KRAS inhibitors and uses thereof

Abstract

The present invention relates to KRAS inhibitors and uses thereof. Specifically, the invention relates to a compound shown as a formula (I) or pharmaceutically acceptable salt, ester, hydrate, solvate or stereoisomer thereof, a pharmaceutical composition thereof, and application of the compound or the composition in preparation of drugs for treating, inhibiting or preventing KRAS related diseases or symptoms.

Description

Technical Field

[0001] This invention relates to a KRAS inhibitor, or a pharmaceutically acceptable salt, ester, hydrate, solvate or stereoisomer thereof, and its use in the preparation of medicaments for treating, inhibiting or preventing KRAS-related diseases. Background Technology

[0002] The KRAS (Kirsten Rat Sarcoma Viral Oncogene Homolog) gene belongs to the RAS family and is one of the most common gene mutations in human cancers. It encodes a small GTPase. The KRAS gene participates in kinase signaling pathways that control gene transcription, thereby regulating cell growth and differentiation. Intracellularly, the KRAS protein alternates between inactive and activated states. When KRAS binds to guanine diphosphate (GDP), it is inactive; when it binds to guanine triphosphate (GTP), it is activated and can activate downstream signaling pathways. In most cells, KRAS is inactive. When activated, it can activate downstream signaling pathways including the MAPK signaling pathway, the PI3K signaling pathway, and the Ral-GEF signaling pathway. These signaling pathways play important roles in promoting cell survival, proliferation, and cytokine release, thus influencing tumorigenesis and development.

[0003] KRAS gene mutations include KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D, and KRAS Q61H. In human cancers, KRAS gene mutations are found in nearly 90% of pancreatic cancers, approximately 30% to 40% of colon cancers, about 17% of endometrial cancers, and about 15% to 20% of lung cancers (mostly non-small cell lung cancer, NSCLC). It also occurs in other cancer types such as bile duct cancer, cervical cancer, bladder cancer, liver cancer, and breast cancer. In other words, a high proportion of these cancers contain KRAS gene mutations. Most KRAS missense mutations occur at codon 12, resulting in the replacement of glycine with another amino acid. Depending on the specific mutation present, G12C, G12D, and G12R are the most common KRAS mutations in patients, such as KRAS G12D and KRAS G12V mutations, both of which are found in approximately 90% of pancreatic cancers.

[0004] Therefore, the development of drugs targeting these KRAS mutations is urgently needed. With the successful market launch of drugs targeting G12C, it is anticipated that cancer patients receiving these treatments will develop drug resistance. To address this issue, the development of new inhibitors against multiple KRAS mutations is of great significance. Summary of the Invention

[0005] The main technical problem solved by this invention is to provide a KRAS inhibitor. It can inhibit at least one of wild-type KRAS (WideType, KRAS WT) and KRAS mutations such as KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D, or KRAS Q61H. The applicant has discovered that compounds of formula (I), or their pharmaceutically acceptable salts, esters, hydrates, solvates, or stereoisomers, possess excellent antitumor activity.

[0006] This application provides compounds of formula (I):

[0007]

[0008] in,

[0009] A is selected from C, N, S, or O;

[0010] R 1 R 2 Independently selected from H, substituted or unsubstituted hydrocarbon groups, or absent; wherein R 1 R 2 Not both methyl;

[0011] Or, R 1 R 2 The A rings that are connected to it form substituted or unsubstituted heterocycles.

[0012] In some implementations, R 1 R2 is independently selected from substituted or unsubstituted hydrocarbon groups, wherein the hydrocarbon group is selected from C1-C6 alkyl groups (which may be C1-C6 alkyl groups). 1，2，3，4，5，6 alkyl), C3-C6 cycloalkyl (can be C 3，4，5，6 Cycloalkyl); further, the substituents are selected from halogens, C1-C4 alkyl groups (which can be C1-C4 alkyl groups). 1，2，3，4 Alkyl), hydroxyl, C1-C4 alkoxy (can be C 1，2，3，4 alkoxy group), C1-C4 carboxyl group (can be C 1，2，3，4 Carboxyl group), C1-C4 ester group (can be C 1，2，3，4 Ester group), C1-C4 amide group (can be C 1，2，3，4Amide group), substituted or unsubstituted 3-14 membered carbon rings or heterocyclic rings (which can be 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 membered carbon rings or heterocyclic rings); wherein R 1 R 2 They are not both methyl groups.

[0013] In some such embodiments, the substituents in the substituted 3-14 membered carbon rings or heterocyclic rings are selected from hydroxyl, halogen, amino, -CF3, -NH (C1-C3 alkyl), -N (C1-C3 alkyl)2, =O, -CN, -O-(C1-C3 alkyl), -(C1-C3 alkyl)-OH, -C(=O)OH, -C(=O)(C1-C3 alkyl), -C(=O)O(C1-C3 alkyl), aryl, arylalkyl, cycloalkyl, or heterocyclic alkyl; wherein the C1-C3 alkyl group can be C 1，2，3 alkyl.

[0014] In some of these embodiments, the heteroatoms in the aforementioned carbon heterocycle are N, O, or S, and the number of heteroatoms is 1, 2, 3, or 4.

[0015] In some implementations, when A is selected from O, R 1 It does not exist, R 2 It is independently selected from substituted or unsubstituted hydrocarbon groups; hydrocarbon groups are defined as above.

[0016] In some implementations, when A is selected from N, R 1 and R 2 It combines with the commonly linked N atom to form a substituted or unsubstituted 5-14 membered heterocycle, preferably a 5-14 membered heteroaryl group, and more preferably a substituted or unsubstituted pyrrole, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, quinolinyl, isoquinolinyl, purinyl, or carbazole group; wherein the substituent is selected from hydroxyl, halogen, amino, -CF3, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, =O, -CN, -O-(C1-C3 alkyl), -(C1-C3 alkyl)-OH, -C(=O)OH, -C(=O)(C1-C3 alkyl), -C(=O)O(C1-C3 alkyl), aryl, arylalkyl, cycloalkyl, or heterocyclic alkyl; wherein the C1-C3 alkyl group can be C 1，2，3 alkyl.

[0017] Furthermore, A and R 1 R 2 Together they form the following structure:

[0018]

[0019]

[0020] In some implementations, A is selected from N, R 1 Selected from methyl, R 2 Selected from B is selected from substituted or unsubstituted aromatic rings or five- or six-membered carbon heterocycles.

[0021] Furthermore, in some embodiments, the five- or six-membered carbon heterocycle is selected from pyrrole, furan, thiophene, pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, pyridazine, pyrimidine, and pyrazine.

[0022] In some implementations, A is selected from N, R 1 Selected from methyl, R 2 Selected from B is selected from substituted or substituted aromatic rings or polycyclic heterocycles. Furthermore, the polycyclic heterocycle is selected from indole, benzoxazole, benzofuran, isoindole, isobenzofuran, indole, benzoisoxazole, quinoline, isoquinoline, cyclophosphine, phthalazine, quinazoline, and quinoxaline.

[0023] In some implementations, B can be selected from the following structure:

[0024]

[0025] Substituents can be substituted from any substituted site.

[0026] Furthermore, in some implementations, A and R 1 R 2 Together they can form the following structure:

[0027]

[0028] In some embodiments, the compound is a compound shown in Table 1 below, or a pharmaceutically acceptable salt, ester, hydrate, solvate, or stereoisomer thereof:

[0029] Table 1

[0030]

[0031]

[0032]

[0033] In some embodiments, this application provides compounds of formula (II) or their pharmaceutically acceptable salts, esters, hydrates, solvates, or stereoisomers:

[0034]

[0035] Where B' is selected from the following groups:

[0036] In some embodiments, the compound is a compound shown in Table 2 below, or a pharmaceutically acceptable salt, ester, hydrate, solvate, or stereoisomer thereof:

[0037] Table 2

[0038]

[0039] The above-mentioned compounds possess good biological activity and can be used to treat diseases or conditions related to KRAS. In some embodiments, the compounds provided in this application can treat diseases or conditions related to wild-type KRAS. In some embodiments, the compounds provided in this application can treat diseases or conditions related to KRAS G12A. In some embodiments, the compounds provided in this application can treat diseases or conditions related to KRAS G12C. In some embodiments, the compounds provided in this application can treat diseases or conditions related to KRAS G12D. In some embodiments, the compounds provided in this application can treat diseases or conditions related to KRAS G12R. In some embodiments, the compounds provided in this application can treat diseases or conditions related to KRAS G12S. In some embodiments, the compounds provided in this application can treat diseases or conditions related to KRAS G12V. In some embodiments, the compounds provided in this application can treat diseases or conditions related to KRAS G13D. In some embodiments, the compounds provided in this application can treat diseases or conditions related to KRAS Q61H.

[0040] In some embodiments, the compounds provided in this application can simultaneously inhibit two or more wild-type or mutant proteins among KRAS WT, KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D, or KRAS Q61H.

[0041] In some embodiments, the compounds provided in this application can simultaneously inhibit three or more mutant proteins selected from KRAS WT, KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D, or KRAS Q61H. In some embodiments, the compounds provided in this application can simultaneously inhibit four or more mutant proteins selected from KRAS WT, KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D, or KRAS Q61H.

[0042] In some embodiments, the compounds provided in this application may be compounds with natural abundance or with isotopic substitution, and the isotopes may be... 1 H, D, T, 18 O、 17 O、 15 N and 13 C, etc.

[0043] The present invention also provides a pharmaceutical composition comprising any of the compounds described above or a pharmaceutically acceptable salt, ester, hydrate, solvate or stereoisomer thereof.

[0044] Furthermore, it also includes at least one pharmaceutically acceptable excipient, carrier, or diluent.

[0045] Furthermore, pharmaceutically acceptable excipients include one or more of binders, fillers, disintegrants, lubricants, and flow aids.

[0046] Furthermore, pharmaceutically acceptable carriers include one or more of creams, emulsions, gels, liposomes, and nanoparticles.

[0047] Furthermore, the composition is suitable for parenteral, intraperitoneal, intradermal, intracardiac, intraventricular, intracranial, intraspinal, intrasynovial, intrathecal, intrathecal, intramuscular, intravitreal, intravenous, intra-arterial, oral, oral, sublingual, transdermal, intratracheal, rectal, subcutaneous, and local administration.

[0048] This application also provides the use of any of the compounds described above, or their pharmaceutically acceptable salts, esters, isomers, hydrates, or compositions, in the preparation of a medicament for treating, inhibiting, or preventing hyperplasia. Furthermore, the present invention provides a method for treating, inhibiting, or preventing hyperplasia, comprising administering an effective amount of the compounds and / or pharmaceutical compositions described above to a subject, thereby achieving a therapeutic effect on the relevant disease.

[0049] In some implementations, the hyperplasia condition is a malignant tumor or cancer associated with at least one KRAS mutation.

[0050] Furthermore, the aforementioned malignant tumors or cancers are selected from:

[0051] Sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma;

[0052] Lung tumors or cancers: bronchial carcinoma (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar (bronchial) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroma, mesothelioma;

[0053] Gastrointestinal tumors or cancers: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyoma, lymphoma), stomach (cancer, lymphoma, leiomyoma), pancreas (ductal adenocarcinoma, insulinoma, glucosidoma, gastrinoma, carcinoid tumor, vasodilator peptide tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hematoma, leiomyoma);

[0054] Tumors or cancers of the urogenital tract: kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminomatous sarcoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoid tumor, lipoma);

[0055] Liver: Hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma;

[0056] Biliary tract tumors or cancers: gallbladder cancer, ampoule cancer, bile duct cancer;

[0057] Bone tumors or cancers: osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor, string tumor, osteochondroma, benign chondroma, chondroblastoma, chondromycinoma, osteomyxofibroma, osteoid osteoma and giant cell tumor;

[0058] Nervous system tumors or cancers: Skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), Meninges (meningioma, meningeal sarcoma, glioma), Brain (astrocytoma, myeloma, glioma, epididymal tumor, germ cell tumor (pineal tumor), glioblastoma, oligodendroglioma, glioma, retinoblastoma, congenital tumor), spinal cord neurofibroma, meningioma, glioma, sarcoma);

[0059] Gynecological tumors or cancers: Uterus (endometrial cancer (serous bladder cancer, mucinous bladder cancer, unclassified carcinoma), granulosa cell tumor, serum stromal cell tumor, dysplasia, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, uveal sarcoma (embryonic rhabdomyosarcoma);

[0060] Hematologic malignancies or cancers: Leukemia (acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma.

[0061] Dermatological tumors or cancers: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, Morse's nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis;

[0062] Adrenal tumor or cancer: neuroblastoma.

[0063] In some embodiments, the malignant tumor is one or more of non-small cell lung cancer, small cell lung cancer, pancreatic cancer, colorectal cancer, bile duct cancer, cervical cancer, bladder cancer, liver cancer, or breast cancer.

[0064] This application also provides a kit comprising any of the compounds described above or pharmaceutically acceptable salts, esters, hydrates, solvates or stereoisomers, or any of the compositions described above, which can be used to prepare a medicament for treating, inhibiting or preventing one or more KRAS mutation-related diseases or conditions.

[0065] The compound provided in this application, or its pharmaceutically acceptable salt, ester, isomer, or hydrate, has a good KRAS inhibitory effect and can be used in the preparation of drugs for treating, inhibiting, or preventing diseases or conditions associated with at least one wild-type or mutated KRAS. Detailed Implementation

[0066] To provide a clear and consistent understanding of the terminology used in this specification, some definitions are provided below. Furthermore, unless otherwise specified, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0067] When used in conjunction with the term "comprising" in the claims and / or specification, the word "a" can mean "one," but it also aligns with the meanings of "one or more," "at least one," and "one or more." Similarly, the word "another" can mean at least a second or more.

[0068] As used in this specification and claims, the words “comprising” (and any form of inclusion, such as “comprising” and “including”), “having” (and any form of having, “having,” “including,” and “containing”) are inclusive and open-ended and do not exclude additional unlisted elements or processing steps. The terms “about” or “approximately” are used to indicate that the value includes errors introduced by the instruments and methods used in determining the value.

[0069] The term "pharmaceuticalally acceptable" as used in this invention means that the drug, pharmaceutical product, inert ingredient, etc., described by the term is suitable for contact with the tissues of humans and lower animals without abnormal toxicity, incompatibility, instability, irritation, allergic reactions, etc., and is commensurate with a reasonable benefit / risk ratio.

[0070] A "pharmaceutically acceptable stereoisomer" of a compound refers to an isomer resulting from different spatial arrangements of atoms in a molecule. More specifically, isomers arising from the same order of connection of atoms or groups of atoms in a molecule but different spatial arrangements are called stereoisomers. These are mainly divided into two categories: stereoisomers caused by bond lengths, bond angles, the presence of double bonds, or the presence of rings are called configuration stereoisomers. Generally, configuration stereoisomers cannot or are very difficult to interconvert. Stereoisomers resulting solely from the rotation of single bonds are called conformational stereoisomers, sometimes also called rotational stereoisomers. When rotation in a rotational isomer is hindered and cannot occur, it becomes a "stereoisomer." For example, in the biphenyl structure, when there are large and different substituents at the α- and α'- positions, the rotation of the single bond between the two benzene rings cannot rotate freely due to the obstruction between the substituents, thus producing two stereoisomers.

[0071] The allocation of amino acid codons and residue positions for human KRAS was confirmed based on the amino acid sequence in UniProtKB / Swiss-ProtP01116.

[0072] As used herein, the term "wild-type KRAS" refers to the non-mutated form of the mammalian KRAS protein. The term "wild-type KRAS inhibitor" as used herein refers to compounds of this invention, as shown in formula (I), which are capable of negatively regulating or inhibiting all or part of the enzymatic activity of wild-type KRAS. As used herein, "wild-type KRAS-related disease or condition" refers to a disease or condition associated with, mediated by, or possessing wild-type KRAS. A non-limiting example of a wild-type KRAS-related disease or condition is wild-type KRAS-related cancer.

[0073] As used herein, the term "KRAS G12A" refers to a mutant form of the mammalian KRAS protein containing an alanine-glycine substitution at amino acid position 12. The term "KRAS G12A inhibitor" as used herein refers to compounds of the present invention, as described herein, capable of negatively regulating or inhibiting all or part of the enzymatic activity of KRAS G12A. As used herein, "KRAS G12A-related disease or condition" refers to a disease or condition associated with, mediated by, or having a KRAS G12A mutation. A non-limiting example of a KRAS G12A-related disease or condition is KRAS G12A-related cancer.

[0074] As used herein, the term "KRAS G12C" refers to a mutant form of the mammalian KRAS protein containing a cysteine-glycine substitution at amino acid position 12. The term "KRAS G12C inhibitor" as used herein refers to compounds of the present invention as described herein that negatively regulate or inhibit all or part of the enzymatic activity of KRAS G12C. The term "KRAS G12C-related disease or condition" as used herein refers to a disease or condition associated with, mediating, or having a KRAS G12C mutation. A non-limiting example of a KRAS G12C-related disease or condition is KRAS G12C-related cancer.

[0075] As used herein, the term "KRAS G12D" refers to a mutant form of the mammalian KRAS protein containing an aspartic acid substitution for glycine at amino acid position 12. As used herein, "KRAS G12D inhibitor" refers to compounds of this invention that negatively regulate or inhibit all or part of the enzymatic activity of KRAS G12D. As used herein, the term "KRAS G12D-related disease or condition" refers to a disease or condition associated with, mediated by, or possessing a KRAS G12D mutation. A non-limiting example of a KRAS G12D-related disease or condition is KRAS G12D-related cancer.

[0076] As used herein, the term "KRAS G12R" refers to a mutant form of the mammalian KRAS protein containing an arginine-glycine substitution at amino acid position 12. As used herein, the term "KRAS G12R inhibitor" refers to compounds of the present invention as described herein that negatively regulate or inhibit all or part of the enzymatic activity of KRAS G12R. As used herein, the term "KRAS G12R-related disease or condition" refers to a disease or condition associated with, mediated by, or having a KRAS G12R mutation. A non-limiting example of a KRAS G12R-related disease or condition is KRAS G12R-related cancer.

[0077] As used in this invention, the term "KRAS G12S" refers to a mutant form of the mammalian KRAS protein containing a serine substitution for glycine at amino acid position 12. The term "KRAS G12S inhibitor" as used in this invention refers to compounds of the present invention as described herein, which are capable of negatively regulating or inhibiting all or part of the enzymatic activity of KRAS G12S. The term "KRAS G12S-related disease or condition" as used in this invention refers to a disease or condition associated with, mediated by, or possessing a KRAS G12S mutation. A non-limiting example of a KRAS G12S-related disease or condition is KRAS G12S-related cancer.

[0078] As used in this invention, the term "KRAS G12V" refers to a mutant form of the mammalian KRAS protein containing a valine substitution for glycine at amino acid position 12. The term "KRAS G12V inhibitor" as used in this invention refers to compounds such as those described in this invention, which are capable of negatively regulating or inhibiting all or part of the enzymatic activity of KRAS G12V. The term "KRAS G12-related disease or condition" as used in this invention refers to a disease or condition associated with, mediated by, or having a KRAS G12V mutation. A non-limiting example of a KRAS G12V-related disease or condition is KRAS G12V-related cancer.

[0079] As used herein, the term "KRAS G13D" refers to a mutant form of the mammalian KRAS protein containing an aspartic acid substitution for glycine at amino acid position 13. The term "KRAS G13D inhibitor" as used herein refers to compounds of the present invention as described herein that negatively regulate or inhibit all or part of the enzymatic activity of KRAS G13D. The term "KRAS G13D-related disease or condition" as used herein refers to a disease or condition associated with, mediating, or having a KRAS G13D mutation. A non-limiting example of a KRAS G13D-related disease or condition is KRAS G13D-related cancer.

[0080] As used herein, the term "KRAS Q61H" refers to a mutant form of the mammalian KRAS protein containing a histidine substitution for glutamine at amino acid position 61. The term "KRAS Q61H inhibitor" as used herein refers to compounds of the present invention as described herein that negatively regulate or inhibit all or part of the enzymatic activity of KRAS Q61H. The term "KRAS Q61H-related disease or condition" as used herein refers to a disease or condition associated with, mediating, or having a KRAS Q61H mutation. A non-limiting example of a KRAS Q61H-related disease or condition is KRAS Q61H-related cancer.

[0081] The term "pharmaceutically acceptable salt" refers to a salt of a pharmaceutically acceptable compound. Ideally, a salt (basic, acidic, or charged functional group) of a compound should retain or improve the biological activity and properties of the parent compound as defined in this invention, and should not be biologically undesirable. Pharmaceutically acceptable salts can be synthesized from parent compounds containing basic or acidic segments using conventional chemical methods. Typically, such salts are prepared by reacting a compound (free acid or base) with an equistoichiometric base or acid in water, an organic solvent, or a mixture of both. Salts can be prepared in situ during the final separation or purification of the pharmaceutical preparation, or by reacting a purified compound of this invention in its free acid or base form separately with the desired corresponding base or acid and separating the resulting salt. The term "pharmaceutically acceptable salt" also includes zwitterionic compounds containing cationic groups covalently bonded to anionic groups, referred to as "internal salts." The compounds of this invention include all acids, salts, bases, and other ionic and nonionic forms. For example, if the compound in this invention is an acid, the salt form of that compound is also included. Similarly, if the compound in this invention is a salt, the acidic and / or basic forms of the compound are also included.

[0082] As used in this invention, the term "ester" refers to a compound that can be represented by the general formula RCOOR (carboxylic acid ester). These compounds are typically obtained by reacting a carboxylic acid with an alcohol (eliminating one molecule of water).

[0083] The terms "substituted" or "having substituents" refer to a parent compound or part having at least one substituent group. The terms "unsubstituted" or "not having substituents" refer to a parent compound or part having no other substituents except for an undetermined valence chemically saturated with hydrogen atoms.

[0084] In some embodiments, as mentioned in this invention, alkyl, acyl, cycloalkyl, heterocycloalkyl, alkoxy, aryloxy, heteroalkoxy, heteroaryloxy, aryl, heteroaryl group, amino acid residue, oligopeptide (dipeptide, tripeptide, tetrapeptide) residue, phosphoryl, phosphonyl, aminophosphonyl, sulfonyl, thioacyl, benzyl, alkoxycarbonyl, aminocarbonyl, mercaptothiocarbonyl, alkylthio, thiocarbonyl, benzyloxycarbonyl, glycosidic, glycosidic acid glycosidic, are optionally substituted (e.g., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" heterocyclic, "substituted" or "unsubstituted" aryl, or "substituted" or "unsubstituted" heteroaryl group).

[0085] Unless otherwise indicated, a “substituted” group has one or more substituents at one or more substituted positions of the group, and when substitution occurs at more than one position in any given structure, the substituents are the same or different at each position.

[0086] As described herein, "substituent" or "substituent group" refers to a group selected from halogens (F, Cl, Br or I), hydroxyl, mercapto, amino, nitro, carbonyl, carboxyl, alkyl, alkoxy, alkylamino, aryl, aryloxy, arylamino, acyl, thionyl, sulfonyl, phosphonyl, or other organic moieties conventionally used and accepted in organic chemistry.

[0087] The terms "cycloalkyl," "alicyclic," "carbocyclic," and their equivalents refer to groups comprising saturated or partially unsaturated carbocyclic rings in monocyclic, spirocyclic (sharing a single atom), or fused (sharing at least one bond) carbocyclic systems having 3 to 15 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopenten-1-yl, cyclopenten-2-yl, cyclopenten-3-yl, cyclohexyl, cyclohexen-1-yl, cyclohexen-2-yl, cyclohexen-3-cycloheptyl, bicyclo[4,3,0]nonyl, norbornyl, etc. The term cycloalkyl includes both unsubstituted and substituted cycloalkyl groups.

[0088] As used in this invention, the terms "aryl" and "aromatic" refer to an aromatic group having "4n+2" (π) electrons and 6 to 14 ring atoms in a conjugated monocyclic or polycyclic system (fused or unfused), where n is an integer from 1 to 3. A polycyclic system includes at least one aromatic ring. Aryl groups can be directly linked or linked via C1-C3 alkyl groups (also called arylalkyl or aralkyl groups). Examples of aryl groups include, but are not limited to, phenyl, benzyl, phenethyl, 1-phenylethyl, tolyl, naphthyl, biphenyl, terphenyl, indene, benzocyclooctenyl, benzocycloheptenyl, azulel, acenaphthel, fluorenyl, phenanthrene, anthracene, etc. The term aryl includes both unsubstituted and substituted aryl groups.

[0089] As used in this invention, the term "aromatic heterocycle" includes substituted or unsubstituted six-membered aromatic heterocycles and substituted or unsubstituted five-membered aromatic heterocycles, wherein the substituents are selected from C. 1-4 The compounds include straight-chain or branched hydrocarbon groups, halogen-substituted C1-4 straight-chain or branched hydrocarbon groups, F, Cl, Br, NO2, CN, methylenedioxy, cyclopropyl, cyclopropylmethylene, substituted or unsubstituted cyclobutyl, and substituted or unsubstituted cyclopentyl; the benzene ring, nitrogen-containing six-membered aromatic heterocycle, and five-membered aromatic heterocycle may be monosubstituted or polysubstituted; the six-membered aromatic heterocycle may contain one N atom or multiple nitrogen atoms; the five-membered aromatic heterocycle may contain one heteroatom or multiple heteroatoms, and the heteroatom may be selected from O, N, and S; the number of heteroatoms may be 1, 2, or 3; the halogens include F, Cl, and Br.

[0090] As used in this invention, the term "aromatic heterocycle" includes substituted or unsubstituted six-membered aromatic heterocycles and substituted or unsubstituted five-membered aromatic heterocycles, wherein the substituents are selected from:

[0091] (a)C 1-8 Straight-chain or branched hydrocarbon groups, halogen-substituted C 1-8 Straight-chain or branched hydrocarbon groups, F, Cl, Br, NO2, CN, methylenedioxy, OR 1 SR 2 NR 3 R 1 NR 4 COR 2 COOR 5 CONR 6 R 3 NR 7 COOR 4 SO2NR 8 R 5 (CH2) 1，2，3 NR 9 R 6 ;、(CH2) 1，2，3 OR 10 ; wherein R1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 Independently selected from H, substituted or unsubstituted C 1-8 Straight-chain or branched alkyl, substituted or unsubstituted C 2-8 Straight-chain or branched alkenyl, substituted or unsubstituted C 2-8 The substituents are selected from F, Cl, Br, CN, and OR. The substituents may be linear or branched alkynyl groups, substituted or unsubstituted 3-7 membered cyclic hydrocarbon groups, substituted or unsubstituted 3-8 membered oxocyclic hydrocarbon groups, substituted or unsubstituted 3-8 membered azocyclic hydrocarbon groups, substituted or unsubstituted phenyl groups, substituted or unsubstituted six-membered aromatic heterocycles, or substituted or unsubstituted five-membered aromatic heterocycles. a1 SR a2 NR a3 R b1 COOR a4 CONR a5 R b2 NR a6 COOR b3 SO2NR a7 R b4 NR a8 COR b5 The R mentioned therein a1 R a2 R a3 R b1 R a4 R a5 R b2 R a6 R b3 R a7 R b4 R a8 R b5 Independently selected from H, C1-4 straight-chain or branched hydrocarbon groups, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl; the 3-8 membered ring oxoheterocyclic hydrocarbon group or nitrogen-heterocyclic hydrocarbon group may contain one heteroatom or multiple heteroatoms at the same time;

[0092] (b) Substituted or unsubstituted C 3-7 Cycloalkyl, substituted or unsubstituted 3-8 membered ring oxocyclic hydrocarbon group, substituted or unsubstituted 3-8 membered ring azocyclic hydrocarbon group, wherein the substituent is selected from C 1-5 Straight-chain or branched hydrocarbon groups, F, Cl, Br, CN, OR a1 SRa2 NR a3 R b1 COOR a4 CONR a5 R b2 NR a6 COOR b3 SO2NR a7 R b4 NR a8 COR b5 The R mentioned therein a1 R a2 R a3 R b1 R a4 R a5 R b2 R a6 R b3 R a7 R b4 R a8 R b5 Independently selected from H, C1-4 straight-chain or branched hydrocarbon groups, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl; the 3-8 membered ring oxoheterocyclic hydrocarbon group or nitrogen-heterocyclic hydrocarbon group may contain one heteroatom or multiple heteroatoms at the same time;

[0093] (c) A substituted or unsubstituted phenyl group, a substituted or unsubstituted six-membered aromatic heterocycle, or a substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from F, Cl, Br, CN, OR. a1 SR a2 NR a3 R b1 COOR a4 CONR a5 R b2 NR a6 COOR b3 SO2NR a7 R b4 NR a8 COR b5 The R mentioned therein a1 R a2 R a3 R b1 R a4 R a5 R b2 R a6 R b3 R a7 R b4 R a8 R b5 Independently selected from H and C 1-4The halogens are straight-chain or branched hydrocarbon groups, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, and cyclohexyl; the six-membered or five-membered aromatic heterocycles may be monosubstituted or polysubstituted; the six-membered aromatic heterocycle may contain one nitrogen atom or multiple nitrogen atoms; the five-membered aromatic heterocycle may contain one heteroatom or multiple heteroatoms, and the heteroatom is selected from O, N, and S; the halogens mentioned include F, Cl, and Br.

[0094] As used in this invention, the terms "aromatic ring" and "aromatic heterocycle" include substituted or unsubstituted aromatic fused rings or fused heterocycles, including substituted or unsubstituted naphthalene rings, substituted or unsubstituted benzo6-membered heterocycles, and substituted or unsubstituted benzo5-membered heterocycles, wherein the substituents are selected from C1-4 straight-chain or branched hydrocarbon groups, halogen-substituted C1-4 straight-chain or branched hydrocarbon groups, F, Cl, Br, NO2, CN, methylenedioxy, OR s1 SR s2 NR s3 R t1 NR s4 COR t2 COOR s5 CONR s6 R t3 NR s7 COOR t4 SO2NR s8 R t5 (CH2) 1，2，3 NR s9 R t6 (CH2) 1，2，3 OR s10 The R mentioned therein s1 R s2 R s3 R t1 R s4 R t2 R s5 R s6 R t3 R s7 R t4 R s8 R t5 R s9 R t6 R s10 Independently selected from H and C 1-4 The hydroxyl group is a straight-chain or branched hydrocarbon group, cyclopropyl, cyclopropylmethylene, cyclobutyl, or cyclopentyl; wherein the naphthalene ring, benzo[6] fused heterocycle, or benzo[5] fused heterocycle may be monosubstituted or polysubstituted; the benzo[6] fused heterocycle or benzo[5] fused heterocycle may contain one heteroatom or multiple heteroatoms, and the heteroatom is selected from O, N, and S; wherein the halogen includes F, Cl, and Br.

[0095] The term "hydrocarbon group" includes, but is not limited to, saturated hydrocarbon groups, unsaturated hydrocarbon groups, aromatic hydrocarbon groups, oxane hydrocarbon groups, nitrogen hydrocarbon groups, sulfur hydrocarbon groups, phosphorus hydrocarbon groups, and mixed hydrocarbon groups with different heteroatoms. The chain length of the hydrocarbon group or the hydrocarbon group is 1 to 20 atoms. When it is a hydrocarbon group, the hydrocarbon group contains 1 to 5 heteroatoms, and the chemical valence of the heteroatoms is satisfied by hydrogen, oxygen, nitrogen, etc., in a corresponding bonding manner as needed.

[0096] The terms "cyclogroup," "alicyclic," "cyclohydrogroup," and their equivalents refer to groups that contain saturated or partially unsaturated carbon rings in monocyclic, spirocyclic (sharing a single atom), or fused (sharing at least one bond) carbocyclic systems, wherein the carbocyclic system has 3 to 15 carbon atoms. The term "cyclohydrogroup" includes composite groups consisting of cyclogroups and hydrocarbon groups.

[0097] As used in this invention, the terms "carbon heterocyclic," "heterocyclic alkyl," and equivalent expressions refer to groups comprising saturated or partially unsaturated carbon rings in monocyclic, spirocyclic (sharing a single atom), or fused (sharing at least one bond) carbocyclic systems, having 3 to 15 carbon atoms, including groups with 1 to 6 heteroatoms (e.g., N, O, S, P) or containing heteroatoms (e.g., NH, NRx (Rx is alkyl, acyl, aryl, heteroaryl, or cycloalkyl), PO2, SO, SO2, etc.). The heterocyclic alkyl group may be connected to a C atom or to a heteroatom (e.g., through a nitrogen atom). "Carbocyclic" or "carbon heterocyclic" includes heterocyclic alkyl and heteroaryl groups. Examples of heterocycles include, but are not limited to, acridine, acridine, benzimidazolyl, benzofuranyl, benzothiophenyl, benzothiophenyl, benzoxazolyl, benzotriazolyl, benzotetrazolyl, benzoisoxazolyl, benzoisothiazolyl, 4αH-carbazolyl, carbaolinyl, benzodihydropyranyl, chromenyl, cinnamyl, decahydroquinolinyl, 2H,6H-1,5,2-di-thiazinyl, dihydrofurano[2,3-b]tetrahydrofuran, and furan. Furazanyl, imidazoalkyl, imidazolinyl, imidazolyl, 1H-indazole, dihydroindolyl, 3H-indolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthidyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolylalkyl, oxazolyl, pyrimidinyl, phenanthridine, phenanthroxolinyl yl, phenazinyl, phenothiazinyl, phenotoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidinoneyl, 4-piperidinoneyl, piperinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolylyl, pyrazolyl, pyridazinyl, pyridoxazole, pyridinium-imidazazole, pyridothiazazole, pyridinyl, pyrroleyl, quinazolinyl, quinolinyl, 4H-quinazinyl, quinoxalyl, quininecycloyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinoline The terms include triazolyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thiaanthryl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 3,4-triazolyl, xanthonyl, etc. The term "carbocyclic" includes both unsubstituted and substituted carbocyclic groups.

[0098] As used in this invention, the term "acyl" refers to the -C(=O)R group left after the dehydroxylation of a molecule of carbonic acid. a The term "acyl" refers to a compound or fragment in which at least one carbon or heteroatom is covalently bonded to a carbon atom on a -C=O group. The terms "amine" or "amino" as used in this invention refer to unsubstituted or substituted groups of the general formula -NR. b R c A fragment. Ra R b and R c Each can be independently substituted or unsubstituted hydrogen, hydrocarbon, aryl, cyclic, or heterocyclic groups, or R b and R c Together with the nitrogen atoms they are attached to, they form heterocycles. The term "amide" refers to a structure where the amino group is directly linked to the acyl group -C(=O)NR b R c The term "amide group" refers to a compound or fragment in which at least one carbon or heteroatom is covalently bonded to a carbon atom on the amide group.

[0099] As used in this invention, the term "alkoxy" or "lower alkoxy" refers to a structure in which an alkyl group is bonded to an oxygen atom. Representative alkoxy groups include those having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, tert-butoxy, etc. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, propoxy, butoxy, pentoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, etc. The term "alkoxy" includes unsubstituted or substituted alkoxy groups, as well as perhaloalkoxy groups.

[0100] As used in this invention, the term "esterifying group" or "ester" refers to a structure containing an ester functional group -RCOOR' (R' is generally an alkyl or other non-H group). R is, for example, a lower alkyl or aryl group, such as methylene, ethylene, isopropylene, phenylene, etc., but not limited thereto; R' is, for example, a lower alkyl or aryl group, such as methyl, ethyl, propyl, isopropyl, butyl, phenyl, etc., but not limited thereto. For example, the term "C1-C4 ester group" refers to a group with a -COOC1-3 hydrocarbon group or a C1-3 hydrocarbon group -COO- structure, such as a -COOC1-3 alkyl group or a C1-3 alkyl-COO- structure. The term "salt-forming moiety" as used in this invention refers to a moiety capable of forming a salt with an acidic group, such as a carboxyl group, for example, but not limited to, sodium, potassium, tetraethylamine, tetrabutylamine, etc.

[0101] Pharmaceutically acceptable salts of compounds can be those mentioned by Berge et al. in "Pharmaceutical Salts", J. Pharm. Sci. 66, 1-19 (1977). These include, but are not limited to:

[0102] (1) Salts formed by adding acids to basic or positively charged functional groups. Inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, aminosulfonic acid, nitric acid, phosphoric acid, and carbonic acid. Organic acids include acetic acid, propionic acid, lactic acid, oxalic acid, glycolic acid, neopentanoic acid, tert-butylacetic acid, β-hydroxybutyric acid, valeric acid, hexanoic acid, cyclopentanepropionic acid, pyruvic acid, malonic acid, succinic acid, malic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, and cyclohexyl... Aminosulfonic acid, benzenesulfonic acid, sulfanilic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 3-phenylpropionic acid, laurylsulfonic acid, lauryl sulfate, oleic acid, palmitic acid, stearic acid, lauric acid, pyruvic acid, pantothenic acid, lactobionic acid, alginic acid, galactobionic acid, galacturonic acid, gluconic acid, glucoheponic acid, glutamic acid, naphthoic acid, hydroxynaphthoic acid, salicylic acid, ascorbic acid, mucoconic acid, etc.

[0103] (2) When the parent compound contains an acidic proton or is replaced by a metal ion, a base can be added to obtain a salt. The metal ions include basic metal ions (e.g., lithium, sodium, potassium), alkaline earth metal ions (magnesium, calcium, barium), or other metal ions such as aluminum, zinc, and iron. Organic bases include, but are not limited to, N,N′-dibenzylethylenediamine, ethanolamine, diethanolamine, triethanolamine, aminobutanetriol, N-methylglucosamine, piperazine, chloroprocaine, procaine, choline, and lysine.

[0104] The term "spirocyclic" or "spirocyclic" refers to an organic compound exhibiting a twisted structure of two or more rings (ring systems), wherein two or three rings are linked together by a common atom. Spirocyclic compounds can be fully carbocyclic (all-carbon), such as spiro[5.5]undecane, or heterocyclic (having one or more non-carbon atoms), including but not limited to carbocyclic spirocyclic compounds, heterocyclic spirocyclic compounds, and polycyclic spirocyclic compounds.

[0105] The term "bridged ring" or "bridging ring" refers to a carbon ring or heterocyclic portion in which two or more atoms are shared in two or more ring structures, wherein the shared atoms are C, N, S, or other heteroatoms arranged in a chemically rationally substituted pattern. An atom at any position on the main ring is bonded to a second atom on the main ring by a chemical bond or an atom other than a bond, and does not actually constitute part of the main ring structure. The first and second atoms may be adjacent to each other or not adjacent to each other in the main ring.

[0106] The term "fused ring" or "fused ring" refers to a polycyclic system containing a fused ring. Typically, a fused ring system comprises 2 or 3 rings and / or up to 18 ring atoms. As mentioned above, cycloalkyl, aryl, and heterocyclic groups can form fused ring systems. Therefore, fused ring systems can be aromatic, partially aromatic, or non-aromatic and can contain heteroatoms. By this definition, spirocyclic systems are not fused polycyclic, but the fused polycyclic systems of the present invention can themselves have a spirocycle attached to a single ring atom of the system. Examples of fused ring systems include, but are not limited to, naphthyl (e.g., 2-naphthyl), indenyl, phenanthryl, anthraceneyl, pyrene, benzimidazole, benzothiazole, etc.

[0107] Pharmaceutically acceptable salts can be synthesized from parent compounds containing basic or acidic fragments using conventional chemical methods. Typically, such salts are prepared by reacting a compound (free acid or base) with an equistoichiometric base or acid in water, an organic solvent, or a mixture of both. Salts can be prepared in situ during the final separation or purification of the pharmaceutical preparation, or by reacting a purified compound of the invention in free acid or base form separately with the desired corresponding base or acid and then separating the resulting salt. The term "pharmaceutically acceptable salt" also includes zwitterionic compounds containing cationic groups covalently bonded to anionic groups, which are referred to as "internal salts." The compounds of the present invention include all acids, salts, bases, and other ionic and nonionic forms. For example, if the compound in the present invention is an acid, the salt form of that compound is also included. Similarly, if the compound in the present invention is a salt, the acidic and / or base forms of that compound are also included.

[0108] As used herein, the term "effective amount" refers to the quantity or dose of a therapeutic agent (e.g., a compound) that, when administered to a subject in a single or multiple doses, provides the desired therapeutic, diagnostic, or prognostic effect in the subject. The effective amount can be readily determined by the attending or diagnostic physician using known techniques and by observing results obtained in similar circumstances. In determining the effective amount or dose of the administered compound, many factors are considered, including but not limited to: the subject's weight, age, and general health condition; the specific disease involved; the extent or severity of the disease or condition to be treated; the individual subject's response; the specific compound administered; the administration modality; the bioavailability characteristics of the administered formulation; the chosen dosing regimen; the use of concomitant medications; and other relevant considerations.

[0109] The present invention also provides pharmaceutical compositions, in some embodiments of which include: a compound disclosed herein or a pharmaceutically acceptable salt, ester, isomer, or hydrate thereof, and a pharmaceutically acceptable excipient, carrier, or diluent.

[0110] Specifically, pharmaceutically acceptable excipients include one or more of binders, fillers, disintegrants, lubricants, and flow aids. Pharmaceutically acceptable carriers or diluents include one or more of creams, emulsions, gels, liposomes, and nanoparticles.

[0111] "Pharmaceutical composition" means comprising compounds as described herein, and at least one component depending on the requirements of the route of administration and dosage form, including pharmaceutically acceptable carriers, diluents, adjuvants, excipients, or loads, such as preservatives, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, aromatizers, antimicrobial agents, antifungal agents, lubricants, and dispersants. "Prevention" or "protection" is used to indicate at least a reduction in the likelihood of acquiring a disease or condition (or susceptibility) or developing a disease or disorder (i.e., preventing the development of clinical symptoms of at least one disease into patients who may be exposed to or susceptible to the disease but have not yet experienced or displayed symptoms of the disease).

[0112] The term "subject" refers to animals including mammals and humans, especially humans.

[0113] The term "prodrug" or its equivalents refer to a reagent that is directly or indirectly converted into its active form in vitro or in vivo (see, for example, R.B. Silverman, 1992, "The Organic Chemistry of Drug Design and Drug Action", Academic Press, Chap. 8; Bundgaard, Hans; Editor. Neth. (1985), "Design of Prodrugs", 360pp. Elsevier, Amsterdam; Stella, V.; Borchardt, R.; Hageman, M.; Oliyai, R.; Maag, H.; Tilley, J. (Eds.) (2007), "Prodrugs: Challenges and..."). Rewards, XVIII, 1470p. Springer. Prodrugs can be used to alter the biodistribution (e.g., preventing the drug from normally entering protease reaction sites) or pharmacokinetics of a specific drug. A variety of groups have been used to modify compounds to form prodrugs, such as esters, ethers, phosphate esters / salts, etc. When a prodrug is administered to a subject, the group is cleaved away enzymatically or non-enzymatically, reductively, oxidatively, or hydrolyzed, or otherwise releases the active compound. As used herein, “prodrug” includes pharmaceutically acceptable salts or esters, or pharmaceutically acceptable solvates or chelates, and any of the crystalline forms described above.

[0114] Other diseases, disorders, and conditions that can be treated or prevented, either wholly or partially, by inhibiting KRAS activity are also candidate indications for the KRAS inhibitor compounds and compositions provided in this invention.

[0115] The term "treatment" refers to the initiation of action (e.g., administration of a KRAS inhibitor or a pharmaceutical composition comprising it) after a disease, disorder, or condition or its symptoms have been diagnosed or observed, in order to temporarily or permanently eliminate, reduce, suppress, alleviate, or improve at least one underlying cause of the disease, disorder, or condition afflicting a subject, or symptoms associated with the disease, disorder, or condition afflicting the subject. Therefore, treatment includes suppressing (e.g., preventing or alleviating the development or further development of a disease, disorder, or condition or its associated clinical symptoms) an active disease. Specifically, the term "treatment" as used herein is used to specifically refer to administering a therapeutic agent comprising a compound or composition according to the invention to a patient already suffering from an infection. The term "treatment" also relates to administering a compound or composition according to the invention, optionally together with one or more antimicrobial agents, to reduce or alleviate one or more symptoms associated with wild-type KRAS or KRAS mutations; or to alleviate the development of one or more symptoms associated with wild-type KRAS or KRAS mutations; or to reduce the severity of KRAS mutations or the severity of one or more symptoms associated with KRAS mutations; or to suppress the clinical manifestations of KRAS mutations; or to suppress the manifestation of adverse symptoms of KRAS mutations.

[0116] The term "prevention" refers to initiating action (e.g., administering a KRAS inhibitor or a pharmaceutical composition containing it) in a certain way (e.g., before the onset of a disease, disorder, condition, or its symptoms) to temporarily or permanently prevent, inhibit, suppress, or reduce the risk of a subject having a disease, disorder, or condition (as determined by, for example, the absence of clinical symptoms) or, in the case of a subject susceptible to a particular disease, disorder, or condition, delay its onset. In some cases, the term also refers to slowing the progression of a disease, disorder, or condition or inhibiting its development into a harmful or other undesirable state. Specifically, as used in this application, the term "prevention" is used to mean administering a compound or composition according to the invention to prevent the occurrence of diseases related to KRAS mutations. The term "prevention" also covers the prevention of at least one KRAS mutation by administering a compound or composition according to the invention to a patient susceptible to or at risk of KRAS mutations.

[0117] As used herein, the term "KRAS-related disease" or other synonymous expressions refer to any disease, condition, or other pathological symptom in which wild-type KRAS or known mutated KRAS plays a role. Therefore, in some embodiments, this application relates to treating or alleviating the severity of one or more diseases in which KRAS is known to play a role. Specifically, KRAS mutation-related diseases are hyperproliferative diseases, such as malignancies, preferably lung cancers such as non-small cell lung cancer, pancreatic cancer, bile duct cancer, cervical cancer, bladder cancer, liver cancer, or breast cancer.

[0118] In some embodiments, the present invention further provides the use of the KRAS inhibitor compounds and compositions described herein in combination with one or more additional agents. These additional agents may have KRAS-modifying activity and / or they may act through different mechanisms of action. In some embodiments, such agents comprise radiation (e.g., local or total radiotherapy) and / or other forms of treatment of a non-pharmacological nature. When using combination therapy, the KRAS inhibitor and an additional agent may be in the form of a single composition or multiple compositions, and the treatment may be administered simultaneously, sequentially, or through some other regimen. For example, in some embodiments, an implementation is provided where a chemotherapy phase follows a radiation phase. Combination therapy may have additive or synergistic effects.

[0119] Pharmaceutical compositions containing an active ingredient (e.g., a KRAS inhibitor) can be in forms suitable for oral administration, such as tablets, capsules, lozenges, sugar tablets, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups, solutions, microbeads, or elixirs. Pharmaceutical compositions for oral administration can be prepared according to any method known in the art for manufacturing pharmaceutical compositions, and such compositions can contain one or more agents, such as sweeteners, flavoring agents, coloring agents, and preservatives, to provide a pharmaceutically acceptable formulation. Tablets, capsules, etc., typically contain the active ingredient mixed with a non-toxic, pharmaceutically acceptable carrier or excipient suitable for manufacturing tablets. These carriers or excipients can be, for example, diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrants such as corn starch or alginate; binders such as starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc.

[0120] In some embodiments, the composition is an injectable formulation. In other embodiments, the composition is formulated for oral administration to a subject.

[0121] In some embodiments, the pharmaceutical composition is contained in a single-use container (e.g., a single-use vial, ampoule, syringe, or autoinjector), while in other embodiments, it is contained in a reusable container (e.g., a reusable vial).

[0122] The formulation may also include a carrier to protect the composition from rapid degradation or disappearance from the body, such as controlled-release formulations, including liposomes, hydrogels, and microencapsulated delivery systems. For example, delayed-release materials, such as glyceryl monostearate or glyceryl stearate alone, or in combination with waxes, may be used. Any drug delivery device can be used to deliver KRAS inhibitors, including implants (e.g., implantable pumps) and catheter systems, slow-infusion pumps, and devices. All of these are well known to those skilled in the art.

[0123] Pharmaceutical compositions can also be in the form of sterile injectable aqueous or oily suspensions. These suspensions can be formulated using suitable dispersants or wetting agents and suspending agents mentioned in this application, according to known techniques. Sterile injectable formulations can also be sterile injectable solutions or suspensions in non-toxic, parenteral-acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable diluents, solvents, and dispersion media that can be used include water, Ringer's solution, isotonic sodium chloride solution, Cremophor ELTM (BASF, Parsippany, NJ) or phosphate-buffered saline (PBS), alcohols, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. Additionally, sterile fixative oils are commonly used as solvents or suspension media. For this purpose, any mild fixative oil can be used, including synthetic monoglycerides or diglycerides. Furthermore, fatty acids (such as oleic acid) can be used to prepare injectable formulations. Prolonged absorption of specific injectable formulations can be achieved by including agents that delay absorption (e.g., aluminum monostearate or gelatin).

[0124] The KRAS inhibitor compounds and compositions provided by this invention can be administered to subjects in any suitable manner known in the art. Suitable routes of administration include, but are not limited to, oral; parenteral, such as intramuscular, intravenous, subcutaneous (e.g., injection or implantation), intraperitoneal, intracisional, intra-articular, intracranial (within the brain parenchyma and ventricles; nasal; vaginal; sublingual; intraocular; rectal; local (e.g., transdermal); oral and inhalation. Accumulated injection, typically administered subcutaneously or intramuscularly, can also be used to release the KRAS inhibitors disclosed in this application within a defined time period.

[0125] This invention also provides kits comprising KRAS inhibitor compounds or compositions. Kits are typically in the form of a physical structure containing various components and can be used, for example, to implement the methods provided in this application. For example, a kit may include one or more KRAS inhibitors disclosed in this invention (e.g., provided in a sterile container), which may be in the form of a pharmaceutical composition suitable for administration to a subject. KRAS inhibitors may be provided in ready-to-use form (e.g., tablets or capsules) or in form requiring, for example, reconstitution or dilution before administration (e.g., powder). When the KRAS inhibitor is in a form requiring reconstitution or dilution by the user, the kit may also include diluents (e.g., sterile water), buffers, pharmaceutically acceptable excipients, etc., packaged together with or separately from the KRAS inhibitor. When using combination therapy, the kit may contain several therapeutic agents independently, or they may already be combined in the kit. Each component of the kit may be packaged in a separate container, and all the various containers may be in a single package. The kits of this invention may be designed to maintain the components contained therein under the conditions required (e.g., refrigeration or freezing).

[0126] To better understand the present invention and to more clearly demonstrate how to implement it, features of embodiments according to the present invention are now illustrated by way of example.

[0127] Example

[0128] The invention will be more readily understood by referring to the following embodiments, which are used to illustrate the invention and should not be construed as limiting the scope of the invention in any way.

[0129] Unless otherwise defined or the context clearly requires, all technical and scientific terms used in this application have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. It should be understood that any methods and materials similar to or equivalent to those described in this application may be used in the practice or testing of this invention. Unless otherwise stated, all materials and instruments used in this application are commercially available.

[0130] Preparation example:

[0131] Example 1: Synthesis of Compound 1

[0132]

[0133] 1,1-Cyclopropanediethanol (267.84 mg, 2.62 mmol, 3 eq) was dispersed in tetrahydrofuran (5 mL), followed by the addition of compound 1-1 (300 mg, 874.17 μmol, 1 eq). The mixture was cooled to 0°C under nitrogen protection, and then 60% sodium hydride (104.8 mg, 2.62 mmol, 3 eq) was added, followed by stirring at 0°C for 0.5 h. The reaction mixture was brought to room temperature, and dichloromethane was added and stirred for 10 min, followed by washing with water and brine. The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (MeOH / CH2Cl2 = 0-3%) to give compound 1-2 (180 mg, yield 50.4%). m / z, (ESI) + ): 409.5.

[0134] Compounds 1-2 (180 mg, 440.26 μmol, 1 eq) were dispersed in a mixed solution of dioxane (10 mL) and water (1 mL), followed by the sequential addition of 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxoborane (317.18 mg, 880.51 μmol, 2 eq), potassium phosphate (280.36 mg, 1.32 mmol, 3 eq), and cataCXiumAPd G3 (64.04 mg, 88.05 μmol, 0.2 eq). The reaction mixture was purged three times with nitrogen, heated to 90°C and stirred for 3 hours under nitrogen protection, and then cooled to room temperature. Dichloromethane was added to the reaction mixture and stirred for 10 minutes, followed by washing with water and brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (MeOH / CH2Cl2 = 0-2%) to give compounds 1-3 (200 mg, yield 74.9%). m / z, (ESI) + ): 607.9.

[0135] Compounds 1-3 (200 mg, 329.67 μmol, 1 eq) were dispersed in dichloromethane (10 mL), followed by the sequential addition of triphenylphosphine (259.41 mg, 989.02 μmol, 3 eq), imidazole (67.33 mg, 989.02 μmol, 3 eq), and iodine (167.35 mg, 659.35 μmol, 2 eq). The reaction mixture was stirred at 25°C for 1 hour, then concentrated to dryness under vacuum. The residue was purified by column chromatography (MeOH / CH2Cl2 = 0-1%) to give compounds 1-4 (220 mg, yield 93.1%). m / z, (ESI) + ): 717.3.

[0136] Compounds 1-4 (60 mg, 83.73 μmol, 1 eq) were dispersed in DMF (2 mL), and N-methyl-4-pyrimidinemethylamine (20.7 mg, 167.46 μmol, 2 eq) and N,N-diisopropylethylamine (108.2 mg, 837.34 μmol, 10 eq) were added. The reaction mixture was stirred at 50 °C for 16 h, and then cooled to room temperature. Ethyl acetate was added to the reaction mixture and stirred for 10 min, followed by washing with water and brine. The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (MeOH / CH2Cl2 = 0-9%) to give compound 1 (17 mg, 23.88 μmol, yield 28.5%).

[0137] 1 H NMR (400MHz, CD3OD) δppm 9.31 (d, J=6.2Hz, 1H), 9.01 (d, J=1.4Hz, 1H), 8.54 (d, J=5.2Hz, 1H), 7.74-7.67 (m, 2H), 7.35 (d, J =2.7Hz, 1H), 7.29 (t, J = 9.4Hz, 1H), 7.14 (d, J = 2.6Hz, 1H), 4.80-4.70 (m, 1H), 4.65-4.53 (m, 4H), 4 .51-4.44 (m, 2H), 3.85 (t, J=12.9Hz, 1H), 3.78 (d, J=11.5Hz, 2H), 2.68-2.49 (m, 6H), 2.45 (d, J=7. 8Hz, 3H), 2.01 (s, 3H), 0.85 (dt, J=7.6, 3.8Hz, 3H), 0.76 (d, J=12.0Hz, 3H), 0.58 (d, J=4.8Hz, 2H). 19 F NMR (376MHz, CD3OD) δppm -121.10 (d, J=8.5Hz, 1F), -139.09 (d, J=49.5Hz, 1F).m / z, (ESI + ): 712.4.

[0138] Example 2: Synthesis of Compound 2

[0139]

[0140] The synthesis steps of compound 2 are the same as those of compound 1, using methyl(pyrimidin-5-ylmethyl)amine as the starting material. 1H NMR (400MHz, CD3OD) δ9.32 (dd, J=7.2, 1.8Hz, 1H), 9.24-8.71 (m, 3H), 7.72 (ddd, J= 8.8, 5.9, 1.8Hz, 1H), 7.35 (d, J=2.5Hz, 1H), 7.29 (t, J=9.4Hz, 1H), 7.13 (d, J=2.6H z, 1H), 4.81-4.47 (m, 7H), 3.85 (t, J=12.7Hz, 1H), 3.68-3.43 (m, 2H), 3.19-3.11 (m , 1H), 2.66-2.48(m, 5H), 2.41-2.15(m, 4H), 2.10-1.81(m, 4H), 0.94-0.81(m, 6H). 19 F NMR (376MHz, CD3OD) δ-121.12 (s, 1F), -139.17 (d, J=39.3Hz, 1F).m / z (ESI + ): 668.4.

[0141] Example 3: Synthesis of Compound 3

[0142]

[0143] The synthesis steps of compound 3 are the same as those of compound 1, using pyrazine-2-methyl-amino acid methyl ester as the starting material. 1 H NMR (400MHz, CD3OD) δ9.31 (d, J=8.0Hz, 1H), 8.71 (s, 1H), 8.48 (t, J=2.1Hz, 1H), 8.42 (s , 1H), 7.72 (dd, J=9.0, 5.9Hz, 1H), 7.37-7.24 (m, 2H), 7.13 (d, J=2.3Hz, 1H), 4.76-4.38 (m, 7H), 3.88 (td, J=13.6, 2.4Hz, 2H), 3.54-3.47 (m, 1H), 2.60-2.45 (m, 6H), 2.33 (d, J= 12.9Hz, 1H), 2.24 (d, J=9.8Hz, 1H), 2.10-1.80 (m, 4H), 0.89-0.73 (m, 6H), 0.62 (s, 2H). 19 F NMR (376MHz, CD3OD) δ-121.15 (s, 1F), -139.16 (d, J=39.5Hz, 1F).m / z (ESI + ): 668.2.

[0144] Example 4: Synthesis of Compound 4

[0145]

[0146] The synthesis steps of compound 4 are the same as those of compound 1, using N-methyl-4-fluorobenzylamine as the starting material. 1 H NMR (400MHz, CD3OD) δ9.33 (d, J=7.2Hz, 1H), 7.72 (dd, J=9.0, 5.8Hz, 1H), 7.47 (s, 2H), 7.35 ( d, J=2.7Hz, 1H), 7.29 (t, J=9.4Hz, 1H), 7.13 (d, J=2.6Hz, 1H), 6.98 (d, J=9.4Hz, 2H), 4.78-4. 46 (m, 7H), 3.87 (t, J=14.3Hz, 2H), 3.53-3.43 (m, 1H), 2.53 (dt, J=17.0, 5.5Hz, 7H), 2.34 (d, J=13.2Hz, 1H), 2.23 (t, J=7.6Hz, 1H), 2.11-1.80 (m, 4H), 0.86 (t, J=6.4Hz, 5H), 0.68 (s, 2H). 19 F NMR (376MHz, CD3OD) δ-121.09 (s, 1F), -139.22 (d, J=45.4Hz, 2F).m / z, (ESI + ): 684.5.

[0147] Example 5: Synthesis of Compound 5

[0148]

[0149] The synthesis steps of compound 5 are the same as those of compound 1, using N-methyl-N-(4-trifluoromethyl)benzylamine as the starting material. 1H NMR (400MHz, CD3OD) δ9.32 (d, J=5.6Hz, 1H), 7.72 (dd, J=9.0, 5.8Hz, 1H), 7.50 (q, J=8.2Hz, 4H), 7.35 (d, J=2.6Hz, 1H), 7.29 (t, J=9.4Hz, 1H), 7.13 (d, J=2.6Hz, 1H), 4.80-4.34 (m, 7H), 3.88 (dd, J=17.6, 13.6Hz, 1H), 3.75-3.62 (m, 2H), 3.5 4-3.41 (m, 1H), 2.52 (td, J=12.1, 10.0, 6.9Hz, 4H), 2.35 (s, 4H), 2.26-2.19 (m, 1H), 2.13-2.05 (m, 1H), 1.98 (ddd, J=13 .7, 9.9, 3.7Hz, 1H), 1.84 (qd, J=8.4, 5.1, 4.1Hz, 1H), 0.84 (td, J=7.3, 4.3Hz, 3H), 0.77 (s, 2H), 0.57 (d, J=4.9Hz, 2H). 19 F NMR (376MHz, CD3OD) δ-63.71 (s, 3F), -121.12 (t, J=7.8Hz, 1F), -139.00 (d, J=60.2Hz, 1F).m / z, (ESI + ): 734.5.

[0150] Example 6: Synthesis of Compound 6

[0151]

[0152] The synthesis steps of compound 6 are the same as those of compound 1, using N-methyl-N-(3-trifluoromethyl)benzylamine as the starting material. 1H NMR (400MHz, CD3OD) δ9.31 (d, J=9.1Hz, 1H), 7.72 (dd, J=9.1, 5.8Hz, 1H), 7.64-7.44 (m, 3H), 7.39 (t, J=7. 7Hz, 1H), 7.34 (d, J=2.7Hz, 1H), 7.29 (t, J=9.4Hz, 1H), 7.12 (d, J=2.6Hz, 1H), 4.71-4.42 (m, 6H), 3.88 (t, J =13.4Hz, 1H), 3.68 (s, 2H), 3.49 (ddd, J = 16.0, 8.1, 5.2Hz, 1H), 2.61-2.47 (m, 5H), 2.34 (s, 5H), 2.10-1.9 4 (m, 2H), 1.84 (dd, J=9.1, 5.0Hz, 1H), 0.85 (q, J=6.9Hz, 3H), 0.76 (d, J=4.9Hz, 2H), 0.57 (d, J=5.2Hz, 2H). 19 F NMR (376MHz, CD3OD) δ-63.93 (s, 3F), -121.11 (s, 1F), -139.03 (d, J=33.8Hz, 1F).m / z, (ESI + ): 734.4.

[0153] Example 7: Synthesis of Compound 7

[0154]

[0155] The synthesis steps of compound 7 are the same as those of compound 1, using 1-(3-fluoro-4-methoxyphenyl)-N-methylmethylamine as the starting material. 1 H NMR (400MHz, CD3OD) δ9.33 (d, J=5.5Hz, 1H), 7.73 (dd, J=9.1, 5.8Hz, 1H), 7.54-7.24 (m, 3H), 7.12 (d, J=2.6Hz, 1H), 6.68 (s, 2H), 4.69-4.46 (m, 7H), 3.95-3.80 (m, 2H), 3.75 (d, J=1.8Hz, 3H), 3.57-3.49 (m, 1H), 2.57 -2.48(m, 4H), 2.38-2.19(m, 3H), 2.13-1.92(m, 3H), 0.94-0.80(m, 7H). 19 F NMR (376MHz, CD3OD) δ-76.91 (s, 1F), -121.07 (s, 2F).m / z, (ESI + ): 714.6.

[0156] Example 8: Synthesis of Compound 8

[0157]

[0158] The synthesis of compound 8 follows the same steps as that of compound 1, using (3S,4S)-4-fluoro-3-pyrrolol as the starting material. 1 H NMR (400MHz, CD3OD) δ9.13 (d, J=13.6Hz, 1H), 7.72 (dd, J=9.0, 5.8Hz, 1H), 7.3 5 (d, J=2.7Hz, 1H), 7.31 (d, J=9.5Hz, 1H), 7.13 (d, J=2.6Hz, 1H), 4.69-4.54 (m , 12H), 3.84-3.79 (m, 1H), 3.64 (q, J=7.3Hz, 1H), 3.51 (q, J=1.7Hz, 1H), 3.17 ( q, J=1.7Hz, 1H), 2.57-2.48 (m, 4H), 2.36-2.26 (m, 3H), 0.91 (q, J=7.3Hz, 8H). 19 F NMR (376MHz, CD3OD) δ-120.84 (d, J=8.2Hz, 1F), -142.57 (s, 1F), -142.65 (s, 1F).m / z, (ESI + ): 650.2.

[0159] Example 9: Synthesis of Compound 9

[0160]

[0161] The synthesis steps of compound 9 are the same as those of compound 1, using 3-cyanopyrrolidine as the starting material. 1H NMR (400MHz, CD3OD) δ9.28 (d, J=7.6Hz, 1H), 7.72 (dd, J=9.0, 5.8Hz, 1H), 7.34 (d, J=2.7Hz, 1H), 7.29 (t, J=9.4H z, 1H), 7.11 (t, J=2.1Hz, 1H), 4.74-4.53 (m, 5H), 4.45-4.38 (m, 1H), 3.86 (t, J=13.0Hz, 1H), 3.53-3.43 (m, 1H), 3 .15 (dtd, J=10.2, 5.1, 2.3Hz, 1H), 2.87 (dtd, J=29.6, 9.4, 4.7Hz, 3H), 2.67-2.49 (m, 6H), 2.34-2.20 (m, 3H), 2.1 0-1.95 (m, 3H), 1.86 (d, J = 10.6Hz, 1H), 0.85 (q, J = 7.2Hz, 3H), 0.77 (q, J = 3.8, 3.0Hz, 2H), 0.57 (d, J = 1.6Hz, 2H). 19 F NMR (376MHz, CD3OD) δ-121.13 (t, J=7.8Hz, 1F), -139.13 (d, J=38.6Hz, 1F).m / z, (ESI + ): 641.4.

[0162] Example 10: Synthesis of Compound 10

[0163]

[0164] The synthesis steps of compound 10 are the same as those of compound 1, using N-methyl-3-thiophene methylamine as the starting material. 1H NMR (400MHz, CD3OD) δ9.31 (d, J=3.3Hz, 1H), 7.72 (dd, J=9.0, 5.8Hz, 1H), 7.35 (d, J=2.7Hz, 1H), 7.32-7.22 (m , 3H), 7.12 (d, J=2.6Hz, 1H), 7.06 (d, J=4.9Hz, 1H), 4.76-4.42 (m, 7H), 3.88 (dd, J=15.0, 13.6Hz, 1H), 3.70 (s, 2H), 3.55-3.43 (m, 1H), 2.57 (ddd, J=11.8, 6.1, 2.9Hz, 4H), 2.36 (d, J=10.9Hz, 4H), 2.27-2.17 (m, 1H), 2.09- 1.95 (m, 2H), 1.86 (d, J = 8.8Hz, 1H), 0.86 (td, J = 7.4, 5.4Hz, 3H), 0.78 (d, J = 4.8Hz, 2H), 0.58 (d, J = 5.2Hz, 2H). 19 F NMR (376MHz, CD3OD) δ-121.10 (t, J=8.3Hz, 1F), -139.02 (d, J=41.2Hz, 1F).m / z, (ESI + ): 672.6.

[0165] Example 11: Synthesis of Compound 11

[0166]

[0167] The synthesis steps of compound 11 are the same as those of compound 1, using (3-furanylmethyl)methylamine as the starting material. 1H NMR (400MHz, CD3OD) δ9.31 (d, J=3.1Hz, 1H), 7.72 (dd, J=9.1, 5.8Hz, 1H), 7.57 (d, J=1.7Hz, 1H), 7.43 (t, J=1.6Hz, 1H ), 7.35 (d, J=2.7Hz, 1H), 7.30 (t, J=9.4Hz, 1H), 7.12 (d, J=2.6Hz, 1H), 6.51 (s, 1H), 4.68-4.44 (m, 6H), 3.87 (dd, J=15 .3, 13.6Hz, 1H), 3.54-3.45 (m, 1H), 2.78 (d, J=29.0Hz, 3H), 2.60-2.52 (m, 3H), 2.49 (s, 2H), 2.44 (s, 3H), 2.34 (d, J= 13.1Hz, 1H), 2.21 (ddd, J=14.2, 7.0, 3.0Hz, 1H), 1.99 (s, 1H), 1.87 (d, J=7.7Hz, 1H), 0.88-0.82 (m, 5H), 0.65 (s, 2H). 19 F NMR (376MHz, CD3OD) δ-121.10 (t, J=7.8Hz, 1F), -139.15 (d, J=45.8Hz, 1F).m / z, (ESI + ): 656.5.

[0168] Example 12: Synthesis of Compound 12

[0169]

[0170] The synthesis of compound 12 was performed following the same procedure as compound 1, using N-methyl(thiazolyl-5-yl)methylamine as the starting material. 1H NMR (400MHz, CD3OD) δ9.30 (d, J=2.8Hz, 1H), 8.84 (d, J=3.3Hz, 1H), 7.76 (s, 1H), 7.72 (dd, J=9.1, 5.8H z, 1H), 7.34 (d, J=2.7Hz, 1H), 7.29 (t, J=9.4Hz, 1H), 7.13 (d, J=2.6Hz, 1H), 4.78-4.47 (m, 7H), 3.96-3. 83 (m, 4H), 3.52-3.42 (m, 1H), 2.62-2.51 (m, 5H), 2.38 (s, 3H), 2.21 (ddt, J=11.4, 7.3, 4.3Hz, 1H), 2.0 2-1.95 (m, 1H), 1.88-1.82 (m, 1H), 0.85 (q, J=3.3Hz, 3H), 0.77 (d, J=4.8Hz, 2H), 0.57 (d, J=5.2Hz, 2H). 19 F NMR (376MHz, CD3OD) δ-121.10 (t, J=7.9Hz, 1F), -138.96 (d, J=49.3Hz, 1F).m / z, (ESI + ): 673.5.

[0171] Example 13: Synthesis of Compound 13

[0172]

[0173] The synthesis steps of compound 13 are the same as those of compound 1, using N-methyl-N-furanylamine as the starting material. 1 H NMR (400MHz, CD3OD) δ9.32 (d, J=3.1Hz, 1H), 7.72 (dd, J=9.1, 5.8Hz, 1H), 7.48 (s, 1H), 7.35 (d, J=2.7Hz, 1H), 7.30 (t, J=9.4Hz, 1H), 7.12 (dd, J=2.7, 1.3Hz, 1H), 6.50 (s, 1H), 6.39 (dd, J=3.3, 1.9Hz, 1H), 4.79-4.45 (m, 7H), 4.02 (s , 2H), 3.87 (dd, J=15.0, 13.6Hz, 1H), 3.55-3.42 (m, 1H), 2.97-2.81 (m, 2H), 2.61-2.50 (m, 6H), 2.34 (d, J=13.1Hz, 1 H), 2.22 (dtd, J=14.6, 7.3, 2.9Hz, 1H), 2.01 (s, 1H), 1.89-1.81 (m, 1H), 0.85 (dd, J=13.6, 6.6Hz, 5H), 0.70 (s, 2H).19 F NMR (376MHz, CD3OD) δ-121.08 (t, J=7.5Hz, 1F), -139.38 (d, J=53.1Hz, 1F).m / z, (ESI + ): 656.6.

[0174] Example 14: Synthesis of Compound 14

[0175]

[0176] The synthesis steps of compound 14 are the same as those of compound 1, using N-methyl-2-thiophene methylamine as the starting material. 1 H NMR (400MHz, CD3OD) δ9.32 (d, J=1.6Hz, 1H), 7.72 (dd, J=9.1, 5.8Hz, 1H), 7.38-7.26 (m, 3H), 7 .12 (d, J=2.6Hz, 2H), 6.98 (d, J=4.9Hz, 1H), 4.75-4.50 (m, 7H), 4.11 (s, 2H), 3.89 (t, J=14.1H z, 1H), 2.83 (s, 3H), 2.55 (td, J=8.9, 8.5, 5.1Hz, 5H), 2.34 (d, J=13.2Hz, 1H), 2.22 (ddt, J=11 .5, 7.4, 4.3Hz, 1H), 2.09-1.97 (m, 2H), 1.86 (s, 1H), 0.85 (td, J=7.3, 5.4Hz, 5H), 0.67 (s, 2H). 19 F NMR (376MHz, CD3OD) δ-121.10 (t, J=7.8Hz, 1F), -139.20 (d, J=50.6Hz, 1F).m / z, (ESI + ): 672.2.

[0177] Example 15: Synthesis of Compound 15

[0178]

[0179] The synthesis of compound 15 was performed following the same procedure as that of compound 1, using N-methyl-1-(pyrazol-3-yl)methylamine as the starting material. 1H NMR (400MHz, CD3OD) δ9.31 (d, J=3.8Hz, 1H), 7.72 (dd, J=9.1, 5.8Hz, 1H), 7.56 (s, 1H), 7.35 (d, J=2.7Hz, 1H), 7.30 (t, J=9.3Hz, 1H), 7.13 (d, J=2.6Hz, 1H), 6.38 (s, 1H), 4.80-4.48 (m, 8H), 3.87 (t, J=13.6Hz, 2H ), 3.52 (dt, J = 3.5, 1.7Hz, 1H), 2.59-2.48 (m, 5H), 2.35 (d, J = 13.2Hz, 2H), 2.22 (td, J = 7.2, 3.1Hz, 1H), 2 .08 (d, J=3.1Hz, 1H), 1.89-1.82 (m, 1H), 0.93 (q, J=5.4, 4.5Hz, 2H), 0.85 (q, J=7.2Hz, 5H), 0.67 (s, 2H). 19 F NMR (376MHz, CD3OD) δ-121.11 (d, J=8.2Hz, 2F).m / z, (ESI + ): 656.5.

[0180] Example 16: Synthesis of Compound 16

[0181]

[0182] The synthesis of compound 16 was performed following the same procedure as that of compound 1, using N-methyl-1-(thiazolyl-4-yl)methylamine as the starting material. 1H NMR (400MHz, CD3OD) δ9.35 (d, J=3.8Hz, 1H), 9.02 (d, J=1.9Hz, 1H), 8.19 (d, J=2.0Hz, 1H), 7.74 (dd, J=9.0, 5.8Hz, 1H), 7. 36 (d, J=2.7Hz, 1H), 7.34-7.28 (m, 1H), 7.12 (t, J=3.1Hz, 1H), 4.80 (dd, J=31.9, 13.7Hz, 2H), 4.68-4.47 (m, 6H), 3.86 (dd, J=13.7, 6.8Hz, 1H), 3.54-3.39 (m, 3H), 3.02 (s, 3H), 2.59-2.46 (m, 3H), 2.37 (d, J=13.3Hz, 1H), 2.23 (dt, J=16.7, 8.2Hz, 1 H), 2.10-1.94 (m, 2H), 1.85 (dt, J=8.5, 5.0Hz, 1H), 1.09-1.04 (m, 2H), 0.97 (d, J=3.3Hz, 2H), 0.84 (td, J=7.3, 3.4Hz, 3H). 19 F NMR (376MHz, CD3OD) δ-77.22 (s, 9F), -120.98 (d, J=7.8Hz, 1F), -139.79 (s, 1F).m / z, (ESI + ): 671.1.

[0183] Example 17: Synthesis of Compound 17

[0184]

[0185] The synthesis of compound 17 was performed following the same procedure as compound 1, using N-methyl-1-(imidazol-4-yl)methylamine as the starting material. 1H NMR (400MHz, CD3OD) δ9.30 (d, J=5.0Hz, 1H), 7.72 (dd, J=9.1, 5.8Hz, 1H), 7.61-7.55 (m, 1H), 7.34 (d, J=2.7Hz , 1H), 7.29 (t, J=9.4Hz, 1H), 7.13 (d, J=2.6Hz, 1H), 6.94 (s, 1H), 4.79-4.46 (m, 7H), 3.86 (dd, J=17.6, 13.6Hz , 1H), 3.65 (d, J=3.8Hz, 2H), 3.54-3.45 (m, 1H), 2.54 (td, J=9.5, 7.7, 3.9Hz, 5H), 2.27 (d, J=21.0Hz, 4H), 2.0 7-1.94 (m, 2H), 1.90-1.80 (m, 1H), 0.85 (td, J=7.4, 5.1Hz, 3H), 0.77 (d, J=5.0Hz, 2H), 0.57 (d, J=5.0Hz, 2H). 19 F NMR (376MHz, CD3OD) δ-121.21 (s, 1F), -139.34 (s, 1F).m / z, (ESI + ): 671.1.

[0186] Example 18: Synthesis of Compound 18

[0187]

[0188] The synthesis of compound 18 was performed following the same procedure as that of compound 1, using 3-azabicyclo[3.1.0]hexane as the starting material. 1 H NMR (400MHz, CD3OD) δ9.29 (d, J=4.3Hz, 1H), 7.72 (dd, J=9.1, 5.8Hz, 1H), 7.34 (d, J=2.7Hz, 1H), 7.2 9 (t, J=9.4Hz, 1H), 7.11 (d, J=2.6Hz, 1H), 4.76-4.41 (m, 9H), 3.87 (dd, J=15.4, 13.6Hz, 1H), 3.55-3. 42 (m, 2H), 2.59-2.48 (m, 4H), 2.33 (d, J = 13.0Hz, 1H), 2.25-2.18 (m, 1H), 1.99 (d, J = 20.0Hz, 3H), 1.8 5 (s, 1H), 1.51 (s, 2H), 0.85 (td, J=7.4, 5.1Hz, 4H), 0.76 (s, 2H), 0.71 (d, J=4.5Hz, 1H), 0.60 (s, 2H). 19F NMR (376MHz, CD3OD) δ-121.12 (t, J=7.9Hz, 1F), -139.08 (d, J=44.1Hz, 1F).m / z, (ESI + ): 628.6.

[0189] Example 19: Synthesis of Compound 19

[0190]

[0191] The synthesis of compound 19 was performed following the same procedure as compound 1, using 5-azaspiro[2,4]heptane as the starting material. 1 H NMR (400MHz, CD3OD) δ9.33 (d, J=6.7Hz, 1H), 7.73 (dd, J=9.1, 5.9Hz, 1H), 7.35 (d, J=2.7Hz, 1H), 7. 30 (t, J=9.5Hz, 1H), 7.11 (t, J=2.8Hz, 1H), 4.82-4.49 (m, 9H), 3.84 (dd, J=13.7, 8.5Hz, 1H), 3.24 ( q, J=7.3Hz, 4H), 2.54 (t, J=8.3Hz, 4H), 2.35 (d, J=13.3Hz, 1H), 2.23 (td, J=7.3, 2.9Hz, 1H), 2.07 ( d, J=12.3Hz, 3H), 2.01-1.93 (m, 2H), 1.89-1.80 (m, 2H), 0.90 (s, 2H), 0.84 (td, J=7.3, 4.5Hz, 6H). 19 F NMR (376MHz, CD3OD) δ-121.05 (s, 1F), -139.51 (d, J=53.0Hz, 1F).m / z, (ESI + ): 642.6.

[0192] Example 20: Synthesis of Compound 20

[0193]

[0194] The synthesis of compound 20 was performed following the same procedure as compound 1, using N-methyl-1,2,4-triazol-5-methylamine as the starting material. 1H NMR (400MHz, CD3OD) δ9.35 (d, J=5.3Hz, 1H), 7.73 (dd, J=9.1, 6.0Hz, 1H), 7.36 (d, J=2.3Hz, 1H), 7.30 (t, J =9.3Hz, 1H), 7.12 (d, J = 2.5Hz, 1H), 4.83-4.73 (m, 1H), 4.64-4.43 (m, 5H), 3.85 (dd, J = 13.7, 8.4Hz, 1H), 3 .48 (dd, J=20.5, 10.7Hz, 1H), 3.24-3.14 (m, 2H), 2.77 (s, 3H), 2.54 (h, J=8.1Hz, 3H), 2.36 (d, J=13.3Hz, 1 H), 2.27-2.17 (m, 1H), 2.08-1.93 (m, 2H), 1.86 (s, 1H), 1.32 (s, 1H), 0.90 (ddt, J=33.2, 11.9, 7.3Hz, 8H). 19 F NMR (376MHz, CD3OD) δ-77.27 (s, 9F), -120.99 (t, J=7.8Hz, 1F), -140.02 (d, J=54.0Hz, 1F).m / z, (ESI + ): 642.6.

[0195] Example 21: Synthesis of compound 1a

[0196]

[0197] (2,6-Dimethylenetetrahydro-1H-pyrrololin-7a(5H)-yl)methanol (165.2 mg, 1.00 mmol, 3 eq) was dispersed in tetrahydrofuran (10 mL), followed by the addition of compound 1-1 (112.9 mg, 0.33 mmol, 1 eq). The mixture was cooled to 0°C under nitrogen protection, and then 60% sodium hydride (40.0 mg, 1.00 mmol, 3 eq) was added, followed by stirring at 0°C for 3 hours. The reaction mixture was brought to room temperature, and dichloromethane was added and stirred for 10 minutes, followed by washing with water and brine. The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (MeOH / CH2Cl2 = 0.2%) to give compound 1a-1 (263.9 mg, yield 56.0%). m / z, (ESI+): 472.2.

[0198] Compound 1a-1 (200 mg, 423.8 μmol, 1 eq) was dispersed into a mixed solution of dioxane (10 mL) and water (1 mL), followed by the sequential addition of 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxoborane (305.3 mg, 847.6 μmol, 2 eq), potassium phosphate (280.36 mg, 1.32 mmol, 3 eq), and cataCXiumAPdG3 (64.04 mg, 88.05 μmol, 0.2 eq). The reaction mixture was purged with nitrogen three times, heated to 90°C and stirred for 3 hours under nitrogen protection, and then cooled to room temperature. Dichloromethane was added to the reaction mixture and stirred for 10 minutes, followed by washing with water and brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (MeOH / CH2Cl2 = 0-2%) to give compound 1a-2 (200 mg, yield 69.0%). m / z, (ESI) + ): 670.5

[0199] Compound 1a-2 (100 mg, 149.3 μmol, 1 eq) was dispersed in dichloromethane (2 mL), and trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred at 25°C for 25 min, and then concentrated to dryness under vacuum. The residue was purified by preparative chromatography (0.05% NH3 aqueous solution / acetonitrile) to give compound 1a (15.4 mg, yield 16.6%). 1 H NMR (400MHz, CD3OD) δ9.32 (d, J=5.3Hz, 1H), 7.72 (dd, J=9.1, 5.8Hz, 1H), 7.35 (d, J=2.6Hz, 1H), 7. 29 (t, J=9.4Hz, 1H), 7.11 (d, J=2.6Hz, 1H), 5.17 (dt, J=4.7, 2.2Hz, 4H), 4.80-4.45 (m, 7H), 4.08 (d , J=14.9Hz, 2H), 3.86 (t, J=13.2Hz, 1H), 3.63 (d, J=14.8Hz, 2H), 3.55-3.40 (m, 1H), 3.00-2.91 (m, 2H), 2.74 (d, J=16.5Hz, 2H), 2.57-2.47 (m, 3H), 2.33 (d, J=13.3Hz, 1H), 2.21 (dtd, J=14.4, 7.2, 3.0 Hz, 1H), 2.01-1.94 (m, 1H), 1.83 (td, J=8.1, 7.3, 3.9Hz, 1H), 0.87-0.82 (m, 3H). 19F NMR (376MHz, CD3OD) δ-121.08 (t, J=8.0Hz, 1F), -139.16 (d, J=45.9Hz, 1F).m / z, (ESI + ): 626.6.

[0200] Biological assay

[0201] Test Example 1. GTP Binding Experiment

[0202] Remove the KRAS G12D GTP binding kit (Cisbio, 63ADK000CB27PEG) from the -80℃ freezer and place it on ice. Dilute 100X Human KRAS G12D 6His-tagged protein to 1X working solution with PPI Europium assay buffer (Cisbio, 61DB9RDF). Add 5 μL / well to a 384-well plate (PerkinElmer, 6008289) and centrifuge at 2000 rpm for 50 seconds. Prepare a 10 mM stock solution of the test compound with DMSO (Sigma, D2650), serially dilute it, and then prepare working solutions of different concentrations with PPI Europium assay buffer. Add 5 μL / well to a 384-well plate and centrifuge at 2000 rpm for 50 seconds. Prepare 50 nM GDP working solution and add 5 μL / well to a 384-well plate. Centrifuge at 2000 rpm for 50 seconds, seal the plate with a membrane, and incubate at room temperature for 30 minutes. Dilute 50X 6His Eu cryptate antibody and GTP-Red reagent with PPI Europium detection buffer to prepare 1X working solution. Add 5 μL / well to a 384-well plate, centrifuge at 2000 rpm for 50 seconds, seal the plate with a membrane, and incubate at room temperature for 30 minutes. Detect the TR-FRET luminescence value using a microplate reader (PE, Victor) and calculate the inhibition percentage according to the following formula.

[0203]

[0204] ("Highest signal" is the luminescence value measured in the DMSO control well, "lowest signal" is the luminescence value measured in the control well containing the maximum inhibitory concentration of GDP, and "measured value" is the luminescence value measured after compound treatment.)

[0205] IC50 was calculated using GraphPad Prism to fit inhibition curves with a four-parameter equation. Specific data for some compounds are shown in Table 3.

[0206] Table 3

[0207] compound IC50(nM) compound IC50(nM) 1 60.76 11 22.03 2 22.09 12 36.53 3 21.96 13 30.61 4 27.39 14 81.05 5 231.5 15 13.66 6 182.2 16 19.14 7 100.4 17 8.16 8 468.5 18 4.727 9 22.42 19 8.473 10 47.77

[0208] Test Example 2. Cell Proliferation Experiment

[0209] AsPC-1 (Cobioer, CBP60546), NCI-H358 (Cobioer, CBP60544), and NCI-H727 (Cobioer, CBP60182) cell lines in logarithmic growth phase were collected, and the cell density was adjusted to 3.15 x 10⁻⁶ cells / year. 4 If cells are seeded at a rate of 95 μL / well in a 96-well cell culture plate (Greiner, 655090), the cell count per well will be 3 x 10⁹ cells / mL. 3 The plates were then incubated overnight at 37°C in a 5% CO2 incubator. The next day, the test compounds were prepared as 10 mM stock solutions using DMSO (Sigma, D2650), serially diluted, and then used complete culture medium to prepare working solutions of different concentrations. These solutions were added to the corresponding wells of the plates and incubated at 37°C in a 5% CO2 incubator for 72 hours. After 72 hours, the cell culture plates were removed, and CellTiter Glo (Promega, G7573) was added at 100 μL / well. After incubation at room temperature for 10 minutes, the luminescence value was measured using a microplate reader (PE, Victor), and the inhibition percentage was calculated using the following formula.

[0210]

[0211] ("Highest signal" refers to the luminescence value measured in the DMSO control well, "lowest signal" refers to the luminescence value measured in each well on day zero, and "measured value" refers to the luminescence value measured after compound treatment.)

[0212] The experimental results for some compounds are shown in Table 4. “-” indicates that the compound was not detected in this cell line.

[0213] Table 4. IC50 of compounds inhibiting KRAS genotype cells 50 value

[0214]

[0215] The data in Table 4 show that the compounds provided in this application have inhibitory effects against more than one wild-type KRAS or KRAS mutant.

[0216] Although the invention has been described in detail with reference to embodiments thereof, these embodiments are provided for illustration and not limitation. Other embodiments that can be obtained according to the principles of the invention fall within the scope defined by the claims of the invention.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, ester, hydrate, solvate or stereoisomer thereof: in, A is selected from C, N, S, or O; R 1 R 2 Independently selected from H, substituted or unsubstituted hydrocarbon groups, or absent; or R 1 R 2 The A rings that are connected together with it form substituted or unsubstituted heterocycles; Where R 1 R 2 They are not both methyl groups.

2. The compound according to claim 1, wherein A is N and R 1 It is methyl, R 2 for B is selected from substituted or unsubstituted aromatic rings or five- or six-membered carbon heterocycles.

3. The compound according to claim 2, wherein B is selected from the following structures: The substituents are substituted from any substituted site.

4. The compound according to claim 1, wherein, R 1 R 2 The A ring connected to it forms a substituted or unsubstituted 5-14 membered heterocycle; the substituent is selected from hydroxyl, halogen, amino, -CF3, -NH (C1-C3 alkyl), -N (C1-C3 alkyl)2, =O, -CN, -O- (C1-C3 alkyl), -(C1-C3 alkyl)-OH, -C(=O)OH, -C(=O)(C1-C3 alkyl), -C(=O)O(C1-C3 alkyl), aryl, arylalkyl, cycloalkyl or heterocyclic alkyl.

5. The compound according to claim 4, R 1 R 2 The A atoms that are connected together form the following groups:

6. The compound according to claim 1, wherein, The compound is one of the following compounds or its pharmaceutically acceptable salt, ester, hydrate, solvate or stereoisomer:

7. A pharmaceutical composition comprising the compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt, ester, hydrate, solvate, or stereoisomer thereof; further comprising: At least one pharmaceutically acceptable excipient, such as one or more of binders, fillers, disintegrants, lubricants, and flow aids; A carrier, such as one or more of creams, emulsions, gels, liposomes, and nanoparticles; or a diluent.

8. The pharmaceutical composition according to claim 7, characterized in that, The composition is suitable for administration via parenteral, intraperitoneal, intradermal, intracardiac, intraventricular, intracranial, intraspinal, intrasynovial, intrathecal, intrathecal, intramuscular, intravitreal, intravenous, intra-arterial, oral, intraoral, sublingual, transdermal, intratracheal, rectal, subcutaneous, and local administration.

9. The use of the compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt, ester, isomer, or hydrate thereof, or the pharmaceutical composition of any one of claims 7 to 8, in the preparation of a medicament for treating, preventing, or inhibiting hyperplasia, particularly for treating, preventing, or inhibiting malignancies or cancers associated with wild-type KRAS or KRAS mutations, such as those associated with at least one of KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D, or KRAS Q61H; Preferably, the malignant tumor or cancer is selected from: Sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma; Lung tumors or cancers: bronchial carcinoma (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar (bronchial) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroma, mesothelioma; Gastrointestinal tumors or cancers: esophageal cancer (squamous cell carcinoma, adenocarcinoma, leiomyoma, lymphoma), gastric cancer (carcinoma, lymphoma, leiomyoma), pancreatic cancer (ductal adenocarcinoma, insulinoma, glucosidoma, gastrinoma, carcinoid tumor, vasodilator intestinal peptide tumor), small intestinal cancer (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), colorectal cancer (adenocarcinoma, tubular adenoma, villous adenoma, hematoma, leiomyoma); Tumors or cancers of the urogenital tract: kidney cancer (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma), bladder and urethral cancer (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate cancer (adenocarcinoma, sarcoma), testicular cancer (seminomatous seminoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoid tumor, lipoma); Liver tumors or cancers: liver cancer (hepatocellular carcinoma), bile duct cancer, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract tumors or cancers: gallbladder cancer, ampoule cancer, bile duct cancer; Bone tumors or cancers: osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor, string tumor, osteochondroma, benign chondroma, chondroblastoma, chondromycinoma, osteomyxofibroma, osteoid osteoma and giant cell tumor; Nervous system tumors or cancers: Skull tumors (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meningiomas (meningioma, meningeal sarcoma, gliomatosis), brain tumors (astrocytoma, myeloma, glioma, epididymal tumor, germ cell tumor (pineal tumor), glioblastoma, oligodendroglioma, glioma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma; Gynecological tumors or cancers: Uterine cancer (endometrial cancer (serous bladder cancer, mucinous bladder cancer, unclassified carcinoma), granulosa cell tumor, serum stromal cell tumor, dysplasia, malignant teratoma), vulvar cancer (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vaginal cancer (clear cell carcinoma, squamous cell carcinoma, uveal sarcoma (embryonic rhabdomyosarcoma); Hematologic malignancies or cancers: Leukemia (acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma. Dermatological tumors or cancers: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, Morse's nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; Adrenal tumors or cancers: neuroblastoma; More preferably, the malignant tumor is one or more of the following: non-small cell lung cancer, small cell lung cancer, pancreatic cancer, colorectal cancer, bile duct cancer, cervical cancer, bladder cancer, liver cancer, or breast cancer.

10. Use of the kit in the preparation of medicaments for the treatment, inhibition, or prevention of diseases involving KRAS, wherein, The kit comprises a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt, ester, hydrate, solvate or stereoisomer, or a composition according to any one of claims 7 to 9.

Images