A chimeric compound with targeted degradation / inhibitory activity, and its preparation method and use

Abstract

The present invention provides a series of chimeric compounds with targeted degradation / inhibitory activity, preparation methods and pharmaceutical uses thereof. The compounds can be used to treat or prevent KRAS-mediated diseases and related diseases.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to KRAS inhibition / degradation chimeric compounds and preparation methods thereof, as well as use of the compounds in preparing drugs for treating or preventing KRAS-mediated diseases and related diseases. Background Art

[0002] KRAS mutations account for approximately 30% of activating mutations in human malignancies and are the most common gain-of-function mutations. They are implicated in the pathogenesis of various solid tumors. In cancer treatment, KRAS mutations have been found to be the most prevalent resistance mutation to EGFR drug therapy in colon cancer, while in lung cancer, KRAS mutations have an extremely low response rate to traditional chemotherapy drugs, significantly hindering patient treatment.

[0003] The most common mutation type in pancreatic cancer patients is KRAS mutation. KRAS gene mutation plays a significant role in the development and progression of pancreatic ductal carcinoma, with a mutation rate as high as 90%, and the most common is codon 12 point mutation. KRAS mutations have been identified in 60% to 90% of pancreatic cancers, 35% of colorectal cancers, 20% of serous ovarian cancers, and 15% of thyroid cancers. In pancreatic ductal carcinoma, KRAS mutations occur in up to 90%. Activated KRAS activates multiple downstream signaling pathways, participating in the downstream signaling of growth factors such as RAF-MEK-ERK and PI3K-AKT-mTOR, and has a complex relationship with cancer development and progression.

[0004] The KRAS gene, a member of the RAS gene family, is located on human chromosome 12 and contains four coding exons and one 5′ noncoding exon. The protein it encodes, called KRAS protein (including K-Ras4A and K-Ras4B), consists of 189 amino acids. Its first 165 amino acids are identical to those encoded by proteins from other family members, namely HRAS and NRAS. As a member of the RAS family, KRAS plays an important role in regulating cell growth, proliferation, differentiation, apoptosis, and other life processes. KRAS protein is a type of small G protein that is inactive when bound to GDP. However, after the guanylate exchange factor is recruited to KRAS, GDP is released and a transient nucleotide-free state is formed. The KRAS protein then binds to GTP, causing significant conformational changes in two specific regions of RAS, Switch1 (amino acids 30-40) and Switch 2 (amino acids 60-76), thereby integrating signals and transmitting them to downstream effectors. Finally, due to the intrinsic enzymatic activity of KRAS and the action of GTPase-activating proteins (GAPs), GTPs are hydrolyzed, terminating signal transmission. In this way, KRAS becomes an important molecular switch in the cell.

[0005] G12C is the third most common RAS mutation, ranking first in non-small cell lung cancer and colorectal cancer. Nearly 30,000 new G12C tumors are diagnosed annually. The resulting Cys residue in the mutation can serve as a target for irreversible inhibitors, reducing reliance on the binding pocket. Furthermore, Cys-based irreversible inhibitors have demonstrated relatively high specificity. However, detailed studies have revealed that these compounds only target GDP-bound RAS. Covalent attachment of the compound to G12C induces a previously nonexistent allosteric pocket, S-IIP, beneath Switch II. This has two consequences: 1) increased affinity for GDP, making it less likely to transition to the GTP conformation; and 2) inhibition of GEF-catalyzed nucleotide exchange. Simply put, this locks RAS in an inactive state.

[0006] As a molecular switch, RAS controls the transmission of signals stimulated by growth factors and cytokines within cells by converting its binding to GTP or GDP, thereby regulating vital activities such as cell growth, proliferation, differentiation, and apoptosis. KRAS is the most common mutation in the RAS family during tumor development and progression, with a mutation frequency of up to 97.7% in pancreatic ductal adenocarcinoma. Once KRAS mutates, it loses its GTP hydrolase activity, leading to persistent activation and uncontrolled cell proliferation, leading to cancer. Due to its high mutation rate in tumor tissues and cells and its essential role in maintaining tumor cell growth, KRAS has become a promising target for cancer therapy.

[0007] In addition, Drs. Craig Crews and Raymond Deshaies designed a series of bifunctional chimeric molecules based on peptide compounds to induce the degradation of methionyl aminopeptidase 2 (MetAP-2). They formally proposed the PROTAC concept and applied for related patent WO2002020740A3. However, because these large and bulky peptide-based connecting compounds had difficulty entering cells, the first generation of PROTACs failed.

[0008] In 2008, Crews' team designed the second-generation PROTACs based on the E3 ubiquitin protein ligase MDM2 to degrade the androgen receptor (AR).

[0009] In 2015, Crews' team designed a new generation of PROTACs based on the novel E3 ubiquitin ligase VHL and its CRBN ligand. WO2013106643A3 discloses compounds and methods for enhancing the degradation of target proteins and other peptides via E3 ubiquitin ligases. WO2015160845A2 discloses imide-based proteolysis regulators and related methods of use. Summary of the Invention

[0010] The present invention describes novel KRAS inhibition / degradation chimeric compounds and provides a series of compounds as shown in Formula I.

[0011] ALB(I)

[0012] or a pharmaceutically acceptable salt thereof, wherein

[0013] B is an E3 ligase binding group covalently bound to L;

[0014] L is a linking group covalently bound to B and A;

[0015] A is a protein binding group covalently bonded to L.

[0016] Furthermore, the B is a group that binds to an E3 ligase, wherein the E3 ligase is selected from von Hippel-Lindau (VHL), Cereblon, XIAP, E3A, MDM2, anaphase-promoting complex (APC), UBR5 (EDD1), SOCS / BC-box / eloBC / CUL5 / RING, LNXp80, CBX4, CBLL1, HACE1, HECTD1, HECTD2, HECTD3, HECW1, HECW2, HE RC1, HERC2, HERC3, HERC4, HUWE1, ITCH, NEDD4, NEDD4L, PPIL2, PRPF19, PIAS1, PIAS2, PIAS3, PIAS4, RANBP2, RNF4 , RBX1, SMURF1, SMURF2, STUB1, TOPORS, TRIP12, UBE3A, UBE3B, UBE3C, UBE4A, UBE4B, UBOX5, UBR5, WWP1, WWP2, Park in, A20 / TNFAIP3, AMFR / gp78, ARA54, β-TrCP1 / BTRC, BRCA1, CBL, CHIP / STUB1, E6, E6AP / UBE3A, F-box protein 15 / FBXO1 5. FBXW7 / Cdc4, GRAIL / RNF128, HOIP / RNF31, cIAP-1 / HIAP-2, cIAP-2 / HIAP-1, cIAP(pan), ITCH / AIP4, KAP1, MARCH 8. MindBomb1 / MIB1, MindBomb2 / MIB2, MuRF1 / TRIM63, NDFIP1, NEDD4, NleL, Parkin, RNF2, RNF4, RNF8, RNF168, RN F43, SART1, Skp2, SMURF2, TRAF-1, TRAF-2, TRAF-3, TRAF-4, TRAF-5, TRAF-6, TRIM5, TRIM21, TRIM32, UBR5, or ZNRF3.

[0017] Furthermore, the B is a group that binds to an E3 ligase selected from VHL, Cereblon, MDM2 or cIAP.

[0018] Furthermore, the B is a group that binds to an E3 ligase selected from VHL or Cereblon.

[0019] Furthermore, the B is selected from compounds that bind to VHL, hydroxyproline compounds that bind to VHL, compounds that bind to Cereblon, tetrahydro-benzodiazepines, amide compounds, phthalimide compounds, thalidomide or its derivatives, lenalidomide or its derivatives, and pomalidomide or its derivatives.

[0020] Furthermore, B is selected from the following general formula:

[0021]

[0022] in:

[0023] G is selected from CH2, C=O, S(=O)2, NH or N(C 1-6 alkyl);

[0024] Each R 8 Independently selected from oxo, thio, H, OH, C 1-6 Alkyl or -CH2(3-10 membered heterocyclyl);

[0025] R 8a independently selected from oxo and thio;

[0026] W1, W2, W3, W4 are independently selected from nitrogen, carbon or carbon, and the hydrogen on it is replaced by any one of halogen, methyl, halomethyl, hydroxyl, and deuterated methyl;

[0027] n0 is an integer selected from 0, 1, 2, 3, 4, 5 or 6. In addition, oxo and thioxo refer to ═O and ═S substitution.

[0028] Furthermore, B is selected from the following general formula:

[0029]

[0030] in:

[0031] Each R 8b Independently selected from oxo, thio, H, OH, C 1-6 Alkyl or CH2(3-10 membered heterocyclyl);

[0032] R 8c independently selected from oxo and thio;

[0033] R 8d Independently selected from oxo, thio, C 1-6 Alkyl, -C 3-10 cycloalkyl, halogen or hydrogen;

[0034] Y is selected from N, NH, N(C 1-6 alkyl), N(C 6-10aryl), N(3-10 membered heterocyclyl), N(5-10 membered heteroaryl), N(C 3-10 cycloalkyl), O or S;

[0035] W1, W2, W3, W4 are independently selected from nitrogen, carbon or carbon, and the hydrogen on it is replaced by any one of halogen, methyl, halomethyl, hydroxyl, and deuterated methyl;

[0036] n is an integer selected from 0, 1, 2, 3, 4, 5 or 6;

[0037] It indicates the presence or absence of a bond. In addition, oxo and thioxo refer to =O and =S substitution.

[0038] Furthermore, B is selected from the following general formula:

[0039]

[0040] in:

[0041] G is selected from CH2, C=O, S(=O)2, NH or N(C 1-6 alkyl);

[0042] R 8e independently selected from oxo and thio;

[0043] R 8f independently selected from oxo and thio;

[0044] R 8g Selected from hydrogen, C 1-6 Alkyl, hydroxy or -CH2(3-10 membered heterocyclyl);

[0045] R 8h independently selected from oxo and thio;

[0046] W1, W2, W3, and W4 are independently selected from nitrogen, carbon, or carbon wherein the hydrogen on the carbon is replaced by any of halogen, methyl, halomethyl, hydroxyl, and deuterated methyl.

[0047] Furthermore, wherein B is as follows:

[0048]

[0049] G is selected from CH2, C=O, S(=O)2, NH or N(C 1-6 alkyl)

[0050] R 8j is selected from halogen, methyl, halomethyl, hydroxyl, deuterated methyl, preferably fluorine or chlorine;

[0051] Preferred:

[0052]

[0053] Further, where B is as follows:

[0054]

[0055] in:

[0056] R 9 Selected from hydrogen, deuterium, halogen, nitro, cyano, amino, hydroxyl, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halogenated C 1-6 One of the alkyl groups;

[0057] R 10 Selected from hydrogen, C 1-6 alkyl;

[0058] R 11 Selected from hydrogen, C 1-6 alkyl;

[0059] R 12 Selected from hydrogen, deuterium, halogen, nitro, cyano, amino, hydroxyl, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halogenated C 1-6 One of the alkyl groups;

[0060] R 13 Selected from hydrogen, deuterium, halogen, nitro, cyano, amino, hydroxyl, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halogenated C 1-6 One of the alkyl groups.

[0061] Furthermore, wherein B is as follows:

[0062]

[0063] in:

[0064] R 9 Selected from hydrogen, halogen, nitro, cyano, amino, hydroxyl, C 1-4 One of the alkyl groups, preferably a hydroxyl group;

[0065] R 10 Selected from hydrogen, C 1-4 Alkyl, preferably C 3-4 alkyl;

[0066] R 11 Selected from hydrogen, C 1-3 alkyl;

[0067] R 12 Selected from hydrogen, deuterium, C 1-3 Alkyl, deuterated C 1-3Alkyl or halogenated C 1-3 One of the alkyl groups;

[0068] R 13 Selected from C 1-3 alkyl.

[0069] Furthermore, the B is selected from:

[0070] More preferred

[0071] The A is a group that binds to the following: KRAS, SOS, including all variants, mutants, splice variants, insertions and deletions or fusions thereof.

[0072] Furthermore, the A is selected from KRAS inhibitors and SOS inhibitors.

[0073] Furthermore, the A is a KRAS inhibitor.

[0074] Furthermore, the A is a small molecule targeting KRAS.

[0075] Furthermore, the A is shown in the following formula:

[0076]

[0077] in:

[0078] X1 and X2 are independently selected from C and N, provided that X1 and X2 cannot be N at the same time;

[0079] R 1 Selected from hydrogen, C 1-4 Alkyl, -OC 1-4 Alkyl, -NH2, -NH(C 1-4 alkyl), -N(C 1-4 alkyl)2 or halogen;

[0080] R 2 Selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclic group or 5-10 membered heteroaryl group, preferably phenyl;

[0081] R 3 Selected from hydrogen, C 1-4 Alkyl or halogen;

[0082] R 4 Selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclic group or 5-10 membered heteroaryl group, preferably phenyl;

[0083] R 5 Selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclic group or 5-10 membered heteroaryl group, preferably 6 membered nitrogen heterocyclic group.

[0084] Furthermore, the A is shown in the following formula:

[0085]

[0086] in:

[0087] X1 and X2 are independently selected from C and N, provided that X1 and X2 cannot be N at the same time;

[0088] X0 is selected from C or N;

[0089] R 1 Selected from hydrogen, C 1-4 Alkyl, -OC 1-4 Alkyl, -NH2, -NH(C 1-4 alkyl), -N(C 1-4 alkyl)2 or halogen;

[0090] R 2 Selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclic group or 5-10 membered heteroaryl group, preferably phenyl;

[0091] R 3 Selected from hydrogen, C 1-4 Alkyl or halogen;

[0092] R 4 Selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclic group or 5-10 membered heteroaryl group, preferably phenyl group.

[0093] Furthermore, the A is shown in the following formula:

[0094]

[0095] in:

[0096] X0 is selected from C or N;

[0097] R 6 Selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclic or 5-10 membered heteroaryl; preferably C 1-6 Alkyl, C6 aryl; more preferably phenyl, methyl.

[0098] Furthermore, the A is shown in the following formula:

[0099]

[0100] Wherein: X0 is selected from C or N, preferably N.

[0101] Indicates the linking site between A and L, or the linking site between B and L.

[0102] Furthermore, the compound structure is selected from the following general formula:

[0103]

[0104] X0 is selected from C or N;

[0105] G is selected from CH2, C=O, S(=O)2, NH or N(C 1-6 Alkyl), preferably CH2, C=O;

[0106] R 8j Selected from halogen, methyl, halomethyl, hydroxy, deuterated methyl, preferably fluorine, chlorine.

[0107] Furthermore, the compound structure is selected from the following general formula:

[0108]

[0109]

[0110] The L is selected from the following general formula:

[0111] -[(CH2) m1 -O(CH2) m2 ] p -(X) q -[(CH2)m3 -O(CH2) m4 ] r -(X) s -(CH2) m5 -Z-,

[0112] -(CH2) m7 -(X) t -(CH2) m8 -(X) u -(CH2) m14 -Z-;

[0113] Each X can be independently selected from single bonds, S(=O)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-12 membered heterocyclic group or 5-10 membered heteroaryl, preferably:

[0114]

[0115] Each Z can be independently selected from a single bond, NH(CH2) m9 , C(O)-(CH2) m10 , C(O)NH(CH2) m11 ,NHC(O)-(CH2) m12 -O-(CH2) m13 -;

[0116] When X is a single bond, it means that the X group does not exist; when Z is a single bond, it means that the Z group does not exist;

[0117] m1, m2, m3, m4, m5, m6, m7, m8, m9, m10, m11, m12, m13, m14, p, q, r, s, t, and u are independently selected from integers of 0-20, preferably integers of 0-15, and more preferably integers of 0-12.

[0118] Furthermore, L is selected from the following general formula:

[0119]

[0120]

[0121] n, n1, n2 are independently selected from integers of 0-20, preferably integers of 0-15, integers of 1-15, preferably integers of 0-12, integers of 1-12, It indicates the connection point between L and A or B, wherein the L group can be connected to A at its left end and to B at its right end, or vice versa, unless it is not actually possible to connect.

[0122] Furthermore, the L is selected from the following structures:

[0123]

[0124]

[0125] Furthermore, the compound is one of the following compounds:

[0126]

[0127]

[0128]

[0129]

[0130]

[0131]

[0132] or a pharmaceutically acceptable salt thereof.

[0133] The description provides compounds described herein, including enantiomers, diastereomers, solvates, and polymorphs thereof, including pharmaceutically acceptable salt forms, such as acid and base salt forms.

[0134] The KRAS inhibition / degradation chimeric compounds of the present invention will provide pharmacological benefits to patients with cancers associated with signal transduction dependent on KRAS family proteins. Such cancers targeted by the chimeric compounds include those that exhibit alterations (mutations, gene amplification, overexpression) in components (proteins, genes) within the KRAS family protein pathway.

[0135] The KRAS inhibitory / degrading chimeric compounds described herein will be effective in treating diseases associated with KRAS overexpression, aggregation, and / or overactivation (e.g., aggregation of active KRAS), such as gain-of-function KRAS mutants (i.e., KRAS with gain-of-function mutations). Chimeric small molecule compounds that target KRAS and utilize or enhance the specificity of VHL and cereblon binding ubiquitination tags will be very useful.

[0136] In addition, the chimeric compounds described herein are also expected to provide pharmacological benefits in diseases associated with dysregulation of RAS family protein pathways, such as neurofibromatosis, Noonan syndrome (NS), Noonan syndrome with multiple lentigines (NSML), capillary malformation-arteriovenous malformation syndrome (CM-AVM), Costello syndrome (CS), cardiofacial cutaneous syndrome (CFC), Legius syndrome, and hereditary gingival fibromatosis.

[0137] For therapeutic purposes, the chimeric compounds disclosed in the present invention can effectively prevent the disease, alleviate the symptoms, or prolong the survival of the treated patients.

[0138] The chimeric compounds and pharmaceutically acceptable salts thereof provided by the present invention can be used alone or in combination with at least one other therapeutic agent in therapy.

[0139] The present invention discloses a pharmaceutical composition comprising a chimeric compound of the present invention or a pharmaceutically acceptable salt thereof and one or more other therapeutically active ingredients. The other therapeutically active ingredients may be another biologically active ingredient or at least one of another chimeric compound of the present invention. The other biologically active agent described in the present invention is an anticancer agent, such as an epidermal growth factor receptor inhibitor.

[0140] The present invention discloses a pharmaceutical composition comprising the chimeric compound disclosed in the present invention or a pharmaceutically acceptable salt thereof and one or more pharmaceutical carriers; the pharmaceutical preparation is any clinically acceptable dosage form.

[0141] The chimeric compounds and pharmaceutically acceptable salts thereof provided by the present invention can be formulated into solid dosage forms, such as capsules, tablets, pills, lozenges, sugar-coated tablets, granules, powders, ointments, creams, drops, and the like; the compounds and pharmaceutically acceptable salts thereof provided by the present invention can be formulated into liquid dosage forms, such as elixirs, syrups, emulsions, dispersants, suspensions, solutions, sprays, and the like.

[0142] The pharmaceutically acceptable carriers and / or pharmaceutically acceptable diluents that can be used in the pharmaceutical composition or pharmaceutical preparation of the present invention can be any conventional carriers and / or diluents in the field of pharmaceutical preparations.

[0143] The pharmaceutically acceptable salts of the present invention include acid addition salts and base salts.

[0144] Salt: The term "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions and / or dosage forms that are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reaction, or other problems or complications, and are commensurate with a reasonable benefit / risk ratio, within the scope of sound medical judgment.

[0145] The "pharmaceutically acceptable salts" of the present invention refer to derivatives of the disclosed compounds, wherein the parent compound is modified by preparing its acid or base salts. The pharmaceutically acceptable salts of the present invention include acid salts and base salts.

[0146] Furthermore, the acids used to prepare the pharmaceutically acceptable acid addition salts of the above-mentioned base compounds useful in this aspect are acids that form non-toxic acid addition salts, i.e., salts containing pharmaceutically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, sucrose, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, gentisate, malate, malonate, mandelate, salicylate, succinate, trifluoroacetate, and the like.

[0147] Furthermore, pharmaceutically acceptable base addition salts can also be used to produce pharmaceutically acceptable salt forms of the compounds or derivatives of the present invention, including but not limited to salts derived from such pharmacologically acceptable cations, such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium, zinc and magnesium), ammonium or water-soluble amine addition salts, such as N-methylglucamine-(meglumine), as well as lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines, and the like.

[0148] The compounds described herein include stereoisomers of the compounds. Stereoisomers described herein refer to enantiomers produced when asymmetric carbon atoms are present in the compound as shown in Formula I; cis-trans isomers produced when a carbon-carbon double bond or cyclic structure is present in the compound; and tautomers produced when a ketone or oxime is present in the compound. As a specific embodiment, the stereoisomers described herein include, but are not limited to, enantiomers, diastereomers, racemates, cis-trans isomers, tautomers, geometric isomers, epimers, and mixtures thereof.

[0149] The pharmaceutically acceptable salts of the present invention may exist in unsolvated and solvated forms.

[0150] The chimeric compound of the present invention, or a composition containing the chimeric compound, is administered to a subject in need thereof, wherein the compound is effective in treating or ameliorating at least one symptom of the disease or disorder.

[0151] The diseases or conditions described herein are associated with at least one of accumulation, aggregation and / or overactivation of KRAS, or a combination thereof.

[0152] The disease or disorder of the present invention is a cancer associated with the accumulation, aggregation and / or overactivation of KRAS.

[0153] The diseases or conditions described herein are pancreatic cancer, colon cancer, colorectal cancer, lung cancer, non-small cell lung cancer, biliary tract malignancies, endometrial cancer, cervical cancer, bladder cancer, liver cancer, myeloid leukemia and breast cancer.

[0154] The present invention also provides the use of the above-mentioned chimeric compound or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating and / or preventing tumor-related diseases, wherein the tumor-related diseases include but are not limited to carcinoma, lymphoma, blastoma, sarcoma, leukemia, lymphoid malignancy, squamous cell carcinoma, esophageal cancer, thyroid cancer, melanoma, lung cancer including small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma and lung squamous cell carcinoma, peritoneal cancer, hepatocellular carcinoma, bile duct cancer, gastric cancer or gastric cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, multiple myeloma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, liver cancer, breast cancer, colon cancer, rectal cancer, colorectal cancer, colorectal cancer, endometrial cancer or uterine cancer, salivary gland cancer, kidney cancer or renal cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer, anal cancer, penile cancer, urothelial cancer and head and neck cancer.

[0155] The present invention provides use of the chimeric compound or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating and / or preventing cancers associated with inhibition of KRAS accumulation, aggregation and / or overactivation.

[0156] The present invention also provides the use of the above-mentioned chimeric compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing RAS pathology, wherein the RAS pathology is preferably selected from neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Noonan syndrome with multiple pigmentation (NSML), capillary malformation-arteriovenous malformation syndrome (CM-AVM), Costello syndrome (CS), cardiofacial cutaneous syndrome (CFC), Legius syndrome or hereditary gingival fibromatosis.

[0157] The present invention discloses a method for treating and / or preventing cancer, which comprises administering to a subject an effective therapeutic amount of the above-mentioned compound or a pharmaceutically acceptable salt thereof or the above-mentioned composition, wherein the cancer includes, but is not limited to, carcinoma, lymphoma, blastoma, sarcoma, leukemia, lymphoid malignancy, squamous cell carcinoma, esophageal cancer, thyroid cancer, melanoma, pancreatic cancer, lung cancer including small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma and lung squamous cell carcinoma, peritoneal cancer, hepatocellular carcinoma, bile duct cancer, gastric cancer or gastric cancer including gastrointestinal cancer, glioblastoma, multiple myeloma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, liver cancer, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial cancer or uterine cancer, salivary gland cancer, kidney cancer or renal cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer, anal cancer, penile cancer, urothelial cancer and head and neck cancer.

[0158] The present invention also provides the use of the above-mentioned chimeric compound or a pharmaceutically acceptable salt thereof for treating and / or preventing tumor-related diseases, including but not limited to carcinoma, lymphoma, blastoma, sarcoma, leukemia, lymphoid malignancy, squamous cell carcinoma, esophageal cancer, thyroid cancer, melanoma, pancreatic cancer, lung cancer including small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma and lung squamous cell carcinoma, peritoneal cancer, hepatocellular carcinoma, bile duct cancer, gastric cancer or gastric cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, multiple myeloma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, liver cancer, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial cancer or uterine cancer, salivary gland cancer, kidney cancer or renal cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer, anal cancer, penile cancer, urothelial cancer and head and neck cancer.

[0159] The present invention also provides the use of the above-mentioned chimeric compound or a pharmaceutically acceptable salt thereof in the treatment and / or prophylaxis of RAS pathology, wherein the RAS pathology is preferably selected from neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Noonan syndrome with multiple pigmentation (NSML), capillary malformation-arteriovenous malformation syndrome (CM-AVM), Costello syndrome (CS), cardiofacial cutaneous syndrome (CFC), Legius syndrome or hereditary gingival fibromatosis.

[0160] The compounds described in the present invention are named according to their chemical structural formulas. If the name of the compound and the chemical structural formula do not match when representing the same compound, the chemical structural formula shall prevail.

[0161] In the present invention, unless otherwise specified, scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. However, for a better understanding of the present invention, definitions of some terms are provided below. When the definitions and explanations of the terms provided by the present invention are different from those commonly understood by those skilled in the art, the definitions and explanations provided by the present invention shall prevail.

[0162] Indicates the connection site between groups.

[0163] C x-y (where x and y respectively represent a positive integer (x < y)) indicates that a chain, ring structure or chain-ring structure can consist of a maximum of y and a minimum of x carbon atoms.

[0164] The number of atoms in a group containing one or more heteroatoms (such as heteroaryl, heteroarylalkyl, heterocyclic, heterocyclicalkyl) refers to the total number of atoms in the ring or the number of atoms in the ring and the carbon chain.

[0165] The indication of the number of carbon atoms in a group composed of a combination of a carbon chain and a carbon ring structure (such as cycloalkylalkyl, arylalkyl) refers to the total number of carbon atoms of all carbon ring and carbon chain members. Obviously, the ring structure has at least three members. <00,00667>

[0166] Generally, for a group containing two or more subunits (such as heteroarylalkyl, heterocyclicalkyl, cycloalkylalkyl, arylalkyl), the last named subunit is the group connection point. For example, the substituent aryl C 1-6 Alkyl refers to an aryl bonded to C<00001,30>alkyl, and the latter is bonded to the nucleus or to a group to which a substituent is attached.

[0167] Alkyl represents a monovalent saturated hydrocarbon chain, which can exist in a straight-chain (unbranched) and branched form. If the alkyl is substituted, the substitution can be carried out independently of each other on all carbon atoms carrying hydrogen by single substitution or multiple substitution.

[0168] The term C 1-6Alkyl groups, including, for example, H3C-, H3C-CH2-, H3C-CH2-CH2-, H3C-CH(CH3)-, H3C-CH2-CH2-CH2-, H3C-CH2-CH(CH3)-, H3C-CH(CH3)-CH2-, H3CC(CH3)2-, H3C-CH2-CH2-CH2-CH2-, H3C-CH2-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-CH2-, H3C-CH(CH3)-CH2-CH2-, H3C-CH2-C(CH3)2-, H3CC(CH3)2-CH2-, H3C-CH(CH3)-CH(CH3)- and H3C-CH2-CH(CH2CH3)-, H3C-CH2-CH2-CH2-CH2-CH2-, H3C-CH2-CH2-CH2-CH(CH3)-, CH(H3C-CH2-CH2)(H3C-CH3)-, C(H3C)2(H3C-CH2-CH3)-, H3C-CH2-CH(CH3)-CH(CH3)-, H3C-CH(CH3)-CH2-CH(CH3)-, (H3C-CH2)2-C(CH3)-, (H3C)2-CH-CH(CH2CH3)-, (H3C)2-CH-C(CH3)2-, (H3C)3-C-CH(CH3)-, H3C-CH(CH3)-CH(CH3)-CH2-, H3C-CH2-C(CH3)2-CH2-, (H3C)3-C-CH2-CH2-, H3C-CH2-CH2-CH(CH3)-CH2-, H3C-CH2-CH(CH3)-CH2-CH2-.<0​Other examples of alkyl groups are methyl (Me; -CH3), ethyl (Et; -CH2CH3), 1-propyl (n-propyl; n-Pr; -CH2CH2CH3), 2-propyl (-Pr; isopropyl; -CH(CH3)2), 1-butyl (n-butyl, n-Bu; -CH2CH2CH2CH3), 2-methyl-1-propyl (isobutyl; -Bu; -CH2CH(CH3)2), 2-butyl (sec-butyl; sec-Bu; -CH(CH3)CH2CH3), 2-methyl-2-propyl (tert-butyl; i-Bu; -C(CH3)3), 1-pentyl (n-pentyl; 2), 2-methyl-1-butyl (-CH(CH3)CH(CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 2,2-dimethyl-1-propyl (neopentyl; -CH2C(CH3)3), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (n-hexyl;-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), 2,3- Dimethyl-1-butyl (-CH2CH(CH3)CH(CH3)CH3), 2,2-dimethyl-1-butyl (-CH2C(CH3)2CH2CH3), 3,3-dimethyl-1-butyl (-CH2CH2C(CH3)3), 2-methyl-1-pentyl (-CH2CH(CH3)CH2CH2CH3), 3-methyl-1-pentyl (-CH2CH2CH(CH3) 3) CH2CH3), 1-heptyl (n-heptyl), 2-methyl-1-hexyl, 3-methyl-1-hexyl, 2,2-dimethyl-1-pentyl, 2,3-dimethyl-1-pentyl, 2,4-dimethyl-1-pentyl, 3,3-dimethyl-1-pentyl, 2,2,3-trimethyl-1-butyl, 3-ethyl-1-pentyl, 1-octyl (n-octyl), 1-nonyl (n-nonyl), 1-decyl (n-decyl), etc.;

[0170] The terms propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., without further definition, refer to saturated hydrocarbon radicals having the corresponding number of carbon atoms, including all isomeric forms. 1-3 Alkyl, C 1-4 Alkyl groups are as defined above, i.e. saturated hydrocarbon groups having the corresponding number of carbon atoms, including all isomeric forms.

[0171] If the alkyl group is part of another group, such as C x-y Alkoxy, halogenated C x-y Alkyl, deuterated C x-y Alkyl, etc., the above-mentioned definition of alkyl also applies.

[0172] The term alkylene can also be derived from alkyl. Unlike alkyl, alkylene is divalent, requiring two bonding groups. Formally, the second valency is created by removing a hydrogen atom from the alkyl group. Examples of corresponding groups are -CH3 and -CH2-, -CH2CH3 and -CH2CH2-, or =CHCH3.

[0173] The term "C 1-4 "Alkylene" includes, for example, -(CH2)-, -(CH2-CH2)-, -(CH(CH3))-, -(CH2-CH2-CH2)-, -(C(CH3)2)-, -(CH(CH2CH3))-, -(CH(CH3)-CH2)-, -(CH2-CH(CH3))-, -(CH2-CH2-CH2-CH2)-, -(CH2-CH2-CH(CH3))-, -(CH(CH3)-CH2 -CH2)-, -(CH2-CH(CH3)-CH2)-, -(CH2-C(CH3)2)-, -(C(CH3)2-CH2)-, -(CH(CH3)-CH(CH3))-, -(CH2 -CH(CH2CH3))-, -(CH(CH2CH3)-CH2)-, -(CH(CH2CH2CH3))-, -(CH(CH(CH3)2)- and -C(CH3)(CH2CH3)-.

[0174] Other examples of alkylene groups are methylene, ethylene, propylene, 1-methylethylene, butene, 1-methylpropylene, 1,1-dimethylethylene, 1,2-dimethylethylene, pentene, 1,1-dimethylpropylene, 2,2-dimethylpropylene, 1,2-dimethylpropylene, 1,3-dimethylpropylene, hexene, etc.

[0175] The generic terms propene, butene, pentene, hexene etc. without any further definition refer to all possible isomeric forms having the corresponding number of carbon atoms, i.e. propene includes 1-methylethylene, butene includes 1-methylpropylene, 2-methylpropylene, 1,1-dimethylethylene and 1,2-dimethylethylene.

[0176] If the alkylene group is part of another (bonded) group, e.g. in HO-C x-y Alkyleneamino or H2N-C x-y In the alkyleneoxy group, the above definition of alkylene also applies.

[0177] Unlike an alkyl group, an alkenyl group consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are linked together by a C-C double bond, and a carbon atom can only be part of a C-C double bond. If, in an alkyl group having at least two carbon atoms as defined above, two hydrogen atoms on adjacent carbon atoms are removed and the free valencies are saturated to form a second bond, the corresponding alkenyl group is formed.

[0178] Examples of alkenyl groups are ethenyl (vinyl), prop-1-enyl, allyl (prop-2-enyl), isopropenyl, but-1-enyl, but-2-enyl, but-3-enyl, 2-methyl-prop-2-enyl, 2-methyl-prop-1-enyl, 1-methyl-prop-2-enyl, 1-methyl-prop-1-enyl, 1-methylenepropyl, pent-1-enyl, pent-2-enyl, pent-3-enyl, pent-4-enyl, 3-methyl-but-3-enyl, 3-methyl-but-2-enyl, 3- methyl-but-1-enyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, hex-5-enyl, 2,3-dimethyl-but-3-enyl, 2,3-dimethyl-but-2-enyl, 2-methylene-3-methylbutyl, 2,3-dimethyl-but-1-enyl, hexa-1,3-dienyl, hexa-1,4-dienyl, penta-1,4-dienyl, penta-1,3-dienyl, buta-1,3-dienyl, 2,3-dimethylbut-1,3-diene, etc.

[0179] The generic terms propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, heptadienyl, octadienyl, nonadienyl, decadienyl and the like without any further definition refer to all conceivable isomeric forms having the corresponding number of carbon atoms, i.e. propenyl includes prop-1-ene and prop-2-ene, butene includes but-1-ene, but-2-ene, but-3-ene, 1-methyl-prop-1-ene, 1-methyl-prop-2-ene and the like.

[0180] The alkenyl group may optionally be present in the cis, trans, or Z orientation of the double bond.

[0181] When the alkenyl group is part of another (bonded) group, e.g. in C x-y Alkenylamino or C x-y In the alkenyloxy group, the above definition of alkenyl also applies.

[0182] Unlike an alkylene group, an alkenylene group consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are linked together by a C-C double bond, and a carbon atom can only be part of one C-C double bond. If, in an alkylene group having at least two carbon atoms as defined above, two hydrogen atoms on adjacent carbon atoms are formally removed and the free valences are saturated to form a second bond, the corresponding alkenylene group is formed.

[0183] Examples of alkenylene are vinylene, propenylene, 1-methylvinylene, butenyl, 1-methylpropylene, 1,1-dimethylvinylene, 1,2-dimethylethylene, pentene, 1,1-dimethylpropylene, 2,2-dimethylpropylene, 1,2-dimethylpropylene, 1,3-dimethylpropylene, hexene and the like.

[0184] The generic terms propene, butene, pentene, hexene etc. without any further definition refer to all conceivable isomeric forms having the corresponding number of carbon atoms, i.e. propene includes 1-methylvinylene and butene includes 1-methylpropene, 2-methylpropene, 1,1-dimethylvinylene and 1,2-dimethylvinylene.

[0185] The alkenylene group may optionally be present with the double bond in a cis, trans, or Z orientation.

[0186] The above definition of alkenylene also applies when alkenylene is part of another (bonded) group, e.g. in HO-C x-y Alkenyleneamino or H2N-C x-y In alkenyleneoxy.

[0187] Unlike alkyl groups, alkynyl groups consist of at least two carbon atoms, of which at least two adjacent carbon atoms are linked together by a C-C triple bond. If, in an alkyl group having at least two carbon atoms as defined above, two hydrogen atoms in each case at adjacent carbon atoms are formally removed and the free valencies are saturated to form two further bonds, the corresponding alkynyl group is formed.

[0188] Examples of alkynyl groups are ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, 1-methyl-prop-2-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, 3-methyl-but-1-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, and the like.

[0189] The general terms propynyl, butynyl, pentynyl, hexynyl, heptyl, octyl, nonyl, decyl, etc., without further definition, refer to all conceivable isomeric forms having the corresponding number of carbon atoms, i.e. propynyl includes prop-1-ynyl and prop-2-ynyl, butenyl includes but-1-ynyl, but-2-ynyl, but-3-ynyl, 1-methyl-prop-1-ynyl, 1-methyl-prop-2-ynyl, etc.

[0190] If a hydrocarbon chain carries both at least one double bond and at least one triple bond, it belongs, by definition, to the alkynyl subclass.

[0191] If the alkynyl group is part of another (composite) group, e.g. in C x-y Alkynamine or C x-y For alkynyloxy, the above-mentioned definition of alkynyl also applies.

[0192] Unlike alkylene, alkynylene consists of at least two carbon atoms, at least two adjacent carbon atoms being linked together via a C-C triple bond. If, in an alkylene group as defined above, there are at least two carbon atoms, in each case two hydrogen atoms on adjacent carbon atoms are formally removed and the free valencies are saturated to form two further bonds, the corresponding alkynylene is formed.

[0193] Examples of alkynylene groups are ethynylene, propynylene, 1-methylethynylene, butynyl, 1-methylpropynylene, 1,1-dimethylethynylene, 1,2-dimethylethynylene, pentynyl, 1,1-dimethylpropynylene, 2,2-dimethylpropynylene, 1,2-dimethylpropynyl, 1,3-dimethylpropynyl, hexynyl, etc.

[0194] The generic terms propynylene, butynylene, pentynylene, hexynylene etc., without any further definition, refer to all conceivable isomeric forms having the corresponding number of carbon atoms, i.e. propynylene includes 1-methylethynylene, and butynylene includes 1-methylpropynylene, 2-methylpropynylene, 1,1-dimethylethynylene and 1,2-dimethylethynylene.

[0195] If alkynylene is part of another (bonded) group, the above definition of alkynylene also applies, e.g. in HO-C x-y Alkynylideneamino or H2N-C x-y In alkynyleneoxy.

[0196] Heteroatoms refer to oxygen, nitrogen and sulfur atoms.

[0197] Haloalkyl (haloalkenyl, haloalkynyl) is derived from the previously defined alkyl (alkenyl, alkynyl) groups by replacing one or more hydrogen atoms of the hydrocarbon chain with identical or different halogen atoms, independently of one another. If a haloalkyl (haloalkenyl, haloalkynyl) group is to be further substituted, the substitutions may occur independently of one another in the form of mono- or poly-substitutions on all hydrogen-carrying carbon atoms.

[0198] Examples of haloalkyl (haloalkenyl, haloalkynyl) are -CF3, -CHF2, -CH2F, -CF2CF3, -CHFCF3, -CH2CF3, -CF2CH3, -CHFCH3, -CF2CF2CF3, -CF2CH2CH3, -CF=CF2, -CCI=CH2, -CBr=CH2, -C≡C-CF3, -CHFCH2CH3, -CHFCH2CF3, etc.

[0199] The term haloalkylene (haloalkenylene, haloalkynyl) is also derived from the previously defined haloalkyl (haloalkenyl, haloalkynyl) group. Unlike haloalkyl (haloalkenyl, haloalkynyl) groups, haloalkylene (haloalkenylene, haloalkynyl) groups are divalent and require two binding partners. Formally, the second valence is formed by removing a hydrogen atom from a haloalkyl (haloalkenyl, haloalkynyl) group.

[0200] Corresponding groups are, for example, -CH2F and -CHF-, -CHFCH2F and -CHFCHF- or =CFCH2F and the like.

[0201] The above definitions also apply if the corresponding halogen-containing group is part of another (bonded) group.

[0202] Halogen refers to fluorine, chlorine, bromine and / or iodine atoms.

[0203] Cycloalkyl groups are composed of the subgroups monocyclic hydrocarbon rings, bicyclic hydrocarbon rings, and spirocyclic hydrocarbon rings and are saturated. In bicyclic hydrocarbon rings, the two rings are linked together so that they share at least two carbon atoms. In spiro hydrocarbon rings, one carbon atom (the spiro atom) belongs to both rings.

[0204] If cycloalkyl is to be substituted, the substitutions may occur independently of one another and in each case as mono- or polysubstitutions on all hydrogen-carrying carbon atoms.Cycloalkyl itself can be attached as a substituent to the molecule via any suitable position of the ring system.

[0205] Examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.0]hexyl, bicyclo[3.2.0]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[4.3.0]nonyl (octahydroindenyl), bicyclo[4.4.0]decyl (decahydronaphthyl), bicyclo[2.2.1]heptyl (norbornyl), bicyclo[4.1.0]heptyl (norformyl), bicyclo[3.1.1]heptyl (pinenyl), spiro[2.5]octyl, spiro[3.3]heptyl and the like.

[0206] If the cycloalkyl group is part of another (composite) group, the above definition of cycloalkyl also applies, for example, to C x-y Cycloalkylamino, C x-y Cycloalkoxy or C x-y Cycloalkylalkyl.

[0207] If the free valencies of the cycloalkyl group are saturated, a cycloaliphatic radical is obtained.

[0208] The term cycloalkylene can be derived from the previously defined cycloalkyl group. Unlike cycloalkyl, cycloalkylene is divalent and requires two binding groups. Formally, the second valency is obtained by removing a hydrogen atom from a cycloalkyl group. Examples of corresponding groups include cyclohexyl and cyclohexylene.

[0209] If the cycloalkylene group is part of another (bonded) group (e.g. in HO-C x-y Cycloalkyleneamino or H2N-C x-y cycloalkyleneoxy), the above definition of cycloalkylene also applies.

[0210] Cycloalkenyl groups also consist of the subgroups monocyclic, bicyclic, and spirocyclic hydrocarbon rings. However, these systems are unsaturated, i.e., they contain at least one C-C double bond but no aromatic system. If, in a cycloalkyl group as defined above, two hydrogen atoms on adjacent cyclic carbon atoms are formally removed and the free valences are saturated to form a second bond, the corresponding cycloalkenyl group is obtained.

[0211] If the cycloalkenyl group is to be substituted, the substitutions may occur independently of one another, in each case as mono- or polysubstitutions on all hydrogen-carrying carbon atoms. The cycloalkenyl group itself can be attached as a substituent to the molecule via every suitable position of the ring system.

[0212] Examples of cycloalkenyl groups are cycloprop-1-enyl, cycloprop-2-enyl, cyclobut-1-enyl, cyclobut-2-enyl, cyclopent-1-enyl, cyclopent-2-enyl, cyclopent-3-enyl, cyclohexyl-1-enyl, cyclohex-2-enyl, cyclohex-3-enyl, cyclohept-1-enyl, cyclohept-2-enyl, cyclohept-3-enyl, cyclohept-4-enyl, cyclobuta-1,3-dienyl, cyclopenta-1,4-dienyl, cyclopenta-1,3-enyl, cyclopenta-2,4-enyl, cyclopenta-3-enyl, cyclohex-1,3-enyl, cyclohepta-2,4-enyl, cyclohepta-3-enyl, cyclohepta-4-enyl, cyclobuta-1,3-dienyl, cyclopenta-1,4-dienyl, cyclopenta-1,3-enyl, cyclopenta-2,4-enyl, cyclopenta-3-enyl, cyclohepta-1,3-enyl, cyclohepta-2,4-enyl, cyclohepta-3-enyl, cyclohepta-4-enyl, cyclohepta-1,3-enyl, cyclopenta-1,3-enyl, cyclopenta-1,3-enyl, cyclopenta-2,4-enyl, cyclopenta-3-enyl, cyclohepta-3-enyl, cyclohepta-4-enyl, cyclohepta-1,3-enyl, cyclohepta-2,4-enyl, cyclohepta-3-enyl, cyclohepta-4-enyl, cyclohepta-1,3-enyl, cyclohepta-2,4-en -dienyl, cyclopenta-2,4-dienyl, cyclohexa-1,3-dienyl, cyclohexa-1,5-dienyl, cyclohexa-2,4-dienyl, cyclohexa-1,4-dienyl, cyclohexa-2,5-dienyl, bicyclo[2.2.1]hept-2,5-dienyl (norbornen-2,5-dienyl), bicyclo[2.2.1]hept-2-enyl (norbornenyl), spiro[4,5]dec-2-enyl, etc.

[0213] When cycloalkenyl is part of another (bound) group, the above definition of cycloalkenyl also applies, for example, to C x-y Cycloalkenylamino, C x-y Cycloalkenyloxy or C x-y Cycloalkenylalkyl.

[0214] If the free valencies of the cycloalkenyl radical are saturated, an unsaturated alicyclic radical is obtained.

[0215] The term cycloalkenylene can thus be derived from the previously defined cycloalkenyl. Unlike cycloalkenyl, cycloalkenylene is divalent and requires two binding ligands. Formally, the second valency is obtained by removing a hydrogen atom from a cycloalkenyl. Corresponding groups are, for example, cyclopentenyl and cyclopentenylene.

[0216] If cycloalkenylene is part of another (bonded) group, the above definition of cycloalkenylene also applies, for example in HO-C x-y Cycloalkenyleneamino or H2N-C x-y Cycloalkenyleneoxy.

[0217] Aryl represents a monocyclic, bicyclic or tricyclic carbocyclic ring having at least one aromatic carbocyclic ring. Preferably, it represents a monocyclic group having six carbon atoms (phenyl) or a bicyclic group having nine or ten carbon atoms (two six-membered rings or one six-membered ring with a five-membered ring), wherein the second ring may also be aromatic or may also be partially saturated.

[0218] If an aryl group is to be substituted, the substitutions may occur independently of one another and in each case as mono- or polysubstitutions on all hydrogen-carrying carbon atoms. An aryl group itself can be attached as a substituent to the molecule via every suitable position of the ring system.

[0219] Examples of aryl groups are phenyl, naphthyl, indanyl (2,3-dihydroindenyl), indenyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl (1,2,3,4-tetrahydronaphthyl, tetrahydronaphthyl), dihydronaphthyl (1,2-dihydronaphthyl), fluorenyl, etc. Most preferred is phenyl.

[0220] If aryl is part of another (bonded) group (for example in arylamino, aryloxy or arylalkyl), the above definition of aryl also applies.

[0221] If the free valencies of the aryl group are saturated, an aromatic radical is obtained.

[0222] The term arylene can also be derived from the previously defined aryl group. Unlike aryl, arylene is divalent, requiring two bonding groups. Formally, the second valence is formed by removing a hydrogen atom from the aryl group. Examples of corresponding groups include naphthalene.

[0223] If arylene is part of another (bonded) group (for example in HO-aryleneamino or H2N-aryleneoxy), the above definition of arylene also applies.

[0224] Heterocyclyl represents a ring system derived from the previously defined cycloalkyl, cycloalkenyl and aryl groups by replacing one or more -CH2 groups in the hydrocarbon ring independently of one another by -O-, -S- or -NH- groups or by replacing one or more =CH- groups by =N- groups, wherein a total of not more than five heteroatoms may be present, at least one carbon atom must be present between two oxygen atoms, between two sulfur atoms or between an oxygen and a sulfur atom, and the ring as a whole must be chemically stable. Heteroatoms may optionally be present in all possible oxidation stages (S→sulfoxide -SO-, sulfone -SO2-, N→N-oxide). In heterocyclyl, there are no heteroaromatic rings, i.e., no heteroatoms are part of the aromatic system.

[0225] Derived directly from cycloalkyl, cycloalkenyl and aryl, heterocyclyl consists of the sub-groups monocyclic heterocycles, bicyclic heterocycles, tricyclic heterocycles and spiroheterocycles, which can exist in saturated or unsaturated form.

[0226] Unsaturated means that there is at least one double bond in the ring system in question, but no heteroaromatic system is formed. In a bicyclic heterocycle, the two rings are linked together so that they have at least two (hetero)atoms in common. In a spiro heterocycle, one carbon atom (spiro atom) belongs to both rings.

[0227] If the heterocyclyl group is substituted, the substitutions may occur independently of one another in the form of mono- or poly-substitutions on all hydrogen-bearing carbon and / or nitrogen atoms. The heterocyclyl group itself can be attached as a substituent to the molecule at every suitable position of the ring system. The substituents on the heterocyclyl group do not count towards the number of members of the heterocyclyl group.

[0228] Examples of heterocyclic groups are tetrahydrofuranyl, pyrrolidinyl, pyrrolinyl, imidazolinyl, thiazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, oxiranyl, azacyclidinyl, azetidinyl, 1,4-dioxanthenyl, azaphenanthrenyl, morpholinyl, thiomorpholinyl, homomorpholinyl, homopiperidinyl, homopiperazinyl, homothiomorpholinyl, thiomorpholinyl-S-oxide, thiomorpholinyl-S, S-dioxide, 1,3-dioxolanyl, tetrahydropyranyl, tetrahydrothioninyl , [1,4]-oxaphanyl, tetrahydrothiophenyl, homothiomorpholinyl-S, S-dioxide, oxazolidinyl, dihydropyrazolinyl, dihydropyrrolinyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydrofuranyl, tetrahydrothiophenyl-S-oxide, tetrahydrothiophenyl-S, S-dioxide, homothiomorpholinyl-S-oxide, 2,3-dihydroazacyclo, 2-hydropyrrolyl, 4-hydropyranyl, 1,4-dihydropyridinyl, 8-azabicyclo[3.2.1]octyl, 8- Azabicyclo[5.1.0]octyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 8-oxa-3-azabicyclo[3.2.1]octyl, 2,2-azaspiro[3.5]nonane, 7,2-azaspiro[3.5]nonane, 3,2-azaspiro[5.5]undecane, 3,8-diazabicyclo[3.2.1]octyl, 2,5-diazabicyclo[2.2.1]heptyl, 1-azabicyclo[2.2.2]octyl, 3,8-diazabicyclo[ [3.2.1]octyl, 3,9-diazabicyclo[4.2.1]nonyl, 2,6-diazabicyclo[3.2.2]nonyl, 1,4-dioxaspiro[4.5]decyl, 1-oxa-3,8-diazaspiro[4.5]decyl, 2,6-diazaspiro[3.3]heptyl, 2,7-diazaspiro[4.4]nonyl, 2,6-diazaspiro[3.4]octyl, 3,9-diazaspiro[5.5]undecyl, 2,8-diazaspiro[4,5]decyl and the like.

[0229] Preferably, the heterocyclyl group is 4 to 12 membered monocyclic or bicyclic or spirocyclic and has one or two heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0230] Preferred heterocyclic groups are: piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, azetidinyl, tetrahydropyranyl, tetrahydrofuranyl, azaspironane, azaspiroundecane.

[0231] The above definition of heterocyclyl also applies if heterocyclyl is part of another (bound) group (for example in heterocyclylamino, heterocyclyloxy or heterocyclylalkyl).

[0232] If the free valencies of the heterocyclyl radical are saturated, a heterocyclyl radical is obtained.

[0233] The term heterocyclylene is also derived from the previously defined heterocyclyl. Unlike heterocyclyl, heterocyclylene is divalent and requires two binding groups. Formally, the second valency is obtained by removing a hydrogen atom from the heterocyclyl group. Examples of corresponding groups include piperidinyl and 2,3-dihydro-1H-pyrrolyl, among others.

[0234] If heterocyclylene is part of another (bound) group, for example, in HO-heterocyclyleneimino or H2N-heterocyclyleneoxy, the above definition of heterocyclylene also applies. Heteroaryl is a monocyclic heteroaromatic ring or polycyclic ring with at least one heteroaromatic ring which, in contrast to the corresponding aryl or cycloalkyl (cycloalkenyl) radicals, contains one or more independently selected, identical or different heteroatoms (nitrogen, sulfur and oxygen) instead of one or more carbon atoms, provided that the resulting radical is chemically stable. The presence of a heteroaryl radical presupposes the presence of a heteroatom and a heteroaromatic system.

[0235] If a heteroaryl group is substituted, the substitutions can be made independently of one another in the form of mono- or poly-substitutions on all hydrogen-bearing carbon and / or nitrogen atoms. The heteroaryl group itself can be attached as a substituent to the molecule via a carbon atom and a nitrogen atom at every suitable position in the ring system. The substituents on the heteroaryl group do not count towards the number of members of the heteroaryl group.

[0236] Examples of heteroaryl groups are furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyridyl-N oxide, pyrrolyl-N oxide, pyrimidinyl-N oxide, pyridazinyl-N oxide, pyrazinyl-N oxide, imidazolyl-N oxide, isoxazolyl-N oxide, oxazolyl-N oxide, thiazolyl-N oxide, oxadiazolyl-N oxide, thiadiazolyl-N oxide, triazolyl-N oxide, tetrazolyl-N oxide, indole, isoindolyl, benzofuranyl, benzothienyl, benzothiophene, oxazolyl, benzothiazolyl, benzisoxazolyl, benzimidazolyl, indolazolyl, isoquinolyl, quinolyl, quinolyl, cinnolinyl, zinc phthalate, quinazolinyl, benzotriazinyl, indolizinyl, oxazolinyl, imidazolyl pyridinyl, naphthyridinyl, benzoxazolyl, pyridinyl, pyrimidinyl pyridinyl, purinyl, pteridinyl, benzothiazolyl, imidazolinyl, imidazolyl, quinolyl-N oxide, indolyl-N oxide, isoquinolyl-N oxide, quinazolinyl-N oxide, quinolyl-N oxide, zinc phthalate-N oxide, indolazolyl-N oxide, indolazolyl-N oxide, benzothiazolyl-N oxide, benzimidazolyl-N oxide, etc.

[0237] A further example is the structure shown below, which can be linked via each hydrogen-carrying atom (exchanged for hydrogen):

[0238] Preferably, the heteroaryl group is a 5-6 membered monocyclic ring or a 9-10 membered bicyclic ring, each having 1-4 heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0239] The above definition of heteroaryl also applies if heteroaryl is part of another (bound) group, such as in heteroarylamino, heteroaryloxy or heteroarylalkyl.

[0240] If the free valencies of the heteroaryl group are saturated, a heteroaromatic radical is obtained.

[0241] The term heteroarylene is also derived from the previously defined heteroaryl group. Unlike heteroaryl, heteroarylene is divalent and requires two binding groups. Formally, the second valency is obtained by removing a hydrogen atom from the heteroaryl group. An example of a corresponding group is pyrrolyl.

[0242] If heteroarylene is part of another (bound) group, for example in HO-heteroaryleneamino or H2N-heteroaryleneoxy, the above definition of heteroaryl also applies.

[0243] Substituted means that a hydrogen atom directly bonded to the atom in question is replaced by another atom or another group of atoms (substituent). Depending on the starting conditions (number of hydrogen atoms), an atom can be monosubstituted or polysubstituted. Substitution with a specific substituent is only possible if the number of allowed valence atoms of the substituent and the atom to be replaced corresponds to each other and the substitution results in a stable compound (i.e., a compound that does not spontaneously transform by, for example, rearrangement, cyclization, or elimination).

[0244] Divalent substituents, such as =S, =NR, =NOR, =NNRR, =NN(R)C(O)NRR, =N2, etc., can only be substituents on carbon atoms, while the divalent substituents =O and =NR can also be substituents on sulfur. Generally, substitution can only be made by divalent substituents on the ring system and requires the replacement of a geminal hydrogen atom, i.e., a hydrogen atom bound to the same carbon atom that was saturated before the substitution. Thus, substitution by a divalent substituent is only possible at the ring system at a group -CH2- or a sulfur atom (a =O group or a =NR group, which may have one or two =O groups, or, for example, one =O group and one =NR group, each replacing one free electron pair). BRIEF DESCRIPTION OF THE DRAWINGS

[0245] Figure 1 This is a Western Blot result showing compound C36 degrading endogenous KRAS in MIAPaCa-1 cells;

[0246] Figure 2 This is a Western Blot result diagram verifying the pathway of compound C36 degrading endogenous KRAS in MIAPaCa-1 cells;

[0247] Figure 3 This is the result of Western Blot detection of PROTAC compound C06 on target protein degradation. DETAILED DESCRIPTION

[0248] The present invention is further described in detail below with reference to specific examples. The following examples are used to understand the methods and core ideas of the present invention. For those skilled in the art, any possible changes or substitutions without departing from the concept of the present invention are within the scope of protection of the present invention. The experimental methods for which specific conditions are not specified in the examples of the present invention are generally conventional conditions, or conditions recommended by the raw material or commodity manufacturer; reagents for which the source is not specified are generally conventional reagents available through commercial channels.

[0249] Example 1: C06 compound

[0250] Step 1: Preparation of compound 6-2

[0251]

[0252] Compound 6-1 (240 mg, 0.4 mmol) was dissolved in 1.0 mL of trifluoroacetic acid and 2.0 mL of dichloromethane, stirred at room temperature for 2 hours, and the reaction solution was dried to obtain product 6-2 (240 mg crude product, yield: 100%). LC-MS-MC20-1021-067-A: (ES, m / z): [M+H] + =530.2

[0253] Step 2: Preparation of compound C06

[0254]

[0255] Compound 6-2 (90 mg crude, 0.17 mmol), compound 6-3 (73 mg, 0.17 mmol) and DIEA (44 mg, 0.34 mmol) were dissolved in 1 mL of N,N-dimethylformamide, and HATU (84 mg, 0.22 mmol) was added. The reaction was carried out at room temperature for 2 hours. Reverse preparation (A: 0.3% formic acid, B: acetonitrile; 3% to 97%) was performed, and lyophilization was performed to obtain 61.12 mg (yield: 37%) of the target product C06.

[0256] LC-MS-MC20-1021-072:(ES,m / z):[M+H] + =942.3

[0257] 1H NMR (400MHz, DMSO) δ8.98(s,1H),8.56(t,J=6.0Hz,1H),8.21(d,J=6.9Hz,2H),7.93(d,J=9.3Hz,1H),7.84(d,J =7.6Hz,2H),7.55–7.47(m,5H),7.40(q,J=8.1Hz,4H),7.29(t,J=7.3Hz,1H),6.86(s,1H),5.13(d,J=3.4Hz,1H ),4.56(d,J=9.4Hz,1H),4.48–4.39(m,2H),4.38–4.31(m,1H),4.21–4.24m,1H),3.94–3.81(m,4H),3.70–3.50 (m,10H),2.74–2.65(m,4H),2.61–2.54(m,6H),2.44(s,3H),2.42–2.33(m,1H),2.08–1.86(m,2H),0.94(s,9H).

[0258] Example 2: C07 compound

[0259] Step 1: Preparation of compound 7-2

[0260]

[0261] Dess-Martin periodinane (803 mg, 1.9 mmol) and pyridine (299 mg, 3.8 mmol) were dissolved in dichloromethane (5 mL). A solution of compound 7-1 (300 mg, 1.6 mmol) in dichloromethane (4 mL) was added dropwise. The mixture was stirred at room temperature for 16 h. 5 mL of 5% aqueous sodium thiosulfate solution and 10 mL of saturated aqueous sodium bicarbonate solution were then added. The mixture was extracted with dichloromethane (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and spin-dried to give the crude product 7-2 (295 mg, yield: 99%). LS-MS showed no signal, so the product was used directly in the next step.

[0262] Step 3: Preparation of compound 7-4

[0263]

[0264] Compound 7-2 (188 mg, 1.0 mmol) and compound 7-3 (180 mg, 0.5 mmol) were dissolved in tetrahydrofuran (5 mL), and sodium triacetoxyborohydride (212 mg, 1.0 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated and column chromatography (methanol / dichloromethane, 1:11) was performed to obtain product 7-4 (250 mg, yield: 92%). LC-MS-MC20-1021-112: (ES, m / z): [M+H]+ =542.1

[0265] Step 3: Preparation of compound 7-5

[0266]

[0267] Compound 7-4 (120 mg, 0.22 mmol) was dissolved in 2.0 mL of trifluoroacetic acid and 4.0 mL of dichloromethane, stirred at room temperature for 2 hours, and the reaction solution was dried to give product 7-5 (120 mg crude product, yield: 100%). LC-MS-MC20-1021-119-A1: (ES, m / z): [M+H] + =486.2

[0268] Step 4: Preparation of compound C07

[0269]

[0270] Compound 7-5 (120 mg crude product, 0.22 mmol), compound 7-6 (95 mg, 0.22 mmol) and DIEA (142 mg, 1.1 mmol) were dissolved in 2 mL of N,N-dimethylformamide, and HATU (106 mg, 0.28 mmol) was added. The reaction was carried out at room temperature for 2 days, and the reaction was reversed (A: 0.3% ammonium bicarbonate, B: acetonitrile; 3% to 97%). The target product C07 compound was obtained by lyophilization with 37.70 mg (yield: 19%).

[0271] LC-MS-MC20-1021-124-1:(ES,m / z):[M+H] + =898.6

[0272] 1H NMR (400MHz, DMSO) δ8.96(s,1H),8.55(t,J=6.0Hz,1H),8.20(dd,J=7.9,1.5Hz,2H),7.94(d,J=9.3Hz,1H),7. 83(d,J=7.2Hz,2H),7.55–7.46(m,5H),7.39(q,J=8.4Hz,4H),7.28(t,J=7.4Hz,1H),6.85(s,1H),5.14(d,J=3. 5Hz,1H),4.57(d,J=9.4Hz,1H),4.47–4.32(m,3H),4.21(dd,J=16.0,5.4Hz,1H),3.91–3.80(m,4H),3.69–3.52 (m,6H),2.71–2.64(m,4H),2.62–2.54(m,6H),2.43(s,3H),2.40–2.32(m,1H),2.10–1.83(m,2H),0.95(s,9H).

[0273] Example 3: C18 compound

[0274] Step 1: Preparation of compound 18-3

[0275]

[0276] Compound 18-1 (200 mg, 0.54 mmol) was dissolved in DMF (10 mL), and compound 18-2 (329 mg, 1.08 mmol) and potassium carbonate (224 mg, 1.62 mmol) were added. The mixture was stirred at 80°C for 16 hours, and then 20 mL of aqueous solution was added. The mixture was extracted with ethyl acetate (20 ml*3). The organic phases were combined, washed with saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, and subjected to spin column chromatography (ethyl acetate / petroleum ether, 10:1) to obtain product 18-3 (110 mg, 37%). LC-MS-MC21-96-001F2022796: (ES, m / z): [M+H]+=502.1

[0277] Step 2: Preparation of compound 18-5

[0278]

[0279] Compound 18-3 (100 mg, 0.2 mmol) and compound 18-4 (117 mg, 0.6 mmol) were added to a reaction flask, and 5 ml of tert-butanol was added, followed by potassium tert-butoxide (67 mg, 0.6 mmol) and potassium iodide (100 mg, 0.6 mmol). The mixture was stirred at room temperature for 12 hours, and water (20 ml) was added. The mixture was extracted with ethyl acetate (20 ml*3). The organic phases were combined, washed with saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, and dried by reverse phase preparation (A: 0.3% ammonium bicarbonate, B: acetonitrile; 3% to 97%) to obtain product 18-5 (40 mg, yield: 32%). LC-MS-MC21-96-012-P615: (ES, m / z): [M+H] + =616.3

[0280] Step 3: Preparation of compound 18-6

[0281]

[0282] Compound 18-5 (80 mg, 0.14 mmol) was added to a reaction flask, followed by dichloromethane (5 mL) and trifluoroacetic acid (2 ml). The mixture was stirred at room temperature for 1 hour and then dried to give product 18-6 (30 mg, crude). LC-MS-MC20-1018-112: (ES, m / z): [M+H] + =560.2

[0283] Step 4: Preparation of compound C18

[0284]

[0285] Compound 18-6 (30 mg, 0.05 mmol) was added to a reaction flask, followed by 5 mL of N,N-dimethylformamide, HATU (29 mg, 0.075 mmol), DIEA (32 mg, 0.25 mmol), and compound 18-7 (22 mg, 0.05 mmol). The mixture was reacted for 2 hours, and water (10 ml) was added. The mixture was extracted with ethyl acetate (20 ml*3). The organic phases were combined, washed with saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, and spin-dried. The reverse preparation (A: 0.3% ammonium bicarbonate, B: acetonitrile; 3% to 97%) was used, and lyophilized to obtain 11.93 mg (yield: 22%) of the target product C18.

[0286] LC-MS-MC21-96-018P2-LCMS:(ES,m / z):[M+H] + =972.4

[0287] 1H NMR (400MHz, DMSO) δ8.97(s,1H),8.59(t,J=5.6Hz,1H),8.20(d,J=6.8Hz,2H),7.83(d,J=7 .6Hz,2H),7.54–7.37(m,10H),7.28(t,J=7.6Hz,1H),6.85(s,1H),5.16–5.14(m,1H),4.57( d,J=9.2Hz,1H),4.49–4.31(m,3H),4.26(d,J=5.2Hz,1H),3.98(s,2H),3.84(s,4H),3.61–3 .55(m,12H),2.67(s,4H),2.56(s,5H),2.43(s,3H),2.05(s,1H),1.90(s,1H),0.93(s,9H).

[0288] Example 4: C19 compound

[0289] Step 1: Preparation of compound 19-3

[0290]

[0291] Compound 19-1 (100 mg, 0.27 mmol) was added to a reaction flask, followed by KI (45 mg, 0.27 mmol) and K2CO3 (75 mg, 0.54 mmol). The mixture was stirred at room temperature, and 19-2 (105 mg, 0.54 mmol) and DMF (5 ml) were added. The mixture was reacted at 80°C for 5 hours. Water (50 ml) was added, and the mixture was extracted with ethyl acetate (40 ml*3). The organic phases were combined, washed with saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, and subjected to spin column chromatography (ethyl acetate / petroleum ether, 1:1) to obtain product 19-3 (80 mg). LC-MS-MC20-1086-023-1-2: (ES, m / z): [M+H] + =484.1

[0292] Step 2: Preparation of compound 19-4

[0293]

[0294] Compound 19-3 (80 mg, 0.17 mmol) was added to a reaction flask, followed by 10 ml of methanol, 2 ml of water, and lithium hydroxide monohydrate (26 mg, 0.64 mmol). The mixture was stirred at room temperature for 6 hours, dried under reduced pressure, and extracted with ethyl acetate (20 ml * 3). The organic phases were combined, washed with saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, and dried by column chromatography (methanol / dichloromethane, 1:10) to obtain product 19-4 (60 mg, yield: 79%). LC-MS-MC20-1031-098-R1: (ES, m / z): [M+H] + =470.1

[0295] Step 3: Preparation of compound C19

[0296]

[0297] Compound 19-4 (60 mg, 0.13 mmol) was added to DMF (5 ml), and then HATU (74 mg, 0.20 mmol) and DIEA (33 mg, 0.26 mmol) were added and stirred at room temperature for 10 minutes. Compound 19-5 (66 mg, 0.15 mmol) was added and stirred at room temperature for 3 hours. After filtration, the product C19 (40.86 mg) was obtained by reverse preparation (acetonitrile, 0.1% ammonia water, 5% to 95%).

[0298] LC-MS-MC20-1031-102-LCMS:(ES,m / z):[M+H] + =882.1

[0299] 1 H NMR (400MHz, DMSO) δ8.98(s,1H),8.56(t,J=6.0Hz,1H),8.20(d,J=6.5Hz,2H),7.83–7.88(m,3H),7.51 -7.54(m,5H),7.40(q,J=8.2Hz,4H),7.28(t,J=7.4Hz,1H),5.14(d,J=3.4Hz,1H),4.57(d,J=9.4Hz,1H) ,4.49–4.32(m,3H),4.22–4.24(m,1H),3.86(s,4H),3.67(s,2H),2.62–2.55(m,7H),2.44(s,3H),2.40 –2.28(m,3H),2.24–2.13(m,1H),2.03–2.04(m,1H),1.91-1.93(m,1H),1.63–1.45(m,4H),0.94(s,9H).

[0300] Example 5: C21 compound

[0301] Step 1: Preparation of compound 21-3

[0302]

[0303] Compound 21-1 (150 mg, 0.41 mmol) was added to a reaction flask, followed by Cu(OAc)2 (82 mg, 0.41 mmol) and CuI (78 mg, 0.41 mmol), and stirred at room temperature. Compound 21-2 (263 mg, 2.05 mmol) and H2O (5 ml) were added, and the mixture was reacted at 100°C for 16 hours. Ethyl acetate (20 ml*3) was added for extraction, and the organic phases were combined, washed with saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, and subjected to spin column chromatography (ethyl acetate / petroleum ether, 1:1) to obtain product 21-3 (80 mg). LC-MS (ES, m / z): [M+H] + =498.2

[0304] Step 2: Preparation of compound 21-4

[0305]

[0306] Compound 21-3 (80 mg, 0.16 mmol) was added to a reaction flask, followed by 10 ml of DCM and 5 ml of TFA. The mixture was stirred at room temperature for 6 hours and dried under reduced pressure to give product 21-4 (60 mg, yield: 79%). LC-MS-MC20-1031-104-R1: (ES, m / z): [M+H] + =442.0

[0307] Step 3: Preparation of compound C21

[0308]

[0309] Compound 21-4 (60 mg, 0.14 mmol) was added to DMF (5 ml), and then HATU (80 mg, 0.22 mmol) and DIEA (36 mg, 0.28 mmol) were added and stirred at room temperature for 10 minutes. Compound 21-5 (70 mg, 0.16 mmol) was added and stirred at room temperature for 3 hours. After filtration, the product C21 (23.36 mg) was obtained by reverse preparation (acetonitrile, 0.1% ammonia water, 5% to 95%).

[0310] LC-MS-MC20-1031-107-LCMS:(ES,m / z):[M+H] + =854.1

[0311] 1 H NMR (400MHz, DMSO) δ8.85(s,1H),8.60(t,J=5.9Hz,1H),8.54(d,J=9.5Hz,1H),8.27–8.08(m,2H ),7.83(d,J=7.3Hz,2H),7.56–7.45(m,5H),7.44–7.38(m,2H),7.37–7.22(m,3H),6.83(s,1H),5 .16(d,J=3.4Hz,1H),4.59(d,J=9.4Hz,1H),4.49–4.40(m,2H),4.37(s,1H),4.19–4.17(m,1H), 3.93(s,4H),3.69–3.67(m,2H),2.82–2.52(m,10H),2.36–2.34(m,,4H),2.12–1.99(m,1H),1.99

[0312] –1.84(m,1H),0.98(s,9H).

[0313] Example 6: C22 compound

[0314] Step 1: Preparation of compound 22-3

[0315]

[0316] Compound 22-1 (100 mg, 0.27 mmol) was added to a reaction flask, followed by 22-2 (104 mg, 0.54 mmol) and K2CO3 (112 mg, 0.81 mmol). The mixture was stirred at room temperature for 6 hours. Water (20 ml) and ethyl acetate (20 ml*3) were added for extraction. The organic phases were combined, washed with saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, and subjected to spin column chromatography (ethyl acetate / petroleum ether, 1:1) to obtain product 22-3 (60 mg). LC-MS (ES, m / z): [M+H] + =484.1

[0317] Step 2: Preparation of compound 22-4

[0318]

[0319] Compound 22-3 (40 mg, 0.16 mmol) was added to a reaction flask, and 10 ml of DCM and 5 ml of TFA were added. The mixture was stirred at room temperature for 6 hours and dried under reduced pressure to obtain product 22-4 (40 mg). LC-MS: (ES, m / z): [M+H] + =428.2

[0320] Step 3: Preparation of compound C22

[0321]

[0322] Compound 22-4 (40 mg, 0.09 mmol) was added to DMF (5 ml), and then HATU (45 mg, 0.12 mmol) and DIEA (58 mg, 0.45 mmol) were added and stirred at room temperature for 10 minutes. Compound 22-5 (40 mg, 0.09 mmol) was added and stirred at room temperature for 3 hours. After filtration, the product C22 (24.39 mg) was obtained by reverse preparation (acetonitrile, 0.1% ammonia water, 5% to 95%).

[0323] LC-MS-MC20-1086-017-LCMS:(ES,m / z):[M+H] + =840.1

[0324] 1 H NMR (400MHz, DMSO) δ8.88(s,1H),8.59(d,J=5.7Hz,1H),8.21(d,J=6.2Hz,2H),7.93–7.78(m,3H),7 .4717.62(m,5H),7.37–7.44(m,4H),7.29(t,J=7.4Hz,1H),6.90(s,1H),5.17(d,J=3.1Hz,1H),4.5 6(d,J=9.6Hz,1H),4.38–4.48(m,3H),4.27–4.29(m,1H),3.92(s,4H),3.66–3.69(m,2H),3.10–3.2 2(m,2H),2.78(s,4H),2.50(s,3H),2.40(s,3H),2.12–2.02(m,1H),1.98–1.85(m,1H),0.98(s,9H).

[0325] Example 7: C23 compound

[0326] Step 1: Preparation of compound 23-3

[0327]

[0328] Compound 23-1 (100 mg, 0.27 mmol) and compound 23-2 (70 mg, 0.33 mmol) were dissolved in tetrahydrofuran (10 mL), and sodium triacetoxyborohydride (286 mg, 1.4 mmol) was added. The mixture was stirred at 60°C for 16 hours and then dried by column chromatography (ethyl acetate / petroleum ether, 8:1) to obtain product 23-3 (70 mg). LC-MS: (ES, m / z): [M+H] +=567.3

[0329] Step 2: Preparation of compound 23-4

[0330]

[0331] Compound 23-3 (70 mg, 0.12 mmol) was added to a reaction flask, followed by 5 ml of dichloromethane and trifluoroacetic acid (2 mL). The mixture was stirred at room temperature for 2 hours and dried to give product 23-4 (60 mg). LC-MS: (ES, m / z): [M+H] + =467.3

[0332] Step 3: Preparation of compound C23

[0333]

[0334] Compound 23-4 (60 mg, 0.13 mmol) was added to a reaction flask, followed by N,N-dimethylformamide (5 mL), CDI (32 mg, 0.2 mmol), and DMAP (35 mg, 2.9 mmol). After stirring at room temperature for 1 hour, compound 23-5 (56 mg, 0.13 mmol) was added, and the mixture was stirred at room temperature for 16 hours. Water (10 mL) was added, and then extracted with ethyl acetate (20 ml*3). The organic phase was washed with saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, and spin-dried. The reverse preparation (A: 0.3% ammonium bicarbonate, B: acetonitrile; 3% to 97%) was then obtained, and lyophilized to obtain 13.66 mg of the target product C23.

[0335] LC-MS-MC20-1086-024-LCMS:(ES,m / z):[M+H] + =923.1

[0336] 1H NMR (400MHz, DMSO) δ8.98(s,1H),8.54(d,J=5.8Hz,1H),8.20(d,J=7.0Hz,2H),7.84(d,J=7.6Hz,2H),7.46– 7.56(m,5H),7.40(s,4H),7.28(t,J=7.3Hz,1H),6.86(s,1H),5.77(d,J=8.5Hz,1H),5.11(d,J=3.3Hz,1H), 4.50–4.33(m,4H),4.22–4.27(m,1H),3.86–4.01(m,5H),3.68–3.71(m,2H),2.78–2.59(m,6H),2.57(s,3H) ,2.45(s,3H),2.24(d,J=6.0Hz,2H),2.09–1.98(m,1H),1.91(s,1H),1.72–1.76(m,3H),1.17–0.76(m,11H).

[0337] Example 8: C26 compound

[0338] Step 1: Preparation of compound 26-3

[0339]

[0340] Compound 26-1 (800 mg, 2.17 mmol) and compound 26-2 (1.3 g, 6.51 mmol) were added to a reaction flask, followed by 10 ml of tetrahydrofuran and sodium triacetoxyborohydride (2.3 g, 10.85 mmol). The mixture was stirred at 60°C for 12 hours, quenched with water (40 ml), and extracted with ethyl acetate (40 ml*3). The organic phases were combined, washed with saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, and subjected to spin column chromatography (ethyl acetate / petroleum ether, 10:1) to obtain product 26-3 (700 mg, yield: 58%). LC-MS-MC20-1018-130P1: (ES, m / z): [M+H] + =553.1

[0341] Step 2: Preparation of compound 26-4

[0342]

[0343] Compound 26-3 (400 mg, 0.88 mmol) was added to a reaction flask, followed by dichloromethane (6 mL) and trifluoroacetic acid (3 mL). The mixture was stirred at room temperature for 2 hours, and water (10 mL) was added. The pH was adjusted to 7 with saturated sodium bicarbonate. The mixture was extracted with ethyl acetate (20 mL*3). The organic phases were combined, washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, and subjected to spin column chromatography (methanol / dichloromethane, 5:1) to obtain product 26-4 (320 mg, crude product). LC-MS-MC21-96-006O1: (ES, m / z): [M+H] + =453.2

[0344] Step 3: Preparation of compound 26-6

[0345]

[0346] Compound 26-4 (450 mg, 1.0 mmol), compound 26-5 (342 mg, 2.0 mmol) and acetic acid (60 mg, 1.0 mmol) were added to a reaction flask, and 10 ml of tetrahydrofuran was added. The mixture was stirred at room temperature for 30 minutes, and then sodium triacetoxyborohydride (1.06 g, 5.0 mmol) was added. The mixture was stirred at 50°C for 2 hours, and then quenched with water (40 ml). The mixture was extracted with ethyl acetate (40 ml*3). The organic phases were combined, washed with saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, and subjected to spin column chromatography (methanol / dichloromethane, 1:10) to give product 26-6 (320 mg, yield: 52%). LC-MS-MC21-96-011P2: (ES, m / z): [M+H] + =608.3

[0347] Step 4: Preparation of compound 26-7

[0348]

[0349] Compound 26-6 (60 mg, 0.1 mmol) was added to a reaction flask, followed by dichloromethane (3 mL) and trifluoroacetic acid (2 ml). The mixture was stirred at room temperature for 2 hours and then dried to give product 26-7 (50 mg, crude). LC-MS-MC21-96-019F2: (ES, m / z): [M+H] + =508.3

[0350] Step 5: Preparation of compound 26-10

[0351]

[0352] Compound 26-8 (500 mg, 1.2 mmol) was added to a reaction flask, followed by 10 mL of N,N-dimethylformamide, HATU (836 mg, 1.8 mmol), DIEA (774 mg, 6.0 mmol), and compound 26-9 (137 mg, 0.14 mmol). The reaction was allowed to proceed at room temperature for 16 hours. The product 26-10 (300 mg, yield: 53%) was obtained by reverse preparation (A: 0.3% ammonium bicarbonate, B: acetonitrile; 3% to 97%). LC-MS-MC21-96-040P1: (ES, m / z): [M+H] + =489.2

[0353] Step 6: Preparation of compound 26-11

[0354]

[0355] Compound 26-10 (200 mg, 0.41 mmol) was dissolved in dichloromethane (10 mL), and Dess-Martin (348 mg, 0.82 mmol) was added. The mixture was stirred at room temperature for 16 hours, and 20 mL of saturated aqueous sodium thiosulfate solution was added. The mixture was extracted with dichloromethane (20 ml*3). The organic phases were combined, washed with saturated sodium chloride (20 ml), and dried over anhydrous sodium sulfate to give product 26-11 (180 mg, crude product).

[0356] Step 7: Preparation of compound C26

[0357]

[0358] Compound 26-7 (66 mg, 0.13 mmol) and compound 26-11 (90 mg, 0.19 mmol) were added to a reaction flask, 10 ml of tetrahydrofuran was added, and then sodium triacetoxyborohydride (83 mg, 0.39 mmol) was added. The mixture was reacted at room temperature for 2 hours, and the mixture was dried by reverse preparation (A: 0.3% ammonium bicarbonate, B: acetonitrile; 3% to 97%). The target product C26 (8.37 mg, yield: 7%) was obtained by lyophilization.

[0359] LC-MS-MC21-96-050-P1-LCMS:(ES,m / z):[M+H] + =978.5

[0360] 1H NMR (400MHz, DMSO) δ8.98(s,1H),8.60(t,J=6.0Hz,1H),8.25–8.16(m,2H),7.84(d,J=7.2Hz,2H),7.52(dt ,J=18.0,8.8Hz,7H),7.41(s,3H),7.28(t,J=7.2Hz,1H),6.85(s,1H),5.16–5.14(m,1H),4.59–4.18(m,5H) ,3.85(s,5H),3.72–3.54(m,2H),3.45(s,2H),3.10(s,1H),2.93(s,2H),2.73(s,7H),2.57(s,3H),2.45(s, 3H),2.26(s,1H),2.10–2.01(m,1H),1.94–1.88(m,1H),1.79–1.77(m,4H),1.45–1.43(m,2H),0.93(s,9H).

[0361] Example 9: C27 compound

[0362] Step 1: Preparation of compound 27-3

[0363]

[0364] Compound 27-1 (800 mg, 2.17 mmol) and compound 27-2 (1.3 g, 6.51 mmol) were added to a reaction flask, followed by 10 ml of tetrahydrofuran and sodium triacetoxyborohydride (2.3 g, 10.85 mmol). The mixture was stirred at 60°C for 12 hours, quenched with water (40 ml), and extracted with ethyl acetate (40 ml*3). The organic phases were combined, washed with saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, and subjected to spin column chromatography (ethyl acetate / petroleum ether, 10:1) to obtain product 27-3 (700 mg, yield: 58%). LC-MS-MC20-1018-130P1: (ES, m / z): [M+H] + =553.1

[0365] Step 2: Preparation of compound 27-4

[0366]

[0367] Compound 27-3 (400 mg, 0.88 mmol) was added to a reaction flask, followed by dichloromethane (6 mL) and trifluoroacetic acid (3 mL). The mixture was stirred at room temperature for 2 hours, and water (10 mL) was added. The pH was adjusted to 7 with saturated sodium bicarbonate. The mixture was extracted with ethyl acetate (20 mL*3). The organic phases were combined, washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, and subjected to spin column chromatography (methanol / dichloromethane, 5:1) to obtain product 27-4 (320 mg, crude product). LC-MS-MC21-96-006O1: (ES, m / z): [M+H] + =453.2

[0368] Step 3: Preparation of compound 27-6

[0369]

[0370] Compound 27-4 (450 mg, 1.0 mmol), compound 27-5 (342 mg, 2.0 mmol) and acetic acid (60 mg, 1.0 mmol) were added to a reaction flask, and 10 ml of tetrahydrofuran was added. The mixture was stirred at room temperature for 30 minutes, and then sodium triacetoxyborohydride (1.06 g, 5.0 mmol) was added. The mixture was stirred at 50°C for 2 hours, and quenched by adding water (40 ml). The mixture was extracted with ethyl acetate (40 ml*3). The organic phases were combined, washed with saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, and subjected to spin column chromatography (methanol / dichloromethane, 1:10) to give product 27-6 (320 mg, yield: 52%). LC-MS-MC21-96-011P2: (ES, m / z): [M+H] + =608.3

[0371] Step 4: Preparation of compound 27-7

[0372]

[0373] Compound 27-6 (60 mg, 0.1 mmol) was added to a reaction flask, followed by dichloromethane (3 mL) and trifluoroacetic acid (2 ml). The mixture was stirred at room temperature for 2 hours and then dried to give product 27-7 (50 mg, crude). LC-MS-MC21-96-019F2: (ES, m / z): [M+H] + =508.3

[0374] Step 5: Preparation of compound C27

[0375]

[0376] Compound 27-7 (70 mg, 0.13 mmol) was added to a reaction flask, followed by THF (5 mL), DIEA (67 mg, 0.52 mmol), and 27-9 (42 mg, 0.21 mmol). The mixture was stirred at -20°C for 1 hour. Compound 27-8 (71 mg, 0.17 mmol) was added at this temperature, and the temperature was gradually raised to room temperature for 2 hours. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (20 ml*3). The organic phase was washed with saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, and spin-dried. The reverse preparation (A: 0.3% ammonium bicarbonate, B: acetonitrile; 3% to 97%) was then obtained, and lyophilized to give 12.61 mg of the target product C27.

[0377] LC-MS-MC21-105-009-LCMS:(ES,m / z):[M+H] + =964.5

[0378] 1 H NMR(400MHz, DMSO)δ8.98(s,1H),8.56(t,J=5.9Hz,1H),8.24–8.16(m,2H),7.84(d,J=7.3Hz,2H),7.57–7.44(m,6 H),7.44–7.37(m,4H),7.28(t,J=7.4Hz,1H),6.85(s,1H),5.74(d,J=9.5Hz,1H),5.13(s,1H),4.38–4.46(m,4H),4 .21–4.24(m,1H),3.92–3.81(m,6H),3.62–3.64(m,4H),3.06–2.96(m,1H),2.84–2.70(m,6H),2.57(s,3H),2.45(s ,3H),2.29-2.32(m,1H),2.00–2.04(m,1H),1.95–1.87(m,1H),1.77–1.80(m,3H),1.46–1.49(m,2H),0.94(s,9H).

[0379] Example 10: C29 compound

[0380] Step 1: Preparation of compound 29-3

[0381]

[0382] Compound 29-1 (80 mg, 0.19 mmol) and compound 29-2 (94 mg, 0.47 mmol) were dissolved in tetrahydrofuran (5 mL) and reacted at room temperature for 1 hour. NaBH(OAc)3 (200 mg, 0.94 mmol) was then added and stirred at 50°C for 1 hour. The reaction solution was directly dried and column chromatography (ethyl acetate / petroleum ether, 9:1) was performed to obtain product 29-3 (80 mg, yield: 69%). LC-MS-MC21-313-44-R1-1: (ES, m / z): [M+H] + =608.4

[0383] Step 2: Preparation of compound 29-4

[0384]

[0385] Compound 29-3 (80 mg, 0.13 mmol) was added to a reaction flask, followed by 1 ml of dichloromethane and 1 ml of trifluoroacetic acid. The mixture was reacted at room temperature for 1 hour, and then dried to give a crude product 29-4 (60 mg). LC-MS-MC21-78-47-R1: (ES, m / z): [M+H] + =508.3

[0386] Step 3: Preparation of compound C29

[0387]

[0388] Compound 29-4 (60 mg, 0.12 mmol) and compound 29-5 (69 mg, 0.14 mmol) were added to a reaction flask, and THF (5 mL) was added. The mixture was stirred at room temperature for 2 hours, and STAB (51 mg, 0.24 mmol) was added. The reaction was allowed to react at room temperature for 2 hours. The mixture was quenched by adding 10 ml of water and extracted with ethyl acetate (20 ml*3). The organic phase was washed with saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, and spin-dried. The reverse preparation (A: 0.3% ammonium bicarbonate, B: acetonitrile; 3% to 97%) was used, and lyophilized to obtain 6.03 mg of the target product C29.

[0389] LC-MS-MC21-96-052P-LCMS:(ES,m / z):[M+H] + =978.5

[0390] 1H NMR (400MHz, DMSO) δ8.99(s,1H),8.60(t,J=5.8Hz,1H),8.21(d,J=6.5Hz,2H),7.83(t,J=9.4Hz,3H),7.47–7.55(m, 6H),7.45–7.37(m,4H),7.28(t,J=7.4Hz,1H),6.86(s,1H),5.14(d,J=3.4Hz,1H),4.49–4.34(m,3H),4.30–4.22(m,1 H),3.84–3.86(m,4H),3.61–3.63(m,2H),3.34–3.36(m,4H),3.31–3.28(m,1H),3.05–2.67(m,8H),2.57(s,3H),2.4 6(s,3H),2.16–2.19(m,2H),2.02–2.04(m,2H),1.90-1.93(m,1H),1.66–1.69(m,2H),1.22–1.26m,2H),0.93(s,9H).

[0391] Example 11: C30 compound

[0392] Step 1: Preparation of compound 30-3

[0393]

[0394] Compound 30-1 (800 mg, 2.17 mmol), compound 30-2 (1.1 g, 6.51 mmol) and acetic acid (130 mg, 2.17 mmol) were added to a reaction flask, and 10 ml of tetrahydrofuran was added. The mixture was stirred at room temperature for 1 hour, and then sodium triacetoxyborohydride (2.3 g, 10.85 mmol) was added. The mixture was stirred at 60°C for 16 hours and dried by column chromatography (ethyl acetate / petroleum ether, 10:1) to obtain product 30-3 (700 mg, yield: 61%). LC-MS-MC21-96-021P1: (ES, m / z): [M+H] + =525.3

[0395] Step 2: Preparation of compound 30-4

[0396]

[0397] Compound 30-3 (700 mg, 1.34 mmol) was added to a reaction flask, followed by dichloromethane (10 mL) and trifluoroacetic acid (5 mL). The mixture was stirred at room temperature for 2 hours, and water (10 mL) was added. The pH was adjusted to 7 with saturated sodium bicarbonate. The mixture was extracted with ethyl acetate (20 mL*3). The organic phases were combined, washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, and dried to give product 30-4 (500 mg, crude). LC-MS-MC21-96-024P2: (ES, m / z): [M+H] + =425.2

[0398] Step 3: Preparation of compound 30-5

[0399]

[0400] Compound 30-4 (500 mg, 1.2 mmol), compound 30-2 (616 mg, 3.6 mmol) and acetic acid (72 mg, 1.2 mmol) were added to a reaction flask, and 10 ml of tetrahydrofuran was added. The mixture was stirred at room temperature for 30 minutes, and then sodium triacetoxyborohydride (1.27 g, 6.0 mmol) was added. The mixture was stirred at 60°C for 2 hours and then dried by column chromatography (methanol / dichloromethane, 1:10) to obtain product 30-5 (400 mg, yield: 57%). LC-MS-MC21-96-029P2: (ES, m / z): [M+H] + =580.4

[0401] Step 4: Preparation of compound 30-6

[0402]

[0403] Compound 30-5 (400 mg, 0.7 mmol) was added to a reaction flask, followed by dichloromethane (10 mL) and trifluoroacetic acid (5 ml). The mixture was stirred at room temperature for 2 hours and then dried to give product 30-6 (350 mg, crude). LC-MS-MC21-96-034R2: (ES, m / z): [M+H] + =480.2

[0404] Step 5: Preparation of compound C30

[0405]

[0406] Compound 30-6 (60 mg, 0.13 mmol) and compound 30-7 (90 mg, 0.19 mmol) were added to a reaction flask, 10 ml of tetrahydrofuran was added, and then sodium triacetoxyborohydride (83 mg, 0.39 mmol) was added. The mixture was reacted at room temperature for 2 hours, and the mixture was dried by reverse preparation (A: 0.3% ammonium bicarbonate, B: acetonitrile; 3% to 97%). The target product C30 (10.92 mg, yield: 9%) was obtained by lyophilization.

[0407] LC-MS-MC21-96-050-P1-LCMS:(ES,m / z):[M+H] + =950.5

[0408] 1 H NMR (400MHz, DMSO) δ8.97(d,J=8.0Hz,1H),8.59(t,J=6.0Hz,1H),8.23–8.18(m,2H),7.86–7.81(m, 2H),7.60–7.45(m,7H),7.39(s,3H),7.28(t,J=7.2Hz,1H),6.90–6.82(m,1H),5.16–5.14(d,J=3.2H z,1H),4.56–4.11(m,5H),3.86(s,5H),3.74–3.48(m,3H),3.38(s,4H),3.30–3.28(m,1H),3.14–2. 95(m,8H),2.57–2.55(m,4H),2.46–2.44(m,3H),2.12–1.99(m,1H),1.94–1.88(m,1H),0.93(s,9H).

[0409] Example 12: C31 compound

[0410] Step 1: Preparation of compound 31-3

[0411]

[0412] Compound 31-1 (800 mg, 2.17 mmol), compound 31-2 (1.1 g, 6.51 mmol) and acetic acid (130 mg, 2.17 mmol) were added to a reaction flask, and 10 ml of tetrahydrofuran was added. The mixture was stirred at room temperature for 1 hour, and then sodium triacetoxyborohydride (2.3 g, 10.85 mmol) was added. The mixture was stirred at 60°C for 16 hours and dried by column chromatography (ethyl acetate / petroleum ether, 10:1) to obtain product 31-3 (700 mg, yield: 61%). LC-MS-MC21-96-021P1: (ES, m / z): [M+H] + =525.3

[0413] Step 2: Preparation of compound 31-4

[0414]

[0415] Compound 31-3 (700 mg, 1.34 mmol) was added to a reaction flask, followed by dichloromethane (10 mL) and trifluoroacetic acid (5 mL). The mixture was stirred at room temperature for 2 hours, and water (10 mL) was added. The pH was adjusted to 7 with saturated sodium bicarbonate. The mixture was extracted with ethyl acetate (20 mL*3). The organic phases were combined, washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, and dried to give product 31-4 (500 mg, crude). LC-MS-MC21-96-024P2: (ES, m / z): [M+H] + =425.2

[0416] Step 3: Preparation of compound 31-5

[0417]

[0418] Compound 31-4 (500 mg, 1.2 mmol), compound 31-2 (616 mg, 3.6 mmol) and acetic acid (72 mg, 1.2 mmol) were added to a reaction flask, and 10 ml of tetrahydrofuran was added. The mixture was stirred at room temperature for 30 minutes, and then sodium triacetoxyborohydride (1.27 g, 6.0 mmol) was added. The mixture was stirred at 60°C for 2 hours and dried by column chromatography (methanol / dichloromethane, 1:10) to obtain product 31-5 (400 mg, yield: 57%). LC-MS-MC21-96-029P2: (ES, m / z): [M+H] + =580.4

[0419] Step 4: Preparation of compound 31-6

[0420]

[0421] Compound 31-5 (400 mg, 0.7 mmol) was added to a reaction flask, followed by dichloromethane (10 mL) and trifluoroacetic acid (5 ml). The mixture was stirred at room temperature for 2 hours and then dried to give product 31-6 (350 mg, crude). LC-MS-MC21-96-034R2: (ES, m / z): [M+H] + =480.2

[0422] Step 5: Preparation of compound C31

[0423]

[0424] Compound 31-6 (80 mg, 0.17 mmol) was added to a reaction flask, followed by THF (5 mL), DIEA (67 mg, 0.52 mmol), and compound 31-8 (42 mg, 0.21 mmol). The mixture was stirred at -20°C for 1 hour. Compound 31-7 (71 mg, 0.17 mmol) was added at this temperature, and the temperature was gradually raised to room temperature for 2 hours. Water (10 mL) was added, followed by extraction with ethyl acetate (20 ml*3). The organic phase was washed with saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, and spin-dried. The reverse preparation (A: 0.3% ammonium bicarbonate, B: acetonitrile; 3% to 97%) was then obtained, and lyophilized to give 10.34 mg of the target product C31.

[0425] LC-MS-MC21-105-008-LCMS:(ES,m / z):[M+H] + =936.5

[0426] 1 H NMR (400MHz, DMSO) δ8.98(s,1H),8.55(t,J=5.8Hz,1H),8.20(d,J=6.5Hz,2H),7.84(d,J=7.3Hz,2H),7.46– 7.54(m,6H),7.307.39(m,4H),7.28(t,J=7.4Hz,1H),6.86(s,1H),5.79(d,J=9.3Hz,1H),5.12(d,J=3.5Hz, 1H),4.32–4.45(m,4H),4.23–4.25(m,1H),3.79–3.88(m,6H),3.66–3.55(m,4H),3.32–3.39(m,3H),3.06–2 .91(m,3H),2.57(s,3H),2.50–2.53(m,3H),2.44(s,3H),2.08–1.99(m,1H),1.96–1.85(m,1H),0.94(s,9H).

[0427] Example 13: C32 Compound

[0428] Step 1: Preparation of compound 32-3

[0429]

[0430] Compound 32-1 (200 mg, 0.54 mmol) and compound 32-2 (194 mg, 0.81 mmol) were dissolved in tetrahydrofuran (10 mL). Acetic acid (33 mg, 0.54 mmol) was added and the mixture was allowed to react at room temperature for 1 hour. NaBH(OAc)3 (575 mg, 2.71 mmol) was then added and the mixture was allowed to react at 50°C for 1 hour. The reaction mixture was dried and column chromatography (methanol / dichloromethane, 1:5) was performed to obtain the yellow product 32-3 (90 mg, yield: 62%). LC-MS-MC21-78-30-R4: (ES, m / z): [M+H] + =593.3

[0431] Step 2: Preparation of compound 32-4

[0432]

[0433] Compound 32-3 (90 mg, 0.15 mmol) was added to a reaction flask, followed by 2 ml of dichloromethane and 2 ml of trifluoroacetic acid. The mixture was reacted at room temperature for 1 hour, and then dried to give a crude product 32-4 (70 mg). LC-MS-MC21-78-34-R2: (ES, m / z): [M+H] + =493.8

[0434] Step 3: Preparation of compound 32-6

[0435]

[0436] Compound 32-4 (60 mg, 0.12 mmol) and compound 32-5 (27 mg, 0.18 mmol, 50% in water) were added to a reaction flask, followed by tetrahydrofuran (2 mL) and NaBH(OAc)3 (78 mg, 0.37 mmol). The mixture was reacted at room temperature for 1 hour, and the mixture was spin-dried and reversely prepared (A: 0.3% formic acid, B: acetonitrile; 3% to 97%). The product 32-6 (50 mg, yield: 74%) was obtained by lyophilization. LC-MS-MC21-78-38-11-18: (ES, m / z): [M+H] + =551.3

[0437] Step 4: Preparation of compound C32

[0438]

[0439] Compound 32-6 (50 mg, 0.09 mmol) and compound 32-7 (43 mg, 0.10 mmol) were added to a reaction flask, and then 0.5 mL of N,N-dimethylformamide and 0.5 mL of dimethyl sulfoxide were added. The mixture was spin-dried and the reverse preparation (A: 0.3% ammonium bicarbonate, B: acetonitrile; 3% to 97%) was prepared. The mixture was lyophilized to obtain 9.24 mg of yellow solid C32 compound (yield: 10.6%).

[0440] LC-MS-MC21-78-42-P1-1:(ES,m / z):[M+H] + =963.4

[0441] 1 H NMR (400MHz, DMSO) δ8.99(s,1H),8.61(t,J=6.0Hz,1H),8.20(d,J=6.4Hz,2H),7.84(d,J=7.4Hz,2H),7.66(d,J=9.2H z,1H),7.55–7.46(m,5H),7.41(q,J=8.2Hz,4H),7.28(t,J=7.4Hz,1H),6.84(s,1H),5.15(d,J=3.2Hz,1H),4.50–4.36 (m,4H),4.28–4.22(m,1H),3.83(s,4H),3.71–3.55(m,2H),3.19–2.96(m,6H),2.71(s,4H),2.57(s,3H),2.45(s,3H), 2.29–2.23(m,1H),2.08–1.87(m,4H),1.72(d,J=10.8Hz,2H),1.41(t,J=11.6Hz,2H),1.32–1.19(m,2H),0.94(s,9H).

[0442] Example 14: C33 Compound

[0443] Step 1: Preparation of compound 33-3

[0444]

[0445] Compound 33-1 (200 mg, 0.54 mmol) and compound 33-2 (194 mg, 0.81 mmol) were dissolved in tetrahydrofuran (10 mL). Acetic acid (33 mg, 0.54 mmol) was added and the mixture was allowed to react at room temperature for 1 hour. NaBH(OAc)3 (575 mg, 2.71 mmol) was then added and the mixture was allowed to react at 50°C for 1 hour. The reaction mixture was dried and purified by column chromatography (methanol / dichloromethane, 1:5) to afford the yellow product 33-3 (210 mg, yield: 65%). LC-MS-MC21-78-30-R4: (ES, m / z): [M+H] + =593.3

[0446] Step 2: Preparation of compound 33-4

[0447]

[0448] Compound 33-3 (210 mg, 0.35 mmol) was added to a reaction flask, followed by 3 ml of dichloromethane and 1.5 ml of trifluoroacetic acid. The mixture was reacted at room temperature for 1 hour, and then dried to give a crude product 33-4 (170 mg). LC-MS-MC21-78-89-R1: (ES, m / z): [M+H] + =493.3

[0449] Step 3: Preparation of compound 33-6

[0450]

[0451] Compound 33-4 (350 mg, 0.81 mmol) was added to a reaction flask, followed by methanol (20 mL), compound 33-5 (172 mg, 1.21 mmol), DBU (161 mg, 4.06 mmol), and water (10 ml). The mixture was stirred at room temperature for 1 hour, adjusted to pH 6 with 10% dilute hydrochloric acid, and then extracted with ethyl acetate (20 ml*3). The organic phase was washed with saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, and dried to give product 33-6 (300 mg, yield: 92%). LC-MS-MC21-78-96-R1: (ES, m / z): [M+H] + =621.4

[0452] Step 4: Preparation of compound 33-7

[0453]

[0454] Compound 33-6 (130 mg, 0.21 mmol) was added to a reaction flask, followed by 2 ml of dichloromethane and 1 ml of trifluoroacetic acid. The mixture was reacted at room temperature for 1 hour, and then dried to give a crude product 33-7 (118 mg). LC-MS-MC21-78-100-R1: (ES, m / z): [M+H] + =565.3

[0455] Step 5: Preparation of compound C33

[0456]

[0457] Compound 33-7 (118 mg, 0.21 mmol) and compound 33-8 (108 mg, 0.25 mmol) were added to a reaction flask, and then 2 mL of N,N-dimethylformamide, HATU (120 mg, 0.31 mmol), and DIEA (136 mg, 1.05 mmol) were added. The reaction was carried out at room temperature for 1 hour, and the mixture was dried by reverse preparation (A: 0.3% ammonium bicarbonate, B: acetonitrile; 3% to 97%). The mixture was lyophilized to obtain 37.05 mg of yellow C33 (yield: 18.14%).

[0458] LC-MS-MC21-78-101-P1:(ES,m / z):[M+H] + =977.5

[0459] 1 H NMR (400MHz, DMSO) δ8.97(s,1H),8.67(d,J=8.0Hz,1H),8.60(t,J=6.0Hz,1H),8.21–8.19(m,2H),7.85–7.83(m,2H),7.55–7.42(m,7 H),7.37(d,J=8.0Hz,2H),7.28(t,J=7.4Hz,1H),6.83(s,1H),5.13(s,1H),4.55–4.52(m,1H),4.51–4.41(m,2H),4.36(s,1H),4.22- 4.18(m,1H),3.80(s,4H),3.69–3.61(m,2H),3.18–2.92(m,2H),2.89–2.82(m,1H),2.74–2.59(m,5H),2.58–2.52(m,4H),2.44(s,3H ),2.23–2.09(m,3H),2.07–1.99(m,1H),1.97–1.86(m,3H),1.68(d,J=9.8Hz,2H),1.40–1.35(m,2H),1.31–1.18(m,2H),0.95(s,9H).

[0460] Example 15: C34 compound

[0461] Step 1: Preparation of compound 34-3

[0462]

[0463] Compound 34-1 (100 mg, 0.27 mmol) and compound 34-2 (78 mg, 0.32 mmol) were added to a reaction flask, followed by 10 ml of tetrahydrofuran and sodium triacetoxyborohydride (171 mg, 0.81 mmol). The mixture was stirred at 60°C for 6 hours, quenched with water (20 ml), and extracted with ethyl acetate (20 ml*3). The organic phases were combined, washed with saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, and subjected to spin column chromatography (ethyl acetate / petroleum ether, 10:1) to afford product 34-3 (80 mg, yield: 50%). LC-MS-MC20-105-030-A1: (ES, m / z): [M+H] + =593.4

[0464] Step 2: Preparation of compound 34-4

[0465]

[0466] Compound 34-3 (80 mg, 0.14 mmol) was added to a reaction flask, followed by dichloromethane (10 mL) and trifluoroacetic acid (5 ml). The mixture was stirred at room temperature for 2 hours and then dried to give product 34-4 (60 mg, crude). LC-MS-MC21-105-032-2R1: (ES, m / z): [M+H] + =493.3

[0467] Step 3: Preparation of compound 34-5

[0468]

[0469] Compound 34-4 (60 mg, 0.12 mmol) and tert-butyl bromoacetate (60 mg, 0.12 mmol) were added to a reaction flask, followed by potassium carbonate (36 mg, 0.26 mmol), potassium iodide (8 mg, 0.06 mmol), and DMF (5 ml). The mixture was reacted at 60°C for 3 hours, quenched by addition of water (20 ml), and extracted with ethyl acetate (20 ml*3). The organic phases were combined, washed with saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, and subjected to spin column chromatography (methanol / dichloromethane, 1:10) to obtain product 34-5 (50 mg, crude product). LC-MS-MC21-105-040-FX1: (ES, m / z): [M+H-56] +=551.3

[0470] Step 4: Preparation of compound 34-6

[0471]

[0472] Compound 34-5 (50 mg, 0.08 mmol) was added to a reaction flask, followed by dichloromethane (3 mL) and trifluoroacetic acid (2 ml). The mixture was stirred at room temperature for 2 hours and then dried to give product 34-6 (50 mg, crude). LC-MS-MC21-105-040-FX1: (ES, m / z): [M+H] + =551.3

[0473] Step 5: Preparation of compound C34

[0474]

[0475] Compound 34-6 (50 mg, 0.09 mmol) was added to a reaction flask, followed by DMF (5 mL), DIEA (67 mg, 0.52 mmol), and HATU (52 mg, 0.14 mmol). The mixture was stirred at 25°C for 10 minutes, and compound 34-7 (46 mg, 0.11 mmol) was added. The mixture was reacted at room temperature for 2 hours. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (20 ml*3). The organic phase was washed with saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, and spin-dried to obtain a reverse preparation (A: 0.3% ammonium bicarbonate, B: acetonitrile; 3% to 97%). The mixture was lyophilized to obtain 3.5 mg of the target product C34.

[0476] LC-MS-MC21-105-041-LCMS:(ES,m / z):[M+H] + =963.5

[0477] 1H NMR (400MHz, DMSO) δ9.00 (s, 1H), 8.61 (t, J = 6.0Hz, 1H), 8.27–8.15 (m, 2H), 7.84 (d, J = 7. 3Hz,3H),7.41–7.48(m,9H),7.28(t,J=7.4Hz,1H),6.86(s,1H),5.15(d,J=3.3Hz,1H),4. 52–4.21(m,5H),3.87(s,4H),3.71–3.55(m,3H),3.40-3.45(m,3H),3.05–2.61(m,5H),2 .57(s,3H),2.45(s,3H),2.36(s,2H),2.09–1.85(m,4H),1.66–1.46(m,6H),0.93(s,9H).

[0478] Example 16: C35 Compound

[0479] Step 1: Preparation of compound 35-3

[0480]

[0481] Compound 35-1 (100 mg, 0.27 mmol) and compound 35-2 (85 mg, 0.32 mmol) were added to a reaction flask, followed by 10 ml of tetrahydrofuran and sodium triacetoxyborohydride (171 mg, 0.81 mmol). The mixture was stirred at 60°C for 6 hours, quenched with water (20 ml), and extracted with ethyl acetate (20 ml*3). The organic phases were combined, washed with saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, and subjected to spin column chromatography (ethyl acetate / petroleum ether, 10:1) to obtain product 35-3 (80 mg, yield: 48%). LC-MS: (ES, m / z): [M+H] + =619.4

[0482] Step 2: Preparation of compound 35-4

[0483]

[0484] Compound 35-3 (80 mg, 0.13 mmol) was added to a reaction flask, followed by dichloromethane (10 mL) and trifluoroacetic acid (5 ml). The mixture was stirred at room temperature for 1 hour and then dried to give product 35-4 (50 mg, crude product). LC-MS: (ES, m / z): [M+H] + =519.4

[0485] Step 3: Preparation of compound 35-5

[0486]

[0487] Compound 35-4 (65 mg, 0.13 mmol) and tert-butyl bromoacetate (60 mg, 0.12 mmol) were added to a reaction flask, followed by potassium carbonate (36 mg, 0.26 mmol), potassium iodide (8 mg, 0.06 mmol), and DMF (5 ml). The mixture was reacted at 60°C for 3 hours, quenched with water (20 ml), and extracted with ethyl acetate (20 ml*3). The organic phases were combined, washed with saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, and subjected to spin column chromatography (methanol / dichloromethane, 1:10) to obtain product 35-5 (60 mg, crude product). LC-MS: (ES, m / z): [M+H-56] + =635.4

[0488] Step 4: Preparation of compound 35-6

[0489]

[0490] Compound 35-5 (60 mg, 0.09 mmol) was added to a reaction flask, followed by dichloromethane (3 mL) and trifluoroacetic acid (2 ml). The mixture was stirred at room temperature for 2 hours and then dried to give product 35-6 (40 mg, crude). LC-MS-MC21-105-042-R1: (ES, m / z): [M+H] + =579.4

[0491] Step 5: Preparation of compound C35

[0492]

[0493] Compound 35-6 (40 mg, 0.07 mmol) was added to a reaction flask, followed by DMF (5 mL), DIEA (36 mg, 0.28 mmol), and HATU (52 mg, 0.14 mmol). The mixture was stirred at 25°C for 10 minutes, and compound 35-7 (46 mg, 0.11 mmol) was added. The mixture was reacted at room temperature for 2 hours. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (20 ml*3). The organic phase was washed with saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, and spin-dried. The reverse preparation (A: 0.3% ammonium bicarbonate, B: acetonitrile; 3% to 97%) was used, and lyophilized to obtain 5.28 mg of the target product C35.

[0494] LC-MS-MC21-105-043-LCMS:(ES,m / z):[M+H] + =991.4

[0495] 1H NMR (400MHz, DMSO) δ8.99(s,1H),8.61(t,J=5.7Hz,1H),8.20(d,J=6.9Hz,2H),7.88(t, J=24.6Hz,3H),7.39–7.49(m,9H),7.28(t,J=7.3Hz,1H),6.85(s,1H),5.15(d,J=2.9Hz ,1H),4.56–4.19(m,5H),3.84(s,4H),3.61–3.67(m,2H),3.06–2.64(m,8H),2.57(s,3H ),2.44(s,3H),2.31–2.40(m,1H),1.90-2.05(m,2H),1.74–1.04(m,14H),0.95(s,9H).

[0496] Example 17: C36 Compound

[0497] Step 1: Preparation of compound 36-3

[0498]

[0499] Compound 36-1 (200 mg, 0.51 mmol) and compound 36-2 (196 mg, 0.77 mmol) were added to a reaction flask, and 10 ml of tetrahydrofuran was added. The mixture was reacted at 50°C for 5 hours, cooled to room temperature, and sodium triacetoxyborohydride (216 mg, 1.02 mmol) was added. The mixture was stirred at room temperature for 3 hours, quenched by adding water (20 ml), and extracted with ethyl acetate (20 ml*3). The organic phases were combined, washed with saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, and subjected to spin column chromatography (ethyl acetate / petroleum ether, 10:1) to obtain product 36-3 (50 mg, yield: 15.7%). LC-MS-MC20-105-068-G1: (ES, m / z): [M+H] + =621.4

[0500] Step 2: Preparation of compound 36-4

[0501]

[0502] Compound 36-3 (50 mg, 0.08 mmol) was added to a reaction flask, followed by dichloromethane (10 mL) and trifluoroacetic acid (5 ml). The mixture was stirred at room temperature for 2 hours and then dried to give product 36-4 (40 mg, crude product). LC-MS-MC21-105-071-A1: (ES, m / z): [M+H] + =521.3

[0503] Step 3: Preparation of compound C36

[0504]

[0505] Compound 36-4 (40 mg, 0.08 mmol) and compound 36-5 (45 mg, 0.09 mmol) were added to a reaction flask, 10 ml of tetrahydrofuran was added, and the mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (34 mg, 0.16 mmol) was then added and the mixture was reacted at room temperature for 2 hours. Water (20 ml) was added to quench the mixture, and the mixture was extracted with ethyl acetate (20 ml*3). The organic phases were combined, washed with saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, and spin-dried to obtain the reverse preparation (A: 0.3% ammonium bicarbonate, B: acetonitrile; 3% to 97%). The target product C36 (17.89 mg) was lyophilized.

[0506] LC-MS-MC21-105-072-LCMS:(ES,m / z):[M+H] + =991.5

[0507] 1 H NMR (400MHz, DMSO) δ8.99(s,1H),8.61(t,J=5.9Hz,1H),8.21(d,J=7.5Hz,2H),7.83(t,J=8.2Hz,3H),7.4 0–7.51(m,9H),7.28(t,J=7.4Hz,1H),6.85(s,1H),5.14(d,J=3.3Hz,1H),4.65(d,J=11.9Hz,2H),4.52–4 .33(m,4H),4.23-4.27(m,1H),3.69–3.56(m,2H),3.46–3.36(m,1H),3.13–2.86(m,4H),2.57(s,3H),2.4 2–2.46(m,10H),2.00–2.08(m,1H),1.97–1.84(m,3H),1.66–1.68(m,2H),1.40-1.42(m,9H),0.93(s,9H).

[0508] Example 18: C37 Compound

[0509] Step 1: Preparation of compound 37-3

[0510]

[0511] Compound 37-1 (100 mg, 0.27 mmol) and compound 37-2 (172 mg, 0.68 mmol) were dissolved in tetrahydrofuran (5 mL). Acetic acid (33 mg, 0.54 mmol) was added and the mixture was allowed to react at room temperature for 1 hour. NaBH(OAc)3 (286 mg, 1.36 mmol) was then added and the mixture was allowed to react at 50°C for 1 hour. The reaction mixture was dried and column chromatography (methanol / dichloromethane, 1:5) was performed to obtain the yellow product 37-3 (40 mg, yield: 24%). LC-MS: (ES, m / z): [M+H] + =607.3

[0512] Step 2: Preparation of compound 37-4

[0513]

[0514] Compound 37-3 (40 mg, 0.066 mmol) was added to a reaction flask, followed by 1 ml of dichloromethane and 1 ml of trifluoroacetic acid. The mixture was reacted at room temperature for 1 hour and then dried to give a crude product 37-4 (32 mg). LC-MS: (ES, m / z): [M+H] + =507.3

[0515] Step 3: Preparation of compound C37

[0516]

[0517] Compound 37-4 (32 mg, 0.063 mmol) and compound 37-5 (31 mg, 0.063 mmol) were dissolved in tetrahydrofuran (10 mL). Acetic acid (8 mg, 0.13 mmol) was added and the mixture was allowed to react at room temperature for 2 hours. NaBH(OAc)3 (575 mg, 2.71 mmol) was then added and the mixture was allowed to react at room temperature for another hour. The mixture was then spin-dried with the reversed preparation (A: 0.3% ammonium bicarbonate, B: acetonitrile; 3% to 97%) and lyophilized to afford 6.39 mg of compound C37 as a yellow solid (yield: 10.4%).

[0518] LC-MS-MC21-313-13-P1:(ES,m / z):[M+H] + =977.5

[0519] 1H NMR (400MHz, DMSO) δ8.99(s,1H),8.62(s,1H),8.20(d,J=8.0Hz,2H),7.84(d,J=8.0Hz,3H),7.53–7.47(m, 5H),7.45–7.41(m,4H),7.30–7.27(m,1H),6.84(s,1H),5.17(s,1H),4.51–4.44(m,4H),4.28–4.25(m,1H) ,3.84(s,4H),3.65-3.61(m,2H),3.59–3.40(m,2H),3.02–2.98(m,1H),2.62(s,4H),2.57(s,3H),2.45(s, 4H),2.09–2.04(m,1H),1.98–1.87(m,2H),1.77(s,1H),1.62–1.37(s,8H),1.31-1.23(m,2H),0.95(s,9H).

[0520] Example 19: C38 Compound

[0521] Step 1: Preparation of compound C38

[0522]

[0523] Compound 38-1 (35 mg, 0.072 mmol) and compound 38-2 (35 mg, 0.072 mmol) were dissolved in tetrahydrofuran (5 mL). Acetic acid (8 mg, 0.14 mmol) was added and the mixture was allowed to react at room temperature for 2 hours. NaBH(OAc)3 (46 mg, 0.22 mmol) was then added and the mixture was allowed to react for another hour at room temperature. The mixture was then spin-dried with the reversed preparation (A: 0.3% ammonium bicarbonate, B: acetonitrile; 3% to 97%) and lyophilized to afford 3.42 mg of compound C38 as a yellow solid (yield: 4.99%).

[0524] LC-MS-MC21-313-18-P1:(ES,m / z):[M+H] + =963.5

[0525] 1H NMR (400MHz, DMSO) δ8.99 (s, 1H), 8.61 (s, 1H), 7.93 (d, J = 7.2Hz, 2H), 7.73–7.60 (m, 3H), 7.60–7.52 (m, 3H), 7.47–7.3 7(m,6H),7.34(d,J=7.2Hz,1H),7.04(s,1H),5.16(d,J=3.4Hz,1H),4.53–4.34(m,4H),4.27(s,1H),3.93(s,4H),3.65 (s,1H),3.68–3.64(m,1H),3.61–3.58(m,1H),3.14–2.98(m,6H),2.66(s,3H),2.45(s,3H),2.43(s,2H),2.23(s,1H) ,2.09–2.02(m,1H),2.00–1.87(m,3H),1.73(d,J=9.6Hz,2H),1.41(t,J=12.4Hz,2H),1.29-1.15(m,4H),0.94(s,9H).

[0526] Example 20: C39 Compound

[0527] Step 1: Preparation of compound 39-3

[0528]

[0529] Compound 39-1 (200 mg, 0.54 mmol) was dissolved in DMF (10 mL), followed by the addition of compound 39-2 (329 mg, 1.08 mmol) and potassium carbonate (224 mg, 1.62 mmol). The mixture was stirred at 80°C for 16 hours, followed by the addition of 20 mL of aqueous solution. The mixture was extracted with ethyl acetate (20 mL*3). The organic phases were combined, washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, and subjected to spin column chromatography (ethyl acetate / petroleum ether, 10:1) to afford product 39-3 (110 mg, 37%). LC-MS-MC21-96-001F2022796: (ES, m / z): [M+H] + =502.1

[0530] Step 2: Preparation of compound 39-5

[0531]

[0532] Compound 39-3 (100 mg, 0.2 mmol) and compound 39-4 (117 mg, 0.6 mmol) were added to a reaction flask, followed by 5 ml of tert-butanol, potassium tert-butoxide (67 mg, 0.6 mmol), and potassium iodide (100 mg, 0.6 mmol). The mixture was stirred at room temperature for 12 hours, and then water (20 ml) was added and extracted with ethyl acetate (20 ml*3). The organic phases were combined, washed with saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, and spin-dried using a reverse phase preparation (A: 0.3% ammonium bicarbonate, B: acetonitrile; 3% to 97%) to give product 39-5 (40 mg, yield: 32%). LC-MS-MC21-96-012-P615: (ES, m / z): [M+H] + =616.3

[0533] Step 3: Preparation of compound 39-6

[0534]

[0535] Compound 39-5 (80 mg, 0.14 mmol) was added to a reaction flask, followed by dichloromethane (5 mL) and trifluoroacetic acid (2 ml). The mixture was stirred at room temperature for 1 hour and then dried to give product 39-6 (30 mg, crude). LC-MS-MC20-1018-112: (ES, m / z): [M+H] + =560.2

[0536] Step 4: Preparation of compound C39

[0537]

[0538] Compound 39-6 (30 mg, 0.05 mmol) was added to a reaction flask, followed by 5 mL of N,N-dimethylformamide, HATU (29 mg, 0.075 mmol), DIEA (32 mg, 0.25 mmol), and compound 39-7 (22 mg, 0.05 mmol). The mixture was reacted for 2 hours, and water (10 ml) was added. The mixture was extracted with ethyl acetate (20 ml*3). The organic phases were combined, washed with saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, and spin-dried. The reverse preparation (A: 0.3% ammonium bicarbonate, B: acetonitrile; 3% to 97%) was used, and lyophilized to obtain 11.93 mg (yield: 22%) of the target product C39.

[0539] LC-MS-MC21-96-018P2-LCMS:(ES,m / z):[M+H] + =972.4

[0540] 1H NMR (400MHz, DMSO) δ8.97(s,1H),8.59(t,J=5.6Hz,1H),8.20(d,J=6.8Hz,2H),7.83(d,J=7 .6Hz,2H),7.54–7.37(m,10H),7.28(t,J=7.6Hz,1H),6.85(s,1H),5.16–5.14(m,1H),4.57( d,J=9.2Hz,1H),4.49–4.31(m,3H),4.26(d,J=5.2Hz,1H),3.98(s,2H),3.84(s,4H),3.61–3 .55(m,12H),2.67(s,4H),2.56(s,5H),2.43(s,3H),2.05(s,1H),1.90(s,1H),0.93(s,9H).

[0541] Example 21: C42 Compound

[0542] Step 1: Preparation of compound 42-3

[0543]

[0544] Compound 42-1 (100 mg, 0.3 mmol) was dissolved in DMF (10 mL), and compound 42-2 (296 mg, 1.5 mmol), potassium iodide (100 mg, 0.6 mmol), and potassium carbonate (207 mg, 1.5 mmol) were added. The mixture was stirred at 80°C for 16 hours, and then 20 mL of aqueous solution was added. The mixture was extracted with ethyl acetate (20 ml*3). The organic phases were combined, washed with saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, and subjected to spin column chromatography (ethyl acetate / petroleum ether, 10:1) to obtain product 42-3 (70 mg, 47%). LC-MS-MC21-530-046P1026192: (ES, m / z): [M+H] + =486.3

[0545] Step 2: Preparation of compound 42-4

[0546]

[0547] Compound 42-3 (60 mg, 0.12 mmol) was added to 5 ml of HCl in dioxane solution, stirred at room temperature for 6 hours, and then dried to give product 42-4 (50 mg, crude). LC-MS-MC21-530-049R5: (ES, m / z): [M+H] + =412.2

[0548] Step 3: Preparation of compound C42

[0549]

[0550] Compound 42-4 (60 mg, 0.15 mmol) was added to a reaction flask, followed by 5 mL of THF, compound 42-5 (74 mg, 0.23 mmol), and FA (0.02 mL). The mixture was reacted at room temperature for half an hour. NaBH(AcO)3 (159 mg, 0.75 mmol) was added and the mixture was reacted at room temperature for half an hour. The mixture was spin-dried, column chromatography (methanol / dichloromethane, 2:5) was performed, and reverse preparation (A: 0.3% ammonium bicarbonate, B: acetonitrile; 3% to 97%) was performed. The mixture was lyophilized to obtain 7.36 mg (yield: 6%) of the target product C42.

[0551] LC-MS-MC21-530-052P1-LCMS:(ES,m / z):[M+H] + =724.5

[0552] 1 H NMR(400MHz,DMSO)δ10.95(s,1H),8.26–8.16(m,2H),7.90–7.78(m,2H),7.56 –7.46(m,6H),7.32–7.24(m,1H),7.11–7.05(m,2H),6.87(s,1H),5.13–4.99( m,1H),4.31–4.23(m,2H),3.94–3.80(m,4H),3.44–3.36(m,6H),3.00–2.80(m ,2H),2.71(s,3H),2.64–2.56(m,10H),2.40–2.32(m,1H),2.01–1.91(m,1H).

[0553] Example 22: C43 Compound

[0554] Step 1: Preparation of compound 43-2

[0555]

[0556] Oxalyl chloride (1.60 g, 12.6 mmol) was dissolved in DCM (10 mL), DMSO (2.04 g, 25.2 mmol) was added at -78°C, and the reaction was continued at -78°C for 0.5 h. Compound 43-1 (1.0 g, 4.35 mmol) was reacted at -78°C for 2 h, and TEA (3.44 g, 34.0 mmol) was reacted at -78°C for 0.5 h. The reaction was monitored by TLC. The reaction solution was extracted with DCM (30 ml*3), and the organic phases were combined, washed with saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, and spin-dried by column chromatography (ethyl acetate / petroleum ether, 3:1) to obtain a yellow oily product 43-2 (500 mg, yield: 50%).

[0557] Step 2: Preparation of compound 43-4

[0558]

[0559] Compound 43-3 (200 mg, 0.54 mmol) and compound 43-2 (247 mg, 1.08 mmol) were dissolved in tetrahydrofuran (10 mL). Acetic acid (65 mg, 1.08 mmol) and NaBH(OAc)3 (345 mg, 1.63 mmol) were added and reacted at 50°C for 1 hour. The reaction mixture was spin-dried and purified by column chromatography (methanol / dichloromethane, 1:10) to afford the yellow product 43-4 (60 mg, yield: 19%). LC-MS-MC21-78-110-R1: (ES, m / z): [M+H] + =582.4

[0560] Step 3: Preparation of compound 43-5

[0561]

[0562] Compound 43-4 (60 mg, 0.10 mmol) was added to a reaction flask, followed by 2 ml of dichloromethane and 2 ml of trifluoroacetic acid. The mixture was reacted at room temperature for 1 hour, and then dried to give a crude product 43-5 (50 mg). LC-MS-MC21-78-34-R2: (ES, m / z): [M+H] + =482.3

[0563] Step 4: Preparation of compound C43

[0564]

[0565] Compound 43-5 (50 mg, 0.10 mmol) and compound 43-6 (50 mg, 0.10 mmol) were added to a reaction flask, followed by 4 mL of tetrahydrofuran, acetic acid (12 mg, 0.20 mmol), and NaBH(OAc)3 (66 mg, 0.31 mmol). The mixture was allowed to react at room temperature for 2 hours. The reverse preparation (A: 0.3% ammonium bicarbonate, B: acetonitrile; 3% to 97%) was then spin-dried and lyophilized to afford 9.56 mg (9.65% yield) of yellow solid C43.

[0566] LC-MS-MC21-313-21-P1:(ES,m / z):[M+H] + =952.5

[0567] 1 H NMR (400MHz, DMSO) δ8.98 (s, 1H), 8.60 (s, 1H), 8.21 (d, J = 6.8Hz, 2H), 7.87–7.76 (m, 3H), 7.56–7.45 (m,5H),7.45–7.38(m,4H),7.28(t,J=7.8Hz,1H),6.86(s,1H),5.14(d,J=3.2Hz,1H),4.54–4.20(m ,5H),3.85(s,4H),3.73–3.55(m,2H),3.31–3.13(m,4H),3.07–3.00(m,1H),2.96–2.88(m,1H),2.6 6(s,5H),2.57(s,4H),2.47–2.30(m,7H),2.21–1.97(m,2H),1.90(s,1H),1.24(s,1H),0.95(s,9H).

[0568] Example 23: C44 Compound

[0569] Step 1: Preparation of compound 44-3

[0570]

[0571] Compound 44-1 (200 mg, 0.51 mmol) and compound 44-2 (174 mg, 0.77 mmol) were added to a reaction flask, and 10 ml of tetrahydrofuran was added. The mixture was reacted at 50°C for 5 hours, cooled to room temperature, and sodium triacetoxyborohydride (216 mg, 1.02 mmol) was added. The mixture was stirred at room temperature for 3 hours, quenched by adding water (20 ml), and extracted with ethyl acetate (20 ml*3). The organic phases were combined, washed with saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, and subjected to spin column chromatography (ethyl acetate / petroleum ether, 10:1) to give product 44-3 (60 mg, yield: 19.7%). LC-MS-MC20-105-070-A1: (ES, m / z): [M+H] + =593.4

[0572] Step 2: Preparation of compound 44-4

[0573]

[0574] Compound 44-3 (60 mg, 0.10 mmol) was added to a reaction flask, followed by dichloromethane (10 mL) and trifluoroacetic acid (5 ml). The mixture was stirred at room temperature for 2 hours and then dried to give product 44-4 (46 mg, crude). LC-MS-MC21-105-075-R1: (ES, m / z): [M+H] + =493.3

[0575] Step 3: Preparation of compound C44

[0576]

[0577] Compound 44-4 (46 mg, 0.09 mmol) and compound 44-5 (55 mg, 0.11 mmol) were added to a reaction flask, 10 ml of tetrahydrofuran was added, and the mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (51 mg, 0.24 mmol) was then added and the mixture was reacted at room temperature for 2 hours. Water (20 ml) was added to quench the mixture, and the mixture was extracted with ethyl acetate (20 ml*3). The organic phases were combined, washed with saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, and spin-dried to obtain the reverse preparation (A: 0.3% ammonium bicarbonate, B: acetonitrile; 3% to 97%). The target product C44 (3.44 mg) was lyophilized.

[0578] LC-MS-MC21-105-076-LCMS:(ES,m / z):[M+H] + =963.5

[0579] 1H NMR (400MHz, DMSO) δ8.99(s,1H),8.61(s,1H),8.20(s,2H),7.84(d,J=7.1Hz,2H),7.64(s ,1H),7.49–7.51(m,5H),7.41–7.43(m,4H),7.28(s,1H),6.85(s,1H),5.16(s,1H),4.64( s,2H),4.53–4.19(m,6H),3.60-3.66(m,5H),3.06–3.09(m,8H),2.63–2.65(m,1H),2.58( s,3H),2.45(s,3H),2.00–2.06(m,1H),1.89–1.91(m,3H),1.68-1.72(m,6H),0.94(s,9H).

[0580] Example 24: C45 Compound

[0581] Step 1: Preparation of compound 45-3

[0582]

[0583] Compound 45-1 (100 mg, 0.26 mmol) and compound 45-2 (75 mg, 0.31 mmol) were added to a reaction flask, and 10 ml of tetrahydrofuran was added. The mixture was reacted at 50°C for 5 hours, cooled to room temperature, and sodium triacetoxyborohydride (165 mg, 0.78 mmol) was added. The mixture was stirred at room temperature for 3 hours, quenched by adding water (20 ml), and extracted with ethyl acetate (20 ml*3). The organic phases were combined, washed with saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, and subjected to spin column chromatography (ethyl acetate / petroleum ether, 10:1) to obtain product 45-3 (70 mg, yield: 44.3%). LC-MS-MC20-105-060-A1: (ES, m / z): [M+H] + =607.4

[0584] Step 2: Preparation of compound 45-4

[0585]

[0586] Compound 45-3 (70 mg, 0.12 mmol) was added to a reaction flask, followed by dichloromethane (10 mL) and trifluoroacetic acid (5 ml). The mixture was stirred at room temperature for 2 hours and then dried to give product 45-4 (60 mg, crude). LC-MS-MC21-105-065-A1: (ES, m / z): [M+H] + =507.4

[0587] Step 3: Preparation of compound C45

[0588]

[0589] Compound 45-4 (60 mg, 0.12 mmol) and compound 45-5 (70 mg, 0.14 mmol) were added to a reaction flask, 10 ml of tetrahydrofuran was added, and the mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (51 mg, 0.24 mmol) was then added and the mixture was reacted at room temperature for 2 hours. Water (20 ml) was added to quench the mixture, and the mixture was extracted with ethyl acetate (20 ml*3). The organic phases were combined, washed with saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, and spin-dried. The reverse preparation (A: 0.3% ammonium bicarbonate, B: acetonitrile; 3% to 97%) was used, and lyophilized to obtain the target product C45 (5.81 mg).

[0590] LC-MS-MC21-105-066-LCMS:(ES,m / z):[M+H] + =977.7

[0591] 1 H NMR(400MHz,DMSO)δ8.98(s,1H),8.59(s,1H),8.20(s,2H),7.83(s,3H),7.41–7.50(m,10H),6.85(s,1H),5.13(s,1H),4.61–4.14(m,7H),3.6 1–3.65(m,2H),2.91–2.98(m,2H),2.50-2.58(m,6H),2.32–2.45(m,9H) ,1.94-2.01(m,5H),1.52–1.54(m,8H),1.21–1.24(m,1H),0.94(s,9H).

[0592] Example 25: C46 Compound

[0593] Step 1: Preparation of compound 46-2

[0594]

[0595] Compound 46-1 (200 mg, 1.1 mmol) was dissolved in DCM (10 mL), and Pyridine (205 mg, 2.3 mmol) was added. Dess-Martin (551 mg, 1.1.3 mmol) was added at 0°C, and stirred at room temperature for 16 hours. The mixture was filtered, washed with DCM, and the filtrate was washed with sodium bicarbonate solution and saturated sodium chloride, dried over anhydrous sodium sulfate, and spin-dried by column chromatography (ethyl acetate / petroleum ether, 2:1) to give product 46-2 (100 mg, crude product).

[0596] Step 2: Preparation of compound 46-4

[0597]

[0598] Compound 46-2 (100 mg, 0.53 mmol) and compound 46-3 (100 mg, 0.27 mmol) were added to a reaction flask, 10 ml of tetrahydrofuran was added, and then NaBH(AcO)3 (286 mg, 1.35 mmol) was added. The mixture was stirred at room temperature for 1 hour and then dried by column chromatography (methanol / dichloromethane, 5:1) to obtain product 46-4 (50 mg, crude product). LC-MS-MC21-96-122P1: (ES, m / z): [M+H] + =542.3

[0599] Step 3: Preparation of compound 46-5

[0600]

[0601] Compound 46-4 (50 mg, 0.14 mmol) was added to a reaction flask, followed by dichloromethane (5 mL) and trifluoroacetic acid (2 ml). The mixture was stirred at room temperature for 1 hour and then spin-dried to dryness. The product 46-5 (30 mg, yield: 57%) was obtained by reverse preparation (A: 0.3% formic acid, B: acetonitrile; 3% to 97%). LC-MS-MC21-96-123P5: (ES, m / z): [M+H] + =486.2

[0602] Step 4: Preparation of compound C46

[0603]

[0604] Compound 46-5 (30 mg, 0.06 mmol) was added to a reaction flask, followed by 5 mL of N,N-dimethylformamide, HATU (34 mg, 0.09 mmol), DIEA (39 mg, 0.3 mmol), and compound 46-6 (26 mg, 0.06 mmol). The mixture was reacted at room temperature for 2 hours. Water (10 ml) was added, and the mixture was extracted with ethyl acetate (20 ml*3). The organic phases were combined, washed with saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, and spin-dried. The reverse preparation (A: 0.3% ammonium bicarbonate, B: acetonitrile; 3% to 97%) was used, and lyophilized to obtain 3.96 mg (yield: 7%) of the target product C46.

[0605] LC-MS-MC21-96-126P1-LCMS:(ES,m / z):[M+H] + =898.4

[0606] 1 H NMR(400MHz,DMSO)δ8.96(s,1H),8.57(s,1H),7.99–7.89(m,3H),7.68–7.50(m,6 H),7.44–7.34(m,7H),7.04(s,1H),5.15(s,1H),4.57(d,J=9.2Hz,1H),4.43(d,J= 7.2Hz,2H),4.36(s,1H),7.23–7.20(m,1H),3.95(s,5H),3.65–3.55(s,7H),2.62 (s,5H),2.43(d,J=6.0Hz,6H),2.08–2.00(m,1H),1.97–1.85(m,1H),0.95(s,9H).

[0607] Compound identification and characterization

[0608] The examples provide the preparation of representative compounds represented by formula (I) and related structural identification data. 1 H NMR spectra were obtained using a Bruker instrument (400 MHz), and chemical shifts are expressed in ppm using tetramethylsilane as an internal standard (0.00 ppm). 1 H NMR notation: s = singlet, d = doublet, t = triplet, m = multiplet, br = broadened, dd = doublet of a doublet, dt = doublet of a triplet. Coupling constants, when given, are given in Hz.

[0609] Mass spectra were obtained using LC / MS, and the ionization method could be ESI or APCI.

[0610] Thin layer chromatography silica gel plates were used, such as Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates, for thin layer chromatography (TLC).

[0611] The silica gel plates used are 0.15mm to 0.2mm in size, and the thin layer chromatography separation and purification products are 0.4mm to 0.5mm in size. Column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as the carrier.

[0612] In the following examples, unless otherwise indicated, all temperatures are in degrees Celsius. Unless otherwise indicated, various starting materials and reagents are commercially available or synthesized according to known methods. Commercially available raw materials and reagents are used directly without further purification. Unless otherwise indicated, commercial manufacturers include but are not limited to Aldrich Chemical Company, ABCR GmbH & Co. KG, Acros Organics, Shanghai Bid Pharmaceutical Technology Co., Ltd. and Shanghai Shaoyuan Reagent Co., Ltd.

[0613] CD3OD: deuterated methanol.

[0614] CDCl3: deuterated chloroform.

[0615] DMSO-d6: deuterated dimethyl sulfoxide.

[0616] T3P: tripropylphosphoric anhydride.

[0617] DPPA: diphenylphosphoryl azide.

[0618] DIEA: N,N-diisopropylethylamine.

[0619] Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

[0620] The compound is purified using an eluent system for column chromatography and thin-layer chromatography, wherein the system is selected from: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: dichloromethane and ethyl acetate system; D: dichloromethane and ethanol system, wherein the volume ratio of the solvent varies according to the polarity of the compound, and a small amount of acidic or alkaline reagents, such as acetic acid or triethylamine, may also be added to adjust the conditions.

[0621] Chimeric small molecule compounds such as:

[0622]

[0623] Biological test methods

[0624] The compound's growth inhibitory activity on tumor cells and its degradation of the target protein KRAS. The inhibition rate (IC 50 ) Through CCK8 experiment, the instrument uses BioTec microplate reader, IC 50 The unit is nM.

[0625] The target protein KRAS was detected by Western blot. Western blot electrophoresis and transfer were performed using Bio-Rad instruments. Chemiluminescence imaging was performed using a Tanon 5200 Multi.

[0626] (1) Testing instruments and reagents

[0627]

[0628]

[0629] (2) CCK8 method to detect the inhibitory effect of compounds on tumor cell growth 1. Drug dilution process:

[0630] ① Take 1 vial of solution with a concentration of 25mM and dilute it with DMSO to a series of concentrations of 1000× the stock solution. The dilution process is as follows:

[0631]

[0632]

[0633] ② Take 2 μL of each diluted solution and add it to different 1 mL complete culture medium to obtain 2x drug working solution.

[0634] 2. Experimental steps for detecting the inhibitory effects of compounds on tumor cell growth using the CCK8 method

[0635] The tumor cells selected were KRAS-expressing G12C Human non-small cell lung cancer tumor cells NCI-H358 and KRAS mutations G12C Homozygous mutation in the human pancreatic cancer cell line MIAPaCa-2.

[0636] ①Tumor cells in the logarithmic growth phase were digested with trypsin, centrifuged at 200 g for 5 min, and resuspended in complete culture medium; the cells were diluted to 3×10 4 The cell suspension was placed in a separatory tank and transferred to a 96-well plate using a multi-channel pipette. 100 μL was added to each well and the plates were incubated at 37°C, 5% CO2 for 24 h. After culturing for 24 h, 100 μL of 2X drug working solution was added in sequence, gently shaken, and incubated at 37°C, 5% CO2 for 72 h. After culturing for 72 h, 20 μL of CCK-8 was added and the reaction was incubated at 37°C, 5% CO2 for 3 h. The plates were fully shaken before detection using a microplate reader and the results were measured at 450 nm.

[0637] ②Data Analysis: *Cell viability: Cell proliferation activity or cytotoxic activity. Cell viability* (%) = [A(drug added) - A(blank)] / [A(0 drug added) - A(blank)] × 100. A(drug added): absorbance of wells containing cells, CCK8 solution, and drug solution;

[0638] A (blank): absorbance of wells with culture medium without cells, CCK8 solution, and no drug solution;

[0639] A (0 drug addition): absorbance of a well containing cells and CCK8 solution but no drug solution.

[0640] Data were statistically analyzed using Graphpad 8.0 and IC was calculated. 50 The IC of the compound is obtained using the following nonlinear fitting formula: 50 (50% inhibitory concentration):

[0641] Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*Hill Slope))

[0642] X: log value of compound concentration; Y: inhibition rate (% inhibition).

[0643] 3. Experimental results of CCK8 method to detect compound activity

[0644] 3.1 Inhibitory effect of compounds on NCI-H358 cell growth

[0645] ① Digest the NCI-H358 cells in the logarithmic growth phase with trypsin, centrifuge at 200g for 5 minutes, and resuspend in 1640 complete medium. ② Dilute the above cells to 3×10 4 Cells were suspended in a dispensing tank and transferred to a 96-well plate using a multichannel pipette. 100 μL was added to each well and incubated at 37°C, 5% CO2 for 24 hours. ③ After 24 hours of incubation, 100 μL of the 2x drug working solution was added sequentially, gently shaken to mix, and incubated at 37°C, 5% CO2 for 72 hours. After 72 hours of incubation, 20 μL of CCK-8 was added and the reaction was incubated at 37°C, 5% CO2 for 3 hours. The reaction was thoroughly shaken before detection using a microplate reader and the results were measured at 450 nm.

[0646] Compound <![CDATA[IC 50 (nM)]]> C06 4851 C07 4880 C19 4303 C32 2467.8

[0647] 3.2 Inhibitory effect of compounds on MIAPaCa-1 cell growth

[0648] ① Digest MIA-PaCa cells in the logarithmic growth phase with trypsin, centrifuge at 200g for 5 minutes, and resuspend in complete DMEM medium. ② Dilute the cells to 3×10⁴ cells / mL with complete DMEM medium. Place the cell suspension in a dispenser and transfer to a 96-well plate using a multichannel pipette. Add 100 μL to each well and incubate at 37°C, 5% CO₂ for 24 hours. ③ After 24 hours of incubation, add 100 μL of 2x drug working solution in the order indicated, gently shake to mix, and incubate at 37°C, 5% CO₂ for 72 hours. ④ After 72 hours of incubation, add 20 μL of CCK-8 and incubate the reaction at 37°C, 5% CO₂ for 3 hours. Shake thoroughly before analysis using a microplate reader. Measure the results at 450 nm.

[0649] Compound <![CDATA[IC 50 (nM)]]> Y01 20948 Y02 20386 C06 3016.84 C32 1620.22 C33 1503.29 C34 3178.77 C35 3177.47 C36 850.89 C37 4508.4 C38 818.74 C39 7016.2 C42 299.96 C43 2930.39 C44 1633.03 C45 1816.3 C46 1608.4

[0650] Comparison of KRAS activity IC values ​​of the chimeric head small molecule compounds Y01 and Y02 50The value is above 20 μM, indicating that the head small molecule has poor inhibitory activity against KRAS. However, by forming the chimeric molecule compound of the present invention, it has better KRAS inhibitory activity, and some compounds even have an IC value below 1000 nM. 50 level.

[0651] 3.3 Effects of Compounds on KRAS-Containing G12D Role of mutated SKLU-1 in human non-small cell lung cancer tumor cells

[0652] ① Digest logarithmically growing SKLU-1 cells with trypsin, centrifuge at 200g for 5 minutes, and resuspend in MEM complete medium. ② Dilute the cells to 3×10⁴ cells / mL with MEM complete medium. Place the cell suspension in a dispenser and transfer to a 96-well plate using a multichannel pipette. Add 100 μL to each well and incubate at 37°C, 5% CO₂ for 24 hours. ③ After 24 hours of incubation, add 100 μL of 2x drug working solution in the order indicated, gently shake to mix, and incubate at 37°C, 5% CO₂ for 72 hours. ④ After 72 hours of incubation, add 20 μL of CCK-8 and incubate the reaction at 37°C, 5% CO₂ for 3 hours. Shake thoroughly before analysis using a microplate reader. Measure the results at 450 nm.

[0653] Compound <![CDATA[IC 50 (nM)]]> C06 7876.6 C07 5608.6 C32 686 C33 1010 C36 679.88 C43 4047.5 C44 1504.8 C38 1415.1 C42 2397.5

[0654] (3) Western Blot analysis of the concentration effect of compounds on KRAS degradation and degradation detection

[0655] 1. Experimental Procedure

[0656] Western Blot analysis of the concentration effect of compounds on KRAS degradation and degradation detection experimental steps: ① MIAPaCa-1 cells were seeded in T75 flasks, and when the cells grew to 70%, the cells were digested with trypsin and counted, and then seeded in 6 cm dishes at 1.5×10 6Cells were treated with compounds after adherence. A compound concentration gradient was set (DMSO, 0.01μM, 0.05μM, 0.1μM, 0.25μM, 0.5μM, 1μM, 2μM, 2.5μM, 3μM, 4μM, 5μM). ② Sample processing: Cells were scraped off and collected and stored in a -80°C freezer. ③ Western blotting analysis: Resuspend cells in an appropriate amount of PBS and add 1 / 3 volume of 4×SDS loading buffer (130mM Tris-Cl pH 6.8, 4% SDS, 0.04% bromophenol blue, 20% glycerol). Boil for 10 minutes, centrifuge to remove insoluble matter, and use the supernatant for Western blotting analysis. Samples and protein molecular weight markers were electrophoresed using 12% SDS-PAGE. The initial voltage was 80V. After the sample entered the separation gel, the voltage was changed to 120V. Electrophoresis was stopped when the bromophenol blue front was 1 cm from the edge of the gel. Soak two 2.5 mm thick filter papers (Bio-Rad, Inc.) and a PVDF membrane (6 x 9 cm) in 1× transfer buffer (39 mmol / L glycine, 48 mmol / L Tris, 0.037% SDS, and 20% methanol) for 30 seconds. Then, place them on a semi-dry transfer apparatus (Bio-Rad, Inc.) in the order of "filter paper - gel - PVDF membrane - filter paper" from top to bottom, removing as much air as possible from the interlayer. Transfer at 18 V. After 1.5 hours, remove the PVDF membrane and add 5 mL of blocking buffer (1× PBST containing 5% BSA). Incubate the membrane on a gentle horizontal shaker at room temperature for 1 hour. After blocking, wash the membrane three times with 1× PBST for 5-10 minutes each. Prepare an unlabeled primary antibody specific for the target protein in PBST; prepare a secondary antibody in PBST containing 5% BSA. After incubating the blocked PVDF membrane with the primary antibody at room temperature for 1 hour, wash the membrane three times with 1×PBST, each time for 5 to 10 minutes; then add the enzyme-labeled secondary antibody (1:5000), incubate at room temperature for 1 hour, and then wash the membrane three times with 1×PBST, each time for 5 to 10 minutes. The above incubation processes are all carried out on a horizontal shaker. Finally, perform the chemiluminescence reaction. Evenly drop the color development solution on the PVDF membrane, absorb the color development solution after 1 minute of reaction, and take pictures in the automatic mode of the developer. ④ Data analysis: Use Image J software for grayscale statistics, and Graphpad 8.0 for data analysis and calculation of DC 50 (Concentration at which protein degradation reaches 50%).

[0657] Y=Bottom+(Top-Bottom) / (1+10^((LogDC 50 -X)*Hill Slope))

[0658] X: log value of compound concentration; Y: degradation rate (% Degradation).

[0659] 2. Results of the compound's ability to degrade endogenous KRAS in MIAPaCa-1 cells:

[0660] Compound Dmax <![CDATA[DC 50 ]]> C36 59％ 0.7675μM

[0661] Depend on Figure 1 It can be seen that compound C36 can degrade endogenous KRAS in MIAPaCa-1 cells, DC 50 =0.7675 μM, and Dmax of compound C36 =59%.

[0662] 3. Confirmation of the pathway by which the compound degrades endogenous KRAS in MIAPaCa-1 cells

[0663] The function of PROTAC molecules depends on proteasome function and target protein ubiquitination. Therefore, during the process of drug action in cells, selective proteasome inhibitors such as epoxomicin and protein ubiquitination inhibitors (pevonedistat) were added to observe the effects on the PROTAC mechanism. By adding epoxomicin and MLN4924 pretreatment, KRAS degradation caused by the compounds of the present invention can be inhibited. Therefore, it can be concluded that compound C36 causes KRAS degradation through the PROTAC mechanism-ubiquitin proteasome pathway.

[0664] Detection method: Western Blot was used to detect the effect of compounds on the protein expression level of MIAPaCa-1 cells. MIAPaCa-1 cells were seeded in T75 flasks and when the cells grew to 90%, the cells were digested with trypsin and counted. The cells were then seeded in 6 cm dishes at 2 × 10 cells per dish. 6 Cells were plated 18 hours later and allowed to adhere before treatment with compound treatment. A gradient of compound concentrations (DMSO, 0.1 μM, 1 μM, 2.5 μM, 5 μM) was established. Four 6-cm dishes were pretreated with epoxomicin at a concentration of 1 μM (referred to as MLN in the accompanying figures) in two of the four 6-cm dishes. After 1 hour, fresh medium or a drug-containing medium containing the compound (2.5 μM) was replaced. Two additional dishes were pretreated with MLN4924 at a concentration of 1 μM (referred to as MLN in the accompanying figures). After 1 hour, fresh medium or a drug-containing medium containing the compound (2.5 μM) was replaced. Cells were harvested 24 hours later, protein was extracted, and Western blot analysis was performed to determine endogenous KRAS protein levels.

[0665] The results are as follows Figure 2As shown: Compound C36 can significantly degrade endogenous KRAS G12C mutant protein in cells at a dose of 2.5μM. The degradation ability decreases at higher concentrations, which also reflects the "hook" effect unique to the PROTAC mechanism. When a proteasome inhibitor (Epoxomicin) and a protein ubiquitination inhibitor (MLN4924) are added, the degradation of endogenous KRAS protein induced by compound C36 can be inhibited.

[0666] 4. Western Blot detection of PROTAC molecules on the degradation of target proteins.

[0667] like Figure 3 As shown, with Tubulin as the internal reference (housekeeping gene), compound C06 at 100 nm had an inhibitory effect on KRAS G12C When the proteasome inhibitor MG132 was added, the degradation process was inhibited, proving that the compound C06 of the present invention has a KRAS G12C Degradation effect, and the degradation process is achieved through the PROTAC mechanism.

[0668] The compounds of the present invention have an effect on KRAS G12C IC 50 Below 10 μM, preferably below 3000 nM, more preferably below 1500 nM, indicating that the compound of the present invention has a strong effect on KRAS G12 C mutant tumor cells have good inhibitory activity, indicating that the compounds of the present invention are effective in treating KRAS G12C Furthermore, the compounds of the present invention have good application potential in KRAS-mediated diseases. G12D IC 50 The compounds of the present invention have an inhibitory effect on KRAS at a concentration below 10 μM, preferably below 3000 nM, and more preferably below 1500 nM. G12D The compound has good inhibitory activity on KRAS mutant tumor cells and good in vitro activity, indicating that the compound of the present invention is effective in treating KRAS mutant tumor cells. G12D The compounds of the present invention have good application potential in the treatment of diseases mediated by KRAS. Therefore, the compounds of the present invention have good application potential in the treatment of diseases mediated by KRAS. The present invention discloses a novel chimeric compound through PROTAC technology, which comprises a KRAS targeting portion and an E3 ligase binding portion (e.g., VHL, CRBN binding group), which can be connected through an L linker. The chimeric compound disclosed in the present invention actively inhibits and / or degrades KRAS, resulting in inhibition of cell proliferation or induction of cell apoptosis.

[0669] The present invention has been described above, providing chimeric compounds for inhibiting / degrading KRAS and their applications. Specific examples are used herein to illustrate the principles and implementation methods of the present invention. The description of these examples is intended only to facilitate understanding of the methods and central concepts of the present invention. It should be noted that those skilled in the art will appreciate that various improvements and modifications may be made to the present invention without departing from the principles of the present invention, and such improvements and modifications fall within the scope of protection of the present invention.

Claims

1. A compound, characterized in that The compound is selected from the following compounds: or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

3. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing cancer.

4. The method of claim 3, wherein the cancer is selected from the group consisting of lymphoma, blastoma, sarcoma, leukemia, squamous cell carcinoma, esophageal cancer, thyroid cancer, melanoma, pancreatic cancer, lung cancer, peritoneal cancer, bile duct cancer, gastric cancer, glioblastoma, multiple myeloma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, breast cancer, colorectal cancer, endometrial cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, anal cancer, penile cancer, urothelial cancer, and head and neck cancer.

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