KRAS G12D protein degradation agent and application thereof

Abstract

The invention provides a KRAS G12D protein degradation agent and application thereof in medicine, and particularly provides a compound with a structure as shown in a formula (I) and application of a stereoisomer or a prodrug molecule containing the compound or pharmaceutically acceptable salt of the compound as medicine. The compound can degrade KRAS G12D protein in a targeted manner through a ubiquitin-proteasome way, so that the compound can be used for treating indications mediated by abnormal expression of the KRAS G12D protein. Wherein each group in the formula (I) is defined in the specification. # imgabs0 #

Description

[0001] This application claims the priority benefit of the prior application filed by the applicant with the State Intellectual Property Office of China on June 20, 2023, with patent application number 202310735189.8 and titled “A class of KRAS G12D protein degraders and uses thereof”. The entire text of the prior application is incorporated into the present invention by reference. Technical Field

[0002] The present invention relates to the field of medicine, and in particular to a class of KRAS G12D protein degraders and uses thereof. Background Art

[0003] RAS is one of the earliest identified oncogenes, and about 30% of malignant tumors are related to its mutation; RAS includes three subtypes: KRAS, NRAS, and HRAS. KRAS is the main mutation subtype of the RAS family, accounting for about 85%. KRAS is a signal transducer in cells that can be activated by growth factors, chemokines, Ca 2+ Or receptor tyrosine kinase (RTK) activation, controlling multiple signal cascades, including RAF-MEK-ERK, PI3K-AKT-mTOR, and RALGDS-RAL signaling pathways; abnormal activation of KRAS will lead to the activation of numerous downstream signals, stimulating abnormal cell proliferation and migration, and ultimately leading to the occurrence and development of tumors.

[0004] KRAS has an extremely high mutation rate in human malignancies. About 17% of solid tumors carry KRAS mutations, while the KRAS mutation rates in pancreatic cancer, colorectal cancer, and lung cancer are 90%, 50%, and 25%, respectively. Among them, KRAS G12D mutation is one of the main mutation types of KRAS, accounting for about 41% of KRAS mutations. KRAS G12D mutations are particularly prominent in pancreatic cancer and colorectal cancer, with about 37% of pancreatic cancer and 12.5% ​​of colorectal cancer patients carrying KRAS-G12D mutations.

[0005] KRAS protein has a picomolar affinity for the substrate guanylate, which severely limits the development of KRAS non-covalent inhibitors. At present, covalent inhibitors for KRAS G12C mutations have made good progress, but there is still a lack of effective inhibitors for mutation types such as G12D. Therefore, the discovery of efficient G12D regulators has important clinical significance.

[0006] At present, protein targeted chimeric degradation (PROTAC) technology is widely used in drug development. PROTAC achieves ubiquitination tagging of target proteins by recruiting E3 ubiquitin ligases, and then degrades target proteins through the proteasome pathway. Compared with traditional small molecule inhibitors, PROTAC molecules have a higher tolerance to the affinity of target proteins, which can be as low as micromolar levels, and have the advantages of small dosage, low resistance, and high safety. At present, multiple PROTAC molecules have entered clinical research. Summary of the invention

[0007] The purpose of the present invention is to provide a compound capable of degrading KRAS G12D protein through the ubiquitin-proteasome pathway, and a pharmaceutical composition and application thereof.

[0008] In the first aspect of the present invention, there is provided a compound as shown in formula (I) or a pharmaceutically acceptable salt thereof, or a stereoisomer or a prodrug molecule thereof,

[0009]

[0010] in,

[0011] R 1 is selected from unsubstituted or optionally substituted with one, two or more R 11 Substituted with the following groups: C 6-14 Aryl or 5-14 membered heteroaryl; each R 11 are the same or different and are independently selected from H, D, CN, NO2, OH, NH2, halogen, unsubstituted or optionally substituted by one, two or more R 12 Substituted from the following groups: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C1-C6 alkoxy, OH, NH2; each R 12 are the same or different and are independently selected from H, D, CN, NO2, OH, NH2, halogen, C1-C6 alkyl, C1-C6 alkoxy;

[0012] R 2 is selected from unsubstituted or optionally substituted with one, two or more R 21 Substitute the following groups: 3-12 membered heterocyclic groups containing 1-4 heteroatoms or The 3-12 membered heterocyclic ring may be a monocyclic, spirocyclic, fused or bridged ring structure; wherein the heteroatom is selected from oxygen, nitrogen and sulfur atoms; each R 21 are the same or different and are independently selected from H, OH, CN, OH, NH2, halogen, C1-C6 alkyl, C1-C6 alkoxy;

[0013] R 3is selected from unsubstituted or optionally substituted with one, two or more R 31 Substituted with the following groups: C1-C 10 Alkyl, 3-12 membered cyclic hydrocarbon group, 3-12 membered heterocyclic group containing 1-4 heteroatoms, C6-C 10 Aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms; wherein the 3-12 membered cycloalkyl or 3-12 membered heterocyclic group may be a monocyclic, spirocyclic, fused or bridged ring structure; wherein the heteroatom is selected from oxygen, nitrogen and sulfur atoms; each R 31 are the same or different and are independently selected from H, unsubstituted or optionally substituted with one, two or more R 32 Substituted with the following groups: OH, NH2, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclic group; each R 32 are the same or different and are independently selected from H, D, OH, NH2, halogen, C1-C6 alkyl, hydroxy C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkoxy;

[0014] R 4a , R 4b are the same or different and are each independently selected from H, D, F, unsubstituted or optionally substituted with one, two or more R 41 Substituted with the following groups: C1-C4 alkyl, C3-C6 cycloalkyl; or R 4a and R 4b Together with the carbon atom to which it is attached, it forms an unsubstituted or optionally substituted group with one, two or more R 42 A substituted 3-6 membered cycloalkane ring; each R 41 or R 42 are the same or different and are independently selected from H, D, OH, halogen, C1-C6 alkyl, C1-C6 alkoxy;

[0015] R 5 is selected from unsubstituted or optionally substituted with one, two or more R 51 The following groups substituted: C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclic group containing 1-3 heteroatoms; wherein the heteroatoms are selected from oxygen atoms, nitrogen atoms, sulfur atoms; each R 51 are the same or different and are independently selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy;

[0016] R 6a , R 6b are the same or different and are each independently selected from H, D, halogen, unsubstituted or optionally substituted by one, two or more R 61 Substituted C1-C6 alkyl; or R 6a and R 6bTogether with the carbon atom to which it is attached, it forms an unsubstituted or optionally substituted group with one, two or more R 62 Substitute the following groups: C3-C6 cycloalkane ring, 3-6 membered heterocyclic ring containing 1-3 heteroatoms; wherein the heteroatoms are selected from oxygen atoms, nitrogen atoms, and sulfur atoms; each R 61 or R 62 are the same or different and are independently selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy;

[0017] R 7a , R 7b are the same or different and are each independently selected from H, D, halogen, unsubstituted or optionally substituted by one, two or more R 71 Substituted with the following groups: C1-C6 alkyl, C3-C6 cycloalkyl; or R 7a and R 7b Together with the carbon atom to which it is attached, it forms an unsubstituted or optionally substituted group with one, two or more R 72 Substitute the following groups: C3-C6 cycloalkane ring, 3-6 membered heterocyclic ring containing 1-3 heteroatoms; wherein the heteroatoms are selected from oxygen atoms, nitrogen atoms, and sulfur atoms; each R 71 or R 72 are the same or different and are independently selected from H, OH, NH2, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-NH-, (C1-C6 alkyl)2-NH-;

[0018] R 8 is selected from H, halogen, unsubstituted or optionally substituted with one, two or more R 81 Substituted from the following groups: C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclic group containing 1-3 heteroatoms, C6-C 10 Aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms; wherein the heteroatoms are selected from oxygen atoms, nitrogen atoms, and sulfur atoms; each R 81 are the same or different and are independently selected from H, OH, halogen, oxo (=O), C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, halogenated C1-C6 alkyl;

[0019] X is selected from -N-, -CR 9 -; where R 9 is selected from H, halogen, unsubstituted or optionally substituted with one, two or more R 91 Substituted with the following groups: C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl; each R 91 are the same or different and are independently selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy;

[0020] Y is selected from -O-, -S-, -S(O)-, -S(O)2-, -CR 10a R 10b -、-NR 10a -, -CONH-, -NHCO-, -C≡C-, -CH=CH-, -C(O)-,

[0021] -P(=O)-, -P(O)2(OH)-, -NH-S(O)-NH-, -C(O)O-, -OC(O)-, -NHCONH-; wherein R 10a , R 10b is selected from hydrogen atom, halogen, unsubstituted or optionally substituted with one, two or more R 101 Substituted with the following groups: C1-C6 alkyl, C3-C6 cycloalkyl; R 10a and R 10b Together with the carbon atom to which it is attached, it forms an unsubstituted or optionally substituted group with one, two or more R 102 Substituted from the following groups: C3-C6 cycloalkane ring, 3-6 membered heterocyclic ring containing 1-3 heteroatoms; each R 101 or R 102 are the same or different and are independently selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy;

[0022] Z is selected from unsubstituted or optionally substituted with one, two or more R Z1 Substituted with the following groups: C1-C6 alkyl, C3-C 12 Cycloalkane ring, 3-12 membered heterocyclic ring containing 1-4 heteroatoms, C6-C 10 Aromatic ring, 5-10 membered heteroaromatic ring containing 1-3 heteroatoms; wherein C3-C 12 The cycloalkane ring and the 3-12 membered heterocyclic ring may be a monocyclic, spirocyclic, fused or bridged ring structure; the heteroatom is selected from oxygen atom, nitrogen atom and sulfur atom; each R Z1 are the same or different and are independently selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy;

[0023] L is selected from -NR L1 -, unsubstituted or optionally substituted with one, two or more R L2 Substituted with the following groups: C3-C 12 Cycloalkane ring, 3-12 membered heterocyclic ring containing 1-4 heteroatoms, C6-C 10 Aromatic ring, 5-10 membered heteroaromatic ring containing 1-4 heteroatoms; wherein each R L1 , R L2 Selected from H, C1-C6 alkyl; C3-C 12The cycloalkane ring and the 3-12-membered ring may be a monocyclic, spirocyclic, fused or bridged ring structure; the heteroatom is selected from oxygen, nitrogen, sulfur and selenium atoms; each R L1 or R L2 are the same or different and are independently selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy;

[0024] W is selected from unsubstituted or optionally substituted with one, two or more R W Substituted from the following groups: benzene ring, 6-membered heteroaromatic ring containing 1-4 nitrogen atoms; each R W The same or different, independently selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy.

[0025] According to an embodiment of the present invention, R 1 is selected from unsubstituted or optionally substituted with one, two or more R 11 Substituted with the following groups: C 6-10 Aryl or 5-10 membered heteroaryl;

[0026] According to an embodiment of the present invention, R 1 is selected from unsubstituted or optionally substituted with one, two or more R 11 Substituted: indazolyl, indolyl, benzothiazolyl, benzothiophenyl, phenyl, naphthyl, pyridyl;

[0027] According to an embodiment of the present invention, R 1 Selected from Among them, R 1a , R 1b , R 1c , R 1d , R 1e , R 1f , R 1g The same or different, independent of each other with R 11 the definitions stated;

[0028] According to an embodiment of the present invention, each R 11 are the same or different and are independently selected from H, D, CN, OH, NH2, halogen, C1-C3 alkyl, halogenated C1-C3 alkyl, deuterated C1-C3 alkyl, C3-C6 cycloalkyl;

[0029] According to an embodiment of the present invention, each R 11 are the same or different and are independently selected from H, D, F, Cl, CN, OH, NH2, methyl, trifluoromethyl, trideuterated methyl, cyclopropyl;

[0030] According to an embodiment of the present invention, R 1 Selected from

[0031]

[0032] According to an embodiment of the present invention, R 2 is selected from unsubstituted or optionally substituted with one, two or more R 21 Substituted 6-9 membered heterocyclic group or

[0033]

[0034] According to an embodiment of the present invention, R 2 is selected from unsubstituted or optionally substituted with one, two or more R 21 a substituted 7-9 membered nitrogen-containing heterocyclic group;

[0035] According to an embodiment of the present invention, each R 21 The same or different, independently selected from H, OH, C1-C3 alkyl;

[0036] According to an embodiment of the present invention, each R 21 The same or different, are independently selected from H, OH, methyl.

[0037] According to an embodiment of the present invention, R 2 Selected from

[0038] According to an embodiment of the present invention, R 3 is selected from unsubstituted or optionally substituted with one, two or more R 31 Substituted with the following groups: C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclic group; each R 31 are the same or different and are independently selected from H, unsubstituted or optionally substituted with one, two or more R 32 Substituted with the following groups: OH, NH2, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclic group; each R 32 are the same or different and are independently selected from H, D, OH, C1-C6 alkyl, hydroxy C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkoxy;

[0039] According to an embodiment of the present invention, R 3 Selected from

[0040] According to an embodiment of the present invention, R 4a and R 4b are the same or different and are independently selected from H, D, methyl; or R 4a and R4b Together with the attached carbon atom it forms a cyclopropane ring.

[0041] According to an embodiment of the present invention, R 5 Selected from C1-C6 alkyl, C3-C6 cycloalkyl;

[0042] According to an embodiment of the present invention, R 5 Selected from ethyl, isopropyl, tert-butyl, cyclopropyl, cyclopentyl.

[0043] According to an embodiment of the present invention, R 6a selected from H, F; and R 6b Selected from H.

[0044] According to an embodiment of the present invention, R 7a , R 7b are the same or different and are each independently selected from H, D, unsubstituted or optionally substituted with one, two or more R 71 Substituted C1-C6 alkyl; or R 7a and R 7b Together with the carbon atom to which it is attached, it forms an unsubstituted or optionally substituted group with one, two or more R 72 Substituted C3-C6 cycloalkane ring;

[0045] According to an embodiment of the present invention, each R 71 or R 72 are the same or different and are independently selected from H, OH, F, NH2, methyl, methylamino, dimethylamino;

[0046] According to an embodiment of the present invention, R 7a Selected from H, D, methyl, hydroxymethyl, hydroxyethyl, R 7b is selected from H, D, methyl; or R 7a and R 7b Together with the attached carbon atom it forms a cyclopropane ring.

[0047] According to an embodiment of the present invention, R 8 is selected from unsubstituted or optionally substituted with one, two or more R 81 Substituted 5-6 membered heteroaryl;

[0048] According to an embodiment of the present invention, R 8 Selected from

[0049] According to an embodiment of the present invention, each R 81 are the same or different and are independently selected from H, OH, methyl, ethyl, isopropyl, cyclopropyl, trifluoroethyl, oxo;

[0050] According to an embodiment of the present invention, R 8 Selected from

[0051] According to an embodiment of the present invention, X is selected from N, CR 9 ; R 9 Selected from cyclopropyl, Cl.

[0052] According to an embodiment of the present invention, Y is selected from O.

[0053] According to an embodiment of the present invention, Z is selected from C6-C 10 Aromatic ring, C3-C8 cycloalkane ring;

[0054] According to an embodiment of the present invention, Z is selected from

[0055] According to an embodiment of the present invention, L is selected from unsubstituted or optionally substituted with one, two or more R L2 The following groups substituted: a 5-membered heterocyclic ring containing 1 to 4 heteroatoms, a 5-membered heteroaromatic ring containing 1 to 4 heteroatoms;

[0056] According to an embodiment of the present invention, L is selected from

[0057] According to an embodiment of the present invention, W is selected from a benzene ring which is unsubstituted or optionally substituted with one, two or more F or methyl;

[0058] According to an embodiment of the present invention, W is selected from

[0059] According to an embodiment of the present invention, the compound described in formula (I) or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or a prodrug molecule thereof has a structure shown in formula (II):

[0060]

[0061] Among them, R 1 , R 2 , R 3 , R 4a , R 4b , R 5 , R 7a , R 7b , R 8 , X, Y, Z, L and W have the definitions described in the present invention.

[0062] According to an embodiment of the present invention, the compound described in formula (I) or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or a prodrug molecule thereof has a structure shown in formula (III):

[0063]

[0064] Among them, R 1 , R 2 , R 3 , R 4a , R 4b , R 5 , R 7a , R 7b , R 8 , X, Y, Z and L have the definitions described in the present invention.

[0065] According to an embodiment of the present invention, the compound described in formula (I) or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or a prodrug molecule thereof has a structure shown in formula (III-1) or formula (III-2):

[0066]

[0067] Among them, R 11 , R 31 , R 4a , R 4b , R 6a , R 71 , R 81 , R W Has the definition described in the present invention.

[0068] According to an embodiment of the present invention, the compound described in formula (I) is selected from:

[0069]

[0070]

[0071]

[0072]

[0073]

[0074]

[0075]

[0076]

[0077]

[0078]

[0079]

[0080]

[0081]

[0082]

[0083]

[0084]

[0085]

[0086]

[0087]

[0088]

[0089]

[0090]

[0091]

[0092]

[0093]

[0094]

[0095]

[0096]

[0097]

[0098]

[0099]

[0100]

[0101]

[0102]

[0103]

[0104]

[0105]

[0106]

[0107]

[0108]

[0109] According to an embodiment of the present invention, the compound described by formula (I) is selected from compound I-1 to compound I-18 in the examples.

[0110] In a second aspect of the present invention, a pharmaceutical composition for treating and / or preventing tumors is provided, comprising:

[0111] (1) a therapeutically effective amount of a compound represented by formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a prodrug molecule thereof;

[0112] (2) Optional pharmaceutically acceptable carrier.

[0113] In the third aspect of the present invention, provided is the use of a compound of formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a prodrug molecule thereof, or the pharmaceutical composition thereof in the preparation of a drug for treating and / or preventing diseases or conditions related to abnormal KRAS G12D expression.

[0114] According to an embodiment of the present invention, the drug is a KRAS G12D protein degrader.

[0115] According to an embodiment of the present invention, the disease or condition is selected from at least one of the following groups: hematological tumors, gastrointestinal stromal tumors, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell cancer, colorectal cancer, kidney cancer, gastric cancer, head and neck cancer or nasopharyngeal cancer.

[0116] In the fourth aspect of the present invention, a non-diagnostic and non-therapeutic method for degrading KRASG12D in a subject in need thereof is provided, comprising administering to the subject a compound represented by formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a prodrug molecule thereof, or the pharmaceutical composition.

[0117] The present invention also provides a method for treating and / or preventing diseases or conditions related to abnormal KRAS G12D expression, comprising administering to a subject a compound represented by formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a prodrug molecule thereof, or the pharmaceutical composition.

[0118] According to an embodiment of the present invention, the disease or condition is selected from at least one of the following groups: hematological tumors, gastrointestinal stromal tumors, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell cancer, colorectal cancer, kidney cancer, gastric cancer, head and neck cancer or nasopharyngeal cancer.

[0119] According to an embodiment of the present invention, the subject is a human.

[0120] According to an embodiment of the present invention, the compound shown in formula (I) of the present invention, its pharmaceutically acceptable salt, its stereoisomer or its prodrug molecule can be used in combination with at least another therapeutic agent. For this purpose, the pharmaceutical composition or drug described above may contain at least another therapeutic agent, or the compound shown in formula (I) of the present invention, its pharmaceutically acceptable salt, its stereoisomer or its prodrug molecule is used together with another therapeutic agent for treating and / or preventing a method for treating a disease or condition related to abnormal KRASG12D expression.

[0121] The present invention also provides the use of the compound represented by formula (I), its pharmaceutically acceptable salt, its stereoisomer or its prodrug molecule, or the pharmaceutical composition in improving the therapeutic effect of another therapeutic agent.

[0122] The present invention also provides the use of the compound represented by formula (I), its pharmaceutically acceptable salt, its stereoisomer or its prodrug molecule, or the pharmaceutical composition in the preparation of a drug for improving the therapeutic effect of another therapeutic agent; for example, when the other therapeutic agent is lapatinib or tariquida, it is the use in the preparation of a drug for improving the broad-spectrum anti-tumor effect of lapatinib or tariquida.

[0123] According to an embodiment of the present invention, the another therapeutic agent is selected from drugs known to be used for treating tumors or cancers.

[0124] According to an embodiment of the present invention, an example of the other therapeutic agent may be lapatinib or tariquida.

[0125] According to an embodiment of the present invention, the molar ratio of the compound represented by formula (I) to another therapeutic agent is selected from (0.001-1.5):1, for example (0.002-1):1, such as (0.002-0.02):1 or (0.2-0.8):1, such as 0.002:1, 0.003:1, 0.005:1, 0.01:1, 0.015:1, 0.02:1, 0.2:1, 0.3:1, 0.4:1, 0.5:1, 0.6:1, 0.7:1, 0.8:1, 0.9:1.

[0126] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here.

[0127] Beneficial Effects

[0128] The present invention prepares a class of compounds capable of targeted ubiquitination degradation of KRAS G12D protein and a pharmaceutical composition thereof. The compounds can efficiently and selectively degrade KRAS G12D protein in cells, can effectively inhibit the growth of various tumor cells, can be used to prepare anti-tumor drugs, and have potential uses for treating indications related to abnormal expression of KRAS G12D protein.

[0129] Definition and explanation of terms

[0130] Unless otherwise specified, the definitions of groups and terms recorded in the specification and claims of this application, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, definitions of specific compounds in examples, etc., can be arbitrarily combined and combined with each other. The definitions of groups and compound structures after such combinations and combinations should be understood to be within the scope of the specification and / or claims of this application.

[0131] In the compounds described in the present invention, when any variable (such as R 1 , R 2 If a (, etc.) compound occurs more than once in any component, its definition at each occurrence is independent of its definition at every other occurrence. Likewise, combinations of substituents and variables are permitted so long as such combinations result in stable compounds. A line drawn from a substituent into the ring system indicates that the indicated bond may be attached to any substitutable ring atom. If the ring system is polycyclic, this means that such bonds are attached only to any suitable carbon atom of an adjacent ring. It is to be understood that one of ordinary skill in the art can select substituents and substitution patterns for the compounds of the invention to provide compounds that are chemically stable and that can be readily synthesized from readily available raw materials by techniques in the art and the methods set forth below. If a substituent is itself substituted with more than one group, it is to be understood that these groups may be on the same carbon atom or on different carbon atoms so long as the structure is stable.

[0132] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention belongs. The terms used in the description are for the purpose of describing particular embodiments only and are not intended to limit the invention.

[0133] The following terms are used to describe the present invention. Where a term is not specifically defined herein, it is given the art-recognized meaning by one of ordinary skill in the art in which the term is applied in the context of its use to describe the present invention.

[0134] The term "ubiquitin ligase" as used herein refers to a protein family that promotes the transfer of ubiquitin to a specific substrate protein, thereby targeting the substrate protein for degradation. For example, Von Hippel-Lindau E3 ubiquitin ligase is such a protein: it alone or in combination with E2 ubiquitin conjugating enzymes causes the connection of ubiquitin to lysine on the target protein, and then targets a specific protein substrate for degradation by the proteasome. Thus, the E3 ubiquitin ligase that forms a complex alone or with the E2 ubiquitin conjugating enzyme is responsible for the transfer of ubiquitin to the target protein. In general, the ubiquitin ligase participates in polyubiquitination, so that the second ubiquitin is connected to the first ubiquitin; the third ubiquitin is connected to the second ubiquitin, and so on. Polyubiquitination marks proteins for degradation by the proteasome. However, there are some ubiquitination events limited to monoubiquitination, in which only a single ubiquitin is added to the substrate molecule by the ubiquitin ligase. Monoubiquitinated proteins are not targeted to the proteasome for degradation, but instead may be altered in their cellular location or function, for example, by binding to other proteins with domains capable of binding ubiquitin. Further complicating the situation is that different lysines on ubiquitin can be targeted by E3 to form chains. The most common lysine is Lys48 on the ubiquitin chain. This is the lysine used to make polyubiquitin recognized by the proteasome.

[0135] It should be understood that herein, when describing one, two or more, "more" should refer to an integer greater than 2, for example, greater than or equal to 3, for example 3, 4, 5, 6, 7, 8, 9 or 10.

[0136] The term "optional" (or "optionally", "optionally") means substituted by zero, one or more substituents, for example, "optionally substituted by one, two or more R" means that it may not be substituted by R (unsubstituted) or may be selectively substituted by one, two or more R.

[0137] The term "halogen" refers to fluorine, chlorine, bromine and iodine.

[0138] The term "C 1- C 12 "Alkyl" is understood to mean a straight-chain or branched saturated monovalent hydrocarbon group having 1 to 12 carbon atoms. For example, "C 1- C 10 "Alkyl" means straight chain and branched chain alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. 1-"C8 alkyl" means straight chain and branched chain alkyl groups having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. 1- The term "C6 alkyl" refers to straight-chain and branched alkyl groups having 1, 2, 3, 4, 5 or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, or the like or isomers thereof.

[0139] The term "C 2- "C6 alkenyl" is understood to mean preferably a straight or branched monovalent hydrocarbon radical containing one or more double bonds and having 2 to 6 carbon atoms. For example, a radical having 2 or 3 carbon atoms (i.e., C 2- C3 alkenyl). It will be appreciated that where the alkenyl contains more than one double bond, the double bonds may be separated from one another or conjugated. The alkenyl is, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)- Pent-1-enyl, (Z)-pent-1-enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl , 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2-enyl, (Z)-1-methyl but-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl, (E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl.

[0140] The term "C 2- "C6 alkynyl" is understood to mean a straight or branched monovalent hydrocarbon radical containing one or more triple bonds and having 2 to 6 carbon atoms. For example, a radical having 2 or 3 carbon atoms ("C 2- C3 alkynyl"). The alkynyl group is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpent-5-ynyl, In some embodiments, the alkynyl group is ethynyl, prop-1-ynyl or prop-2-ynyl.

[0141] The term "C 3- C 12 "Cycloalkyl" is understood to mean a saturated monovalent monocyclic, bicyclic (such as condensed, bridged, spiro) hydrocarbon ring or tricyclic alkane having 3 to 12 carbon atoms, preferably "C 3- C 10 Cycloalkyl", more preferably "C 3- C8 cycloalkyl". The term "C 3- C 10 "Cycloalkyl" is understood to mean a saturated monovalent monocyclic, bicyclic (eg bridged, spiro) hydrocarbon ring or tricyclic alkane having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. 3- C 10The cycloalkyl group may be a monocyclic hydrocarbon group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon group such as borneol, indolyl, hexahydroindolyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, 2,7-diazaspiro[3,5]nonyl, 2,6-diazaspiro[3,4]octanyl, or a tricyclic hydrocarbon group such as adamantyl. For example: wait.

[0142] The term "C 3- C 12 Cycloalkyl" contains saturated C 3- C 12 Cycloalkyl and unsaturated C 3- C 12 Cycloalkenyl, C 3- C 12 Cycloalkynyl groups, e.g. wait

[0143] The term "C 1- C 12 "Alkoxy" refers to a group having C 1- C 12 Alkyl-O- structure group, preferably "C 1- C6 alkoxy", such as -OCH3, -OCH2CH3, -OCH2CH2CH3, -O-CH2CH(CH3)2, -OCH2CH2CH2CH3, -O-CH(CH3)2, etc.

[0144] The term "3-12 membered heterocyclyl" refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic cyclic substituent, wherein one or more ring atoms are selected from N, O or S(O)m (wherein m is an integer from 0 to 2) heteroatoms, and the remaining ring atoms are carbon, and the bicyclic or polycyclic rings include spirocyclic, fused and bridged rings. For example: morpholinyl, piperidinyl, tetrahydropyrrolyl, pyrrolidinyl, dihydroimidazolyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, tetrahydrofuranyl, tetrahydrothienyl, etc., and N-oxides thereof. Attachment of the heterocyclic substituents may be via a carbon atom or via a heteroatom.

[0145] The term "C 6- C 14"Aryl" is understood to mean preferably a monovalent aromatic or partially aromatic monocyclic, bicyclic (such as fused, bridged, spiro) or tricyclic hydrocarbon ring having 6 to 14 carbon atoms, which may be a single aromatic ring or a polyaromatic ring fused together, preferably "C 6- C 10 The term "C 6- C 10 The term "aryl" is understood to mean preferably a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6, 7, 8, 9 or 10 carbon atoms, in particular a ring having 6 carbon atoms ("C6 aryl"), for example phenyl or biphenyl, or a ring having 9 carbon atoms ("C9 aryl"), for example indanyl or indenyl, or a ring having 10 carbon atoms ("C 10 aryl), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl, or a ring having 13 carbon atoms ("C 13 aryl), such as fluorenyl, or a ring having 14 carbon atoms ("C 14 aryl”), such as anthracenyl. When the C 6-20 When the aryl group is substituted, it may be monosubstituted or polysubstituted. Also, there is no limitation on the substitution position, for example, it may be substituted at the ortho position, para position or meta position.

[0146] The term "5-14 membered heteroaryl" is understood to include monovalent monocyclic, bicyclic (e.g. fused, bridged, spiro) or tricyclic aromatic ring systems having 5 to 14 ring atoms and containing 1 to 5 heteroatoms independently selected from N, O and S, for example "5-10 membered heteroaryl". The term "5-10 membered heteroaryl" is understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 7, 8, 9 or 10 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms, and containing 1 to 5, preferably 1 to 3 heteroatoms each independently selected from N, O and S and, in each case, furthermore, may be benzo-fused. "Heteroaryl" also refers to a radical in which a heteroaromatic ring is fused to one or more aryl, alicyclic or heterocyclyl rings, wherein the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples include indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, quinolizinyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, carbolyl, phenanthridinyl, acridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenazinyl, benzisoquinolyl, thieno[2,3-b]furanyl, pyrazino[2,3-c]carbazolyl, furano[3,2-b]pyranyl, pyrido[2,3-d]-o-oxazinyl, pyrazolo[2,3-c]carbazolyl, furano[3,2-b]pyranyl, pyrido[2,3-d]-o-oxazinyl, pyrazolo[2,3-d]-o-oxazinyl, pyrazolo[2,3-c]carbazolyl ...d]-o-oxazinyl, pyrazolo[2,3-d]-o-oxazinyl, pyrazolo[2,3-d]-o-oxazinyl, pyrazolo[2,3-d]-o-oxazinyl, pyrazolo[2,3-d]-o-oxazinyl, pyrazolo[2,3 [4,3-d]-oxazolyl, imidazo[4,5-d]thiazolyl, pyrazino[2,3-d]pyridazinyl, imidazo[2,1-b]thiazolyl, furano[3,4-c]cinnolinyl, pyrido[2,3-c]carbazolyl, imidazo[1,2-b][1,2,4]triazinyl, benzo[b]thienyl, benzimidazolyl, benzothiazolyl, benzoxapinyl, benzoxazinyl, pyrrolo[1,2-b][2]benzazepinyl.

[0147] The term "spirocyclic ring" refers to a ring system in which two rings share one ring-forming atom, which may contain an aliphatic ring, a heterocyclic ring, an aromatic ring or a heteroaromatic ring as described above.

[0148] The term "fused ring" refers to a ring system in which two rings share two ring atoms, and may contain an aliphatic ring, a heterocyclic ring, an aromatic ring or a heteroaromatic ring as described above.

[0149] The term "bridged ring" refers to a ring system in which two rings share three or more ring atoms, which may contain an aliphatic ring, a heterocyclic ring, an aromatic ring or a heteroaromatic ring as described above.

[0150] As used herein, the term "subject" refers to a mammal. For example, mammals encompassed by the present invention include humans, primates, and domesticated animals, such as cattle, sheep, pigs, horses, mice, rats, humans,

[0151] Pharmaceutically acceptable salts

[0152] The present invention includes free forms of compounds of formula I, as well as pharmaceutically acceptable salts and stereoisomers thereof. Some specific exemplary compounds herein are protonated salts of amine compounds. The term "free form" refers to amine compounds in non-salt form. Pharmaceutically acceptable salts included include not only the exemplary salts of specific compounds described herein, but also typical pharmaceutically acceptable salts of free forms of all compounds of formula I. The free form of a specific salt of the compound can be isolated using techniques known in the art. For example, the free form can be regenerated by treating the salt with an appropriate dilute aqueous base solution, such as dilute aqueous NaOH, dilute aqueous potassium carbonate, dilute aqueous ammonia, and dilute aqueous sodium bicarbonate. The free form differs somewhat from its respective salt form in certain physical properties, such as solubility in polar solvents, but for the purposes of the invention, such acid and base salts are equivalent to their respective free forms in other pharmaceutical aspects.

[0153] Pharmaceutically acceptable salts of the present invention can be synthesized from compounds of the present invention containing a basic or acidic moiety by conventional chemical methods. Typically, salts of basic compounds are prepared by ion exchange chromatography or by reacting a free base with a stoichiometric amount or excess of an inorganic or organic acid in the desired salt form in an appropriate solvent or combination of solvents. Similarly, salts of acidic compounds are formed by reacting with an appropriate inorganic or organic base.

[0154] Therefore, the pharmaceutically acceptable salts of the compounds of this invention include conventional non-toxic salts of the compounds of this invention formed by reacting alkaline compounds of this invention with inorganic or organic acids. For example, conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc., and also include salts derived from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid, etc.

[0155] If the compound of the present invention is acidic, then suitable "pharmaceutically acceptable salts" refer to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum salts, ammonium salts, calcium salts, copper salts, iron salts, ferrous salts, lithium salts, magnesium salts, manganic salts, manganous salts, potassium salts, sodium salts, zinc salts, etc. Ammonium salts, calcium salts, magnesium salts, potassium salts and sodium salts are particularly preferred. Salts derived from pharmaceutically acceptable organic non-toxic bases, including salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydroxocobalamin, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, guazine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.

[0156] Berg et al., "Pharmaceutical Salts," J. Pharm. Sci. '1977: 66: 1-19, describes in more detail the preparation of the above-mentioned pharmaceutically acceptable salts and other typical pharmaceutically acceptable salts.

[0157] Drug metabolites and prodrugs

[0158] The metabolites of the compounds and pharmaceutically acceptable salts thereof involved in the present invention, as well as prodrugs that can be converted into the structures of the compounds and pharmaceutically acceptable salts involved in the present application in vivo, are also included in the claims of the present invention.

[0159] Pharmaceutical composition and use thereof

[0160] The present invention also provides a pharmaceutical composition, which comprises an active ingredient within a safe and effective amount, and a pharmaceutically acceptable carrier or excipient. Since the active ingredient of the present application, the compound of formula I and its pharmaceutically acceptable salt have a good inhibitory effect on the abnormal expression of KRAS G12D protein, the pharmaceutical composition can be used to treat cancers related to abnormal expression of KRAS G12D protein in humans or other mammals.

[0161] The present invention provides a class of KRAS G12D protein degraders and uses thereof. Specifically, the present invention provides a compound having a structure shown in formula (I) or a pharmaceutically acceptable salt thereof, or a stereoisomer or a prodrug molecule thereof. The compound can degrade KRAS G12D protein through the ubiquitination pathway and can be used to treat indications related to abnormal expression of KRAS G12D.

[0162] In one embodiment, the active ingredient of the present application, or a pharmaceutical composition containing the active ingredient can be used to prevent and / or treat tumors such as prostate cancer, non-small cell lung cancer, malignant melanoma, kidney cancer, bladder cancer, ovarian cancer, colon cancer, rectal cancer, breast cancer, cervical cancer, lung cancer, laryngeal cancer, nasopharyngeal cancer, pancreatic cancer, multiple myeloma, B lymphoma, leukemia, etc., or to prevent tumor recurrence after surgery.

[0163] The "active ingredient" described in the present invention refers to the compound of formula I described in the present invention or its pharmaceutically acceptable salt or its stereoisomer or its prodrug molecule.

[0164] The "active ingredient" and pharmaceutical composition described in the present invention can be used as a KRAS G12D protein degrader and can be used to prepare drugs for preventing and / or treating cancer.

[0165] "Safe and effective amount" means: the amount of active ingredient is sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 1-2000 mg of active ingredient per dose, more preferably, 10-200 mg of active ingredient per dose. Preferably, the "one dose" is one tablet.

[0166] "Pharmaceutically acceptable carrier or excipient" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity.

[0167] "Compatibility" herein means that the components in the composition can be blended with the active ingredient of the present invention and with each other without significantly reducing the efficacy of the active ingredient.

[0168] Examples of pharmaceutically acceptable carriers or excipients include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0169] In another preferred embodiment, the compound of formula I of the present invention can form a complex with a macromolecular compound or a polymer through a non-bonding reaction. In another preferred embodiment, the compound of formula I of the present invention as a small molecule can also be connected to a macromolecular compound or a polymer through a chemical bond. The macromolecular compound can be a biological macromolecule such as a high polysaccharide, protein, nucleic acid, polypeptide, etc.

[0170] There is no particular limitation on the administration of the active ingredient or pharmaceutical composition of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), etc.

[0171] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.

[0172] In these solid dosage forms, the active ingredient is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients:

[0173] (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid;

[0174] (b) binders, for example, hydroxymethylcellulose, alginate, gelatin, polyvinyl pyrrolidone, sucrose and gum arabic;

[0175] (c) humectants, for example, glycerin;

[0176] (d) disintegrating agents, for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate;

[0177] (e) a buffering solvent, such as paraffin;

[0178] (f) absorption accelerators, for example, quaternary ammonium compounds;

[0179] (g) wetting agents, such as cetyl alcohol and glyceryl monostearate;

[0180] (h) adsorbents, for example, kaolin; and

[0181] (i) Lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain a buffering agent.

[0182] The solid dosage forms can also be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They can contain opacifying agents, and the release of the active ingredient in such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes.

[0183] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active ingredient, the liquid dosage form may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances. In addition to these inert diluents, the composition may also contain adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and spices.

[0184] In addition to the active ingredients, suspensions may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances.

[0185] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0186] The compounds of the present invention may be administered alone or in combination with other therapeutic agents.

[0187] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage, and for a person weighing 60 kg, the daily dosage is usually 1 to 2000 mg, preferably 20 to 500 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the health status of the patient, which are all within the skill of a skilled physician.

[0188] Combination medication

[0189] The compound of formula I can be used in combination with other drugs known to treat or improve similar conditions. When administered in combination, the administration method and dosage of the original drug remain unchanged, and the compound of formula I is taken simultaneously or subsequently. When the compound of formula I is taken simultaneously with one or more other drugs, it is preferred to use a pharmaceutical composition containing one or more known drugs and the compound of formula I. Drug combination also includes taking the compound of formula I and one or more other known drugs in overlapping time periods. When the compound of formula I is used in combination with one or more other drugs, the dosage of the compound of formula I or the known drug may be lower than when they are used alone.

[0190] The drugs or active ingredients that can be used in combination with the compounds of formula I include, but are not limited to, estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxins / cytostatics, antiproliferative agents, protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protein kinase inhibitors, reverse transcriptase inhibitors, angiogenesis inhibitors, cell proliferation and survival signal inhibitors, drugs that interfere with cell cycle checkpoints and apoptosis inducers, cytotoxic drugs, tyrosine protein inhibitors, EGFR inhibitors, VEGFR inhibitors, serine / threonine protein inhibitors, Bcr-Abl inhibitors, c-Kit inhibitors, Met inhibitors, Raf inhibitors, MEK inhibitors, MMP inhibitors, topoisomerase inhibitors, histidine deacetylase inhibitors, proteasome inhibitors, CDK inhibitors, Bcl-2 family protein inhibitors, MDM2 family protein inhibitors, IAP family protein inhibitors, STAT family protein inhibitors, PI3K inhibitors, AKT inhibitors, integrin blockers, interferon-α, interleukin-12, COX-2 inhibitors, p53, p53 activators, VEGF antibodies, EGF antibodies, JAK inhibitors, P-glycoprotein (P-gp) inhibitors, P-glycoprotein (P-gp) regulators, MDR1 inhibitors, EGFR / HER2 dual-target inhibitors, EGFR monoclonal antibodies, etc.

[0191] In one embodiment, the drugs or active ingredients that can be used in combination with the compound of formula I include but are not limited to: lapatinib, Tariquidar (XR9576), Zosuquidar (LY335979), Cetuximab, afatinib, gefitinib, Osimertinib, limertinib (ASK120067), Firmonertinib, aldesleukin, alendronic acid, interferon, atrenoin, allopurinol, allopurinol sodium, palonosetron hydrochloride, hexamethylmelamine, amino Glutenin, amifostine, amrubicin, anastrozole, dolasetron, aranesp, arglabin, arsenic trioxide, aranosine, 5-azacytidine, azathioprine, bacillus Calmette-Guérin or ticé bacillus Calmette-Guérin, betadine, betamethasone acetate, betamethasone sodium phosphate, bexarotene, bleomycin sulfate, bromourea, bortezomib, busulfan, calcitonin, alezosumab injection, capecitabine, carboplatin, casodex, cefone, simoleukin, daunorubicin, chlorambucil, cisplatin, cladribine, cladribine, clodronate, cyclophosphamide, cytarabine, dacarbazine, actinomycin D, daunorubicin liposomal, dexamethasone, dexamethasone phosphate, estradiol valerate, denibrazol Interleukin-2, Depomet, Deslorelin, Delazosane, Diethylstilbestrol, Diflucan, Docetaxel, Doxil, Doxorubicin, Dronabinol, Chin-166-chitosan complex, Eligard, Rasburicase, Epirubicin hydrochloride, Aprepitant, Epirubicin, Alfa Epoetine, Erythropoietin, Epoetin, Levamisole tablets, Estradiol preparations, 17-β-estradiol, Estramustine sodium phosphate, Ethinyl estradiol, Amifostine, Hydroxyphosphodiesterol, Fanbifu, Etoposide, Fadrozole, Tamoxifen preparations, Filgrastim, Finasteride, Filasteride, Floxuridine, Fluconazole, Fludarabine, 5-fluorodeoxyuridine monophosphate, 5-fluorouracil, Fluoxymesterone, Flutamide, Formestane, 1-β-D-arabinofuranosylcytosyl-5' - Stearoyl phosphate, fotemustine, fulvestrant, gamma globulin, gemcitabine, gemtuzumab, imatinib mesylate, carmustine glutinous rice paper capsule, goserelin, granisiron hydrochloride, histrelin, andmeixin, hydrocortisone, erythro-hydroxynonyl adenine, hydroxyurea, tentan isobemomab, idarubicin, ifosfamide, interferon α, interferon-α2, interferon α-2A, interferon α-2B, interferon α-nl, interferon α-n3, interferon β, interferon γ-la, interleukin-2, intron A, Iressa, irinotecan, Kateri, lentinan sulfate, letrozole, leucovorin, leuprorelin acetate, levomisole, levofolinic acid calcium salt, levothyroxine sodium,Levothyroxine sodium preparations, lomustine, lonidamine, dronabinol, nitrogen mustard, methylcobalamin, medroxyprogesterone acetate, megestrol acetate, melphalan, esterified estrogen, 6-mercaptopurine, mesna, methotrexate, methyl aminolevulinate, miltefosine, minocycline, mitomycin C, mitotane, mitoxantrone, trilostane, liposomal doxorubicin citrate, nedaplatin, pegfilgrastim, oprelvekin, neupogen, nilutamide, tamoxifen, NSC-631570, recombinant human interleukin 1-β, octreotide, ondansetron hydrochloride, prednisone oral solution, oxaliplatin, paclitaxel, prednisone sodium phosphate preparations, pegaspargase, PEGylated, pentostatin, lysin preparations, picostatin hydrochloride Lucarpine, Pirubicin, Plicamycin, Porfimer Sodium, Prednimustine, Stivaril, Prednisone, Premarin, Procarbazine, Recombinant Human Erythropoietin, Raltitrexed, Rebif, Etidronate Rhenium-186, Rituximab, Dextran-A, Romotide, Pilocarpine Hydrochloride Tablets, Octreotide, Sarmustine, Semustine, Sizoran, Sobuzosen, Sodium Methylprednisolone, Pafosic Acid, Stem Cell Therapy, Streptozocin, Strontium-89 Chloride, Levothyroxine Sodium, Tamoxifen, Tamsulosin, Tasonamin, Tastolactone, Taxotere, Tesithiozine, Temozolomide, Teniposide, Testosterone Propionate, Methyltestosterone, Thioguanine, Thiotepa, Thyroid Stimulating Hormone, Tiludronic Acid, Topotecan, Toremifene, Tositumomab , trastuzumab, treotuzumab, tretinoin, methotrexate tablets, trimethylmelamine, trimetrexate, triptorelin acetate, triptorelin pamoate, eufodine, uridine, valrubicin, veslanone, vinblastine, vincristine, vinblastine, vinorelbine, virulizine, dexrazoxane, statins ester, zofranil, paclitaxel protein stabilizer, acolbifene, interferon r-lb, affinitak, aminopterin, arzoxifene, asoprisnil, atamestane, atrasentan, BAY43-9006, Avastin, CCI-779, CDC-501, Celebrex, cetuximab, clenatol, cyproterone acetate, decitabine, DN-101, doxorubicin -MTC, dSLIM, dutasteride, edotecarin, eflornithine, exotecan, fenretinide, histamine dihydrochloride, histrelin hydrogel implant, holmium-166DOTMP, ibandronic acid, interferon gamma, intron-PEG, ixabepilone, keyhole limpet hemocyanin, L-651582, lanreotide, lasofoxifene, libra, lonafamib, miproxifene, minocycline, MS-209, liposomal MTP-PE, MX-6, nafarelin, nemorubicin, neovastat, noratript, oblimersen, onco-TCS, osidem, paclitaxel polyglutamate, sodium bromoglutamate, PN-401, QS-21, quasi-sea,R-1549, raloxifene, ranpirnase, 13-cis retinoic acid, satraplatin, ciocalcitol, T-138067, tarceva, paclitaxel docosahexaenoic acid, thymosin αl, gazofurin, tipifarnib, tirapazamine, TLK-286, toremifene, trans-MID-lo7R, valspodar, vapreotide, vatalanib, verteporfin, vinflunine, Z-100 and zoledronic acid or a combination thereof. DETAILED DESCRIPTION

[0192] The technical scheme of the present invention will be further described in detail below in conjunction with specific embodiments. It should be understood that the following embodiments are only exemplary descriptions and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are included in the scope that the present invention is intended to protect.

[0193] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0194] Example 1: Synthesis of Compound I-1

[0195]

[0196] Step 1:

[0197] In a round-bottomed reaction bottle with a stirrer, 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinazoline (10 g, 23.7 mmol) was dissolved in dichloromethane (80 mL), and triethylamine (20 mL, 142 mmol) was added. Then, the mixture was moved to a low-temperature bath at 0°C, and (1S, 4S)-2-Boc-2,5-diazabicyclo[2.2.1]heptane (4.7 g, 23.7 mmol) was added. The mixture was reacted at 0°C for 10 minutes. TLC showed that the reaction was complete, and the solvent was dried by spin drying. 14 g of compound 2 was obtained by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1). LC-MS: (M+H) + :539.8.

[0198] Step 2:

[0199] In a round-bottomed reaction bottle with a stirrer, compound 2 (14 g, 23.7 mmol) obtained in step 1 was dissolved in 80 mL of dimethyl sulfoxide, and then cesium fluoride (7.29 g, 47.4 mmol) and (S)-(+)-2-methoxypropanol (4.3 g, 47.4 mmol) were added, and then moved to 100°C to react overnight. LC-MS monitored the reaction to be complete, and 200 mL of water and 200 mL of ethyl acetate were added for extraction three times. The organic layer was spin-dried and 13.8 g of yellow solid compound 3 was obtained by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1). LC-MS: (M+H) + :593.4.

[0200] Step 3:

[0201] Compound 3 (200 mg, 0.3 mmol), cyclopropylphenylboronic acid (28 mg, 0.3 mmol), Pd(dppf)Cl2 (57 mg, 0.07 mmol), and potassium phosphate (200 mg, 0.9 mmol) obtained in step 2 were added to a 25 mL Schleck tube. After argon replacement twice, 3 mL 1,4-dioxane and 1 mL water were added. After argon replacement once, the mixture was reacted at 65°C for 24 h. LC-MS monitored the reaction to be complete, 20 mL water and 20 mL ethyl acetate were added for extraction three times, the organic layer was spin-dried, and 108 mg of yellow oily compound 4 was obtained by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1). LC-MS: (M+H) + :551.3.

[0202] Step 4:

[0203] 4-Methoxybenzyl alcohol (30 mg, 0.2 mmol), NaH (18 mg, 0.5 mmol) and 3 mL THF were added to a 25 mL eggplant-shaped bottle, and the mixture was stirred at room temperature for 30 minutes, and then compound 4 (93 mg, 0.2 mmol) obtained in step 3 was added and continued to stir until the reaction was complete. After the reaction, 1 mL of water was added to quench the reaction, and the mixture was extracted with ethyl acetate, concentrated under reduced pressure, and separated by C18 column chromatography to obtain yellow solid compound 5. LC-MS: (M+H) + :669.1.

[0204] Step 5:

[0205] Compound 5 obtained in step 4 was placed in a 25 mL Schleck tube, and then 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-indazole (40 mg, 0.1 mmol), palladium acetate (3 mg, 0.01 mmol), Antphos (11 mg, 0.03 mmol), potassium phosphate (49 mg, 0.2 mmol) were added respectively. After argon was replaced three times, 2 mL of 1,4-dioxane and 0.6 mL of water were added, and the mixture was reacted at 95° C. overnight. After concentration under reduced pressure, the mixture was separated by C18 column chromatography to obtain a light yellow solid compound 6. LC-MS: (M+H) + :805.5.

[0206] Step 6:

[0207] The solid compound 6 (80 mg, 0.1 mmol) obtained in step 5 was dissolved in THF / MeOH (6 mL, 3:1), 10% Pd / C (containing about 55% water, 80 mg) was added, and the mixture was stirred for 12 hours under a hydrogen atmosphere at room temperature and pressure. Spot plate detection, after the reaction was complete, diatomaceous earth was filtered, washed with dichloromethane (50 mL), and concentrated to obtain a light yellow foam solid compound 7. LC-MS: (M+H) + :684.8.

[0208] Step 7:

[0209] Compound 7 (322 mg, 0.5 mmol) obtained in step 6 was dissolved in DMF (3.0 mL), 1-(bromomethyl)-4-ethynylbenzene (138 mg, 0.7 mmol), K2CO3 (130 mg, 0.9 mmol), KI (156 mg, 0.9 mmol) were added, and stirred at 80°C for 12 hours. A large amount of solid was precipitated by adding water, which was filtered and dried to obtain a light yellow solid compound 8. LC-MS: (M+H) + :799.4.

[0210] Step 8:

[0211] Compound 8 (60 mg, 0.1 mmol) obtained in step 7 was dissolved in 2 mL of DMF, and VHL ligand (2R, 3R, 4S)-1-((S)-2-azido-3-methylbutyryl)-3-fluoro-4-hydroxy-N-((R)-2-hydroxy-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (35 mg, 0.1 mmol) and cuprous thiophene-2-carboxylate (57 mg, 0.3 mmol) were added, and stirred at room temperature for 30 minutes. The mixture was separated by C18 column chromatography, and the elution system was CH3CN:H2O to obtain a light yellow foam solid compound 9. LC-MS: (M+H)+ :1271.4.

[0212] The synthesis of VHL ligand (2R, 3R, 4S)-1-((S)-2-azido-3-methylbutanoyl)-3-fluoro-4-hydroxy-N-((R)-2-hydroxy-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide refers to J.Am.Chem.Soc.2018,140,9299 and Nature 2019,574,86.

[0213] Step 9:

[0214] Compound 9 (50 mg, 0.03 mmol) obtained in step 8 was dissolved in methanol (1.0 mL), and 1.0 mL of 4M HCl 1,4-dioxane solution was added, and stirred at room temperature for 3 hours. After concentration, a light yellow foam solid compound Ⅰ-1 was obtained in quantitative conversion. HRMS (ESI) for C 59 H 66 FN 12 O7S[M+H] + : Calculated value 1105.4877, experimental value 1105.4881. HPLC purity: >95%.

[0215] Example 2: Synthesis of Compound I-2

[0216]

[0217] The preparation method refers to the synthesis of Ⅰ-1. HRMS (ESI) for C 60 H 69 FN 13 O7[M+H] + : Calculated value 1102.5421, experimental value 1102.5414. HPLC purity: >95%.

[0218] Example 3: Synthesis of Compound I-3

[0219]

[0220] The preparation method refers to the synthesis of Ⅰ-1. HRMS (ESI) for C 59 H 65 D2N 12 O7S[M+H] + : Calculated value 1089.5096, experimental value 1089.5090. HPLC purity: >95%.

[0221] Example 4: Synthesis of Compound I-4

[0222]

[0223] The preparation method refers to the synthesis of Ⅰ-1. HRMS (ESI) for C 61 H 68 FN 13 O7[M+H] + : Calculated value 1114.5427, experimental value 1114.5430. HPLC purity: >95%.

[0224] Example 5: Synthesis of Compound I-5

[0225]

[0226] The preparation method refers to the synthesis of Ⅰ-1. HRMS (ESI) for C 61 H 67 F2N 13 O7[M+H] + : Calculated value 1132.5333, experimental value 1132.5336. HPLC purity: >95%.

[0227] Example 6: Synthesis of Compound I-6

[0228]

[0229] The preparation method refers to the synthesis of Ⅰ-1. HRMS (ESI) for C 60 H 64 F5N 13 O7[M+H] + : Calculated value 1174.5050, experimental value 1174.5059. HPLC purity: >95%.

[0230] Example 7: Synthesis of Compound I-7

[0231]

[0232] The preparation method refers to the synthesis of Ⅰ-1. HRMS (ESI) for C 60 H 67 F2N 13 O7[M+H] + : Calculated value 1120.5333, experimental value 1120.5331. HPLC purity: >95%.

[0233] Example 8: Synthesis of Compound I-8

[0234]

[0235] The preparation method refers to the synthesis of Ⅰ-1. HRMS (ESI) for C59 H 62 D3F 12 O7S[M+H] + : Calculated value 1108.5070, experimental value 1108.5062. HPLC purity: >95%.

[0236] Example 9: Synthesis of Compound I-9

[0237]

[0238] The preparation method refers to the synthesis of Ⅰ-1. HRMS (ESI) for C 60 H 65 D3F 13 O7[M+H] + : Calculated value 1105.5615, experimental value 1105.5605. HPLC purity: >95%.

[0239] Example 10: Synthesis of Compound I-10

[0240]

[0241] The preparation method refers to the synthesis of Ⅰ-1. HRMS (ESI) for C 61 H 66 F3N 13 O7[M+H] + : Calculated value 1150.5239, experimental value 1150.5235. HPLC purity: >95%.

[0242] Example 11: Synthesis of Compound I-11

[0243]

[0244] The preparation method refers to the synthesis of Ⅰ-1. HRMS (ESI) for C 60 H 66 F3N 13 O7[M+H] + : Calculated value 1138.5239, experimental value 1138.5233. HPLC purity: >95%.

[0245] Example 12: Synthesis of Compound I-12

[0246]

[0247] The preparation method refers to the synthesis of Ⅰ-1. HRMS (ESI) for C 60 H 68 FN 13 O6[M+H]+ : Calculated value 1086.5478, experimental value 1086.5475. HPLC purity: >95%.

[0248] Example 13: Synthesis of Compound I-13

[0249]

[0250] The preparation method refers to the synthesis of Ⅰ-1. HRMS (ESI) for C 60 H 66 D2F2N 13 O7[M+H] + : Calculated value 1122.5453, experimental value 1122.5457. HPLC purity: >95%.

[0251] Example 14: Synthesis of Compound I-14

[0252]

[0253] The preparation method refers to the synthesis of Ⅰ-1. HRMS (ESI) for C 61 H 65 D3F2N 13 O7[M+H] + : Calculated value 1135.5516, experimental value 1135.5520. HPLC purity: >95%.

[0254] Example 15: Synthesis of Compound I-15

[0255]

[0256] The preparation method refers to the synthesis of Ⅰ-1. HRMS (ESI) for C 61 H 66 D2F2N 13 O7[M+H] + : Calculated value 1134.5453, experimental value 1134.5452. HPLC purity: >95%.

[0257] Example 16: Synthesis of Compound I-16

[0258]

[0259] The preparation method refers to the synthesis of Ⅰ-1. HRMS (ESI) for C 59 H 65 F2N 12 O7S[M+H] + : Calculated value 1123.4782, experimental value 1123.4786. HPLC purity: >95%.

[0260] Example 17: Synthesis of Compound I-17

[0261]

[0262] The preparation method refers to the synthesis of Ⅰ-1. HRMS (ESI) for C 59 H 62 D3F2N 12 O7S[M+H] + : Calculated value 1126.4771, experimental value 1126.4775. HPLC purity: >95%.

[0263] Example 18: Synthesis of Compound I-18

[0264]

[0265] The preparation method refers to the synthesis of Ⅰ-1. HRMS (ESI) for C 60 H 65 D3F2N 13 O7[M+H] + : Calculated value 1123.5521, experimental value 1123.5528. HPLC purity: >95%.

[0266] Example 19: KRAS G12D protein degradation activity of preferred compounds

[0267] Methods: AsPC-1 cells (or other test cells below, the seeding density is the same) were cultured at 3×10 5 Each well was inoculated in a six-well plate. After the cells adhered to the wall, the test compound was added in gradient dilutions and continued to be treated in the incubator for 24 hours. After 24 hours, the supernatant culture medium was discarded, washed twice with ice-cold PBS and discarded, and then 200μL SDS lysis buffer was added for lysis. The lysate was collected and BCA quantification and subsequent WB sample preparation procedures were performed. WB samples were subjected to traditional WB experimental operations using 12% polyacrylamide gel. The transfer conditions were: 0.45μM PVDF membrane, voltage 90V, 60min, and primary antibodies used Ras (G12DMutant Specific) (14429) and β-Actin (8457). The obtained WB images were cropped using Photoshop, grayscale analysis was performed using ImageJ, and calculations and graphing were performed using Excel and Grahpad software. The concentration that achieved 50% degradation activity compared to the DMSO control group was defined as DC 50 .

[0268] Table 1 Compounds' degradation activity on KRAS G12D protein in AsPC cells

[0269]

[0270]

[0271] Example 20: Proliferation inhibition activity of preferred compounds on AsPC cells

[0272] Methods: CCK-8 method was used to detect the inhibitory activity of compounds on AsPC-1 cell proliferation. Cells in the logarithmic growth phase were inoculated into 96-well plates at 4000 cells / well. The next day, the test compound was diluted with culture medium and added to the plate with cells (starting at 10μM, 1 / 3 gradient dilution, ten concentration points), and cultured for 72 hours; 3 days later, 10μL CCK-8 reagent was added to each well and incubated for 3-6 hours; then the absorbance at 450 and 650nm was measured with an enzyme reader. The half inhibitory concentration (IC) was calculated using GraphPadPrism8.0.0 50 Cell survival rate (%) = [(Zs-Zc) / (Zb-Zc)] × 100%] (Zs: experimental well; Zb: vehicle control well; Zc: blank well).

[0273] Table 2 Inhibitory activity of compounds on AsPC cells

[0274] Compound <![CDATA[IC 50 (nM)]]> Compound <![CDATA[IC 50 (nM)]]> Ⅰ-1 55.9 Ⅰ-10 53.8 Ⅰ-2 73.7 Ⅰ-11 37.7 Ⅰ-3 41.5 Ⅰ-12 77.3 Ⅰ-4 58.7 Ⅰ-13 22.0 Ⅰ-5 47.7 Ⅰ-14 21.6 Ⅰ-6 85.0 Ⅰ-15 27.5 Ⅰ-7 24.5 Ⅰ-16 20.3 Ⅰ-8 43.1 Ⅰ-17 22.5 Ⅰ-9 67.8 Ⅰ-18 23.9

[0275] Example 21: Evaluation of the anti-tumor effect of the preferred compound on mice bearing human pancreatic cancer PK-59 cells

[0276] Human PK-59 cells were cultured in RPMI Medium 1640 containing 10% heat-inactivated fetal bovine serum (FBS) at 37°C in the presence of 5% CO2. Cells in the logarithmic growth phase were taken, resuspended in an appropriate amount of HBSS, counted, and the cell density was adjusted to 3.25×107cell / mL. An equal amount of Matrigel was added and placed on ice for later use. 6 cells / cells were inoculated into the right back of 7-9 week old BA LB / c-nude mice, 0.2 mL was inoculated subcutaneously. The growth of the tumor was observed after inoculation, and the long and short diameters of the tumor were measured with a vernier caliper twice a week, and the tumor volume was calculated. When the average tumor volume reached about 200 (100-300) mm 3The test was conducted with 4 mice in each vehicle control group and test group. The compounds of Implementation Case I-7, Implementation Case I-16, Implementation Case I-17 and Implementation Case I-18 were dissolved in a solvent of 5% DMSO + 10% Solutol + 85% Saline. Each compound or vehicle dissolved in a solvent was administered through the tail vein. The drug was administered 8 times at an interval of twice a week. The tumor size and body weight were observed twice a week. The tumor volume was calculated using the following formula.

[0277] [Tumor volume (mm 3 )] = [long diameter of tumor (mm)] ×] short diameter of tumor (mm)] 2 ×0.5;

[0278] Tumor growth inhibition rate TGI (%) = [1-(Ti-T0) / (Vi-V0)] × 100

[0279] Among them, Ti is the average tumor volume of the drug-treated group after the start of drug administration, T0 is the average tumor volume of the drug-treated group at the first drug administration; V0 is the average tumor volume of the vehicle control group at the first drug administration, and Vi is the average tumor volume of the vehicle control group after the start of drug administration.

[0280] Table 3 Antitumor activity of compounds in PK-59 tumor-bearing mice

[0281] EX. Dosage (mg / kg) 4 weeks after first administration (%) Ⅰ-7 10 77 Ⅰ-16 10 64 Ⅰ-17 10 73 Ⅰ-18 10 76

[0282] Example 22 2D proliferation inhibitory activity of preferred compounds on various KRAS G12D mutant cell lines

[0283] Method: Same as Example 22.

[0284] Table 4 2D proliferation inhibitory activity of preferred compounds on KRAS G12D mutant cells

[0285]

[0286]

[0287] Example 23 3D proliferation inhibitory activity of preferred compounds on various KRAS G12D mutant cell lines

[0288] Methods: Cells were seeded at 2000 cells / well in ultra-low attachment round-bottom 96-well plates (corning, 7007) and incubated overnight. Cells were then treated with graded dilutions of compounds (10 μM, 1 / 3 dilution, ten concentration points) and incubated for 7 days. Cell viability was assessed using the Cell Titer Glo (CTG) 3D Cell Viability Assay Kit (Promega, G9682). CTG reagent (50 μL / well) was added, and the sample plate was then placed on a plate shaker for 15 minutes to ensure complete cell lysis before evaluating the luminescent signal. Chemiluminescence detection was performed using a Synergy H1 microplate reader.

[0289] Table 5 3D proliferation inhibitory activity of preferred compounds on KRAS G12D mutant cells

[0290]

[0291] Example 24 Lapatinib or Tariquidar (XR9576) combined with the preferred compound significantly enhances the proliferation inhibitory activity of insensitive KRAS G12D mutant cells

[0292] Method: Same as Example 22. The specific operation method of the compound combination is to use a culture medium containing 2 times the target concentration of the drug (such as 4 μM lapatinib) to gradient dilute the tested degrader compound and then add it to the cell plate in a volume ratio of 1:1, that is, the lapatinib concentration in the culture medium of each concentration gradient degrader drug-treated cell is fixed to be equal.

[0293] Table 5 2D proliferation inhibitory activity of preferred compounds on KRAS G12D mutant cells

[0294]

[0295] The results show that the compound of the present invention can play a synergistic role when used in combination with lapatinib or talizumab, and has better drug activity after combined use.

[0296] The above is an exemplary description of the implementation of the technical solution of the present invention. It should be understood that the protection scope of the present invention is not limited to the above implementation. Any modification, equivalent substitution, improvement, etc. made by those skilled in the art within the spirit and principle of the present invention should be included in the protection scope of the claims of this application.

Claims

1. A compound as represented by formula (I) or a pharmaceutically acceptable salt thereof, or a stereoisomer or prodrug molecule thereof, in, R 1 is selected from unsubstituted or optionally substituted with one, two or more R 11 Substituted with the following groups: C 6-14 Aryl or 5-14 membered heteroaryl; each R 11 are the same or different and are independently selected from H, D, CN, NO2, OH, NH2, halogen, unsubstituted or optionally substituted by one, two or more R 12 Substituted from the following groups: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C1-C6 alkoxy, OH, NH2; each R 12 are the same or different and are independently selected from H, D, CN, NO2, OH, NH2, halogen, C1-C6 alkyl, C1-C6 alkoxy; R 2 is selected from unsubstituted or optionally substituted with one, two or more R 21 Substitute the following groups: 3-12 membered heterocyclic groups containing 1-4 heteroatoms or Each R 21 are the same or different and are independently selected from H, OH, CN, OH, NH2, halogen, C1-C6 alkyl, C1-C6 alkoxy; R 3 is selected from unsubstituted or optionally substituted with one, two or more R 31 Substituted with the following groups: C1-C 10 Alkyl, 3-12 membered cyclic hydrocarbon group, 3-12 membered heterocyclic group containing 1-4 heteroatoms, C6-C 10 Aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms; each R 31 are the same or different and are independently selected from H, unsubstituted or optionally substituted with one, two or more R 32 Substituted with the following groups: OH, NH2, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclic group; each R 32 are the same or different and are independently selected from H, D, OH, NH2, halogen, C1-C6 alkyl, hydroxy C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkoxy; R 4a , R 4b are the same or different and are each independently selected from H, D, F, unsubstituted or optionally substituted with one, two or more R 41 Substituted with the following groups: C1-C4 alkyl, C3-C6 cycloalkyl; or R 4a and R 4b Together with the carbon atom to which it is attached, it forms an unsubstituted or optionally substituted group with one, two or more R 42 A substituted 3-6 membered cycloalkane ring; each R 41 or R 42 are the same or different and are independently selected from H, D, OH, halogen, C1-C6 alkyl, C1-C6 alkoxy; R 5 is selected from unsubstituted or optionally substituted with one, two or more R 51 Substituted from the following groups: C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclic group containing 1-3 heteroatoms; each R 51 are the same or different and are independently selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy; R 6a , R 6b are the same or different and are each independently selected from H, D, halogen, unsubstituted or optionally substituted by one, two or more R 61 Substituted C1-C6 alkyl; or R 6a and R 6b Together with the carbon atom to which it is attached, it forms an unsubstituted or optionally substituted group with one, two or more R 62 Substitute the following groups: C3-C6 cycloalkane ring, 3-6 membered heterocyclic ring containing 1-3 heteroatoms; each R 61 or R 62 are the same or different and are independently selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy; R 7a , R 7b are the same or different and are each independently selected from H, D, halogen, unsubstituted or optionally substituted by one, two or more R 71 Substituted with the following groups: C1-C6 alkyl, C3-C6 cycloalkyl; or R 7a and R 7b Together with the carbon atom to which it is attached, it forms an unsubstituted or optionally substituted group with one, two or more R 72 Substitute the following groups: C3-C6 cycloalkane ring, 3-6 membered heterocyclic ring containing 1-3 heteroatoms; each R 71 or R 72 are the same or different and are independently selected from H, OH, NH2, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-NH-, (C1-C6 alkyl)2-NH-; R 8 is selected from H, halogen, unsubstituted or optionally substituted with one, two or more R 81 Substituted from the following groups: C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclic group containing 1-3 heteroatoms, C6-C 10 Aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms; each R 81 are the same or different and are independently selected from H, OH, halogen, oxo (=O), C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, halogenated C1-C6 alkyl; X is selected from -N-, -CR 9 -; where R 9 is selected from H, halogen, unsubstituted or optionally substituted with one, two or more R 91 Substituted with the following groups: C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl; each R 91 are the same or different and are independently selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy; Y is selected from -O-, -S-, -S(O)-, -S(O)2-, -CR 10a R 10b -、-NR 10a -, -CONH-, -NHCO-, -C≡C-, -CH=CH-, -C(O)-, -P(=O)-, -P(O)2(OH)-, -NH-S(O)-NH-, -C(O)O-, -OC(O)-, -NHCONH-; wherein R 10a , R 10b is selected from hydrogen atom, halogen, unsubstituted or optionally substituted with one, two or more R 101 Substituted with the following groups: C1-C6 alkyl, C3-C6 cycloalkyl; R 10a and R 10b Together with the carbon atom to which it is attached, it forms an unsubstituted or optionally substituted group with one, two or more R 102 Substituted from the following groups: C3-C6 cycloalkane ring, 3-6 membered heterocyclic ring containing 1-3 heteroatoms; each R 101 or R 102 are the same or different and are independently selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy; Z is selected from unsubstituted or optionally substituted with one, two or more R Z1 Substituted with the following groups: C1-C6 alkyl, C3-C 12 Cycloalkane ring, 3-12 membered heterocyclic ring containing 1-4 heteroatoms, C6-C 10 Aromatic ring, 5-10 membered heteroaromatic ring containing 1-3 heteroatoms; each R Z1 are the same or different and are independently selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy; L is selected from -NR L1 -, unsubstituted or optionally substituted with one, two or more R L2 Substituted with the following groups: C3-C 12 Cycloalkane ring, 3-12 membered heterocyclic ring containing 1-4 heteroatoms, C6-C 10 Aromatic ring, 5-10 membered heteroaromatic ring containing 1-4 heteroatoms; wherein each R L1 , R L2 Selected from H, C1-C6 alkyl; C3-C 12 The cycloalkane ring and the 3-12-membered ring may be a monocyclic, spirocyclic, fused or bridged ring structure; the heteroatom is selected from oxygen, nitrogen, sulfur and selenium atoms; each R L1 or R L2 are the same or different and are independently selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy; W is selected from unsubstituted or optionally substituted with one, two or more R W Substituted from the following groups: benzene ring, 6-membered heteroaromatic ring containing 1-4 nitrogen atoms; each R W The same or different, independently selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, characterized in that: R 1 is selected from unsubstituted or optionally substituted with one, two or more R 11 Substituted with the following groups: C 6-10 Aryl or 5-10 membered heteroaryl; Preferably, R 1 is selected from unsubstituted or optionally substituted with one, two or more R 11 Substituted: indazolyl, indolyl, benzothiazolyl, benzothiophenyl, phenyl, naphthyl, pyridyl; Preferably, R 1 Selected from Among them, R 1a , R 1b , R 1c , R 1d , R 1e , R 1f , R 1g The same or different, independent of each other with R 11 the definitions stated; Preferably, each R 11 are the same or different and are independently selected from H, D, CN, OH, NH2, halogen, C1-C3 alkyl, halogenated C1-C3 alkyl, deuterated C1-C3 alkyl, C3-C6 cycloalkyl; Preferably, each R 11 are the same or different and are independently selected from H, D, F, Cl, CN, OH, NH2, methyl, trifluoromethyl, trideuterated methyl, cyclopropyl; Preferably, R 1 Selected from 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or a prodrug molecule thereof, characterized in that: R 2 is selected from unsubstituted or optionally substituted with one, two or more R 21 Substituted 6-9 membered heterocyclic group or Preferably, R 2 is selected from unsubstituted or optionally substituted with one, two or more R 21 a substituted 7-9 membered nitrogen-containing heterocyclic group; Preferably, each R 21 The same or different, independently selected from H, OH, C1-C3 alkyl; Preferably, each R 21 The same or different, are independently selected from H, OH, methyl. Preferably, R 2 Selected from Preferably, R 3 is selected from unsubstituted or optionally substituted with one, two or more R 31 Substituted with the following groups: C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclic group; each R 31 are the same or different and are independently selected from H, unsubstituted or optionally substituted with one, two or more R 32 Substituted with the following groups: OH, NH2, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclic group; each R 32 are the same or different and are independently selected from H, D, OH, C1-C6 alkyl, hydroxy C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkoxy; Preferably, R 3 Selected from 4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, characterized in that: R 4a and R 4b are the same or different and are independently selected from H, D, methyl; or R 4a and R 4b Together with the carbon atom to which it is attached, it forms a cyclopropane ring; Preferably, R 5 Selected from C1-C6 alkyl, C3-C6 cycloalkyl; Preferably, R 5 Selected from ethyl, isopropyl, tert-butyl, cyclopropyl, cyclopentyl; Preferably, R 6a selected from H, F; and R 6b Selected from H; Preferably, R 7a , R 7b are the same or different and are each independently selected from H, D, unsubstituted or optionally substituted with one, two or more R 71 Substituted C1-C6 alkyl; or R 7a and R 7b Together with the carbon atom to which it is attached, it forms an unsubstituted or optionally substituted group with one, two or more R 72 Substituted C3-C6 cycloalkane ring; Preferably, each R 71 or R 72 are the same or different and independently selected from H, OH, F, NH2, methyl, methylamino, dimethylamino; Preferably, R 7a Selected from H, D, methyl, hydroxymethyl, hydroxyethyl, R 7b is selected from H, D, methyl; or R 7a and R 7b Together with the carbon atom to which it is attached, it forms a cyclopropane ring; Preferably, R 8 is selected from unsubstituted or optionally substituted with one, two or more R 81 Substituted 5-6 membered heteroaryl; Preferably, R 8 Selected from Preferably, each R 81 are the same or different and are independently selected from H, OH, methyl, ethyl, isopropyl, cyclopropyl, trifluoroethyl, oxo; Preferably, R 8 Selected from 5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, characterized in that: X is selected from N, CR 9 ; R 9 Selected from cyclopropyl, Cl. Preferably, Y is selected from O; Preferably, Z is selected from C6-C 10 Aromatic ring, C3-C8 cycloalkane ring; Preferably, Z is selected from Preferably, L is selected from unsubstituted or optionally substituted with one, two or more R L2 The following groups substituted: a 5-membered heterocyclic ring containing 1 to 4 heteroatoms, a 5-membered heteroaromatic ring containing 1 to 4 heteroatoms; Preferably, L is selected from Preferably, W is selected from a benzene ring which is unsubstituted or optionally substituted with one, two or more F or methyl groups; Preferably, W is selected from 6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, characterized in that: The compound described in formula (I) or its pharmaceutically acceptable salt, or its stereoisomer or its prodrug molecule has the structure shown in formula (II): Among them, R 1 , R 2 , R 3 , R 4a , R 4b , R 5 , R 7a , R 7b , R 8 , X, Y, Z, L and W have the definitions as described in any one of claims 1 to 5; Preferably, the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or a prodrug molecule thereof has a structure shown in formula (III): Among them, R 1 , R 2 , R 3 , R 4a , R 4b , R 5 , R 7a , R 7b , R 8 , X, Y, Z and L have the definitions as described in any one of claims 1 to 5; Preferably, the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or a prodrug molecule thereof has a structure shown in formula (III-1) or formula (III-2): Among them, R 11 , R 31 , R 4a , R 4b , R 6a , R 71 , R 81 , R W The definition as claimed in any one of claims 1 to 5.

7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, characterized in that: The compound is selected from the following structures: Preferably, the compound is selected from Compound I-1 to Compound I-18 in Examples.

8. A pharmaceutical composition for treating and / or preventing tumors, comprising: (1) a therapeutically effective amount of a compound according to any one of claims 1 to 7, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a prodrug molecule thereof; (2) Optional pharmaceutically acceptable carrier.

9. Use of the compound according to any one of claims 1 to 7, its pharmaceutically acceptable salt, its stereoisomer or its prodrug molecule, or the pharmaceutical composition according to claim 8 in the preparation of a medicament for treating and / or preventing diseases or conditions related to abnormal KRAS G12D expression; Preferably, the drug is a KRAS G12D protein degrader; Preferably, the disease or condition is selected from the group consisting of hematological tumors, gastrointestinal stromal tumors, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell cancer, colorectal cancer, kidney cancer, gastric cancer, head and neck cancer or nasopharyngeal cancer.

10. A non-diagnostic, non-therapeutic method for degrading KRAS G12D in a subject in need thereof, characterized in that: The method comprises administering to a subject a compound according to any one of claims 1 to 7, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a prodrug molecule thereof, or a pharmaceutical composition according to claim 8; Preferably, the subject is a human.

11. A combined pharmaceutical composition comprising at least one of the compound of formula (I) according to any one of claims 1 to 7, its pharmaceutically acceptable salt, its stereoisomer or its prodrug molecule or the pharmaceutical composition according to claim 8, and another therapeutic agent; Preferably, the other therapeutic agent is a drug for treating tumors or cancer, such as lapatinib or taliciquida; Preferably, the molar ratio of the compound represented by formula (I) to the other therapeutic agent is selected from (0.001-1.5):1, for example (0.002-1):1, such as (0.002-0.02):1 or (0.2-0.8):1.

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