80(m,8H),0.83(t,J=7.4Hz,3H); 13C NMR (151MHz, CDCl3) δ165.1, 164.6, 158.7 (d, J = 240.3Hz), 154.1 (d, J = 2.3Hz), 150.9, 150.1, 149.1, 147.8, 144.1 (d, J = 6.5Hz) ,134.0(d,J=5.7Hz),133.6,127.9(d,J=10.1Hz),126.6(d,J=5.1Hz),125.4(d,J=15.3Hz),123.5,116.8(d,J=28.3Hz),110.7 ,98.1(d,J=176.1Hz),81.9(d,J=171.1Hz),74.0(d,J=3.1Hz),72.6,67.4(d,J=20.7Hz),60.5(d,J=19.5Hz),57.2,56.0(dd,J =50.2,20.1Hz),55.0,43.0(d,J=20.4Hz),36.2(d,J=4.2Hz),28.5(d,J=3.0Hz),25.8,22.5,19.4(d,J=6.6Hz),14.5.MS:[M+1] + 651.3.

[0202] Example 4: KRAS G12D ligand (GT-2-60), its synthetic route is as follows:

[0203] Step 1: Dissolve GT-2-58 (550 mg, 1.0 mmol, 1.0 eq.), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)naphth-1-yl)ethynyl)triisopropylsilane (768 mg, 1.5 mmol, 1.5 eq.), Pd(PPh3)4 (23.0 mg, 0.02 mmol, 0.02 eq.), and cesium carbonate (2.0 g, 6.3 mmol, 2.5 eq.) in 1,4-epoxyhexane (10 mL) and water (8 mL) to obtain a solution. Bubble the solution with nitrogen for 10 minutes, then heat to 95 °C and maintain the reaction at this temperature for 6 hours. Cool the reaction product to room temperature and dilute with 15 mL of water. The organic and aqueous phases of the diluted product were separated. The aqueous phase was extracted three times with ethyl acetate (15 mL × 3). The organic phases and the extracted organic phases were combined. The organic phase was dried with anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The remaining crude product was dried under high vacuum for 0.5 h and then used directly in the next reaction.

[0204] Step 2: The crude product obtained in Step 2 was dissolved in anhydrous N,N-dimethylformamide (DMF, 10 mL), and cesium fluoride (604 mg, 4.0 mmol, 4.0 eq.) was added to the resulting solution. The reaction system was heated to 50 °C and maintained at 50 °C for 2 h. Water was added dropwise to quench the reaction. The reaction product was extracted three times with ethyl acetate (20 mL × 3), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The remaining crude product was purified by column chromatography to obtain the target product GT-2-60-1, 290 mg, with a yield of 39% for Steps 1-2.

[0205] Step 3: Dissolve GT-2-60-1 (186 mg, 0.25 mmol, 1.0 eq.) in dichloromethane (10 mL) and cool to 0 °C to obtain a cooled solution. At 0 °C, slowly add 0.5 mL of 4N HCl in 1,4-dioxane to the cooled solution. After the addition is complete, maintain the reaction system at 0 °C and continue stirring for 1 h. Bubble the reaction system with nitrogen to remove most of the hydrochloric acid, then remove the solvent by rotary evaporation. The remaining crude product is dried under high vacuum for 1 h and then used directly in the next reaction step.

[0206] Step 4: Add anhydrous acetonitrile (10 mL) to the crude product obtained in Step 3, and add triethylamine (0.5 mL) dropwise to the resulting mixture under stirring. After the addition is complete, stir the reaction system at room temperature for 20 minutes, then add 1-fluoro-2-iodoethane (175 mg, 1.0 mmol, 4.0 eq.) and cesium carbonate (650 mg, 2.0 mmol, 4.0 eq.) to the reaction system, and then heat the reaction system to 50 °C and continue the reaction for 5 h. Filter the reaction product to remove the solid, then remove the solvent by rotary evaporation. The remaining crude product is dried under high vacuum for 1 h and then used directly in the next step of the reaction. Dissolve the obtained crude product in dichloromethane (5 mL) and cool to 0 °C to obtain a cooled solution. At 0 °C, slowly add 3 mL of 4N HCl in a 1,4-dioxane solution. After the addition was complete, the reaction system was slowly raised to room temperature and maintained at room temperature for 10 hours. Then, 10 mL of dichloromethane was added to dilute the reaction system, which was cooled to 0°C. The reaction was quenched with a methanol solution of ammonia (7N) and neutralized to pH 7. The solvent was removed from the reaction product by rotary evaporation, and the remaining crude product was purified by column chromatography to obtain the target compound GT-2-60, 42 mg, with a yield of 26% in steps 3-4.

[0207] GT-2-60: 1H NMR (600MHz, CDCl3) δ8.96 (s, 1H), 7.80 (dd, J = 9.1, 5.6Hz, 1H), 7.34 (d, J = 2.6Hz, 1H), 7.30–7.27 (m, 2H), 5.34–5.29 (m, 1H), 5.25–5. 20(m,1H),4.88–4.81(m,1H),4.80–4.73(m,1H),4.61(t,J=10.8Hz,1H),4.51(t,J=10.7Hz,1H),4.38(dd,J=5.3,3.2Hz,1H),4.33(dd ,J=5.3,3.2Hz,1H),4.26(dd,J=10.3,7.0Hz,1H),4.14(dd,J=10.3,6.1Hz,1H),3.67(d,J=5.4Hz,3H),3.60(dd,J=12.3,8.5Hz,1H),3 13C NMR (151MHz, CDCl3) δ165.1, 164.4, 163.7 (d, J = 250.8Hz), 155.2 (d, J = 2.4Hz), 151.4 (d, J = 260.8Hz), 149.4 (d, J = 11.4Hz), 145.5 (d, J = 14.7Hz), 143.6 (d, J = 6.6Hz), 132.5, 130.7 (d, J = 9.4Hz), 127.5, 123.4, 116.4 (d, J = 25.8Hz), 110.9, 109.9, 104.7 (d, J = 16.4Hz), 98.1 ( dd,J=176.4,5.4Hz),87.7(d,J=6.4Hz),81.9(d,J=171.2Hz),73.3(d,J=196.5Hz),67.5(d,J=20.9Hz),60.5(d,J=18.4Hz),57.2,56.3 (d,J=17.9Hz),55.7(d,J=17.9Hz),55.0(d,J=9.5Hz),43.0(d,J=20.2Hz),36.2(d,J=3.0Hz),28.5(d,J=2.9Hz),28.4,25.8.MS:[M+1] + 647.3.

[0208] Example 5: KRAS G12D ligand (LQ-1-41), its synthetic route is as follows:

[0209] Step 1: (4aS)-4a-(hydroxymethyl)octahydro-1H-cyclopentyl[b]pyridine-1-carboxylic acid benzyl ester (878 mg, 3.0 mmol, 1.2 eq.) was dissolved in anhydrous tetrahydrofuran (15 mL) and cooled to 0 °C to obtain a cooled solution. NaH (182 mg, 7.5 mmol, 3.0 eq.) was added to the cooled solution, and the mixture was stirred at 0 °C for 1 h to obtain a mixture. GT-2-37 (800 mg, 2.5 mmol, 1.0 eq.) was dissolved in 10 mL of anhydrous tetrahydrofuran, and the resulting solution was added dropwise to the mixture. After the addition was complete, the reaction system was brought to room temperature and the reaction was maintained at room temperature for 6 h. Water was added to quench the reaction. The reaction product was diluted with 20 mL of water, and the tetrahydrofuran was removed by rotary evaporation. The residue was extracted three times with ethyl acetate (30 mL × 3), and the organic phases were combined. The organic phase was dried with anhydrous sodium sulfate, and then the solvent was removed by rotary evaporation. The remaining crude product was purified by column chromatography to obtain the target product GT-2-45, 1.4 g, with a yield of 82%.

[0210] Step 2: Dissolve GT-2-45 (1.1 g, 2.0 mmol, 1.0 eq.), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (1.1 g, 3.0 mmol, 1.5 eq.), Pd(PPh3)4 (46.0 mg, 0.04 mmol, 0.02 eq.), and cesium carbonate (1.6 g, 5.0 mmol, 2.5 eq.) in 1,4-epoxyhexane (15 mL) and water (10 mL). Bubble the resulting solution under nitrogen for 10 minutes. After bubbling, heat the reaction system to 95°C and maintain the reaction at 95°C for 6 hours. Cool the reaction product to room temperature and dilute with 15 mL of water. The organic and aqueous phases of the diluted product were separated. The aqueous phase was extracted three times with ethyl acetate (15 mL × 3). The organic phases and the extracted organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The remaining crude product was purified by column chromatography to obtain the target product GT-2-46, 1.1 g, with a yield of 77%.

[0211] Step 3: Add 10% Pd / C (100 mg) to a methanol (15 mL) solution of GT-2-46 (767 mg, 1.0 mmol, 1.0 eq.) and ammonium formate (315 mg, 5.0 mmol, 5.0 eq.). Under sealed conditions, heat the reaction system to 50 °C and maintain the reaction at 50 °C for 5 h. Filter the reaction product to remove the solid, then remove the solvent by rotary evaporation. The remaining crude product is dried under high vacuum for 1 h and then used directly in the next step of the reaction.

[0212] Step 4: Dissolve the crude product obtained in Step 3 in anhydrous acetonitrile (10 mL), and add triethylamine (0.2 mL) and 3-bromopropyne (177 mg, 1.5 mmol, 1.5 eq.) to the resulting solution. React the resulting reaction system at room temperature for 6 h. Remove the solvent from the reaction product by rotary evaporation, and purify the remaining crude product by column chromatography to obtain the target product GT-2-67-1, 402 mg, with a yield of 60% for Steps 3-4.

[0213] Step 5: Dissolve GT-2-67-1 (134 mg, 0.2 mmol, 1.0 eq.) and 2-azidoethane-1-ol (35 mg, 0.4 mmol, 2.0 eq.) in 5 mL of acetonitrile to obtain a solution. Add CuI (7.6 mg, 0.04 mmol, 0.2 eq.) to the obtained solution. React the resulting reaction system at room temperature with stirring for 5 h. Remove the solid from the reaction product by filtration, then remove the solvent by rotary evaporation. Purify the remaining crude product by column chromatography to obtain the target product, 128 mg, yield 85%.

[0214] Step 6: Under a nitrogen atmosphere, dissolve the target product (76 mg, 0.1 mmol, 1.0 eq.) obtained in Step 5 in 5 mL of anhydrous dichloromethane and cool to -40 °C to obtain a cooled solution. Slowly add diethylaminotrifluoride (48 mg, 0.3 mmol, 3.0 eq.) dropwise to the cooled solution. After the addition is complete, slowly raise the reaction system to room temperature and maintain the reaction at room temperature for 10 h. Then, add 10% sodium bicarbonate solution dropwise to quench the reaction. Dilute the reaction product with 15 mL of water, separate the organic phase and aqueous phase of the dilution, extract the aqueous phase three times with ethyl acetate (15 mL × 3), and combine the organic phase and the extracted organic phase. Dry the organic phase first with anhydrous sodium sulfate, then remove the solvent by rotary evaporation. The remaining crude product is dried under high vacuum for 1 h and then used directly in the next reaction.

[0215] Step 7: Dissolve the crude product obtained in Step 6 in dichloromethane (5 mL) and cool to 0°C to obtain a cooled solution. At 0°C, slowly add 0.5 mL of 4N HCl in a 1,4-dioxane solution. After the addition is complete, maintain the reaction system at 0°C and stir for 1 h. Then, quench the reaction with a 7N methanol solution of ammonia and neutralize to pH 7. Remove the solvent from the reaction product by rotary evaporation. The remaining crude product is purified by column chromatography to obtain the target compound LQ-1-41, 25 mg, with a yield of 35% for steps 6-7.

[0216] LQ-1-41: 1H NMR (600MHz, CDCl3) δ9.01(s,1H),8.98(s,1H),7.48(t,J=7.6Hz,1H),7.42(t,J=7.3 Hz,2H),7.11(s,1H),7.00(s,1H),6.87(s,1H),4.73(s,1H),4.65(s,1H),4.59(t,J=4 .6Hz,1H),4.55-4.49(m,3H),4.36–4.30(m,2H),4.21–4.07(m,6H),4.02-3.99(m,4H) ,3.88–3.78(m,5H),2.49-2.44(m,2H),2.18(s,4H),2.06(s,3H),0.88(t,J=8.4,3H); 13 C NMR (151MHz, CDCl3) δ163.7,163.4,157.2,152.6,144.1,143.8,134.0,133.9,127. 3,124.9,123.4(d,J=13.1Hz),116.7(d,J=29.2Hz),113.1,112.5,110.9,82.1(d,J =43.1Hz),80.8,70.4,70.0,69.6(d,J=7.0Hz),60.6,53.7(d,J=14.2Hz),51.2(d,J =34.9Hz),50.6(d,J=21.1Hz),50.2,34.3,30.3(d,J=15.4Hz),14.6,14.2.MS:[M+1] + 717.3.

[0217] Example 6: Precursor compounds 4a, 4b, 4c, and 4d of the KRAS G12D radiolabeled material have the following structures:

[0218] The synthetic routes for precursor compounds 4a, 4b, 4c, and 4d are as follows (where R... 1 and R 2 Groups as shown in the above structural formula):

[0219] Step 1: Compound 1 (0.5 mmol, 1.0 eq.) was dissolved in dichloromethane (10 mL) and cooled to 0 °C. Then, at 0 °C, a 1,4-dioxane solution of 4N HCl (0.5 mL) was slowly added dropwise to the cooled solution. After the addition was complete, the reaction system was kept at 0 °C and stirred for 1 h. Most of the hydrochloric acid was removed from the reaction product by bubbling with nitrogen, and then the solvent was removed by rotary evaporation. The remaining crude product was dried under high vacuum for 1 h to obtain compound 2, which was directly used in the next step of the reaction.

[0220] Step 2: Anhydrous acetonitrile (10 mL) was added to compound 2 and mixed to obtain a mixture. Triethylamine (0.5 mL) was added dropwise to the mixture under stirring. After the addition was complete, the reaction system was stirred at room temperature for 20 minutes. Then, 2-iodoethanol (350 mg, 2.0 mmol, 4.0 eq.) and cesium carbonate (650 mg, 2.0 mmol, 4.0 eq.) were added to the reaction system, and the reaction was continued at 50 °C for 5 hours. The reaction product was first filtered to remove the solid, then the solvent was removed by rotary evaporation. The remaining crude product was purified by column chromatography to obtain compound 3.

[0221] Step 3: Compound 3 (0.2 mmol) and TsCl (0.4 mmol) were dissolved in 10 mL of dichloromethane to obtain a solution. Then, triethylamine (0.2 mL) was added dropwise to the solution. After the addition was complete, the reaction system was stirred overnight at room temperature. The solvent was removed from the reaction product by rotary evaporation, and the remaining crude product was purified by column chromatography to obtain precursor compound 4.

[0222] Example 7: The precursor compound GT-2-67 of the KRAS G12D radiolabeled compound is synthesized via the following route:

[0223] GT-2-67-1 (223 mg, 0.33 mmol, 1.0 eq., synthesis method see Example 5) was dissolved in dichloromethane (10 mL) and cooled to 0 °C to obtain a cooled solution. At 0 °C, a 1,4-dioxane solution (0.5 mL) of 4N HCl was slowly added dropwise to the cooled solution. After the addition was complete, the reaction system was reacted at 0 °C with stirring for 1 h. The reaction was quenched by adding a methanol solution of ammonia (7N) and neutralized to pH 7. The solvent was removed from the reaction product by rotary evaporation, and the remaining crude product was purified by column chromatography to obtain compound GT-2-67, 188 mg, in 90% yield.

[0224] GT-2-67: 1¹H NMR (600 MHz, CDCl₃) δ 8.99 (d, J=39.5 Hz, 1H), 7.45 (td, J=8.4, 5.8 Hz, 1H), 7.14–7.07 (m, 2H), 7.01 (dd, J=37.4, 2.6 Hz, 1H), 4.45-4.29 (m 2H), 4.22–4.07 (m, 3H), 4.02–3.97 (m, 1H), 3.97–3.93 (m, 1H), 3.90–3.73 (m, 2H), 3.39–3.22 (m, 2H), 3.08 (dt, J=23.0, 6.6 Hz, 1H), 2.62-2.56 (m, 2H), 2.48-2.44 (m, 1H), 2.24–2.08 (m, 4H), 1.88-1.83 (m, 1H), 1.80–1.57 (m, 9H), 1.52-1.46 (m, 1H), 0.81 (td, J=7.3, 5.0 Hz, 3H); 13 ¹³C NMR (151 MHz, CDCl₃) δ 164.6 (d, J=11.3 Hz), 163.6 (d, J=24.0 Hz), 159.2–156.5 (m), 152.4 (d, J=24.0 Hz), 150.7 (d, J=14.8 Hz), 150.1–149.7 (m), 149.0 (d, J=14.8 Hz), 148.4–147.7 (m), 143.7 (d, J=6.3 Hz), 134.0 (d, J=6.1 Hz), 127.5 (d, J=10.3 Hz), 125.5, 124.8 (d, J=15.3 Hz), 123.5, 116.5 (d, J=27.9 Hz), 113.4 (d, J=8.8 Hz), 110.9 (d, J=15.1 Hz), 80.3, 72.7 (d, J=5.3 Hz), 72.6 (d, J=55.3 Hz), 70.5 (d, J=9.6 Hz), 69.6 (d, J=6.9 Hz), 63.9 (d, J=29.6 Hz), 53.7 (d, J=7.7 Hz), 50.6 (d, J=12.5 Hz), 47.7 (d, J=40.6 Hz), 44.9, 44.7 (d, J=23.4 Hz), 32.9 (d, J=8.1 Hz), 30.3 (d, J=10.0 Hz), 27.3 (d, J=7.6 Hz), 23.0–22.3 (m), 21.8, 19.9 (d, J=15.7 Hz), 19.4 (d, J=7.0 Hz), 14.6. [M+1] + 628.3.

[0225] Example 8 KRAS G12D Radiolabel 18F-GT-2-43, 18 F-GT-2-44, 18 F-GT-2-59, 18 The F-GT-2-60 has the following structure:

[0226] 18 The synthesis route for F-GT-2-44 is as follows:

[0227] a. Dissolve 2.0 mg of anhydrous potassium carbonate (K2CO3) in 0.2 mL of water to obtain solution A, and dissolve 8.0 mg of amino polyether (Kryptofix 2.2.2, K222) in 0.8 mL of acetonitrile to obtain solution B. Mix solution A and solution B to obtain reagent No. 1.

[0228] b. Dissolve 1.0 mg of compound 4b in 0.2 mL of anhydrous acetonitrile to obtain reagent 2.

[0229] c. The [prepared by the cyclotron] 18 F] fluoride ions ([ 18 F] - 400 mCi, 2.5 mL) was introduced and adsorbed onto a QMA (Quaternary Methyl Ammonium) anion exchange column, and then the adsorbed material on the QMA anion exchange column was... 18 F] - Elute the product into the reaction flask of the synthesis module with reagent No. 1, then heat the reaction flask to 60°C under the protection of high-purity nitrogen or helium, hold at 60°C for 1.0 min, then heat to 85°C, hold at 85°C for 2.0 min, then heat to 120°C, hold at 120°C for 2.0 min, and finally cool to room temperature.

[0230] d. Add reagent No. 2 to the reaction flask, heat the flask to 100℃, and maintain the temperature at 100℃ for 10.0 min to obtain mixture C. Cool to room temperature, and dilute mixture C with water for injection to 15 mL to obtain mixture D. Pass mixture D through a C18 reversed-phase solid-phase extraction column, and then elute the adsorbate on the C18 reversed-phase solid-phase extraction column with 2.0 mL of water for injection and 2.0 mL of anhydrous ethanol in sequence to obtain mixture E.

[0231] e. Separate the mixture E by preparative liquid chromatography using a synthesizer; the operating conditions for preparative liquid chromatography include: column (YMC C18 column, 250mm × 10mm, 5μm); mobile phase is a mixture of acetonitrile and water (acetonitrile to water volume ratio of 4:6); mobile phase flow rate is 2.0 mL / min; collect the separated products with a retention time of 18-20 min on the γ chromatogram into a 50 mL transfer bottle (containing 25 mL of water for injection).

[0232] f. Pass the separated product through a C18 reversed-phase solid-phase extraction column, then wash with 10 mL of water for injection, followed by elution of the adsorbate on the reversed-phase solid-phase extraction column with 1.5 mL of anhydrous ethanol and 13.5 mL of water for injection sequentially. Filter the eluent through a sterile filter to obtain the desired product. 18 F-GT-2-44 solution (containing 10% ethanol).

[0233] 18 Synthesis of F-GT-2-43: Replace compound 4b in the above steps with an equal mass of compound 4a. The remaining operations are the same as described above.

[0234] 18 F-GT-2-59 and 18 Synthesis of F-GT-2-60: Replace step d above with: Add reagent 2 to the reaction flask, heat the reaction flask to 100℃, and maintain at 100℃ for 10.0 min to obtain mixture C. Cool to room temperature, add 0.5 mL of 4N hydrochloric acid solution to mixture C, heat the reaction system to 100℃, maintain at 100℃ for 10 min, and then cool to room temperature. Add 2 mL of saturated sodium bicarbonate to the reaction product for neutralization, and then add water for injection to dilute to 15 mL to obtain mixture D. Pass mixture D through a C18 reversed-phase solid-phase extraction column, and then elute the adsorbate on the C18 reversed-phase solid-phase extraction column with 2.0 mL of water for injection and 2.0 mL of anhydrous ethanol sequentially to obtain mixture E. The remaining steps are the same as steps ac and ef above.

[0235] Example 9 KRAS G12D radiolabel 18 F-LQ-1-41

[0236] (1) 18 The synthetic route for F-LQ-1-41 is as follows:

[0237] a. Dissolve 2.0 mg of anhydrous potassium carbonate (K2CO3) in 0.2 mL of water to obtain solution A, and dissolve 8.0 mg of amino polyether (Kryptofix 2.2.2, K222) in 0.8 mL of acetonitrile to obtain solution B. Mix solution A and solution B to obtain reagent No. 1.

[0238] b. Dissolve 1.0 mg of 2-azidoethyl-4-methylbenzenesulfonate in 0.2 mL of anhydrous acetonitrile to obtain reagent No. 2.

[0239] c. Dissolve 2.0 mg of compound GT-2-67 in 0.2 mL of anhydrous acetonitrile to obtain reagent No. 3.

[0240] d. Dissolve 5.0 mg copper sulfate and 15.0 mg sodium ascorbate in 0.05 mL of water to obtain reagent No. 4.

[0241] e. The [prepared by the cyclotron] 18 F] fluoride ions ([ 18 F] - 400 mCi, 2.5 mL) was introduced and adsorbed onto the QMA anion exchange column, and then the adsorbed on the QMA anion exchange column [ 18 F] - Elute the product into the reaction flask of the synthesis module with reagent No. 1, then heat the reaction flask to 60°C under the protection of high-purity nitrogen or helium, hold at 60°C for 1.0 min, then heat to 85°C, hold at 85°C for 2.0 min, then heat to 120°C, hold at 120°C for 2.0 min, and finally cool down to 60°C.

[0242] f. Add reagent #2 to the reaction flask, heat the flask to 85°C, and maintain at 85°C for 10.0 min to obtain mixture C. Cool to room temperature, add reagents #3 and #4 to mixture C, heat to 50°C, and maintain at 50°C for 10.0 min to obtain mixture D. Cool mixture D to room temperature and dilute with water for injection to 15 mL to obtain mixture E. Pass mixture E through a C18 reversed-phase solid-phase extraction column, and then elute the adsorbate on the C18 reversed-phase solid-phase extraction column sequentially with 2.0 mL of water for injection and 2.0 mL of anhydrous ethanol to obtain mixture F.

[0243] g. The mixture F was separated by preparative liquid chromatography using a synthesizer; the operating conditions for preparative liquid chromatography included: column (YMC C18 column, 250 mm × 10 mm, 5 μm); mobile phase was a mixture of acetonitrile and water (acetonitrile to water volume ratio of 4:6); mobile phase flow rate was 2.0 mL / min; the separated products with a retention time of 18-20 min on the γ chromatogram were collected in a 50 mL transfer bottle (containing 25 mL of water for injection).

[0244] h. Pass the separated product through a C18 reversed-phase solid-phase extraction column, then wash with 10 mL of water for injection, followed by elution of the adsorbate on the reversed-phase solid-phase extraction column with 1.5 mL of anhydrous ethanol and 13.5 mL of water for injection, and filter the eluent through a sterile filter to obtain the desired product. 18 F-LQ-1-41 solution (containing 10% ethanol by volume).

[0245] The preparation time in this embodiment was approximately 90 minutes, the total radiochemical yield was 21.53 ± 1.46% (n = 3, after decay correction), and the radiochemical purity of the product was greater than 99%.

[0246] The above 18 The preparation steps for F-LQ-1-41 can also be performed manually.

[0247] (2) Detection of KRAS G12D PET probe by radio-high performance liquid chromatography (Radio-HPLC): 18 Taking F-LQ-1-41 as an example, this process also applies. 18 F-GT-2-43, 18 F-GT-2-44, 18 F-GT-2-59 and 18 Testing of F-GT-2-60, etc.

[0248] The prepared 18 The F-LQ-1-41 solution was detected by radiometric high performance liquid chromatography, and its chromatogram is shown in Figure 1.

[0249] The operating conditions for high-performance liquid chromatography (HPLC) included: an octadecyl bonded silica reversed-phase column (YMC C18 column; 250 mm × 4.6 mm, 5 μm); a mobile phase of acetonitrile and water (acetonitrile to water volume ratio of 35:65), with isocratic elution; a mobile phase flow rate of 1.0 mL / min; and the use of a UV detector and a radioactive detector. 18 The retention time of F-LQ-1-41 is 14.5 min. The results were calculated based on the detection results. 18 The radiochemical purity of the F-LQ-1-41 solution is greater than 99%, which is higher than the pharmacopoeia's requirement. 18 The standard for F-deoxyglucose radiochemical purity greater than 90% (Chinese Pharmacopoeia 2020 Edition, Part II).

[0250] (3) Inspection: 18 Taking F-LQ-1-41 as an example, this process also applies. 18 F-GT-2-43, 18 F-GT-2-44, 18 F-GT-2-59 and 18 Testing of F-GT-2-60, etc.

[0251] pH value: 5.0-8.0 (refer to Chinese Pharmacopoeia 2020 edition, Part II, Appendix VI H).

[0252] Bacterial endotoxin test: Take an appropriate amount 18The F-LQ-1-41 solution, diluted 60 times with water for bacterial endotoxin testing, was tested according to standard methods. The endotoxin content of this product was less than 15 EU per milliliter (refer to Chinese Pharmacopoeia 2020 Edition, Part II, Appendix XI E).

[0253] Sterility test: Take an appropriate amount 18 The F-LQ-1-41 solution was tested according to the standard method (refer to the Chinese Pharmacopoeia 2020 edition, Part II, Appendix XI H), and the product met the requirements.

[0254] Radioactive concentration: a precise measurement of a certain volume 18 The F-LQ-1-41 solution was placed in an activity meter to measure its activity, and the radioactivity concentration was calculated based on the solution volume and its activity. The radioactivity concentration of this product is greater than 110 MBq / mL.

[0255] Validity period: 6 hours from the calibration time (refer to the operation manual for determining the validity period).

[0256] Experimental Example 1: Bioactivity Assay of KRAS G12D Ligand

[0257] (1) Day 1: Human pancreatic cancer cells Panc04.03 (KRAS G12D mutant) and Bxpc3 (KRAS wild-type) were digested and counted. They were then diluted to 2×10⁻⁶ mcg / mL with 15% (V / V) FBS / RPMI 1640 (FBS: VivaCell, C04001-500; RPMI 1640: VivaCell, C3010-0500) + 10 μg / mL human insulin and 10% (V / V) FBS / RPMI 1640 (hereinafter referred to as complete medium). 5 cells / mL, at 2×10 4 Add cells / well to a 96-well black-framed transparent plate and incubate in a CO2 incubator for 18 hours.

[0258] (2) The next day:

[0259] a. Weigh 0.5000 mg each of MRTX1133 (see Experimental Example 3 for specific structure) and the compound, and dilute them to 200 μM with dimethyl sulfoxide (DMSO), and then dilute them to 1 μM with complete culture medium to obtain a drug solution containing 0.5% DMSO.

[0260] b. Using the above solution as the starting point for the working concentration, perform a 3-fold serial dilution in a 96-well deep plate with complete medium containing 0.5% DMSO to obtain a series of working drug concentrations: 1000 nM, 333.33 nM, 111.11 nM, 37.037 nM, 12.346 nM, 4.115 nM, 1.372 nM, 0.457 nM, 0.152 nM, 0 nM. Discard the medium from the cell plate, add 100 μL of the above gradient drug solution to each well, set up 3 replicate wells, and incubate in an incubator for 3 h.

[0261] c. After the culture is completed, discard the supernatant and add 150 μL / well of 4% (W / V) paraformaldehyde solution (Lambolid, P4500), shake and fix at room temperature for 20 min.

[0262] d. Discard the supernatant and permeate the cell membrane three times (200 μL / well) with phosphate-buffered saline (PBS) containing 0.1% (w / v) Triton X-100 (Beyotime, ST797), for 10 min each time.

[0263] e. Discard the clean permeation solution, add 100 μL of blocking solution (LI-COR, 927-60001) to each well, and shake at room temperature for 1 h.

[0264] f. Using blocking buffer (LI-COR, 927-60001) containing 0.05% (V / V) Tween 20, the phosphorylated primary antibody (Cell Signaling Technology, 9091L) was diluted at a ratio of 1:500 (V / V), and the GAPDH internal control primary antibody (Merck Millipore, EAB374) was diluted at a ratio of 1:5000 (V / V). The two antibody dilutions were added to the plate at 50 μL / well and incubated at 4°C for 16 h.

[0265] (3) Day 3:

[0266] a. Remove the plate, discard the supernatant, and wash 5 times (150 μL / well) with 0.1% (V / V) Tween 20-phosphate buffer (PBST), 5 min each time;

[0267] b. Using blocking buffer (LI-COR, 927-60001) containing 0.05% (V / V) Tween 20, goat anti-rabbit IgG (LI-COR, 926-32211) and goat anti-mouse IgG (LI-COR, 926-68070) were diluted at a ratio of 1:800 (V / V) respectively. The two antibody dilutions were added to the plate at 50 μL / well and incubated at room temperature with shaking in the dark for 1 h.

[0268] c. Discard the supernatant, wash 4 times with PBST (150 μL / well) for 5 min each time, and wash for 5 min with phosphate buffer (PBS) for the 5th time. Pat dry and wipe the bottom clean for imaging. The well plate can be stored in PBS at 4°C for a long time.

[0269] d. Using 700nm as the reference channel and 800nm ​​as the detection channel, imaging was performed using an imager (LI-COR Odyssey CLX). The images were processed using LI-COR analysis software to obtain normalized data. Finally, a four-parameter curve was fitted using GraphPad Prism 10 to obtain the IC. 50 value.

[0270] The results are shown in Table 1.

[0271] Table 1 IC50 values ​​of KRAS G12D ligands

[0272] The data in the table show that GT-2-60 ligand and LQ-1-41 ligand have strong specific binding affinity to the KRAS G12D mutant, with LQ-1-41 ligand having a stronger binding affinity to the KRAS G12D mutant.

[0273] Experiment Example 2: Tumor Uptake Experiment

[0274] KRAS G12D PET probe ([ 18 F]-LQ-1-41) micro PET scan, with 18 Taking F-LQ-1-41 as an example, this process also applies. 18 F-GT-2-43, 18 F-GT-2-44, 18 F-GT-2-59 and 18 F-GT-2-60 and other KRAS G12D PET probes.

[0275] PET imaging of KRAS G12D mutant and KRAS wild-type tumor-bearing mice: 3×10 6 Human pancreatic cancer cells Panc04.03 (KRAS G12D mutant) and Bxpc3 (KRAS wild-type) were subcutaneously inoculated into the bilateral axillary fossa of 5-week-old female BALB / cNude mice. Approximately 3 weeks after tumor cell inoculation, the mice were injected with 250 μCi of [a specific drug / method] via the tail vein. 18Mice were anesthetized with 2% isoflurane-oxygen at corresponding imaging time points (0.5h, 1.0h, 1.5h, and 2.0h) using F-LQ-1-41 drug, and PET / CT imaging was performed on mice using INVISCAN's microPET / CT. The PET images are shown in Figure 2, where yellow arrows represent wild-type tumors and red arrows represent KRAS G12D mutant tumors. Figure 2 shows that only KRAS G12D mutant tumors were effective against […]. 18 F]-LQ-1-41 exhibits high uptake, while wild-type tumors show no significant uptake.

[0276] One hour after injection, the SUVmax uptake value of KRAS G12D mutant tumors was 5.23 ± 0.58% ID / g, while that of wild-type tumors was 1.05 ± 0.28% ID / g. This indicates that... 18 F-LQ-1-41 uptake in KRAS G12D mutant tumors was significantly higher than in wild-type tumors (P<0.0001), demonstrating... 18 F-LQ-1-41 uptake is specific in KRAS G12D mutant tumors. 18 F-FDG was used as a KRAS G12D PET probe for comparison: A mouse tumor model was established according to the above method. Approximately 3 weeks after tumor cell inoculation, mice were injected with 250 μCi via the tail vein. 18 Mice were anesthetized with 2% isoflurane-oxygen at corresponding imaging time points (0.5h, 1.0h, 1.5h, and 2.0h) using F-FDG drug, and PET and CT imaging was performed on mice using INVISCAN's microPET / CT. The PET imaging at 1.0h is shown in Figure 3, where yellow arrows represent wild-type tumors and red arrows represent KRAS G12D mutant tumors. Figure 3 shows that KRAS G12D mutant tumors and wild-type tumors... 18 Both F-FDG and F-FDG have high uptake rates.

[0277] The above explanation is consistent with 18 Compared to F-FDG, 18 The uptake of F-LQ-1-41 in KRAS G12D mutant tumors was significantly specific, i.e. 18 F-LQ-1-41 can be used for specific imaging of KRAS G12D mutant tumors.

[0278] Experiment Example 3: Blocking Experiment

[0279] To further verify 18The specificity of F-LQ-1-41 in binding to the KRAS G12D mutation site was tested using MRTX1133, a known KRAS G12D mutation-binding drug, as an inhibitor. Mice were first injected with 100 μg of MRTX1133 via the tail vein approximately three weeks after tumor cell inoculation, followed by an injection of 250 μCi of [unspecified drug]. 18 F-LQ-1-41 drug, at 18 PET imaging was performed 1.0 h after F-LQ-1-41 drug administration, as shown in Figure 4. Yellow arrows represent wild-type tumors, and red arrows represent KRASG 12D mutant tumors. Figure 4 demonstrates that after blocking the KRAS G12D mutation target using MRTX1133 binding to it... 18 F-LQ-1-41 uptake was very low in both KRAS G12D mutant and wild-type tumors, further indicating 18 F-LQ-1-41 exhibits high target specificity for the KRAS G12D site.

[0280] Experiment Example 4 18 Biodistribution of F-LQ-1-41 in KRAS G12D mutant and KRAS wild-type tumor-bearing mice

[0281] 3×10 6 Human pancreatic cancer cells Panc04.03 (KRAS G12D mutant) and Bxpc3 (KRAS wild-type) were subcutaneously inoculated into the bilateral axillary fossa of 5-week-old female BALB / c Nude mice. Approximately 3 weeks after tumor cell inoculation, the mice were divided into 4 groups of 4 mice each. Each mouse received an intravenous injection of 50 μCi of [a specific drug / method / treatment]. 18 Mice were sacrificed 0.5h, 1.0h, 1.5h, and 2.0h after administration of F-LQ-1-41 drug. Target organs and tissues (blood, heart, liver, spleen, lung, kidney, intestine, stomach, bone, muscle, brain, and tumor) were collected, weighed, and counted using a fully automated radioactive gamma counter. After radiation decay correction, the percentage of reflective material per gram of tissue relative to the total injected dose (%ID / g) was calculated, and the resulting biodistribution is shown in Figure 5.

[0282] Figure 5 shows that, apart from the liver and kidneys, which are conventional drug metabolism organs, there are relatively high levels of radioactive substances distributed in them. 18 The F-LQ-1-41 drug primarily targets KRAS G12D mutant tumors, showing a significantly increased uptake in KRAS G12D mutant tumors compared to KRAS wild-type tumors (P<0.001), further indicating... 18F-LQ-1-41 has high tumor targeting specificity for KRAS G12D mutants.

Claims

1. A compound represented by Formula I or a pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated compound, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, ###0001### Formula I wherein, A is selected from R 4 selected from halogen, C1-C6alkyl, haloC1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, -(CH2) m1 -5-10 membered heteroaryl-(CH2) m2 R a and -(CH2) m3 -5-10 membered arylene-O-(CH2) m4 R a ; R 2 selected from H and -(CH2) m5 R a ; at least one of said R 4 and said R 2 comprises R a ; said -(CH2) m1 -5-10 membered heteroaryl-(CH2) m2 R a , said -(CH2) m3 -5-10 membered arylene-O-(CH2) m4 R a and said -(CH2) m5 R a R a are each independently selected from a radionuclide or a group chelated by a radionuclide and a chelator; R 1 selected from halogen, C1-C6alkyl, haloC1-C6alkyl, C2-C6alkenyl, and C2-C6alkynyl; R 3 selected from 5-10 membered heterocyclyl unsubstituted or substituted by one or more C1-C6alkyl; X1and X2are each independently selected from halogen; n is each independently selected from 0, 1, 2, 3, 4, 5 and 6; m1, m2, m3, m4and m5are each independently selected from 0, 1, 2, 3, 4,5 and 6.

2. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated compound, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein any one of the following: (1) R 4 selected from halogen, C1-C4-alkyl, halo-C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, -(CH2) m1 -5-8 membered heteroaryl-(CH2) m2 R a and -(CH2) m3 -5-8 membered arylene-O-(CH2) m4 R a ; each of m1, m2, m3 and m4 is independently selected from 1, 2, 3 and 4; (2) R 4 selected from halogen and -(CH2) m1 -5-8 membered heteroaryl-(CH2) m2 R a ; m1 and m2 are each independently selected from 1, 2 and 3; (3) R 4 selected from halogen and -(CH2) m1 -5-6 membered heteroaryl-(CH2) m2 R a wherein 5-6 membered heteroaryl is selected from m1and m2are each independently selected from 1 and 2; (4) R 4 selected from F and n is 1; (5) A is selected from 3. The compound or pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated compound, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof of claim 1 or 2, characterized in that any one of the following: (1) R 2 selected from H and -(CH2) m5 R a ; m5 is selected from 1, 2, 3, and 4; (2) R 2 selected from H and -(CH2)2R a .

4. The compound or pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated compound, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof of any one of claims 1 to 3, characterized in that any one of the following: (1) the radionuclide is selected from the group consisting of 18 F, 19 F, 51 Cr, 59 Fe, 67 Ga, 68 Ga, 81m Kr, 99m Tc, 111 In, 123 I, 124 I, 125 I, 131 I, 133 Xe, 201 Tl, 11 C, 13 N, 15 O, 61 Cu, 62 Cu, 64 Cu, 67 Cu, 82 Rb, 89 Zr, 211 At, 212 Pd, 212 Bi, 213 Bi, 223 Ra, 224 Ra, 225 Ac, 227 Th, 32 P, 89 Sr, 86 Y, 90 Y, 153 Sm, 161 Tb, 166 Ho, 186 Re, 188 Re, 177 Lu, 212 Pb, 43 Sc, 44 Sc, 52 Mn, 152 Tb and 155 Tb; (2) the radionuclides are independently selected from the group consisting of 18 F and 19 F.

5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated compound, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, characterized in that any one of the following: (1) R 3 selected from 5-8 membered heterocyclyl unsubstituted or substituted by one or more C1-C6alkyl; (2) R 3 selected from 5-8 membered heterocyclyl optionally substituted with one or more C1-C4alkyl groups; optionally, the 5-8 membered heterocyclyl is selected from (3) R 3 selected from wherein unsubstituted or substituted each independently by one or more of the following: methyl, ethyl, n-propyl, i-propyl; (4) R 3 selected from (5) R 3 selected from 6. The compound or pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated compound, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof of any one of claims 1 to 5, characterized in that any one of the following: (1) R 1 selected from halogen, C1-C4alkyl, halogenated C1-C4alkyl and C2-C4alkynyl; (2) R 1 selected from F, CI, Br, I, methyl, ethyl, n-propyl, i-propyl, monofluoromethyl, difluoromethyl, trifluoromethyl, (3) R 1 selected from the group consisting of C1-C4alkyl and C2-C4alkynyl; (4) R 1 selected from ethyl, (5) R 1 selected from ethyl and 7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated compound, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, characterized in that one or two of the following: 1) X1and X2are each independently selected from F, Cl, Br and I; optionally, X1and X2are F; 2) n is selected from 1 and 2; optionally, n is 1.

8. The compound or pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated compound, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof of any one of claims 1 to 7, wherein, The structure of the compound is shown as formula I-1, Among them, R 4 Selected from halogens, C1-C6 alkyl groups, halo-C1-C6 alkyl groups, C2-C6 alkenyl groups, and C2-C6 alkynyl groups; R 2 selected from -(CH2) m5 R a ; R a , R 1 , R 3 , X1, X2, n and m5 are as described in any one of claims 1 to 7.

9. The compound of claim 8, or a pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated compound, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein any one of the following: (1) R 4 selected from halogen, C1-C4alkyl, halogenated C1-C4alkyl and C2-C4alkynyl; R 2 selected from -(CH2) m5 R a ; m5 is selected from 1, 2, 3 and 4; (2) R 4 selected from halogen; R 2 selected from -(CH2) m5 R a ; m5 is selected from 1, 2 and 3; (3) R 4 selected from F, CI, Br, and I; R 2 selected from -(CH2)2R a .

10. The compound or pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated compound, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof of any one of claims 1 to 7, wherein, The structure of the compound is shown as formula I-2, wherein R 4 selected from -(CH2) m1 -5-10 membered heteroaryl-(CH2) m2 R a and -(CH2) m3 -5-10 membered arylene-O-(CH2) m4 R a ; R 2 is H; R a , R 1 , R 3 , X1, X2, m1, m2, m3, m4 and n are as described in any one of claims 1 to 7.

11. The compound of claim 10, or a pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated compound, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein any one of the following: (1) R 4 selected from -(CH2) m1 -5-8 membered heteroaryl-(CH2) m2 R a and -(CH2) m3 -5-8 membered arylene-O-(CH2) m4 R a ; each of ml, m2, m3, and m4 is independently selected from 1, 2, 3, and 4; (2) R 4 selected from -(CH2) m1 -5-8 membered heteroaryl-(CH2) m2 R a ; m1and m2are each independently selected from 1, 2 and 3; (3) R 4 selected from -(CH2) m1 -5-6 membered heteroaryl-(CH2) m2 R a wherein the 5-6 membered heteroaryl is selected from m1and m2are each independently selected from 1 and2; (4) R 4 selected from 12. The compound or pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated compound, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof of any one of claims 1 to 11, wherein, The compound is selected from:

13. A compound represented by Formula II or a pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated compound, polymorph, solvate, N-oxide, or isotopically labeled compound thereof, wherein A' is selected from R 6 selected from halogen and C2-C6alkynyl; R 5 selected from H and -(CH2) m6 -p-toluenesulfonyloxy; s is each independently selected from 0, 1, 2, 3, 4, m6is selected from 0, 1, 2, 3, 4, 5, and 6; X 1 , X 2 , R 1 and R 3 as described in any one of claims 1 to 12.

14. The compound of claim 13, or a pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated compound, polymorph, solvate, N-oxide, or isotopically labeled compound thereof, wherein any one of the following: 1) R 6 selected from the group consisting of halogen, optionally F; R 5 selected from the group consisting of -(CH2) m6 -p-toluenesulfonyloxy; m6 is selected from the group consisting of 1, 2, 3 and 4, optionally 1 or 2; 2) R 6 selected from C2-C4alkynyl, optionally substituted by R 5 is H.

15. The compound or pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated compound, polymorph, solvate, N-oxide, or isotopically labeled compound thereof of claim 13 or 14, wherein, The compound is selected from:

16. A pharmaceutical composition comprising a compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated compound, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and a pharmaceutical adjuvant.

17. The pharmaceutical composition of claim 16, further comprising a pharmaceutically active ingredient for treating a tumor.

18. The pharmaceutical composition of claim 16 or 17, which is a pharmaceutical composition for diagnosing and / or treating a tumor; optionally, the tumor is a KRAS G12D mutant tumor; more optionally, the KRAS G12D mutant tumor comprises one or more of lung cancer, pancreatic cancer, colon cancer, rectal cancer, melanoma, multiple myeloma, bladder urothelial cell carcinoma, gastric cancer, breast cancer, bladder cancer, cervical cancer, ovarian cancer, uterine cancer, non-small cell lung cancer, brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, throat cancer, oral cancer, salivary gland cancer, esophageal cancer, liver cancer, kidney cancer, pancreatic cancer, gallbladder cancer, bile duct cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial cancer, urethral cancer, vaginal cancer, fallopian tube cancer, testicular cancer, prostate cancer, hemangioma, leukemia, lymphoma, myeloma, skin cancer, lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma and glioblastoma; optionally, the pharmaceutical composition is an imaging agent, more optionally a PET imaging agent or a SPECT imaging agent.

19. A kit for diagnosing and / or treating a tumor, comprising a compound of any one of claims 1 to 12, or a pharmaceutically-acceptable salt, stereoisomer, tautomer, deuterated compound, polymorph, sol vate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, or a pharmaceutical composition of any one of claims 16 to 18, and an auxiliary reagent. Optionally, the tumor is a KRAS G12D mutant tumor; more optionally, the KRAS G12D mutant tumor comprises one or more of lung cancer, pancreatic cancer, colon cancer, rectal cancer, melanoma, multiple myeloma and bladder urothelial cell carcinoma, gastric cancer, breast cancer, bladder cancer, cervical cancer, ovarian cancer, uterine cancer, non-small cell lung cancer, brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, throat cancer, oral cancer, salivary gland cancer, esophageal cancer, liver cancer, kidney cancer, pancreatic cancer, gallbladder cancer, bile duct cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial cancer, urethral cancer, vaginal cancer, fallopian tube cancer, testicular cancer, prostate cancer, hemangioma, leukemia, lymphoma, myeloma, skin cancer, lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma and glioblastoma; Optionally, the diagnosis is by imaging, more optionally by PET or SPECT imaging.

20. A method of diagnosing and / or treating a tumor, comprising the step of administering to a subject in need thereof an effective amount of a compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated compound, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, or an effective amount of a pharmaceutical composition of any one of claims 16 to 18; Optionally, the tumor is a KRAS G12D mutant tumor; more optionally, theKRAS G12D mutant tumor comprises one or more of lung cancer, pancreatic cancer, colon cancer rectal cancer, melanoma, multiple myeloma and bladder urothelial cell carcinoma gastric cancer, breast cancer, bladder cancer, cervical cancer, ovarian cancer, uterine cancer non-small cell lung cancer, brain cancer, thyroid cancer, head and neck cancer, nasopharangeal cancer, throat cancer, oral cancer, salivary gland cancer, esophageal cancer liver cancer, kidney cancer, pancreatic cancer, gallbladder cancer, bile duct cancer, smallintestine cancer, gastrointestinal stromal tumor, urothelial cancer, urethral cancer, vaginalcancer, fallopian tube cancer, testicular cancer, prostate cancer, hemangioma, leukemia lymphoma, myeloma, skin cancer, lipoma, bone cancer, soft tissue sarcomaneurofibroma, glioma, neuroblastoma and glioblastoma; Optionally, the diagnosing is by imaging, more optionally by PET or SPECT imaging.

21. Use of a compound of any one of claims 1 to 12, or a pharmaceuticallyacceptable salt, stereoisomer, tautomer, deuterated compound, polymorph, solate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof,or a pharmaceutical composition of any one of claims 16 to 18, for the manufacture of a medicament for the diagnosis and / or treatment of a tumor. Optionally, the tumor is a KRAS G12D mutant tumor; more optionally, the KRAS G12D mutant tumor comprises one or more of lung cancer, pancreatic cancer, colon cancer, rectal cancer, melanoma, multiple myeloma, and bladder urothelial cell carcinoma, gastric cancer, breast cancer, bladder cancer, cervical cancer, ovarian cancer, uterine cancer, non-small cell lung cancer, brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, throat cancer, oral cancer, salivary gland cancer, esophageal cancer, liver cancer, kidney cancer, pancreatic cancer, gallbladder cancer, bile duct cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial cancer, urethral cancer, vaginal cancer, fallopian tube cancer, testicular cancer, prostate cancer, hemangioma, leukemia, lymphoma, myeloma, skin cancer, lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma, and glioblastoma. Optionally, the diagnosis is by imaging, more optionally by PET or SPECT imaging.

22. Use of a compound represented by Formula III: ###00018### III or a pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated compound, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, in the manufacture of a radiopharmaceutical. wherein M is selected from R 7 and R 11 each independently is selected from H, halogen, C1-C6alkyl, haloC1-C6alkyl, hydroxyC1-C6alkyl, hydroxyhaloC1-C6alkyl, methylsulfonylC1-C6alkylene, C2-C6alkynyl, 5-10 membered arylC1-C6alkylene, 5-10 membered heteroarylC1-C6alkylene, and C3-C6cycloalkylC1-C6alkylene; wherein the 5-10 membered aryl of the 5-10 membered arylC1-C6alkylene, the 5-10 membered heteroaryl of the 5-10 membered heteroarylC1-C6alkylene, and the C3-C6cycloalkyl of the C3-C6cycloalkylC1-C6alkylene are each independently optionally substituted with one or more substituents selected from halogen, amino, cyano, hydroxy, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, haloC1-C6alkoxy, C1-C6alkoxyC1-C6alkylene; R 8 selected from H, C1-C6alkyl, and haloC1-C6alkyl; R 9 selected from the group consisting of C1-C6alkyl, hydroxy, hydroxyC1-C6alkyl, haloC1-C6alkyl, oxo; R 10 selected from H, halogen, Ci-C6alkyl, and halogenated Ci-C6alkyl; R 12 and R 13 each independently is selected from the group consisting of H, halogen, hydroxyl, C1-C6alkyl, and C1-C6alkylsulfonyl; X 3 and X 4 each independently is selected from H and halogen; each t is independently selected from 0, 1, 2, 3, 4, 5, and 6.

23. Use according to claim 22, characterized in that any one of the following: 1) R 7 and R 11 each independently is selected from the group consisting of H, halogen, C1-C4alkyl, halogenated C1-C4alkyl, hydroxy C1-C4alkyl, hydroxy halogenated C1-C4alkyl, methylsulfonyl C1-C4alkylene, C2-C4alkynyl, 5-8 membered aryl C1-C4alkylene, 5-8 membered heteroaryl C1-C4alkylene, and C3-C5cycloalkyl C1-C4alkylene; wherein the 5-8 membered aryl of the 5-8 membered aryl C1-C4alkylene, the 5-8 membered heteroaryl of the 5-8 membered heteroaryl C1-C4alkylene, and the C3-C5cycloalkyl of the C3-C5cycloalkyl C1-C4alkylene are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, amino, cyano, hydroxy, C1-C4alkyl, halogenated C1-C4alkyl, C1-C4alkoxy, halogenated C1-C4alkoxy, C1-C4alkoxy C1-C4alkylene; 2) R 7 and R 11 each independently is selected from halogen, C1-C4alkyl, halogenated C1-C4alkyl, C2-C4alkynyl, 5-8 membered aryl C1-C4alkylene, and 5-8 membered heteroaryl C1-C4alkylene; wherein the 5-8 membered aryl of the 5-8 membered aryl C1-C4alkylene and the 5-8 membered heteroaryl of the 5-8 membered heteroaryl C1-C4alkylene are each independently optionally substituted with one or more substituents selected from halogen, C1-C4alkyl, halogenated C1-C4alkyl, C1-C4alkoxy, halogenated C1-C4alkoxy; optionally, the 5-8 membered aryl is phenyl; optionally, the 5-8 membered heteroaryl is selected from 3) R 7 and R 11 each independently is selected from the group consisting of halogen, methyl, ethyl, n-propyl, i-propyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethynyl, propargyl, benzyl, phenethyl and wherein benzyl, phenethyl and each independently optionally substituted with one or more of the following: halo, haloC1-C4alkyl, haloC1-C4alkoxy; 4) R 7 and R 11 each independently is selected from the group consisting of F, CI, Br, I, At, methyl, ethyl, n-propyl, i-propyl, monofluoromethyl, difluoromethyl, trifluoromethyl, ethynyl, 5) R 7 and R 11 each independently is selected from F, ethyl, 24. Use according to claim 22 or 23, characterized in that any one of the following: 1) R 8 selected from H, C1-C4alkyl and haloC1-C4alkyl; 2) R 8 selected from H, C1-C4 alkyl and C1-C4 alkyl substituted with one or more F; 3) R 8 selected from H, monofluoromethyl, difluoromethyl, trifluoromethyl, 4) R 8 selected from H and 25. Use according to any one of claims 22 to 24, characterized in that any one of the following: 1) R 9 is selected from the group consisting of 5-8 membered heterocyclyl, wherein the 5-8 membered heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of C1-C4alkyl, hydroxy, hydroxyC1-C4alkyl, haloC1-C4alkyl, oxo; alternatively, the 5-8 membered heterocyclyl is selected from the group consisting of 2) R 9 selected from the group consisting of 5-8 membered heterocyclyl, wherein the 5-8 membered heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of C1-C4alkyl, haloC1-C4alkyl; alternatively, the 5-8 membered heterocyclyl is selected from the group consisting of 3) R 9 selected from wherein, unsubstituted or substituted with one or more of the following: methyl, ethyl, n-propyl, i-propyl; 4) R 9 selected from 26. Use according to any one of claims 22 to 25, characterized in that any one of the following: 1) R 10 selected from H, halogen, C1-C4alkyl and halogenated C1-C4alkyl; 2) R 10 selected from H, halogen and C1-C4alkyl; 3) R 10 is H.

27. Use according to any one of claims 22 to 26, characterized in that any one of the following: 1) R 12 and R 13 each independently is selected from the group consisting of H, halogen, hydroxyl, C1-C4alkyl, and C1-C4alkylsulfonyl; 2) R 12 and R 13 each independently is selected from the group consisting of H, halogen and Ci-C4alkyl; 3) R 12 and R 13 is H.

28. Use according to any one of claims 22 to 27, characterized in that any one or two of the following: 1) X 3 and X 4 are each independently selected from H, F, Cl, Br, I; optionally, X 3 and X 4 are F; 2) each t is independently selected from 1, 2, 3, and 4; optionally, t is 1.

29. Use according to any one of claims 22 to 28, wherein, The compound is selected from:

30. Use according to any one of claims 22 to 29, wherein, the radiopharmaceutical is a PET imaging agent or a SPECT imaging agent.

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