SOS1 protein degrader and its application

Abstract

This application relates to the pharmaceutical field, and particularly to SOS1 protein degraders and their applications. The compounds of this application can effectively inhibit tumor cell proliferation and degrade SOS1 protein in tumor cells, with a maximum degradation rate of 96.15%. Compared with existing small molecule compounds, the compounds of this application exhibit a more sustained inhibitory effect on SOS1 signaling and a more significant inhibitory effect on the growth of human MIA PaCa-2 pancreatic cancer subcutaneous xenografts in mice, with a maximum tumor volume inhibition rate (TGI) of 81.3%.

Description

Technical Field

[0001] This application relates to the pharmaceutical field, and in particular to SOS1 protein degraders and their applications. Background Technology

[0002] RAS proteins are important signal transduction regulators, modulating signal transduction pathways for various biological processes in different tissues and cell types, including cell proliferation, differentiation, migration, and survival. Approximately 30% of cancer patients carry KRAS mutations, with the highest mutation rate (97%) in pancreatic ductal adenocarcinoma, followed by colorectal cancer, multiple myeloma, and lung cancer (52%, 42%, and 32%, respectively). The most common type of KRAS gene mutation is point mutation, including KRAS G12C (14%), KRAS G12D (41%), and KRAS G12V (28%) mutations. KRAS mutations lead to cell carcinogenesis by causing overactivation of downstream signaling pathways. Although the importance of KRAS has long been recognized, the development of KRAS inhibitors has been severely hampered by the lack of small molecule binding pockets. After years of effort, two KRAS G12C inhibitors, Sotorasib (AMG510) and Adagrasib (MRTX849), were approved by the FDA in 2021 and 2022, respectively. Despite the significant success in KRAS G12C inhibitor research, studies have found that after a period of clinical application, some patients develop acquired resistance due to compensatory activation of other proliferation-related signaling pathways or the occurrence of secondary mutations after medication. Furthermore, some patients, even with G12C mutations, remain insensitive to inhibitors, developing primary resistance. In addition, numerous other KRAS mutations exist, such as G12A, G12D, G12R, G12V, G13D, G61L, and G61H, for which no drugs are currently available. Therefore, developing pan-KRAS inhibitors targeting upstream and downstream KRAS pathways may fill relevant clinical needs.

[0003] SOS (Son of Sevenless) is a guanine nucleotide exchange factor (GEF) that activates the GTPase KRAS. In mammalian cells, the SOS family includes two members, SOS1 and SOS2, which can stimulate RAS to release GDP and bind GTP in various signaling pathways initiated by different cell surface receptor tyrosine kinases. SOS1 and SOS2 share many similarities in structure and expression patterns; however, most studies have found that SOS1 dominates under physiological and pathological conditions. Aberrant expression or mutation of SOS1 is closely related to the occurrence of clinical diseases. Neurofibromatosis type I (NF1) and Noonan syndrome (NS) are two common RASopathies. Approximately 11% of Noonan syndrome patients carry gain-of-function SOS1 mutations, and SOS1 mutations are also present in hereditary gingival fibromatosis. As an upstream pathway in the KRAS signaling pathway, SOS1 deficiency reduces the survival rate of tumor cells carrying KRAS mutations but does not reduce the survival rate of wild-type KRAS tumor cells.

[0004] In summary, targeting SOS1 holds potential for treating KRAS-mutant cancers. Currently reported SOS1 inhibitors include Bayer's BAY 293 and Boehringer Ingelheim's BI3406 and BI1701963. While SOS1 inhibitors are effective against various KRAS mutations, preclinical data show limited activity when used alone, exhibiting only moderate antitumor activity. Among SOS1 inhibitors, only BI 1701963 is currently in Phase I clinical trials, intended for use alone or in combination with MEK inhibitors (trametinib) or KRAS G12C inhibitors (sottorazib, adagraxib, or BI1823911) to treat patients with advanced malignant tumors harboring KRAS mutations (NCT04111458, NCT04975256, NCT04973163, NCT04185883). However, due to safety concerns, poor pharmacokinetic profile (PK), and limited efficacy, the drug's clinical development in China has been discontinued. Overall, current small-molecule SOS1 inhibitors exhibit poor activity, and trials are mostly designed for combination therapy. Summary of the Invention

[0005] In view of the shortcomings of the prior art described above, and to address the technical problem of poor activity of small molecule SOS1 inhibitors in the prior art, the inventors of this application have discovered that, compared with traditional small molecule drugs, protein degradation-targeting chimeras (PROTACs) break the traditional mode of action of small molecule drugs. These small molecule degraders can be viewed as bifunctional molecules, with one end binding to the target protein and the other end acting on an E3 ligase. This functional molecule can recruit the target protein to the vicinity of the E3 ligase complex, inducing ubiquitination of the target protein, and ultimately utilizing the intracellular proteasome to selectively induce the degradation of the target protein. The restoration of the target protein's function requires the resynthesis of the protein, thus extending the duration of its therapeutic effect. Therefore, developing SOS1 degraders may solve the deficiencies of existing SOS1 inhibitors and fill unmet clinical needs.

[0006] The purpose of this application is to provide an SOS1 protein degrader and its application to solve the problems in the prior art.

[0007] To achieve the above and other related objectives, the first aspect of this application provides a compound or a pharmaceutically acceptable salt, ester, prodrug, isomer, deuterated product, or solvate, characterized in that the compound has the structural formula shown in Formula I:

[0008]

[0009] Among them, the SOS1 binder can bind to the SOS1 protein;

[0010] E3 ligase ligand is as shown in Equation II:

[0011]

[0012]

[0013] Among them, A is selected from -CH2- and -(C=O)-;

[0014] B, D, Z, and U are each independently selected from CH and N;

[0015] L is selected from -S-, -SO-, -SO2-, -CH2-, -(C=O)-, -NH-, -O-, ethynyl group, or it may not exist;

[0016] LIN represents the linker group that is covalently linked to the SOS1 binder and E3 ligase, respectively.

[0017] A second aspect of this application provides a pharmaceutical composition comprising the compound described in the first aspect, and further comprising a pharmaceutically acceptable carrier, additive, adjuvant, or excipient.

[0018] The third aspect of this application provides the use of the compound described in the first aspect or the pharmaceutical composition described in the second aspect in the preparation of products for SOS1-related hereditary diseases or cancer.

[0019] The fourth aspect of this application provides a treatment method in which a therapeutically effective amount of the compound described in the first aspect or the pharmaceutical composition described in the second aspect is administered to an individual.

[0020] Compared with the prior art, the beneficial effects of this application are as follows:

[0021] 1. The compound of this application can effectively inhibit the proliferation of tumor cells and degrade the SOS1 protein in tumor cells, with a maximum degradation rate of 96.15%.

[0022] 2. Compared with the existing small molecule compound BI3406, the compound of this application has a more sustained inhibitory effect on SOS1 signaling.

[0023] 3. The compounds of this application exhibit good pharmacokinetic properties in mouse models.

[0024] 4. Compared with the existing small molecule compound BI3406, the compound of this application has a more significant inhibitory effect on the growth of human MIA PaCa-2 pancreatic cancer subcutaneous xenografts in mice, with a maximum tumor volume inhibition rate (TGI) of 81.3%. Attached Figure Description

[0025] Figure 1 The image shown is the mass spectrum of compound A1 prepared in Example 3.

[0026] Figure 2 The mass spectrum shown is that of compound A2 prepared in Example 4.

[0027] Figure 3 The mass spectrum shown is that of compound A3 prepared in Example 5.

[0028] Figure 4 The mass spectrum shown is that of compound A4 prepared in Example 6.

[0029] Figure 5 The mass spectrum shown is that of compound A5 prepared in Example 7.

[0030] Figure 6 The mass spectrum shown is that of compound A6 prepared in Example 8.

[0031] Figure 7 The mass spectrum shown is that of compound A7 prepared in Example 9.

[0032] Figure 8 The mass spectrum shown is that of compound A8 prepared in Example 10.

[0033] Figure 9 The image shown is the mass spectrum of compound A9 prepared in Example 11.

[0034] Figure 10 The mass spectrum shown is that of compound A10 prepared in Example 12.

[0035] Figure 11 The mass spectrum shown is that of compound A11 prepared in Example 13.

[0036] Figure 12 The mass spectrum shown is that of compound B1 prepared in Example 14.

[0037] Figure 13 The mass spectrum shown is that of compound B2 prepared in Example 15.

[0038] Figure 14 The mass spectrum shown is that of compound B3 prepared in Example 16.

[0039] Figure 15 The image shown is the mass spectrum of compound B4 prepared in Example 17.

[0040] Figure 16 The image shown is the mass spectrum of compound B5 prepared in Example 18.

[0041] Figure 17 The image shown is the mass spectrum of compound B6 prepared in Example 19.

[0042] Figure 18 The mass spectrum shown is that of compound B7 prepared in Example 20.

[0043] Figure 19 The mass spectrum shown is that of compound B8 prepared in Example 21.

[0044] Figure 20 The mass spectrum shown is that of compound B9 prepared in Example 22.

[0045] Figure 21 The mass spectrum shown is that of compound B10 prepared in Example 23.

[0046] Figure 22 The mass spectrum shown is that of compound B11 prepared in Example 24.

[0047] Figure 23 The mass spectrum shown is that of compound C1 prepared in Example 25.

[0048] Figure 24The mass spectrum shown is that of compound C2 prepared in Example 26.

[0049] Figure 25 The mass spectrum shown is that of compound C3 prepared in Example 27.

[0050] Figure 26 The image shown is the mass spectrum of compound C4 prepared in Example 28.

[0051] Figure 27 The image shown is the mass spectrum of compound C5 prepared in Example 29.

[0052] Figure 28 The image shown is the mass spectrum of compound C6 prepared in Example 30.

[0053] Figure 29 The image shown is the mass spectrum of compound C7 prepared in Example 31.

[0054] Figure 30 The image shown is the mass spectrum of compound C8 prepared in Example 32.

[0055] Figure 31 The image shown is the mass spectrum of compound C9 prepared in Example 33.

[0056] Figure 32 The mass spectrum shown is that of compound C10 prepared in Example 34.

[0057] Figure 33 The mass spectrum shown is that of compound C11 prepared in Example 35.

[0058] Figure 34 The mass spectrum shown is that of compound D1 prepared in Example 36.

[0059] Figure 35 The mass spectrum shown is that of compound D2 prepared in Example 37.

[0060] Figure 36 The image shown is the mass spectrum of compound D3 prepared in Example 38.

[0061] Figure 37 The mass spectrum shown is that of compound D4 prepared in Example 39.

[0062] Figure 38 The image shown is a mass spectrum of compound D5 prepared in Example 40.

[0063] Figure 39 The image shown is a mass spectrum of compound D6 prepared in Example 41.

[0064] Figure 40 The image shown is a mass spectrum of compound D7 prepared in Example 42.

[0065] Figure 41 The image shown is the mass spectrum of compound D8 prepared in Example 43.

[0066] Figure 42 The image shown is the mass spectrum of compound D9 prepared in Example 44.

[0067] Figure 43 The mass spectrum shown is that of compound D10 prepared in Example 45.

[0068] Figure 44 The mass spectrum shown is that of compound D11 prepared in Example 46.

[0069] Figure 45 The data shows the degree of downregulation of SOS1 protein in K562 cells by different concentrations of compounds A10, A11, C11, D7, D8, and D11.

[0070] Figure 46 The data shows the degree of downregulation of SOS1 protein in MIAPaCa-2 cells by different concentrations of compounds A10, A11, C11, D7, D8, and D11.

[0071] Figure 47 The figure shows the degree of downregulation of SOS1 protein in HPAF-II cells by different concentrations of compounds A10, A11, C11, D7, D8 and D11.

[0072] Figure 48 The study showed that A11 degrades SOS1 in K562 cells.

[0073] Figure 49 This demonstrates the effect of A11 on SOS1 DCs in K562 cells. 50 .

[0074] Figure 50 The results show that A11 persistently inhibits the SOS1 signaling pathway in K562 cells.

[0075] Figure 51 The results show the inhibitory activity of A11 on the growth of MIA PaCa-2 nude mouse xenografts. Detailed Implementation

[0076] To make the inventive objectives, technical solutions, and beneficial effects of this application clearer, the following description, in conjunction with embodiments, further illustrates this application. It should be understood that the embodiments described are for illustrative purposes only and are not intended to limit the scope of the application. Unless otherwise specified, the experimental methods used in the following embodiments are conventional methods, and those skilled in the art can easily understand other advantages and effects of this application from the content disclosed in this description.

[0077] The inventors of this application, through extensive research and exploration, discovered SOS1 protein degrading agents and their applications, and completed this application based on this discovery.

[0078] The first aspect of this application provides a compound or a pharmaceutically acceptable salt, ester, prodrug, isomer, deuterated product, or solvate, characterized in that the compound has the structural formula shown in Formula I:

[0079]

[0080] Among them, the SOS1 binder can bind to the SOS1 protein;

[0081] E3 ligase ligand is as shown in Equation II:

[0082]

[0083] Among them, A is selected from -CH2- and -(C=O)-;

[0084] B, D, Z, and U are each independently selected from CH and N;

[0085] L is selected from -S-, -SO-, -SO2-, -CH2-, -(C=O)-, -NH-, -O-, ethynyl group, or it may not exist;

[0086] LIN represents the linker group that is covalently linked to the SOS1 binder and E3 ligase, respectively.

[0087] Unless otherwise specified, the isotopic labeling of the compounds of this invention is also included within the scope of protection of this invention. For example, in compounds having the structure of this invention as given above, at least one hydrogen atom is replaced by deuterium or tritium, or at least one carbon atom is replaced by... 13 C- or 14 C-enriched carbon substitution, or at least one nitrogen being [substituted / replaced / converted]. 15 N-enriched nitrogen substitution.

[0088] In this invention, the term "salt" should be understood to mean any form of active compound used in this invention, wherein the compound may be in ionic form or charged or coupled to a counterion (cation or anion) or in solution. This definition may also include quaternary ammonium salts and complexes of active molecules with other molecules and ions, particularly complexes formed through ionic interactions. This definition particularly includes physiologically acceptable salts, and the term may be understood to be equivalent to "pharmacologically acceptable salts."

[0089] In this invention, the term "pharmaceutically acceptable salt" generally refers to any salt that is physiologically tolerable when used in a suitable manner for treatment (particularly when applied or used in humans and / or mammals). This generally means that it is non-toxic, particularly as a result of an anti-ion. These physiologically acceptable salts can be formed with cations or bases, and in the context of this invention, particularly when administered in humans and / or mammals, they should be understood as salts formed from at least one compound provided according to this invention, typically an acid (deprotonated), such as an anion, and at least one physiologically tolerable cation (preferably an inorganic cation). Specifically, in the context of this invention, this may include salts formed with alkali metals and alkaline earth metals, as well as salts formed with ammonium cations (NH4+). + The salts formed can specifically include, but are not limited to, salts formed with (mono) or (di) sodium, (mono) or (di) potassium, magnesium, or calcium. These physiologically acceptable salts can also be formed with anions or acids, and in the context of this invention, particularly when administered to humans and / or mammals, they should be understood as salts formed by at least one compound provided according to this invention, typically protonated (e.g., on nitrogen), such as a cation, and at least one physiologically tolerable anion. In the context of this invention, salts can specifically include salts formed with physiologically tolerable acids, i.e., salts formed by specific active compounds with physiologically tolerable organic or inorganic acids, specifically including, but not limited to, salts formed with hydrochloric acid, hydrobromic acid, hydroiodic acid; sulfuric acid, persulfate, pyrosulfonic acid; phosphoric acid, nitric acid; methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid; formic acid, acetic acid, acetoacetic acid, trifluoroacetic acid, pyruvic acid, propionic acid, butyric acid, valeric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid; benzoic acid, salicylic acid, 2- (4-Hydroxybenzoyl)benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthylcarboxylic acid, nicotinic acid, pectic acid, 3-phenylpropionic acid, picric acid, terpentine; 2-hydroxyethanesulfonic acid, aminosulfonic acid, dodecyl sulfate, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid; citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, citric acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, aspartic acid, and salts formed from sulfosalicylic acid.

[0090] The compounds of the present invention represented by Formula I above may include enantiomers depending on the presence of a chiral center or isomers depending on the presence of a double bond (e.g., Z, E). Single isomers, enantiomers, diastereomers, or cis-trans isomers and mixtures thereof all fall within the scope of the present invention.

[0091] In this invention, the term "prodrug" is used in its broadest sense and includes those derivatives that can be converted into the compounds of this invention in vivo. Methods for preparing prodrugs of the specified active compounds should be known to those skilled in the art, for example, as disclosed in Krogsgaard-Larsen et al., "Textbook of Drug Design and Discovery," Taylor & Francis (April 2002).

[0092] In this invention, the term "solvent" generally refers to any form of substance obtained by combining the active compound according to the invention with another molecule (usually a polar solvent) via a non-covalent bond, specifically including but not limited to hydrates and alcohols, such as methanols.

[0093] The compound provided in this application is an SOS1 protein degradation-targeting chimera. As a bifunctional molecule, one end of the compound, an SOS1binder, can bind to the target protein SOS1, while the other end, an E3 ligase ligand, can act on an E3 ligase. This compound recruits the target protein SOS1 to the vicinity of the E3 ligase complex, inducing SOS1 ubiquitination, thereby activating the intracellular proteasome system to target and degrade the target protein. The ubiquitination degradation pathway can degrade most ubiquitinated proteins in the cell; for example, it can specifically degrade 80%–90% or higher of ubiquitinated proteins in the cell. If this system can be activated to specifically clear oncogenic proteins and restore normal protein homeostasis in the cell, it is very likely to alleviate or treat cancer. PROTAC technology utilizes this principle, using a specially designed bispecific degradative agent to label the target protein with ubiquitin, thereby achieving targeted degradation. The restoration of target protein function requires the resynthesis of the protein, thus extending the therapeutic effect.

[0094] In the compounds provided in this application, SOS1 binder represents:

[0095]

[0096] Among them, R1, R2, R3, and R4 are each independently selected from H, halogens, and C. 1-10 Alkyl, amino, C 1-10 Haloalkyl, C 1-10 alkynyl group, C 1-10 Alkyl methoxy, aryl methoxy, heteroaryl methoxy, wherein the aryl and heteroaryl methoxy groups are unsubstituted or have one or two groups selected from C10. 1-10 Alkyl, halogen and C 1-10Substituents of haloalkyl groups.

[0097] R5 represents a substituted or unsubstituted heterocyclic group, wherein the heterocyclic group represents a group optionally substituted with C. 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 cycloalkyl, halogenated C 1-3 Substituents of alkyl, halogen, hydroxyl, cyano, amino, or any combination thereof, of the following groups: iminofuranyl, iminozolyl, iminozolyl, iminodizolyl, iminopheneyl, iminozolyl, iminozolyl, iminodizolyl, iminopyrroleyl, iminozolyl, iminozolyl, iminozolyl, iminopyridyl, iminopyridinyl, iminopyridinyl, iminopyridyl, iminopyridyl, iminopyridyl, iminopyridyl, iminopyridyl, iminopyridyl, iminopyridyl, iminopyridyl, iminopyridyl, iminopyrofuranyl , benzofuranyl, benzothiopheneyl, indazoleyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, benzo[2,1,3]oxadiazolyl, benzo[2,1,3]thiadiazolyl, benzo[1,2,3]thiadiazolyl, quinolinyl, isoquinolinyl, naphthidyl, cinolinyl, Quinoxolinyl, Quinoxolinyl, Phthalosazinyl, Pyrazolo[1,5-a]pyridinyl, Pyrazolo[1,5-a]pyrimidineyl, Imidazolo[1,2-a]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, 4H-fluoro[3,2-b]pyrroleyl, Pyrrolo[2,1-b]thiazoleyl, Imidazolo [2,1-b]thiazolyl, azapyrocyclobutyl, oxopyrocyclobutyl, pyrrolyl, imidazoalkyl, pyrazolyl, pyridinyl, triazolyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiaranyl, oxazolyl, thiazoalkyl, piperidinyl, piperazine, morpholinyl, thiomorpholinyl, dioxacyclohexyl or diazacycloheptenyl.

[0098] In this invention, "halogen" or "halogenated" usually refers to fluorine, chlorine, bromine or iodine.

[0099] In this invention, "alkyl" typically refers to a saturated aliphatic group, which can be straight-chain or branched. For example, C 1-10 Alkyl groups typically refer to alkyl groups comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. These alkyl groups can specifically include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decanyl. For example, C... 1-30Alkylene typically refers to an alkylene group comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 carbon atoms. Specifically, the alkylene group may include, but is not limited to, methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, octylene, nonylene, and deuterylene.

[0100] In this application, "halogenated alkyl" generally refers to a halogenated saturated aliphatic group, which may be straight-chain or branched, and optionally independently selected from fluorine, chlorine, bromine, or iodine mono- or poly-substituted. For example, C 1-10 Haloalkyl groups typically refer to haloalkyl groups comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. Specifically, the haloalkyl groups may include, but are not limited to, halomethyl, haloethyl, halopropyl, halobutyl, halopentyl, halohexyl, haloheptyl, halooctyl, halononyl, and halodecyl.

[0101] In this application, "aryl" generally refers to a group having at least one aromatic ring but no heteroatoms. The aryl group may optionally be mono- or poly-substituted by substituents independently selected from alkyl, halogen, haloalkyl, cyano, R7SO2(CH2)sNHCH2-, -OR8, and -NHC(O)R9. Specifically, the aryl group may include, but is not limited to, phenyl, naphthyl, fluorenyl, tetrahydronaphthyl, indenyl, or anthraceneyl. Preferably, the aryl group in this invention is an optionally at least mono-substituted 5- or 6-membered ring system.

[0102] In this application, "heteroaryl" generally refers to a heterocyclic system having at least one aromatic ring and optionally containing one or more heteroatoms selected from N and O, and optionally being mono- or poly-substituted by substituents independently selected from alkyl, halogen, haloalkyl, cyano, R7SO2(CH2)sNHCH2-, -OR8, and -NHC(O)R9. Specifically, the heteroaryl group may include, but is not limited to, furan, benzofuran, pyrrole, pyridine, pyrimidine, pyridazine, quinoline, isoquinoline, phthalazine, triazole, pyrazole, isoxazole, indole, benzotriazole, benzodioxane, benzodioxane, benzimidazole, carbazole, and quinazoline. Preferably, the heteroaryl group in this invention is a 5- or 6-membered ring system that is optionally at least monosubstituted.

[0103] In some embodiments of this application, in Formula III, R1, R2, R3, and R4 are each independently selected from H, haloalkyl, H, and amino. In a preferred embodiment of this application, in Formula III, R1, R2, R3, and R4 are each independently selected from H, CF3, H, and amino.

[0104] In some embodiments of this application, in formula III, R5 is selected from:

[0105]

[0106] In the compounds provided in this application, R5 and LIN are covalently linked and form a group as shown in Formula IV:

[0107]

[0108] Wherein, X and Y independently represent either a optionally substituted methylene group or an optionally substituted straight-chain or branched C group. 1-20 Alkylene chains, wherein the C-chain of the straight or branched chain is... 1-20 The alkylene chain is optionally selected from any or a combination of the following groups: optionally substituted heterocyclic groups, optionally substituted heteroaryl groups, -O-, -S-, -S(O)2O-, -OS(O)2-, -C(O)O-, -OC(O)-, wherein the heterocyclic group and the heteroaryl group are optionally selected independently from C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 cycloalkyl, halogenated C 1-3 Substitution with alkyl, halogen, hydroxyl, cyano, amino, or any combination thereof.

[0109] In some embodiments of this application, the compounds are selected from...

[0110]

[0111] The definitions of X, Y, and L groups are the same as above.

[0112] Furthermore, the compounds in this application are selected from:

[0113]

[0114]

[0115] Wherein, the definitions of X, Y, and L groups are the same as above; n is selected from natural numbers from 1 to 20. In the specific implementation of this application, the compounds are selected from the compounds shown in Table 1:

[0116] Table 1

[0117]

[0118]

[0119]

[0120]

[0121]

[0122]

[0123]

[0124]

[0125]

[0126]

[0127]

[0128]

[0129] A second aspect of this application provides a pharmaceutical composition comprising the compound described in the first aspect, and further comprising a pharmaceutically acceptable carrier, additive, adjuvant, or excipient.

[0130] The pharmaceutical compositions provided in this application may include one or more pharmaceutically acceptable carriers, which generally refer to carriers for therapeutic administration that do not induce antibodies harmful to the individual receiving the composition and do not cause excessive toxicity after administration. These carriers are well known to those skilled in the art; for example, pharmaceutically acceptable carriers are disclosed in Remington's Pharmaceutical Sciences (Mack Pub. Co., NJ 1991). Specifically, the carriers may be one or more combinations of, but not limited to, saline, buffer solutions, glucose, water, glycerol, ethanol, adjuvants, etc.

[0131] The pharmaceutical composition provided in this application may contain a single active ingredient or be combined with other active components to form a combination formulation. These other active components may be various other drugs that can be used to treat tumors, myeloma, or solid tumors and cancers. The content of the active component in the composition is typically a safe and effective amount, which should be adjustable by those skilled in the art. For example, the dosage of the compound and the active ingredient in the pharmaceutical composition typically depends on the patient's weight, the type of application, the condition and severity of the disease. For instance, the dosage of the compound as the active ingredient may typically be 1–1000 mg / kg / day, 20–200 mg / kg / day, 1–3 mg / kg / day, 3–5 mg / kg / day, or 5–10 mg / kg / day. g / day, 10~20mg / kg / day, 20~30mg / kg / day, 30~40mg / kg / day, 40~60mg / kg / day, 60~80mg / kg / day, 80~100mg / kg / day, 100~150mg / kg / day, 150~200mg / kg / day, 200~300mg / kg / day, 300~500mg / kg / day, or 500~1000mg / kg / day.

[0132] The compounds provided in this application are adaptable to any form of administration, including oral or parenteral administration, such as via pulmonary, nasal, rectal, and / or intravenous injection. More specifically, they can be administered intradermally, subcutaneously, intramuscularly, intra-articularly, intraperitoneally, pulmonaryly, orally, sublingually, nasally, percutaneously, vaginally, orally or parenterally. Those skilled in the art can select appropriate formulations based on the administration method. For example, suitable formulations for oral administration include, but are not limited to, pills, tablets, chewable tablets, capsules, granules, drops, or syrups. Similarly, suitable formulations for parenteral administration include, but are not limited to, solutions, suspensions, rehydrated dry formulations, or sprays. Furthermore, suitable formulations for rectal administration are typically suppositories.

[0133] In a further preferred embodiment of this application, other drugs are also included. These other drugs are selected from one or more combinations of KRAS G12C inhibitors, MEK inhibitors, EGFR wild-type or mutant inhibitors, PI3K inhibitors, SHP2 inhibitors, AKT inhibitors, mTOR inhibitors, TOP1 inhibitors, HER2 wild-type or mutant inhibitors, ALK wild-type or mutant inhibitors, BCR-ABL mutant inhibitors, c-MET mutant inhibitors, taxanes, platinum-based drugs, CDK4 or CDK6 inhibitors, metabolic antitumor drugs, PD-1 or PD-L1 monoclonal antibodies, CTLA-4 monoclonal antibodies, anti-angiogenic drugs, apoptosis-inducing drugs, PARP inhibitors, and epigenetic drugs.

[0134] In the pharmaceutical composition provided in this application, among the other drugs, the KRAS G12C inhibitor is selected from one or more combinations of sotorasiib, adagraxib, JDQ-443, GF-105, and GDC-6036. The MEK inhibitor is selected from one or more combinations of trametinib, selmetinib, cobimetinib, bimetinib, and bemettinib. The EGFR wild-type or mutant inhibitor is selected from one or more combinations of erlotinib, gefitinib, afatinib, ametinib, omamotinib, mobocetinib, icotinib, osimertinib, panitumumab, nimotuzumab, cetuximab, and netutumab. The PI3K inhibitor is selected from one or more combinations of duenxib, apelixib, limpruciform, edralanib, and BAY-84-1236. SHP2 inhibitors are selected from one or more combinations of JAB-3068, BR-790, BBP-398, JAB-3312, RMC-4630, and TNO-155. AKT inhibitors are selected from one or more combinations of Ipatasertib Dihydrochloride, Afuresertib, Capivasertib, and TIC-10. mTOR inhibitors are selected from one or more combinations of sirolimus, tesimolimus, everolimus, and desfolimus. TOP1 inhibitors are selected from one or more combinations of irinotecan, topotecan, belotecone, arubicin, and camptothecin. HER2 wild-type or mutant inhibitors are selected from one or more combinations of lapatinib, trastuzumab, and pertuzumab. ALK wild-type or mutant inhibitors are selected from one or more combinations of lolatinib, alectinib, ceritinib, ensartinib, brigatinib, and crizotinib. BCR-ABL mutant inhibitors are selected from one or more combinations of imatinib, dasatinib, and nilotinib. c-MET mutant inhibitors are selected from one or more combinations of terpoxtinib, cevotinib, and carmatinib. Taxanes are selected from paclitaxel or docetaxel. Platinum-based inhibitors are selected from one or more combinations of cisplatin, carboplatin, and oxaliplatin. CDK4 or CDK6 inhibitors are selected from one or more combinations of abeciclib, palbociclib, liberciclib, and dalcilibin. Metabolic antitumor drugs are selected from one or more combinations of 5-fluorouracil, capecitabine, and gemcitabine. PD-1 or PD-L1 monoclonal antibodies are selected from one or more combinations of the following: borolizumab, nivolumab, sintilimab, camrelizumab, toripalimab, cepalimumab, tislelizumab, penaprilimab, cantunilimab, putelizumab, slulizumab, cemiplimab, BMS-986213, prolgolimab, dostarlimab, envorizumab, durvalumab, atezolizumab, avelumab, and sugemalimab.CTLA-4 monoclonal antibody is selected from one or more combinations of ipilimumab, trimemumab, and canducimumab. Anti-angiogenic drugs are selected from bevacizumab or nintedanib. Apoptosis-inducing drugs are selected from one or more combinations of veneclax, lisaftoclax, LP-168, BGB-11417, FCN-338, FCN-011, and pelcitoclax. PARP inhibitors are selected from one or more combinations of olaparib, niraparib, fluzoparib, and pamiparib. Epigenetic drugs are selected from one or more combinations of azacitidine, vorinostat, romidabenamine, evanib, and tazestat.

[0135] The third aspect of this application provides the use of the aforementioned compounds or pharmaceutical compositions in the preparation of products for SOS1-related hereditary diseases or cancers.

[0136] In the purposes provided in this application, the hereditary disease is selected from one or more combinations of neurofibromatosis type I, gingival fibromatosis, and Noonan syndrome. The cancer is selected from one or more combinations of non-melanotic skin cancer, breast cancer, lung cancer, colorectal cancer, prostate cancer, stomach cancer, liver cancer, cervical cancer, esophageal cancer, thyroid cancer, bladder cancer, non-Hodgkin's lymphoma, pancreatic cancer, leukemia, kidney cancer, endometrial cancer, lip / oral cancer, melanoma, ovarian cancer, brain and central nervous system tumors, laryngeal cancer, multiple myeloma, nasopharyngeal carcinoma, gallbladder cancer, bile duct cancer, oropharyngeal cancer, hypopharyngeal cancer, Hodgkin's lymphoma, testicular cancer, salivary gland cancer, vulvar cancer, penile cancer, Kaposi's sarcoma, mesothelioma, and vaginal cancer.

[0137] The fourth aspect of this application provides a treatment method of administering a therapeutically effective amount of the aforementioned compound or the aforementioned pharmaceutical composition to an individual.

[0138] In this application, "individual" generally includes humans and non-human primates such as mammals, dogs, cats, horses, sheep, pigs, cattle, etc., who may benefit from treatment using the said formulation, kit, or combination formulation.

[0139] In this application, "therapeutic effective dose" generally refers to a dose that, after an appropriate period of administration, is effective in treating the diseases listed above.

[0140] The following specific examples illustrate the implementation of the present invention. Those skilled in the art can easily understand other advantages and effects of the present invention from the content disclosed in this specification. The present invention can also be implemented or applied through other different specific embodiments, and various details in this specification can also be modified or changed based on different viewpoints and applications without departing from the spirit of the present invention.

[0141] I. Compound Preparation

[0142] Example 1

[0143] Preparation of substrate S4-1

[0144] The general route is as follows:

[0145]

[0146] The specific process is as follows:

[0147] 1. Preparation of tert-butyl 4-((7-methoxy-2-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)piperidine-1-carboxylic acid (S2-1)

[0148]

[0149] 6-hydroxy-7-methoxy-2-methylquinazolin-4(3H)-one (1.0 g, 4.85 mmol), 1-Boc-4-methanesulfonyloxypiperidine (1.49 g, 5.34 mmol), and cesium carbonate (1.89 g, 5.82 mmol) were added together to a 250 mL egg-shaped flask, followed by the addition of anhydrous N,N-dimethylformamide (10 mL). The mixture was stirred in an oil bath at 100 °C for 12 h. After the reaction was complete, the reaction solution was poured into 200 mL of saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate (2 x 50 mL), and the organic phases were combined. The mixture was washed with water (2 x 50 mL), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The crude product was purified by column chromatography (eluent (v / v): dichloromethane / methanol = 20:1) and rotary evaporated to dryness to give the corresponding intermediate S2-1. NMR (500MHz, MeOD) δ7.70(d,J=28.8Hz,1H),7.14(d,J=21.0Hz,1H),4.74(tt,J=7.2,3. 5Hz,1H),4.03(d,J=5.6Hz,3H),3.73(s,1H),3.48–3.35(m,2H),3.27(ddd,J=12.8,6.5, 4.1Hz,1H),2.67(d,J=10.7Hz,3H),2.22(ddt,J=13.1,9.1,3.6Hz,1H),2.16–2.06(m,1H ),2.00(ddt,J=14.0,7.7,3.8Hz,1H),1.78–1.71(m,1H),1.47(s,9H).HRMS(ESI):calcd for C 20 H 27 N3O5[M + H] + ,390.2023found,390.2021.

[0150] 2. Preparation of tert-butyl-4-((7-methoxy-2-methyl-4-(((2,4,6-triisopropylphenyl)sulfonyl)oxy)quinazolin-6-yl)oxypiperidine-1-carboxylate (S3-1)

[0151]

[0152] Intermediate S2-1 (690 mg, 1.77 mmol) was added to a 150 mL egg-shaped flask, followed by 20 mL of dichloromethane solvent. Triethylamine (740.8 μl, 5.31 mmol) and DMAP (21.6 mg, 0.18 mmol) were then added to the flask, and the mixture was stirred. Subsequently, 2,4,6-triisopropylbenzenesulfonyl chloride (805 mg, 2.66 mmol) was added, and the mixture was stirred at room temperature for 12 h. After the reaction was complete, silica gel was added to the reaction solution, the solvent was evaporated under reduced pressure, and the sample was mixed. The crude product was purified by column chromatography (eluent (v / v): petroleum ether / ethyl acetate = 50%-70%), and then evaporated to dryness to obtain the corresponding intermediate S3-1. NMR(500MHz,DMSO)δ7.57(s,1H),7.11(s,1H),6.95(s,2H),4.77–4.71(m ,1H),4.59–4.53(m,2H),3.92(s,3H),3.67(d,J=5.3Hz,2H),3.20(s,2H), 2.83–2.76(m,1H),2.52(s,3H),1.96–1.90(m,2H),1.58–1.51(m,2H),1.4 1(s,9H),1.16(d,J=6.9Hz,6H),1.10(d,J=6.8Hz,12H).HRMS(ESI):calcd for C 35 H 49 N3O7S[M + H] + ,656.3364found,656.3368.

[0153] 3. Preparation of (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-(piperidin-4-oxy)quinazolin-4-amine (S4-1)

[0154]

[0155] Compound S3-1 (900 mg, 1.37 mmol) was added to a 20 mL reaction flask, followed by 5 mL of dimethyl sulfoxide solvent, then triethylamine (955.6 μl, 6.86 mmol) and (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride (495 mg, 2.06 mmol). The mixture was stirred and heated to 90 °C for 12 h. After the reaction was complete, the reaction solution was poured into 100 mL of water and extracted with ethyl acetate (2 x 50 mL). The organic phases were combined, washed with water (2 x 30 mL), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The crude product was purified by column chromatography (eluent (v / v): dichloromethane / methanol = 20:1) and evaporated to dryness to obtain the corresponding tert-butanol ester intermediate. The corresponding tert-butanol ester intermediate was added to a 50 mL egg-shaped flask, followed by 10 mL of 1 M hydrochloric acid-methanol solution. The mixture was stirred at room temperature for 4 h. After the reaction was complete, the product was purified using a saturated sodium bicarbonate solution, extracted with dichloromethane, and the solution was removed by vacuum distillation. The crude product was then separated using a reverse-phase C18 column (eluent (v / v) acetonitrile / (water + 0.05% HCl) = 10%–100%), the reaction solvent was removed by vacuum distillation, and the product was lyophilized with water to obtain the target compound S4-1. NMR(500MHz,MeOD)δ8.31(s,1H),7.57–7.54(m,2H),7.25(s,1H),7.11(s,1H),5.85(q,J=7.0Hz,1H),5.05(dt,J=6.9,3.6Hz,1H),4.04(s,3 H),3.49–3.43(m,2H),3.38–3.32(m,2H),2.63(s,3H),2.29(q,J=6.7Hz,2H),2.14–2.09(m,2H),1.80(d,J=7.1Hz,3H).HRMS(ESI):calcdfor C 24 H 28 F3N5O2[M + H] + ,476.2268found,476.2265.

[0156] Example 2

[0157] Preparation of substrate S4-2

[0158] The general route is as follows:

[0159]

[0160] The specific process is as follows:

[0161] 1. Preparation of (S)-3-((7-methoxy-2-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (S2-2)

[0162]

[0163] 6-Hydroxy-7-methoxy-2-methylquinazolin-4(3H)-one (1.0 g, 4.85 mmol), (R)-1-BOC-3-methanesulfonyloxypyrrolidine (1.42 g, 5.34 mmol), and cesium carbonate (1.89 g, 5.82 mmol) were added to a 250 mL egg-shaped flask, followed by the addition of anhydrous N,N-dimethylformamide (10 mL). The mixture was stirred in an oil bath at 100 °C for 12 h. After the reaction was complete, the reaction solution was poured into 200 mL of saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate (2 x 50 mL), and the organic phases were combined. The mixture was washed with water (2 x 50 mL), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The crude product was purified by column chromatography (eluent (v / v): dichloromethane / methanol = 20:1) and evaporated to dryness to give the corresponding intermediate S2-2. NMR(500MHz,MeOD)δ7.62(d,J=3.5Hz,1H),7.10(d,J=2.4Hz,1H),5.21–5.13(m,1H),4.02(s,3H),3.71– 3.59(m,2H),3.58–3.45(m,2H),2.68(s,3H),2.28–2.19(m,2H),1.47(d,J=9.1Hz,9H).HRMS(ESI):calcd forC 19 H 25 N3O5[M + H] + ,376.1867;found,376.1866.

[0164] 2. Preparation of tert-butyl-(S)-3-((7-methoxy-2-methyl-4-(((2,4,6-triisopropylphenyl)sulfonyl)oxy)quinazolin-6-yl)oxypyrrolidine-1-carboxylate (S3-2)

[0165]

[0166] Intermediate S2-2 (600 mg, 1.60 mmol) was added to a 150 mL egg-shaped flask, followed by 20 mL of dichloromethane solvent. Triethylamine (668 μl, 4.80 mmol) and DMAP (19.5 mg, 0.16 mmol) were then added to the flask, and the mixture was stirred. Subsequently, 2,4,6-triisopropylbenzenesulfonyl chloride (726 mg, 2.40 mmol) was added, and the mixture was stirred at room temperature for 12 h. After the reaction was complete, silica gel was added to the reaction solution, and the solvent was removed by vacuum distillation. The crude product was purified by column chromatography (eluent (v / v): petroleum ether / ethyl acetate = 50%-70%), and then evaporated to dryness to obtain the corresponding intermediate S3-2. NMR(500MHz,DMSO)δ7.48(s,1H),7.11(s,1H),6.95(s,2H),5.17(d,J=7.6Hz,1H) ,4.56(p,J=6.9Hz,2H),3.92(s,3H),3.43(d,J=7.8Hz,2H),3.34–3.29(m,2H),2. 79(p,J=6.9Hz,1H),2.51(s,3H),2.22–2.13(m,1H),2.09(d,J=19.4Hz,1H),1.40 (d,J=8.8Hz,9H),1.16(d,J=7.0Hz,6H),1.10(d,J=6.8Hz,12H).HRMS(ESI):calcd for C 34 H 47 N3O7S[M + H] + ,642.3207found,642.3199.

[0167] 3. Preparation of N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-(((S)-pyrrolidine-3-yl)oxy)quinazolin-4-amine (S4-2)

[0168]

[0169] Compound S3-2 (900 mg, 1.40 mmol) was added to a 20 mL reaction flask, followed by 5 mL of dimethyl sulfoxide solvent, then triethylamine (977.0 μl, 7.00 mmol) and (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride (506 mg, 2.10 mmol). The mixture was stirred and heated to 90 °C for 12 h. After the reaction was complete, the reaction solution was poured into 100 mL of water, extracted with ethyl acetate (2 x 50 mL), the organic phases were combined, washed with water (2 x 30 mL), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The crude product was purified by column chromatography (eluent (v / v): dichloromethane / methanol = 20:1) and evaporated to dryness to obtain the corresponding tert-butanol ester intermediate. The corresponding tert-butanol ester intermediate was added to a 50 mL egg-shaped flask, followed by 10 mL of 1 M hydrochloric acid-methanol solution, and stirred at room temperature for 4 h. After the reaction was complete, the product was purified using a saturated sodium bicarbonate solution, extracted with dichloromethane, and the solution was removed by vacuum distillation. The crude product was then separated using a reverse-phase C18 column (eluent (v / v) acetonitrile / (water + 0.05% HCl) = 10%–100%), the reaction solvent was removed by vacuum distillation, and the product was lyophilized with water to obtain the target compound S4-2. NMR(500MHz,MeOD)δ8.32(s,1H),7.66(s,2H),7.33(s,1H),7.13(s,1H),5.87(q,J=7.0Hz,1H),5.52(s,1H),4.03(s ,3H),3.73–3.65(m,2H),3.58–3.53(m,2H),2.64(s,3H),2.47–2.39(m,2H),1.82(d,J=7.1Hz,3H).HRMS(ESI):calcd for C 23 H 26 F3N5O2[M + H] + ,462.2111found,462.2113.

[0170] Preparation of Group A SOS1 degrading agents

[0171] The general route is as follows:

[0172]

[0173] Example 3

[0174] Preparation of 3-(4-(2-(4-((((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)oxy)piperidin-1-yl)ethyl)thio)-1-oxoisoindol-2-yl)piperidin-2,6-dione (A1)

[0175]

[0176] Compound S4-1 (20 mg, 0.042 mmol) prepared in Example 1 and compound L1 (see patent CN111606883A, 19.34 mg, 0.05 mmol) were added to a 20 mL reaction flask. Anhydrous N,N-dimethylformamide (1.5 mL) was added, followed by N,N-diisopropylethylamine (20.86 μl, 0.12 equiv) and sodium iodide (3.78 mg, 0.048 equiv). The mixture was stirred at 80 °C for 12 h. After the reaction was completed, one drop of water was added to quench the reaction. The reaction solution was filtered and purified by preparative liquid chromatography (eluent (v / v) acetonitrile / (water + 0.05% HCl) = 10%-100%). The reaction solvent was removed by vacuum distillation, and the solution was lyophilized with water to obtain the target compound A1.

[0177] The results are as follows Figure 1 As shown, 1H NMR (500MHz, MeOD) δ8.31(d,J=43.9Hz,1H),7.84(dd,J=7.7,3.7Hz,1H),7.76(d,J=7.5Hz,1H),7.62(t,J=7.7Hz,1H),7.54(s,1H),7.40(d,J=8.6Hz, 1H),7.18(d,J=30.5Hz,1H),7.10(d,J=15.5Hz,1H),5.89–5.79(m,1H),5. 19(dd,J=13.3,5.1Hz,1H),5.01(d,J=3.7Hz,1H),4.60–4.47(m,2H),4.02( d,J=8.6Hz,3H),3.75(d,J=12.7Hz,1H),3.60–3.56(m,1H),3.53–3.47(m, 2H),3.45–3.37(m,4H),2.97–2.88(m,1H),2.83–2.76(m,1H),2.63(d,J=2. 8Hz,3H),2.60–2.44(m,2H),2.35–2.26(m,2H),2.23–2.18(m,1H),2.06–1 .98(m,1H),1.81(d,J=7.1Hz,1H),1.77(d,J=7.1Hz,2H).HRMS(ESI):calcd for C 39 H 42 F3N7O5S[M + H] + ,778.2993found,778.2997.

[0178] Example 4

[0179] Preparation of 3-(4-((3-(4-)((((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)oxy)piperidin-1-yl)propyl)thio)-1-oxoisoindol-2-yl)piperidin-2,6-dione (A2)

[0180]

[0181] Compound A2 was prepared according to the method for preparing A1 in Example 3, under suitable conditions as understood in the art, except that the ligand used was L2 (see patent CN 111606883 A).

[0182] The results are as follows Figure 2 As shown, 1H NMR (500MHz, MeOD) δ8.27(d,J=46.9Hz,1H),7.78–7.74(m,1H),7.73–7.69(m,1H),7.61–7.56(m,1H),7.38–7.32(m,1H),7.23(d,J=14. 4Hz,1H),7.08(d,J=18.1Hz,1H),7.01(d,1H),5.86–5.76(m,1H),5.22–5.15(m,1H),5.01–4.97(m,1H),4.56–4.42(m,2H),4.02(d,J=13 .4Hz,3H),3.71–3.64(m,1H),3.54–3.49(m,1H),3.38–3.32(m,4H),3.27–3.13(m,2H),2.96–2.87(m,1H),2.83–2.75(m,1H),2.63(d,J= 4.6Hz,3H),2.60–2.43(m,2H),2.34–2.29(m,1H),2.24–2.09(m,4H),2.04–1.93(m,1H),1.77(dd,J=22.4,7.1Hz,3H).HRMS(ESI):calcd for C 40 H 44 F3N7O5S[M + H] + ,792.3149found,792.3148.

[0183] Example 5

[0184] Preparation of 3-(4-(4-((4-(-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)oxy)piperidin-1-yl)butyl)thio)-1-oxoisoindol-2-yl)piperidin-2,6-dione (A3)

[0185]

[0186] Compound A3 was prepared according to the method for preparing A1 in Example 3, under suitable conditions as understood in the art, except that the ligand used was L3 (see patent CN 111606883 A).

[0187] The results are as follows Figure 3 As shown, 1H NMR(500MHz,MeOD)δ8.29(d,J=46.4Hz,1H),7.74–7.65(m,2H),7.55(t,J=7.6Hz,1H),7.40(d,J=11.1Hz,1H),7.29(d,J=13.4Hz,1H),7.13 –7.04(m,2H),5.86–5.78(m,1H),5.22–5.14(m,1H),5.03–4.99(m,1H),4.47(q,J=17.3Hz,2H),4.03(d,J=14.8Hz,3H),3.72–3.64(m,1H), 3.53–3.47(m,1H),3.37–3.33(m,1H),3.22–3.11(m,4H),2.96–2.86(m,1H),2.83–2.75(m,1H),2.63(d,J=3.8Hz,3H),2.60–2.42(m,2H),2 .34–2.29(m,1H),2.26–2.16(m,2H),2.05–1.89(m,3H),1.80(d,J=7.1Hz,1H),1.76(d,J=7.0Hz,3H),1.75–1.68(m,1H).HRMS(ESI):calcd for C 41 H 46 F3N7O5S[M + H] + ,806.3306found,806.3308.

[0188] Example 6

[0189] Preparation of 3-(4-(5-(4-((((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)oxy)piperidin-1-yl)pentyl)thio)-1-oxoisoindol-2-yl)piperidin-2,6-dione (A4)

[0190]

[0191] Compound A4 was prepared according to the method for preparing A1 in Example 3, under suitable conditions as understood in the art, except that the ligand used was L4 (see patent CN 111606883 A).

[0192] The results are as follows Figure 4 As shown, 1H NMR(500MHz,MeOD)δ8.30(d,J=44.4Hz,1H),7.69–7.64(m,2H),7.58–7.49(m,2H),7.38(d,J=9.8Hz,1H),7.19–7.07(m,2H),5.8 9–5.79(m,1H),5.21–5.15(m,1H),5.03–4.99(m,1H),4.50–4.40(m,2H),4.03(d,J=14.6Hz,3H),3.73–3.64(m,2H),3.53–3.49( m,1H),3.37–3.34(m,1H),3.18–3.10(m,4H),2.95–2.87(m,1H),2.79(ddt,J=17.7,4.9,2.5Hz,1H),2.63(d,J=3.1Hz,3H),2.59 –2.43(m,2H),2.34–2.29(m,1H),2.25–2.18(m,2H),2.05–1.93(m,1H),1.84–1.74(m,7H),1.60–1.54(m,2H).HRMS(ESI):calcd for C 42 H 48 F3N7O5S[M+H]+,820.3462found,820.3458.

[0193] Example 7

[0194] Preparation of 3-(4-(6-(4-((((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)oxy)piperidin-1-yl)hexyl)thio)-1-oxoisoindol-2-yl)piperidin-2,6-dione (A5)

[0195]

[0196] Compound A5 was prepared according to the method for preparing A1 in Example 3, under suitable conditions as understood in the art, except that the ligand used was L5 (see patent CN 111606883 A).

[0197] The results are as follows Figure 5 As shown, 1H NMR(500MHz,MeOD)δ8.25(d,J=29.8Hz,1H),7.72–7.59(m,2H),7.57–7.51(m ,1H),7.30–7.18(m,2H),7.10(d,J=13.1Hz,1H),6.97(d,J=21.6Hz,1H),5.8 7–5.77(m,1H),5.25–5.12(m,1H),5.00–4.96(m,1H),4.54–4.38(m,2H),4.0 3(d,J=13.8Hz,3H),3.63–3.47(m,2H),3.35–3.33(m,1H),3.30–3.16(m,1H) ,3.16–3.06(m,4H),2.96–2.84(m,1H),2.83–2.76(m,1H),2.64(d,J=1.4Hz, 3H),2.59–2.50(m,1H),2.48–2.41(m,1H),2.35–2.29(m,1H),2.23–2.16(m, 2H),1.95(dd,J=21.6,11.3Hz,1H),1.78–1.77(m,1H),1.75(d,J=7.3Hz,3H) ,1.73–1.63(m,3H),1.58–1.49(m,2H),1.45–1.38(m,2H).HRMS(ESI):calcd for C 43 H 50 F3N7O5S[M+H]+,834.3619found,834.3620.

[0198] Example 8

[0199] Preparation of 3-(4-(7-(4-((((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)oxy)piperidin-1-yl)heptyl)thio)-1-oxoisoindol-2-yl)piperidin-2,6-dione (A6)

[0200]

[0201] Compound A6 was prepared according to the method for preparing A1 in Example 3, under suitable conditions as understood in the art, except that the ligand used was L6 (see patent CN 111606883 A).

[0202] The results are as follows Figure 6 As shown, 1H NMR(500MHz,MeOD)δ8.28(d,1H),7.69–7.61(m,2H),7.56–7.50(m,1H),7.40(d ,J=11.8Hz,1H),7.31(d,J=12.1Hz,1H),7.13–7.03(m,2H),5.88–5.78(m,1H), 5.23–5.13(m,1H),5.04–4.96(m,1H),4.51–4.38(m,2H),4.03(d,J=14.5Hz,3H ),3.70–3.58(m,1H),3.55–3.47(m,1H),3.29–3.20(m,1H),3.17–3.13(m,2H),3 .12–3.03(m,2H),2.96–2.85(m,1H),2.78(ddd,J=17.7,4.7,2.4Hz,1H),2.64( d,J=1.8Hz,3H),2.59–2.45(m,2H),2.32(d,J=15.2Hz,1H),2.23–2.15(m,2H), 2.05–1.93(m,1H),1.79(d,J=7.0Hz,1H),1.76(d,J=7.0Hz,3H),1.71–1.67(m, 2H),1.53–1.47(m,2H),1.42–1.36(m,4H),1.35–1.27(m,4H).HRMS(ESI):calcd for C 44 H 52 F3N7O5S[M + H] + ,848.3775found,848.3773.

[0203] Example 9

[0204] Preparation of 3-(4-(8-(4-((((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)oxy)piperidin-1-yl)octyl)thio)-1-oxoisoindol-2-yl)piperidin-2,6-dione (A7)

[0205]

[0206] Compound A7 was prepared according to the method for preparing A1 in Example 3, under suitable conditions as understood in the art, except that the ligand used was L7 (see patent CN 111606883 A).

[0207] The results are as follows Figure 7 As shown, 1H NMR(500MHz,MeOD)δ8.33(d,J=39.0Hz,1H),7.66–7.60(m,2H),7.56–7.48(m,2H),7.41(d,1H),7.21–7.08(m,2H),5.89–5.78(m,1H),5.2 2–5.12(m,1H),5.05–4.99(m,1H),4.50–4.36(m,2H),4.03(d,J=15.2Hz,3H),3.71–3.62(m,1H),3.55–3.49(m,1H),3.38–3.33(m,1H),3. 18–3.03(m,4H),2.96–2.85(m,1H),2.83–2.75(m,1H),2.64(d,J=2.7Hz,3H),2.58–2.45(m,2H),2.36–2.29(m,1H),2.27–2.16(m,2H),2. 07–1.95(m,1H),1.81(d,J=7.0Hz,1H),1.78(d,J=7.0Hz,3H),1.70–1.64(m,2H),1.52–1.45(m,2H),1.38–1.29(m,8H).HRMS(ESI):calcd for C 45 H 54 F3N7O5S[M + H] + ,862.3932found,862.3935.

[0208] Example 10

[0209] Preparation of 3-(4-(9-(4-((((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)oxy)piperidin-1-yl)nonyl)thio)-1-oxoisoindol-2-yl)piperidin-2,6-dione (A8)

[0210]

[0211] Compound A8 was prepared according to the method for preparing A1 in Example 3, under suitable conditions as understood in the art, except that the ligand used was L8 (see patent CN 111606883 A).

[0212] The results are as follows Figure 8 As shown, 1H NMR(500MHz,MeOD)δ8.30(d,J=44.5Hz,1H),7.66–7.60(m,2H),7.55–7.50(m ,1H),7.39–7.29(m,1H),7.29–7.22(m,1H),7.14–7.00(m,2H),5.86–5.77(m, 1H),5.20–5.12(m,1H),5.04–4.96(m,1H),4.50–4.35(m,2H),4.03(d,J=14. 9Hz,3H),3.72–3.65(m,1H),3.56–3.50(m,1H),3.38–3.33(m,1H),3.19–3.13 (m,2H),3.10–3.01(m,2H),2.95–2.85(m,1H),2.82–2.74(m,1H),2.64(d,J= 3.3Hz,3H),2.59–2.44(m,2H),2.36–2.30(m,1H),2.28–2.21(m,1H),2.21–2. 15(m,1H),2.06–1.95(m,1H),1.79(d,J=7.1Hz,2H),1.76(d,J=7.1Hz,3H),1 .67(p,J=7.3Hz,2H),1.51–1.43(m,2H),1.40–1.26(m,9H).HRMS(ESI):calcd for C 46 H 56 F3N7O5S[M + H] + ,876.4088found,876.4091.

[0213] Example 11

[0214] Preparation of 3-(4-(10-(4-((((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)oxy)piperidin-1-yl)decyl)thio)-1-oxoisoindol-2-yl)piperidin-2,6-dione (A9)

[0215]

[0216] Compound A9 was prepared according to the method for preparing A1 in Example 3, under suitable conditions as understood in the art, except that the ligand used was L9 (see patent CN 111606883 A).

[0217] The results are as follows Figure 9As shown, 1H NMR (500MHz, MeOD) δ8.35(d,J=34.3Hz,1H),7.61(d,J=7.4Hz,2H),7.57–7.48(m,2H),7.44(d,J=14.7Hz,1H),7.22–7.09(m,2H),5.83(dd,J=12.7,6. 7Hz,1H),5.16(dd,J=11.8,5.7Hz,1H),5.05(s,1H),4.50–4.36(m,2H),4. 03(d,J=17.4Hz,3H),3.74–3.64(m,1H),3.58–3.49(m,1H),3.35(s,1H),3. 20–3.13(m,2H),3.09–3.01(m,2H),2.97–2.85(m,1H),2.83–2.74(m,1H), 2.64(d,J=3.2Hz,3H),2.58–2.44(m,2H),2.36–2.24(m,2H),2.22–2.16(m, 1H),2.09–1.97(m,1H),1.82(d,J=7.0Hz,1H),1.78(d,J=7.1Hz,3H),1.66 (p,J=7.1Hz,2H),1.52–1.43(m,2H),1.41–1.21(m,12H).HRMS(ESI):calcd for C 47 H 58 F3N7O5S[M + H] + ,890.4245found,890.4238.

[0218] Example 12

[0219] Preparation of 3-(4-(11-(4-((((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)oxy)piperidin-1-yl)undecyl)thio)-1-oxoisoindol-2-yl)piperidin-2,6-dione (A10)

[0220]

[0221] Compound A10 was prepared according to the method for preparing A1 in Example 3, under suitable conditions as understood in the art, except that the ligand used was L10 (see patent CN 111606883 A).

[0222] The results are as follows Figure 10As shown, 1H NMR(500MHz,MeOD)δ8.22(d,J=43.1Hz,1H),7.63(d,J=7.2Hz,2H),7.52(t, J=7.6Hz,1H),7.23–7.06(m,3H),6.94(d,J=12.5Hz,1H),5.83–5.76(m,1H), 5.19–5.13(m,1H),4.99–4.96(m,1H),4.48–4.37(m,2H),4.04(d,J=13.6Hz ,3H),3.74–3.67(m,1H),3.56–3.52(m,1H),3.40–3.35(m,1H),3.28–3.22(m ,1H),3.19–3.15(m,2H),3.09–3.03(m,2H),2.95–2.85(m,1H),2.81–2.75( m,1H),2.64(d,J=3.2Hz,3H),2.58–2.44(m,2H),2.36–2.31(m,1H),2.24–2. 16(m,2H),2.05–1.95(m,1H),1.77(d,J=7.1Hz,2H),1.74(d,J=7.1Hz,3H), 1.69–1.64(m,2H),1.48–1.43(m,2H),1.39–1.30(m,12H).HRMS(ESI):calcd for C 48 H 60 F3N7O5S[M + H] + ,904.4401found,904.4402.

[0223] Example 13

[0224] Preparation of 3-(4-((12-(4-(-((((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)oxy)piperidin-1-yl)dodecyl)thio)-1-oxoisoindol-2-yl)piperidin-2,6-dione (A11)

[0225]

[0226] Compound A11 was prepared according to the method of preparation of A1 in Example 3, under suitable conditions as understood in the art, except that the ligand used was L11 (see patent CN 111606883 A).

[0227] The results are as follows Figure 11As shown, 1H NMR(500MHz,MeOD)δ8.32(d,J=40.3Hz,1H),7.60(dd,J=7.7,3.4Hz,2H),7.50(t,J =7.7Hz,1H),7.42(d,J=15.6Hz,1H),7.32(d,J=18.4Hz,1H),7.16–7.05(m,2H),5. 86–5.76(m,1H),5.21–5.12(m,1H),5.07–4.99(m,1H),4.46–4.36(m,2H),4.03(d, J=17.2Hz,3H),3.73–3.66(m,1H),3.57–3.49(m,1H),3.37–3.34(m,1H),3.21–3.1 4(m,2H),3.05(t,J=7.2Hz,2H),2.96–2.88(m,1H),2.89–2.85(m,1H),2.82–2.75( m,1H),2.64(d,J=3.7Hz,3H),2.58–2.45(m,2H),2.35–2.24(m,2H),2.21–2.15(m, 1H),2.09–1.96(m,1H),1.81(d,J=7.1Hz,2H),1.77(d,J=7.1Hz,3H),1.69–1.63(m ,2H),1.49–1.43(m,2H),1.41–1.36(m,4H),1.33–1.28(m,10H).HRMS(ESI):calcd for C 49 H 62 F3N7O5S[M + H] + ,918.4558found,918.4551.

[0228] Preparation of Group B Degrading Agents

[0229] The general route is as follows:

[0230]

[0231] Example 14

[0232] Preparation of 3-(4-(2-(4-((((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)oxy)piperidin-1-yl)-2-oxoethyl)thio)-1-oxoisoindol-2-yl)piperidin-2,6-dione (B1)

[0233]

[0234] Compound L12 (see patent CN 111606883 A, 16.6 mg, 0.046 mmol) was added to a 20 mL reaction flask, followed by anhydrous N,N-dimethylformamide (1.5 mL), then N,N-diisopropylethylamine (20.86 μl, 0.126 mmol) and HATU (24 mg, 0.063 mmol). The mixture was stirred at room temperature for 30 min to activate the compound. Then, compound S4-1 (20 mg, 0.042 mmol) prepared in Example 1 was added, and the mixture was stirred at room temperature for 12 h. After the reaction was complete, a drop of water was added to quench the reaction. The reaction solution was filtered and purified by preparative liquid chromatography (eluent (v / v) acetonitrile / (water + 0.05% HCl) = 10%-100%). The reaction solvent was removed under reduced pressure, and the mixture was lyophilized with water to obtain the target compound B1.

[0235] The results are as follows Figure 12 As shown, 1H NMR(500MHz,MeOD)δ8.06(dd,J=6.2,3.7Hz,1H),7.80(dd,J=7.8,2.4Hz,1H),7.74(dd,J=7.8,3.0Hz,1H),7.61(d d,J=7.5,4.7Hz,1H),7.31(d,J=6.6Hz,2H),7.11–7.07(m,2H),5.82(q,J=7.0Hz,1H),5.20–5.11(m,2H),4.53–4. 40(m,2H),4.03(d,J=1.5Hz,3H),3.85–3.76(m,2H),3.65–3.52(m,2H),3.35–3.32(m,2H),2.96–2.86(m,2H),2.8 4–2.76(m,2H),2.63(s,3H),2.59–2.45(m,2H),2.22–2.15(m,2H),1.75(dd,J=7.1,2.1Hz,3H).HRMS(ESI):calcd for C 39 H 40 F3N7O6S[M + H] + ,792.2786found,792.2788.

[0236] Example 15

[0237] Preparation of 3-(4-((3-(4-)((((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)oxy)piperidin-1-yl)-3-oxopropyl)thio)-1-oxoisoindol-2-yl)piperidin-2,6-dione (B2)

[0238]

[0239] Compound B2 was prepared according to the method for preparing B1 in Example 14, under suitable conditions as understood in the art, except that the ligand used was L13 (see patent CN 111606883 A).

[0240] The results are as follows Figure 13 As shown, 1H NMR(500MHz,MeOD)δ8.00(dd,J=5.6,2.1Hz,1H),7.71(d,J=7.7Hz,1H),7.67(d,J=7.5Hz,1H),7.55(t,J=2.3Hz,1H),7.08(s,1H),6 .99(t,J=2.0Hz,1H),6.97(s,1H),6.83(d,J=2.0Hz,1H),5.76(q,J=3.0Hz,1H),5.22–5.10(m,2H),4.51–4.41(m,2H),4.01(s,3H), 3.86–3.79(m,1H),3.77–3.65(m,1H),3.63–3.53(m,1H),3.50–3.40(m,1H),3.38–3.32(m,2H),2.93–2.86(m,1H),2.82–2.75(m,3H ),2.63(s,3H),2.59–2.49(m,1H),2.22–2.15(m,1H),2.04–1.92(m,2H),1.85–1.73(m,2H),1.71(d,J=7.1Hz,3H).HRMS(ESI):calcd for C 40 H 42 F3N7O6S[M + H] + ,806.2942found,806.2941.

[0241] Example 16

[0242] Preparation of 3-(4-(4-((4-(-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)oxy)piperidin-1-yl)-4-oxobutyl)thio)-1-oxoisoindol-2-yl)piperidin-2,6-dione (B3)

[0243]

[0244]

[0245] Compound B3 was prepared according to the method for preparing B1 in Example 14, under suitable conditions as understood in the art, except that the ligand used was L14 (see patent CN 111606883 A).

[0246] The results are as follows Figure 14 As shown, 1H NMR (500MHz, MeOD) δ8.17(d,J=4.9Hz,1H),7.70–7.66(m,3H),7.61(d,J=7.3Hz,1H),7.51(td,J=7.6,3.1Hz,1H),7.37(s,1H),7.11( s,1H),5.87(q,J=7.2Hz,1H),5.14(dd,J=13.0,4.6Hz,1H),4.96(s,1H),4.48–4.38(m,2H),4.02(s,3H),3.93–3.85(m,1H),3.79–3. 71(m,1H),3.60–3.47(m,2H),3.15–3.09(m,2H),2.94–2.84(m,1H),2.81–2.74(m,1H),2.63(s,3H),2.61–2.56(m,2H),2.51(td,J=1 3.2,5.7Hz,1H),2.21–2.15(m,1H),2.06–2.00(m,2H),1.99–1.93(m,2H),1.81(d,J=6.2Hz,3H),1.78–1.70(m,2H).HRMS(ESI):calcd for C 41 H 44 F3N7O6S[M + H] + ,820.3099found,820.3103.

[0247] Example 17

[0248] Preparation of 3-(4-(5-(4-((((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)oxy)piperidin-1-yl)-5-oxopentyl)thio)-1-oxoisoindol-2-yl)piperidin-2,6-dione (B4)

[0249]

[0250] Compound B4 was prepared according to the method for preparing B1 in Example 14, under suitable conditions as understood in the art, except that the ligand used was L15 (see patent CN 111606883 A).

[0251] The results are as follows Figure 15 As shown, 1H NMR(500MHz,MeOD)δ8.08(dd,1H),7.63(dd,J=14.9,7.6Hz,2H),7.51(t,J=7.6Hz,1H),7.33–7.26(m,2H),7.12–7.04(m,2H),5. 81(q,J=7.0Hz,1H),5.18–5.10(m,2H),4.51–4.37(m,2H),4.04–4.00(m,3H),3.82(dd,J=30.9,14.8Hz,2H),3.60–3.48(m,2H), 3.15–3.04(m,2H),2.88(qd,J=14.4,7.0Hz,2H),2.76(ddt,J=17.6,4.6,2.5Hz,2H),2.63(s,3H),2.56–2.48(m,1H),2.45(t,J= 7.1Hz,2H),2.22–2.14(m,1H),2.08–1.87(m,2H),1.84–1.79(m,1H),1.76(d,J=5.6Hz,3H),1.75–1.69(m,3H).HRMS(ESI):calcd for C 42 H 46 F3N7O6S[M + H] + ,834.3255found,834.3257.

[0252] Example 18

[0253] Preparation of 3-(4-((6-(4-(4-(-((((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)oxy)piperidin-1-yl)-6-oxohexyl)thio)-1-oxoisoindol-2-yl)piperidin-2,6-dione (B5)

[0254]

[0255] Compound B5 was prepared according to the method for preparing B1 in Example 14, under suitable conditions as understood in the art, except that the ligand used was L16 (see patent CN 111606883 A).

[0256] The results are as follows Figure 16As shown, 1H NMR (500MHz, MeOD) δ8.13(d,J=6.7Hz,1H),7.63–7.57(m,2H),7.50(d,J=7.4Hz,1H),7.38(d,J=14.4Hz,2H),7.12(d,J=11 .9Hz,2H),5.82(q,J=6.9Hz,1H),5.18–5.11(m,2H),4.47–4.37(m,2H),4.01(s,3H),3.92–3.84(m,1H),3.82–3.72(m,1H), 3.59–3.45(m,4H),3.08–3.02(m,2H),2.92–2.85(m,1H),2.80–2.72(m,1H),2.63(s,3H),2.57–2.47(m,1H),2.44–2.36(m ,2H),2.22–2.14(m,1H),2.09–1.96(m,2H),1.77(d,J=7.0Hz,3H),1.69–1.60(m,4H),1.54–1.47(m,2H).HRMS(ESI):calcd forC 43 H 48 F3N7O6S[M + H] + ,848.3412found,848.3410.

[0257] Example 19

[0258] Preparation of 3-(4-(7-(4-((((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)oxy)piperidin-1-yl)-7-oxoheptyl)thio)-1-oxoisoindol-2-yl)piperidin-2,6-dione (B6)

[0259]

[0260] Compound B6 was prepared according to the method for preparing B1 in Example 14, under suitable conditions as understood in the art, except that the ligand used was L17 (see patent CN 111606883 A).

[0261] The results are as follows Figure 17As shown, 1H NMR(500MHz,MeOD)δ8.11(dd,J=5.7,2.8Hz,1H),7.65–7.55(m,2H),7.50(t,J=7.0Hz,1H),7.25(d,J=15.5Hz,2H),7.10(s,1H),7.05–6. 99(m,1H),5.80(q,J=7.0Hz,1H),5.19–5.09(m,1H),4.47–4.38(m,2H),4.02(s,3H),3.91–3.75(m,2H),3.61–3.47(m,2H),3.10–3.02(m ,2H),2.93–2.82(m,1H),2.81–2.73(m,1H),2.64(s,3H),2.56–2.48(m,1H),2.40(d,J=7.7Hz,2H),2.21–2.14(m,1H),2.08–1.97(m,2H) ,1.86–1.79(m,1H),1.75(d,J=7.1Hz,3H),1.71–1.64(m,2H),1.61–1.56(m,2H),1.52–1.46(m,2H),1.40–1.27(m,4H).HRMS(ESI):calcd for C 44 H 50 F3N7O6S[M + H] + ,862.3568found,862.3563.

[0262] Example 20

[0263] Preparation of 3-(4-(8-(4-((((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)oxy)piperidin-1-yl)-8-oxooctyl)thio)-1-oxoisoindol-2-yl)piperidin-2,6-dione (B7)

[0264]

[0265] Compound B7 was prepared according to the method for preparing B1 in Example 14, under suitable conditions as understood in the art, except that the ligand used was L18 (see patent CN 111606883 A).

[0266] The results are as follows Figure 18As shown, 1H NMR(500MHz,MeOD)δ8.10(dd,1H),7.65–7.56(m,2H),7.54–7.46(m,1H),7.27–7.18(m,2H),7.09(s,1H),7.03–6.98(m,1H),5.80(q . 83(m,1H),2.82–2.74(m,1H),2.63(s,3H),2.58–2.47(m,1H),2.41(t,J=7.6Hz,2H),2.21–2.14(m,1H),2.10–1.96(m,2H),1.81(d, J=30.5Hz,2H),1.74(d,J=7.1Hz,3H),1.70–1.63(m,2H),1.62–1.55(m,2H),1.51–1.44(m,2H),1.38–1.32(m,4H).HRMS(ESI):calcd for C 45 H 52 F3N7O6S[M + H] + ,876.3725found,876.3721.

[0267] Example 21

[0268] Preparation of 3-(4-((9-(4-(4-(-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)oxy)piperidin-1-yl)-9-oxonononyl)thio)-1-oxoisoindol-2-yl)piperidin-2,6-dione (B8)

[0269]

[0270] Compound B8 was prepared according to the method for preparing B1 in Example 14, under suitable conditions as understood in the art, except that the ligand used was L19 (see patent CN 111606883 A).

[0271] The results are as follows Figure 19As shown, 1H NMR(500MHz,MeOD)δ8.10(dd,1H),7.64–7.56(m,2H),7.53–7.44(m,3H),7.22(d,J=8.0Hz,1H),7.07(d,J=2.8Hz,1H),5.84(q,J=7.0Hz,1H),5 .19–5.11(m,1H),4.94–4.90(m,1H),4.47–4.37(m,2H),4.02(s,3H),3. 83(q,J=12.8Hz,2H),3.62–3.51(m,2H),3.10–3.02(m,2H),2.94–2.84( m,1H),2.81–2.74(m,1H),2.63(s,3H),2.58–2.47(m,1H),2.42(dt,J= 11.8,5.5Hz,2H),2.22–2.14(m,1H),2.09(d,J=4.1Hz,1H),2.06–1.98( m,1H),1.91–1.79(m,2H),1.77(d,J=7.1Hz,3H),1.70–1.64(m,2H),1.62–1.56(m,2H),1.50–1.44(m,2H),1.37–1.32(m,6H).HRMS(ESI):calcd for C 46 H 54 F3N7O6S[M + H] + ,890.3881found,890.3889.

[0272] Example 22

[0273] Preparation of 3-(4-(10-(4-((((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)oxy)piperidin-1-yl)-10-oxodecyl)thio)-1-oxoisoindol-2-yl)piperidin-2,6-dione (B9)

[0274]

[0275] Compound B9 was prepared according to the method for preparing B1 in Example 14, under suitable conditions as understood in the art, except that the ligand used was L20 (see patent CN 111606883 A).

[0276] The results are as follows Figure 20As shown, 1H NMR(500MHz,MeOD)δ8.04(dd,1H),7.59(d,J=6.9Hz,2H),7.51–7.46(m,1H) ,7.07(d,J=6.7Hz,1H),6.99(d,J=18.7Hz,2H),6.82(s,1H),5.76(q,1H),5 .19–5.10(m,1H),4.66–4.59(m,1H),4.45–4.35(m,2H),4.01(s,3H),3.89– 3.79(m,2H),3.61–3.52(m,2H),3.04(t,J=7.2Hz,2H),2.94–2.84(m,1H),2 .83–2.74(m,1H),2.63(s,3H),2.57–2.48(m,1H),2.45–2.39(m,2H),2.21– 2.14(m,1H),2.12–2.06(m,1H),2.04–1.98(m,1H),1.87–1.83(m,1H),1.81 –1.76(m,1H),1.72(d,J=7.0Hz,3H),1.68–1.63(m,2H),1.61–1.56(m,2H), 1.48–1.43(m,2H),1.41–1.36(m,2H),1.34–1.30(m,6H).HRMS(ESI):calcd for C 47 H 56 F3N7O6S[M + H] + ,904.4038found,904.4037.

[0277] Example 23

[0278] Preparation of 3-(4-(11-(4-((((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)oxy)piperidin-1-yl)-11-oxoundecyl)thio)-1-oxoisoindol-2-yl)piperidin-2,6-dione (B10)

[0279]

[0280] Compound B10 was prepared according to the method for preparing B1 in Example 14, under suitable conditions as understood in the art, except that the ligand used was L21 (see patent CN 111606883 A).

[0281] The results are as follows Figure 21As shown, 1H NMR(500MHz,MeOD)δ8.11(d,J=4.9Hz,1H),7.59–7.53(m,2H),7.50–7.43(m,1H), 7.25(d,J=1.9Hz,1H),7.22(d,J=2.7Hz,1H),7.09(s,1H),7.01(d,J=1.9Hz,1H), 5.79(q,J=7.0Hz,1H),5.14(dd,J=13.3,5.2Hz,1H),4.93–4.91(m,1H),4.44–4.3 4(m,2H),4.01(s,3H),3.94–3.86(m,1H),3.86–3.79(m,1H),3.61–3.53(m,2H),3 .02(t,J=6.5Hz,2H),2.93–2.84(m,1H),2.81–2.74(m,1H),2.63(s,3H),2.56–2. 47(m,1H),2.45–2.38(m,2H),2.21–2.14(m,1H),2.14–2.06(m,1H),2.06–1.98(m ,1H),1.88–1.82(m,1H),1.80–1.77(m,1H),1.75(d,J=7.0Hz,3H),1.67–1.62(m, 2H),1.62–1.57(m,2H),1.48–1.41(m,2H),1.35–1.28(m,10H).HRMS(ESI):calcd for C 48 H 58 F3N7O6S[M + H] + ,918.4194found,918.4195.

[0282] Example 24

[0283] Preparation of 3-(4-((12-((((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)oxy)piperidin-1-yl)-12-oxododecyl)thio)-1-oxoisoindol-2-yl)piperidin-2,6-dione (B11)

[0284]

[0285] Compound B11 was prepared according to the method for preparing B1 in Example 14, under suitable conditions as understood in the art, except that the ligand used was L22 (see patent CN 111606883 A).

[0286] The results are as follows Figure 22As shown, 1H NMR(500MHz,MeOD)δ8.04(dd,J=5.0Hz,1H),7.61–7.58(m,2H),7.49(q,J=6 .1Hz,1H),7.20–7.14(m,2H),7.07(d,J=2.9Hz,1H),6.99(s,1H),5.79(q,J= 6.3Hz,1H),5.15(dd,J=13.4,5.1Hz,1H),4.45–4.36(m,2H),4.02(s,3H),3 .88–3.79(m,2H),3.63–3.53(m,2H),3.04(t,J=7.2Hz,2H),2.94–2.85(m,1H ),2.81–2.75(m,1H),2.63(s,3H),2.57–2.48(m,1H),2.47–2.39(m,2H),2. 21–2.14(m,1H),2.12–2.05(m,1H),2.04–1.98(m,1H),1.91–1.83(m,1H),1. 82–1.76(m,1H),1.74(d,J=7.1Hz,3H),1.69–1.64(m,2H),1.63–1.58(m,2H) ,1.48–1.43(m,2H),1.37–1.33(m,4H),1.32–1.29(m,8H).HRMS(ESI):calcd for C 49 H 60 F3N7O6S[M + H] + ,932.4531found,932.4535.

[0287] Preparation of Group C degradation agent

[0288] Example 25

[0289] Preparation of 3-(4-(2-((S)-3-((4-((((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)oxy)pyrrolidine-1-yl)ethyl)thio)-1-oxoisoindol-2-yl)piperidine-2,6-dione (C1)

[0290]

[0291] Compound C1 was prepared according to the method for preparing A1 in Example 3, under suitable conditions as understood in the art, except that the substrate used was S4-2 prepared in Example 2.

[0292] The results are as follows Figure 23As shown, 1H NMR(500MHz,MeOD)δ8.19(d,J=15.8Hz,1H),7.85–7.71(m,2H),7.60(dd,J=17.4,9.5Hz,1H),7.29(d, J=12.7Hz,2H),7.12–7.02(m,2H),5.81(q,J=7.0Hz,1H),5.45(s,1H),5.19(dd,J=13.3,5.2Hz,1H),4 .52(q,J=17.4Hz,2H),4.08–3.90(m,5H),3.64–3.37(m,7H),2.92(ddd,J=18.5,13.6,5.4Hz,1H),2.8 1–2.76(m,1H),2.64(s,3H),2.58–2.44(m,2H),2.19(s,1H),1.77(d,J=7.1Hz,3H).HRMS(ESI):calcd forC 38 H 40 F3N7O5S[M + H] + ,764.2836found,764.2835.

[0293] Example 26

[0294] Preparation of 3-(4-(3-((S)-3-((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)oxy)pyrrolidine-1-yl)propyl)thio)-1-oxoisoindol-2-yl)piperidin-2,6-dione (C2)

[0295]

[0296] Compound C2 was prepared according to the method for preparing A2 in Example 4, under suitable conditions as understood in the art, except that the substrate used was S4-2 prepared in Example 2.

[0297] The results are as follows Figure 24As shown, 1H NMR(500MHz,MeOD)δ8.24(dd,1H),7.77–7.62(m,2H),7.60–7.50(m,1H),7.48–7.40(m,2H),7.13(d,J=21.0Hz,2H ),5.83(q,J=6.9Hz,1H),5.52–5.45(m,1H),5.22–5.12(m,1H),4.56–4.40(m,2H),4.02(d,3H),4.01–3.96(m,1H) ,3.94–3.82(m,1H),3.70–3.56(m,1H),3.56–3.40(m,3H),3.39–3.32(m,1H),3.26–3.13(m,2H),2.97–2.85(m,1H ),2.81–2.75(m,1H),2.64(d,J=6.0Hz,3H),2.58–2.40(m,2H),2.20–2.05(m,3H),1.80(d,3H).HRMS(ESI):calcd for C 39 H 42 F3N7O5S[M + H] + ,778.2993found,778.2998.

[0298] Example 27

[0299] Preparation of 3-(4-(4-((S)-3-((4-(R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)oxy)pyrrolidine-1-yl)butyl)thio)-1-oxoisoindol-2-yl)piperidin-2,6-dione (C3)

[0300]

[0301] Compound C3 was prepared according to the method for preparing A3 in Example 5, under suitable conditions as understood in the art, except that the substrate used was S4-2 prepared in Example 2.

[0302] The results are as follows Figure 25As shown, 1H NMR(500MHz,MeOD)δ8.24(dd,1H),7.77–7.62(m,2H),7.60–7.50(m,1H),7.48–7.40(m,2H),7.13(d,J=21.0Hz,2H ),5.83(q,J=6.9Hz,1H),5.52–5.45(m,1H),5.22–5.12(m,1H),4.56–4.40(m,2H),4.02(d,3H),4.01–3.96(m,1H) ,3.94–3.82(m,1H),3.70–3.56(m,1H),3.56–3.40(m,3H),3.39–3.32(m,1H),3.26–3.13(m,2H),2.97–2.85(m,1H ),2.81–2.75(m,1H),2.64(d,J=6.0Hz,3H),2.58–2.40(m,2H),2.20–2.05(m,3H),1.80(d,3H).HRMS(ESI):calcd for C 39 H 42 F3N7O5S[M + H] + ,778.2993found,778.2998.

[0303] Example 28

[0304] Preparation of 3-(4-(5-((S)-3-((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)oxy)pyrrolidine-1-yl)pentyl)thio)-1-oxoisoindol-2-yl)piperidin-2,6-dione (C4)

[0305]

[0306] Compound C4 was prepared according to the method for preparing A4 in Example 6, under suitable conditions as understood in the art, except that the substrate used was S4-2 prepared in Example 2.

[0307] The results are as follows Figure 26As shown, 1H NMR(500MHz,MeOD)δ8.26(dd,1H),7.68–7.62(m,2H),7.58–7.51(m,3H),7.27–7.23(m,1H),7.12–7.08(m,1H),5.86(q,J=7.1Hz,1H),5. 52–5.46(m,1H),5.20–5.14(m,1H),4.47(d,J=17.3Hz,1H),4.45–4.41(m,1H),4.40(d,1H),4.05–3.96(m,4H),3.93–3.82(m,1H),3.63–3 .52(m,1H),3.46–3.39(m,1H),3.29–3.23(m,2H),3.18–3.02(m,3H),2.95–2.87(m,1H),2.83–2.74(m,2H),2.64(d,J=2.4Hz,3H),2.58– 2.43(m,2H),2.34(dt,J=14.9,7.4Hz,1H),2.22–2.15(m,1H),1.83–1.80(m,3H),1.79–1.69(m,4H),1.61–1.55(m,2H).HRMS(ESI):calcd for C 41 H 46 F3N7O5S[M + H] + ,806.3306found,806.3309.

[0308] Example 29

[0309] Preparation of 3-(4-(6-((S)-3-((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)oxy)pyrrolidine-1-yl)hexyl)thio)-1-oxoisoindol-2-yl)piperidin-2,6-dione (C5)

[0310]

[0311] Compound C5 was prepared according to the method for preparing A5 in Example 7, under suitable conditions as understood in the art, except that the substrate used was S4-2 prepared in Example 2.

[0312] The results are as follows Figure 27As shown, 1H NMR(500MHz,MeOD)δ8.22(dd,J=5.9,3.1Hz,1H),7.69–7.62(m,2H),7.56–7 .49(m,1H),7.43(s,2H),7.15(s,1H),7.12–7.09(m,1H),5.84(q,J=7.3Hz, 1H),5.49–5.43(m,1H),5.19–5.12(m,1H),4.47(d,1H),4.46–4.42(m,1H), 4.40(d,J=8.3Hz,1H),4.03(d,J=4.1Hz,3H),3.99–3.80(m,2H),3.58–3.50( m,1H),3.46–3.33(m,1H),3.25–3.14(m,2H),3.14–3.02(m,2H),2.94–2.85 (m,1H),2.84–2.69(m,2H),2.66–2.63(m,3H),2.58–2.49(m,1H),2.47–2.41 (m,1H),2.34(dt,J=14.4,7.3Hz,1H),2.22–2.15(m,1H),1.84–1.78(m,3H) ,1.75–1.66(m,4H),1.57–1.49(m,2H),1.45–1.38(m,2H).HRMS(ESI):calcd for C 42 H 48 F3N7O5S[M + H] + ,820.3462found,820.3458.

[0313] Example 30

[0314] Preparation of 3-(4-(7-((S)-3-((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)oxy)pyrrolidine-1-yl)heptyl)thio)-1-oxoisoindol-2-yl)piperidin-2,6-dione (C6)

[0315]

[0316] Compound C6 was prepared according to the method for preparing A6 in Example 8, under suitable conditions as understood in the art, except that the substrate used was S4-2 prepared in Example 2.

[0317] The results are as follows Figure 28As shown, 1H NMR(500MHz,MeOD)δ8.23(d,J=10.9Hz,1H),7.67–7.60(m,2H),7.55–7.43( m,3H),7.18(s,1H),7.12–7.08(m,1H),5.84(q,J=7.0Hz,1H),5.50–5.43(m ,1H),5.19–5.13(m,1H),4.49–4.37(m,2H),4.03(d,J=8.7Hz,3H),4.02–3. 93(m,1H),3.91–3.80(m,1H),3.61–3.51(m,1H),3.46–3.35(m,1H),3.24(d t,J=10.6,5.6Hz,1H),3.12–3.01(m,2H),2.94–2.86(m,1H),2.80(dd,J=4. 7,2.3Hz,1H),2.79–2.74(m,1H),2.64(d,J=1.6Hz,3H),2.59–2.41(m,2H), 2.39–2.30(m,1H),2.22–2.14(m,1H),1.79(dt,J=7.2,1.4Hz,3H),1.70(dt ,J=14.6,7.6Hz,4H),1.50(s,2H),1.39(q,J=3.5Hz,4H).HRMS(ESI):calcd for C 43 H 50 F3N7O5S[M + H] + ,834.3619found,834.3614.

[0318] Example 31

[0319] Preparation of 3-(4-(8-((S)-3-((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)oxy)pyrrolidine-1-yl)octyl)thio)-1-oxoisoindol-2-yl)piperidin-2,6-dione (C7)

[0320]

[0321] Compound C7 was prepared according to the method for preparing A7 in Example 9, under suitable conditions as understood in the art, except that the substrate used was S4-2 prepared in Example 2.

[0322] The results are as follows Figure 29As shown, 1H NMR(500MHz,MeOD)δ8.33(d,J=11.2Hz,1H),7.81–7.71(m,2H),7.66–7.58(m, 2H),7.55–7.49(m,1H),7.41(s,1H),7.17–7.09(m,1H),5.88(q,J=7.3Hz,1H) ,5.61–5.46(m,1H),5.21–5.10(m,1H),4.45(d,1H),4.43–4.41(m,1H),4.39( d,J=17.3Hz,1H),4.03(s,3H),4.02–3.95(m,1H),3.92–3.82(m,1H),3.68–3.5 4(m,1H),3.53–3.37(m,1H),3.28–3.21(m,1H),3.14–3.00(m,2H),2.97–2.86 (m,1H),2.86–2.69(m,2H),2.64(s,3H),2.59–2.43(m,2H),2.40–2.29(m,1H) ,2.24–2.13(m,1H),1.83(d,J=6.7Hz,3H),1.80–1.72(m,2H),1.70–1.63(m,2 H),1.51–1.44(m,2H),1.37–1.33(m,4H),1.23–1.21(m,2H).HRMS(ESI):calcd for C 44 H 52 F3N7O5S[M + H] + ,848.3775found,848.3778.

[0323] Example 32

[0324] Preparation of 3-(4-((9-((S)-3-((4-(-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazoline-6-yl)oxy)pyrrolidine-1-yl)nonyl)thio)-1-oxoisoindol-2-yl)piperidin-2,6-dione (C8)

[0325]

[0326] Compound C8 was prepared according to the method for preparing A8 in Example 10, under suitable conditions as understood in the art, except that the substrate used was S4-2 prepared in Example 2.

[0327] The results are as follows Figure 30As shown, 1H NMR(500MHz,MeOD)δ8.30(d,J=12.1Hz,1H),7.65–7.57(m,2H),7.56–7.43(m,3H),7.22–7.09(m,2H),5.83(q,J=6.8Hz,1H),5.56– 5.47(m,1H),5.19–5.11(m,1H),4.47–4.35(m,2H),4.03(s,3H),3.92–3.82(m,1H),3.67–3.50(m,1H),3.48–3.35(m,1H),3.21(q,J =7.3Hz,3H),3.10–3.01(m,2H),2.96–2.70(m,3H),2.64(s,3H),2.58–2.43(m,2H),2.40–2.29(m,1H),2.23–2.14(m,1H),1.80(d, J=6.4Hz,3H),1.70–1.62(m,2H),1.49–1.43(m,2H),1.34–1.32(m,7H),1.31–1.27(m,3H),1.22(d,J=6.3Hz,1H).HRMS(ESI):calcd for C 45 H 54 F3N7O5S[M + H] + ,862.3932found,862.3929.

[0328] Example 33

[0329] Preparation of 3-(4-((10-((S)-3-((4-(-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazoline-6-yl)oxy)pyrrolidine-1-yl)decyl)thio)-1-oxoisoindol-2-yl)piperidin-2,6-dione (C9)

[0330]

[0331] Compound C9 was prepared according to the method for preparing A9 in Example 11, under suitable conditions as understood in the art, except that the substrate used was S4-2 prepared in Example 2.

[0332] The results are as follows Figure 31As shown, 1H NMR(500MHz,MeOD)δ8.18(d,J=4.1Hz,1H),7.66–7.61(m,2H),7.55–7.49( m,1H),7.31–7.23(m,2H),7.10(d,J=4.7Hz,1H),7.03(s,1H),5.82(q,J=7 .0Hz,1H),5.48–5.42(m,1H),5.16(dd,J=13.4,5.1Hz,1H),4.49–4.35(m, 2H),4.03(d,J=3.6Hz,3H),4.02–3.97(m,1H),3.94–3.82(m,1H),3.60–3.5 3(m,1H),3.47–3.40(m,1H),3.27–3.23(m,1H),3.10–3.02(m,2H),2.95–2 .85(m,1H),2.81–2.78(m,1H),2.78–2.74(m,1H),2.64(s,3H),2.58–2.42 (m,2H),2.41–2.29(m,1H),2.23–2.14(m,1H),1.77(d,J=7.1Hz,3H),1.69–1.63(m,2H),1.49–1.43(m,2H),1.40–1.28(m,12H).HRMS(ESI):calcdfor C 46 H 56 F3N7O5S[M + H] + ,876.4088found,876.4094.

[0333] Example 34

[0334] Preparation of 3-(4-(11-((S)-3-((4-((((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)oxy)pyrrolidine-1-yl)undecyl)thio)-1-oxoisoindol-2-yl)piperidine-2,6-dione (C10)

[0335]

[0336] Compound C10 was prepared according to the method for preparing A10 in Example 12, under suitable conditions as understood in the art, except that the substrate used was S4-2 prepared in Example 2.

[0337] The results are as follows Figure 32As shown, 1H NMR(500MHz,MeOD)δ8.24(d,J=7.5Hz,1H),7.66–7.60(m,2H),7.55–7.49(m,1 H),7.49–7.42(m,2H),7.17(s,1H),7.11(d,J=2.2Hz,1H),5.84(q,J=7.1Hz,1 H),5.52–5.45(m,1H),5.16(dd,J=13.3,5.1Hz,1H),4.47–4.37(m,2H),4.03( s,3H),4.03–3.97(m,1H),3.94–3.82(m,1H),3.63–3.53(m,1H),3.47–3.36(m, 1H),3.29–3.24(m,1H),3.10–3.02(m,2H),2.96–2.85(m,1H),2.81–2.79(m,1 H),2.79–2.74(m,1H),2.64(s,3H),2.58–2.43(m,2H),2.39–2.31(m,1H),2.2 2–2.15(m,1H),1.79(d,J=2.1Hz,3H),1.78–1.71(m,2H),1.66(p,J=7.3Hz,2H ),1.49–1.43(m,2H),1.37–1.28(m,11H),1.24–1.20(m,1H).HRMS(ESI):calcd for C 47 H 58 F3N7O5S[M + H] + ,890.4245found,890.4247.

[0338] Example 35

[0339] Preparation of 3-(4-((12-((S)-3-((4-(-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazoline-6-yl)oxy)pyrrolidine-1-yl)dodecyl)thio)-1-oxoisoindol-2-yl)piperidine-2,6-dione (C11)

[0340]

[0341] The method for preparing A11 according to Example 13, and the preparation of compound C11 under suitable conditions as understood in the art, except that the substrate used is S4-2 prepared in Example 2.

[0342] The results are as follows Figure 33As shown, 1H NMR(500MHz,MeOD)δ8.28(d,J=12.1Hz,1H),7.63–7.60(m,2H),7.55–7.48(m,3H),7.22(s,1H),7.12(d,J=13.7Hz,1H),5.84(q,J=7.4Hz, 1H),5.55–5.47(m,1H),5.16(dd,J=13.4,4.7Hz,1H),4.46–4.37(m,2H),4.03(s,3H),3.95–3.82(m,1H),3.64–3.57(m,1H),3.56–3.35(m ,2H),3.27–3.17(m,1H),3.07–3.03(m,2H),2.94–2.86(m,2H),2.80–2.76(m,1H),2.64(s,3H),2.58–2.45(m,2H),2.39–2.31(m,1H),2.2 1–2.16(m,1H),1.81(d,J=6.7Hz,3H),1.68–1.63(m,2H),1.47–1.43(m,2H),1.35–1.28(m,15H),1.22(d,J=6.7Hz,1H).HRMS(ESI):calcd for C 48 H 60 F3N7O5S[M + H] + ,904.4401found,904.4396.

[0343] Preparation of Group D degradation agent

[0344] Example 36

[0345] Preparation of 3-(4-(2-((S)-3-((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)oxy)pyrrolidine-1-yl)-2-oxoethyl)thio)-1-oxoisoindol-2-yl)piperidine-2,(D1)

[0346]

[0347] Compound D1 was prepared according to the method for preparing B1 in Example 14, under suitable conditions as understood in the art, except that the substrate used was S4-2 prepared in Example 2.

[0348] The results are as follows Figure 34As shown, 1H NMR(500MHz,MeOD)δ7.90(dd,1H),7.82–7.72(m,2H),7.59–7.46(m,1H),7.07(d,J=2.7Hz,1H),7.03(d,J=5.6Hz, 2H),6.89(s,1H),5.79(q,J=7.1Hz,1H),5.18(q,1H),5.13(qd,J=11.1,4.9Hz,1H),4.60–4.39(m,2H),4.01(s,3H ),3.90(d,J=5.2Hz,1H),3.88–3.81(m,2H),3.81–3.76(m,2H),3.74–3.69(m,1H),2.93–2.82(m,1H),2.81–2.69( m,1H),2.64(s,3H),2.53–2.45(m,1H),2.39–2.23(m,2H),2.18–2.13(m,1H),1.75–1.71(m,3H).HRMS(ESI):calcd for C 38 H 38 F3N7O6S[M + H] + ,778.2629found,778.2631.

[0349] Example 37

[0350] Preparation of 3-(4-(3-((S)-3-((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)oxy)pyrrolidine-1-yl)-3-oxopropyl)thio)-1-oxoisoindol-2-yl)piperidin-2,6-dione (D2)

[0351]

[0352] Compound D2 was prepared according to the method for preparing B2 in Example 15, under suitable conditions as understood in the art, except that the substrate used was S4-2 prepared in Example 2.

[0353] The results are as follows Figure 35As shown, 1H NMR(500MHz,MeOD)δ7.89(dd,1H),7.76–7.61(m,2H),7.55–7.48(m,1H),7.19(d,J=8.7Hz,2H),7.08–6.99(m,2H) ,5.80(q,J=7.2Hz,1H),5.25–5.08(m,2H),4.48–4.32(m,2H),3.99(d,J=6.2Hz,3H),3.83–3.76(m,1H),3.69(dd,J =23.1,12.3Hz,2H),3.63–3.56(m,1H),3.41–3.33(m,2H),2.90–2.85(m,1H),2.78–2.67(m,3H),2.63(d,J=2.0Hz, 3H),2.49(dq,J=14.1,6.7Hz,1H),2.29(d,J=24.6Hz,2H),2.19–2.13(m,1H),1.78–1.72(m,3H).HRMS(ESI):calcd for C 39 H 40 F3N7O6S[M + H] + ,792.2786found,792.2785.

[0354] Example 38

[0355] Preparation of 3-(4-(4-((S)-3-((4-(R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)oxy)pyrrolidine-1-yl)-4-oxobutyl)thio)-1-oxoisoindol-2-yl)piperidin-2,6-dione (D3)

[0356]

[0357] Compound D3 was prepared according to the method for preparing B3 in Example 16, under suitable conditions as understood in the art, except that the substrate used was S4-2 prepared in Example 2.

[0358] The results are as follows Figure 36As shown, 1H NMR(500MHz,MeOD)δ7.98(dd,1H),7.70–7.61(m,2H),7.59–7.50(m,1H),7.23(d,J=8.6Hz,2H),7.05(d,J=4.2Hz,2H),5 .81(q,J=7.0Hz,1H),5.29(d,1H),5.17–5.14(m,1H),4.53–4.40(m,2H),3.98(d,J=3.0Hz,3H),3.85–3.80(m,1H),3.70( dt,J=18.5,12.4Hz,3H),3.58–3.44(m,1H),3.35(s,1H),3.18–3.11(m,2H),2.93–2.86(m,1H),2.82–2.77(m,1H),2.63( s,3H),2.57–2.52(m,2H),2.38–2.33(m,1H),2.20–2.16(m,1H),2.02–1.97(m,2H),1.78–1.73(m,3H).HRMS(ESI):calcd for C 40 H 42 F3N7O6S[M + H] + ,806.2942found,806.2939.

[0359] Example 39

[0360] Preparation of 3-(4-(5-((S)-3-((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)oxy)pyrrolidine-1-yl)-5-oxopentyl)thio)-1-oxoisoindoline-2-yl)piperidine-2,6-dione (D4)

[0361]

[0362] Compound D4 was prepared according to the method for preparing B4 in Example 17, under suitable conditions as understood in the art, except that the substrate used was S4-2 prepared in Example 2.

[0363] The results are as follows Figure 37As shown, 1H NMR(500MHz,MeOD)δ7.94(dd,1H),7.64–7.58(m,2H),7.52–7.47(m,1H),7.11(d,J=3.7Hz,2H),7.05–7.02(m,1H),6.95(s ,1H),5.80(q,J=7.3Hz,1H),5.20–5.15(m,2H),4.45–4.39(m,2H),4.00–3.97(m,3H),3.86–3.76(m,2H),3.76–3.64(m,3H) ,3.58–3.45(m,1H),3.09–3.04(m,2H),2.92–2.87(m,1H),2.79–2.75(m,1H),2.66(s,3H),2.64–2.64(m,1H),2.61(d,J=2. 0Hz,1H),2.55–2.49(m,1H),2.43–2.41(m,1H),2.23–2.15(m,2H),1.80–1.77(m,2H),1.74–1.72(m,3H).HRMS(ESI):calcd forC 41 H 44 F3N7O6S[M + H] + ,820.3099found,820.3100.

[0364] Example 40

[0365] Preparation of 3-(4-(6-((S)-3-((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)oxy)pyrrolidine-1-yl)-6-oxohexyl)thio)-1-oxoisoindol-2-yl)piperidin-2,6-dione (D5)

[0366]

[0367]

[0368] Compound D5 was prepared according to the method for preparing B5 in Example 18, under suitable conditions as understood in the art, except that the substrate used was S4-2 prepared in Example 2.

[0369] The results are as follows Figure 38As shown, 1H NMR(500MHz,MeOD)δ7.97(dd,1H),7.64–7.60(m,2H),7.52–7.48(m,1H),7.18(d,J=3.7Hz,2H),7.06–7.04(m,1H),7.00(s,1H) ,5.81(q,1H),5.26–5.15(m,2H),4.44–4.41(m,2H),4.00(d,3H),3.87–3.78(m,2H),3.75–3.66(m,3H),3.56–3.46(m,1H),3.08 –3.03(m,2H),2.93–2.86(m,1H),2.80–2.76(m,1H),2.66(d,J=1.2Hz,1H),2.63(dd,J=2.6,1.2Hz,3H),2.56–2.49(m,1H),2.39 –2.36(m,2H),2.32–2.23(m,2H),2.18(d,J=13.7Hz,2H),1.74(dd,J=7.1,2.5Hz,3H),1.67(d,J=11.5Hz,2H).HRMS(ESI):calcd for C 42 H 46 F3N7O6S[M + H] + ,834.3255found,834.3258.

[0370] Example 41

[0371] Preparation of 3-(4-(7-((S)-3-((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)oxy)pyrrolidine-1-yl)-7-oxoheptyl)thio)-1-oxoisoindoline-2-yl)piperidine-2,6-dione (D6)

[0372]

[0373] Compound D6 was prepared according to the method for preparing B6 in Example 19, under suitable conditions as understood in the art, except that the substrate used was S4-2 prepared in Example 2.

[0374] The results are as follows Figure 39As shown, 1H NMR(500MHz,MeOD)δ7.93(dd,1H),7.61–7.56(m,2H),7.51–7.46(m,1H),7.05–7.03(m,2H),7.02(d,J=1.7Hz,1H),6.9 0(s,1H),5.79(q,1H),5.20–5.13(m,2H),4.44–4.37(m,2H),3.99(d,J=4.7Hz,3H),3.90–3.78(m,2H),3.78–3.67(m,3 H),3.60–3.44(m,1H),3.08–3.03(m,2H),2.93–2.86(m,1H),2.82–2.76(m,1H),2.67–2.65(m,1H),2.64–2.62(m,3H), 2.53(d,J=14.0Hz,1H),2.41–2.31(m,4H),2.24–2.14(m,2H),1.74–1.71(m,3H),1.69–1.63(m,4H).HRMS(ESI):calcd for C 43 H 48 F3N7O6S[M + H] + ,848.3412found,848.3410.

[0375] Example 42

[0376] Preparation of 3-(4-(8-((S)-3-((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)oxy)pyrrolidine-1-yl)-8-oxooctyl)thio)-1-oxoisoindoline-2-yl)piperidine-2,6-dione (D7)

[0377]

[0378] Compound D7 was prepared according to the method for preparing B7 in Example 20, under suitable conditions as understood in the art, except that the substrate used was S4-2 prepared in Example 2.

[0379] The results are as follows Figure 40As shown, 1H NMR(500MHz,MeOD)δ7.97(dd,1H),7.63–7.58(m,2H),7.52–7.46(m,1H),7.07–7.02(m,3H),6.89(d,J=3.8Hz,1H),5.78(q,J=6.8Hz,1H),5 .27–5.11(m,2H),4.46–4.36(m,2H),4.00(d,J=2.3Hz,3H),3.89–3.81(m,1H),3.82–3.78(m,1H),3.77–3.72(m,1H),3.72–3.68(m,1H),3. 07–3.01(m,2H),2.94–2.84(m,1H),2.81–2.75(m,1H),2.63(d,J=2.2Hz,3H),2.52(qd,J=13.3,4.7Hz,1H),2.40–2.34(m,2H),2.33–2.22( m,2H),2.20–2.15(m,1H),1.74–1.70(m,3H),1.69–1.59(m,4H),1.52–1.43(m,2H),1.37–1.34(m,2H),1.33–1.28(m,2H).HRMS(ESI):calcd for C 44 H 50 F3N7O6S[M + H] + ,862.3568found,862.3566.

[0380] Example 43

[0381] Preparation of 3-(4-((9-((S)-3-((4-(-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)oxy)pyrrolidine-1-yl)-9-oxonononyl)thio)-1-oxoisoindoline-2-yl)piperidine-2,6-dione (D8)

[0382]

[0383] Compound D8 was prepared according to the method for preparing B8 in Example 21, under suitable conditions as understood in the art, except that the substrate used was S4-2 prepared in Example 2.

[0384] The results are as follows Figure 41As shown, 1H NMR(500MHz,MeOD)δ7.99(dd,1H),7.62–7.58(m,2H),7.49(dd,J=9.7,5.6Hz,1H),7.29(s,2H),7.09(s,1H),7.06–7.04(m ,1H),5.81(q,1H),5.31–5.21(m,1H),5.16–5.12(m,1H),4.43–4.38(m,2H),4.00(d,J=3.2Hz,3H),3.85–3.77(m,2H),3.77 –3.65(m,3H),3.60–3.42(m,1H),3.05–3.02(m,2H),2.90–2.85(m,1H),2.80–2.76(m,1H),2.63(d,J=1.2Hz,3H),2.55–2.4 9(m,1H),2.39–2.35(m,3H),2.32–2.25(m,2H),2.22–2.16(m,2H),1.76–1.73(m,3H),1.68–1.52(m,8H).HRMS(ESI):calcd forC 45 H 52 F3N7O6S[M + H] + ,876.3725found,876.3727.

[0385] Example 44

[0386] Preparation of 3-(4-(10-((S)-3-((4-((((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)oxy)pyrrolidine-1-yl)-10-oxodecyl)thio)-1-oxoisoindol-2-yl)piperidin-2,6-dione (D9)

[0387]

[0388] Compound D9 was prepared according to the method for preparing B9 in Example 22, under suitable conditions as understood in the art, except that the substrate used was S4-2 prepared in Example 2.

[0389] The results are as follows Figure 42As shown, 1H NMR(500MHz,MeOD)δ7.95(dd,1H),7.62–7.58(m,2H),7.50(d,J=7.8Hz,1H),7.11(dd,2H),7.04(d,1H),6.95( d,1H),5.79(q,1H),5.28(d,1H),5.17–5.13(m,1H),4.43–4.37(m,2H),4.00(d,J=3.3Hz,3H),3.84–3.78(m,2 H),3.76–3.67(m,3H),3.59–3.48(m,1H),3.05–3.02(m,2H),2.91–2.86(m,1H),2.80–2.76(m,1H),2.63(d,J= 1.1Hz,3H),2.38–2.31(m,4H),1.72(d,J=7.1Hz,3H),1.64–1.60(m,4H),1.33–1.28(m,10H).HRMS(ESI):calcd for C 46 H 54 F3N7O6S[M + H] + ,890.3881found,890.3883.

[0390] Example 45

[0391] Preparation of 3-(4-(11-((S)-3-((4-((((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)oxy)pyrrolidine-1-yl)-11-oxoundecyl)thio)-1-oxoisoindoline-2-yl)piperidine-2,6-dione (D10)

[0392]

[0393] Compound D10 was prepared according to the method for preparing B10 in Example 23, under suitable conditions as understood in the art, except that the substrate used was S4-2 prepared in Example 2.

[0394] The results are as follows Figure 43As shown, 1H NMR (500MHz, MeOD) δ7.94(dd,1H),7.61(t,J=6.8Hz,2H),7.50(t,J=7.8Hz,1H),7.05(d,J=4.6Hz,1H),6.97(d,J=6.1Hz,2H),6.84( s,1H),5.77(q,J=5.9Hz,1H),5.19–5.13(m,2H),4.47–4.35(m,2H),4.00(d,J=3.2Hz,3H),3.84–3.80(m,1H),3.79–3.70(m,2H),3.7 1–3.64(m,1H),3.35(s,2H),3.04(t,J=7.2Hz,2H),2.81–2.75(m,1H),2.66(s,1H),2.63(s,3H),2.53(dd,J=13.3,4.7Hz,1H),2.39 –2.36(m,2H),2.32–2.25(m,1H),1.71(d,J=7.1Hz,3H),1.66–1.61(m,4H),1.47–1.43(m,2H),1.32–1.28(m,10H).HRMS(ESI):calcd for C 47 H 56 F3N7O6S[M + H] + ,904.4038found,904.4041.

[0395] Example 46

[0396] Preparation of 3-(4-((12-((S)-3-((4-(-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazoline-6-yl)oxy)pyrrolidine-1-yl)-12-oxododecyl)thio)-1-oxoisoindol-2-yl)piperidine-2,6-dione (D11)

[0397]

[0398] Compound D11 was prepared according to the method for preparing B11 in Example 24, under suitable conditions as understood in the art, except that the substrate used was S4-2 prepared in Example 2.

[0399] The results are as follows Figure 44As shown, 1H NMR(500MHz,MeOD)δ8.03(dd,1H),7.60(dd,J=7.6,4.5Hz,2H),7.52–7.48(m,1H),7.34–7.29(m,2H),7.11–7.06(m,2H),5.81(q,J=7 .0Hz,1H),5.35–5.25(m,1H),5.17–5.13(m,1H),4.45–4.37(m,2H),4.00(d,J=2.0Hz,3H),3.84–3.80(m,1H),3.79–3.67(m,3H),3.05 –3.02(m,2H),2.93–2.86(m,1H),2.81–2.76(m,1H),2.63(s,3H),2.56–2.50(m,1H),2.39–2.36(m,2H),2.34–2.29(m,1H),2.28–2.2 4(m,1H),2.20–2.16(m,1H),1.75(dd,J=7.1,3.4Hz,3H),1.66–1.58(m,5H),1.48–1.39(m,3H),1.30–1.25(m,10H).HRMS(ESI):calcd for C 48 H 58 F3N7O6S[M + H] + ,918.4194found,918.4197.

[0400] II. Bioactivity Test

[0401] Example 47

[0402] Western blot assay was used to determine the degradation rate of the compound in SOS1 protein in K562 cells.

[0403] Human chronic myeloid leukemia cells K562 (ATCC) were selected and grown in RPMI 1640 medium containing 10% fetal bovine serum and 1% penicillin antibiotics at 37°C and 5% CO2.

[0404] The specific experimental procedure is as follows: K562 cells were treated with the compound (1 μM) prepared in Examples 3 to 46 of this invention for 24 hours. The cell suspension was collected into EP tubes and centrifuged at 4°C (500×g, 5 min) using a pre-cooled centrifuge. The supernatant was then discarded, and an appropriate amount of SDS protein lysis buffer was added to lyse the cells. The cells were then denatured at 98°C for 10 min using a metal bath. Denatured proteins were separated by 10% SDS-PAGE electrophoresis (upper gel 80V, 40 min; lower gel 120V, 80 min), and then transferred to a PVDF membrane using wet transfer (250mA, 150 min). The membrane was blocked with 5% skim milk for 2 h, incubated overnight at 4°C with primary antibody (SOS1 (CST, 12409S) and β-Tubulin (CST, 2146S), washed three times with TBST buffer (10 min each time), and incubated at room temperature for 2 h with secondary antibody (Millipore, 401315), washed three times with TBST buffer (10 min each time). The membrane was then incubated with enhanced chemiluminescent horseradish peroxidase substrate (ThermoFisher). After incubation and development, the gray values ​​of SOS1 and β-Tubulin in different lanes were analyzed in ImageJ software. The gray value ratio of SOS1 / β-Tubulin for each compound and the relative gray value relative to the negative control group were calculated in Excel. The relative gray value of the negative control group was defined as 1. The degradation rate of SOS1 for different compounds was (1-relative gray value)*100%, as shown in Table 1.

[0405] Table 1. Degradation of SOS1 protein by the compounds in the examples.

[0406] Example Compound numbering SOS1 degradation rate Example Compound numbering SOS1 degradation rate 3 A1 B 25 C1 B 4 A2 B 26 C2 C 5 A3 B 27 C3 B 6 A4 A 28 C4 B 7 A5 B 29 C5 B 8 A6 B 30 C6 B 9 A7 B 31 C7 C 10 A8 B 32 C8 B 11 A9 A 33 C9 B 12 A10 A 34 C10 B 13 A11 A 35 C11 A 14 B1 C 36 D1 B 15 B2 C 37 D2 B 16 B3 C 38 D3 B 17 B4 B 39 D4 B 18 B5 B 40 D5 B 19 B6 B 41 D6 B 20 B7 B 42 D7 A 21 B8 B 43 D8 A 22 B9 B 44 D9 C 23 B10 B 45 D10 B 24 B11 B 46 D11 A

[0407] Note: In the "SOS1 Degradation Rate" column, "A" represents a degradation rate ≥ 50%, "B" represents a degradation rate < 50%, and "C" represents that SOS1 cannot be degraded.

[0408] Table 1 shows that the compounds in several examples can effectively degrade the SOS1 protein, such as in Example 6 (A4), Example 11 (A9), Example 12 (A10), Example 13 (A11), Example 35 (C11), Example 42 (D7), Example 43 (D8), and Example 46 (D11).

[0409] Example 48

[0410] Detection of in vitro proliferation inhibitory activity of compounds by thiazolium blue colorimetric method

[0411] K562 cells in logarithmic growth phase were seeded at a density of 2500 cells / well in 96-well plates (Jet Biofil, TCP011096). Different compounds prepared in Examples 3 to 46 of this invention were added for treatment. The cells were incubated at 37°C with 5% CO2 for 72 h. Then, 10 μL of 3-(4,5-dimethylthiazol-2)-2,5-diphenyltetrazolium bromide (thiazolium blue (Abcone, M59609), 5 mg / mL, dissolved in physiological saline) solution was added to each well, and the cells were incubated at 37°C for another 4 h. Afterward, 100 μL of a triple solution was added to each well, and the cells were incubated at 37°C until the crystals were completely dissolved. OD values ​​were measured at 570 nm and 690 nm using a tunable wavelength microplate reader (TECAN). The OD value was the difference between OD570 and OD690. The cell growth inhibition rate was calculated using the following formula: Inhibition rate (%) = (OD value control wells - OD value drug-treated wells) / OD value control wells × 100%. The half-maximum inhibitory concentration (IC50) was obtained by fitting the data using a nonlinear regression four-parameter fitting algorithm in GraphPad Prism software 8.0.2. 50 The values ​​are shown in Table 2.

[0412] Table 2. Inhibitory activity of compounds in the examples against the proliferation of K562 cells.

[0413] Example Compound numbering <![CDATA[IC 50 ]]> Example Compound numbering <![CDATA[IC 50 ]]> 3 A1 C 25 C1 C 4 A2 C 26 C2 C 5 A3 C 27 C3 C 6 A4 C 28 C4 C 7 A5 B 29 C5 B 8 A6 B 30 C6 C 9 A7 B 31 C7 C 10 A8 A 32 C8 C 11 A9 B 33 C9 C 12 A10 A 34 C10 B 13 A11 A 35 C11 B 14 B1 C 36 D1 C 15 B2 A 37 D2 C 16 B3 C 38 D3 C 17 B4 C 39 D4 C 18 B5 C 40 D5 C 19 B6 C 41 D6 C 20 B7 C 42 D7 C 21 B8 C 43 D8 C 22 B9 C 44 D9 C 23 B10 C 45 D10 C 24 B11 C 46 D11 C

[0414] Note: IC 50 "An 'A' in the column represents IC" 50 ≤500nM, where "B" represents 500 <IC 50 ≤1000nM, "C" represents IC 50 >1000nM.

[0415] Table 2 shows that the compounds in several examples can effectively inhibit the proliferation of K562 cells, such as in Example 10 (A8), Example 12 (A10), Example 13 (A11), and Example 15 (B2).

[0416] Example 49

[0417] Western blot assays were performed to determine the degradation of SOS1 protein in K562, MIA PaCa-2, and HPAF-II cells by the preferred compounds.

[0418] The degradation of SOS1 protein by the compounds was investigated in human chronic myeloid leukemia cells K562, human pancreatic cancer cells MIAPaCa-2 (KRAS G12C mutation), and HPAF-II (KRAS G12D mutation). Cells were derived from ATCC. K562 cells, MIAPaCa-2 cells, and HPAF-II cells were grown in RPMI1640 medium (10% fetal bovine serum) and DMEM medium (1% penicillin-dextrose antibody) at 37°C and 5% CO2, respectively.

[0419] K562, MIA PaCa-2, and HPAF-II cells were treated with the preferred compounds A10, A11, C11, D7, D8, and D11 (0.01, 0.1, and 1 μM), respectively, prepared in Examples 12, 13, 35, 42, 43, and 46 of this invention. Cells were then collected, and an appropriate amount of SDS protein lysis buffer was added to lyse the cells. The mixture was thoroughly pipetted to ensure homogeneity of the cells and lysis buffer. After homogeneity, the cells were denatured in a metal bath at 98°C for 10 min. Denatured proteins were separated by 10% SDS-PAGE electrophoresis (upper gel 80V, 40 min; lower gel 120V, 80 min), and then transferred to a PVDF membrane using wet transfer (250mA, 150 min). The membrane was blocked with 5% skim milk for 2 h, incubated overnight at 4°C with primary antibody (SOS1 (CST, 12409S) and β-Tubulin (CST, 2146S), washed three times with TBST buffer (10 min each time), and incubated at room temperature for 2 h with secondary antibody (Millipore, 401315), washed three times with TBST buffer (10 min each time). The membrane was then incubated with enhanced chemiluminescent horseradish peroxidase substrate (ThermoFisher). After incubation (Scientific, 32106), the samples were developed and the gray values ​​of SOS1 and β-Tubulin in different lanes were analyzed in ImageJ software. The gray value ratio of SOS1 / β-Tubulin under different treatment conditions and the relative gray value relative to the negative control group concentration group were calculated in Excel. The relative gray value of the negative control group was defined as 1. The degradation rate of SOS1 by different compounds was (1-relative gray value)*100%.

[0420] Figures 45-47 This demonstrates the effects of different concentrations (0.01, 0.1, and 1 μM) of compounds A10, A11, C11, D7, D8, and D11 in K562 cells. Figure 45 ), MIAPaCa-2 ( Figure 46 ) and HPAF-II ( Figure 47The degree of downregulation of SOS1 protein was assessed. ImageJ was used to perform grayscale analysis on Western spectroscopy images. The SOS1 grayscale data were divided by the β-Tubulin grayscale data, and a t-test was performed with the control group. ns indicates p > 0.05, * indicates p < 0.05, ** indicates p < 0.01, and *** indicates p < 0.001. The results showed that the compounds in several examples exhibited significant activity against SOS1 protein degradation, with Examples 12 (A10) and 13 (A11) showing the best activity, significantly degrading SOS1 protein at a concentration of 1000 nM.

[0421] Example 50

[0422] Western blot assay to determine the optimal compound A11 in DCs of K562 cells 50

[0423] After treating K562 cells with different concentrations (2000, 1000, 500, 250, 125, 62.5, 31.25, 15.63 and 7.81 nM) of the most preferred embodiment 13 (A11) of the present invention for 24 hours, the cells were collected and lysed with an appropriate amount of SDS protein lysis buffer, and denatured in a metal bath at 98°C for 10 min. Denatured proteins were separated by 10% SDS-PAGE electrophoresis (upper gel 80V, 40 min; lower gel 120V, 80 min), and then transferred to a PVDF membrane using wet transfer (250mA, 150 min). The membrane was blocked with 5% skim milk for 2 h, incubated overnight at 4°C with primary antibody (SOS1 (CST, 12409S) and β-Tubulin (CST, 2146S), washed three times with TBST buffer (10 min each time), and incubated at room temperature for 2 h with secondary antibody (Millipore, 401315), washed three times with TBST buffer (10 min each time). The membrane was then incubated with enhanced chemiluminescent horseradish peroxidase substrate (ThermoFisher). After incubation (Scientific, 32106), the samples were developed. The grayscale values ​​of SOS1 and β-Tubulin in different lanes were analyzed using ImageJ software. The grayscale ratio of SOS1 / β-Tubulin under each treatment condition and its relative grayscale value compared to the control group were calculated in Excel. The relative grayscale value of the control group was defined as 1. The degradation rate of SOS1 for different concentrations of the compound was (1 - relative grayscale value) * 100%. The DC value was obtained by fitting the data using a nonlinear regression four-parameter fitting algorithm in GraphPad Prism software 8.0.2. 50 (Concentration value that leads to 50% degradation of the target protein) See Figures 48-49 .

[0424] Figure 48 and Figure 49 The half-maximum degradation concentration (DC) of Example 13 (A11) is shown. 50 The compound A11 can induce the degradation of SOS1 protein in K562 cells, with a half-maximal degradation concentration of 64.03 nM and a maximum degradation degree of 96.15%.

[0425] Example 51

[0426] Western blotting assay to detect the sustained inhibition of the SOS1 signaling pathway by compound A11

[0427] K562 cells were treated with 1000 nM compounds: A11, A11-NC (negative control), and BI3406 for 12 h. Cells were then centrifuged (500 g / min, 5 min), and the supernatant containing the compounds was discarded. The cell pellet was resuspended in fresh culture medium and centrifuged again. This process was repeated once more. The cell suspension was then transferred to new multi-well plates and cultured at 37°C in a 5% CO2 incubator for 0, 24, 48, and 72 h. Afterward, the cell suspension from each well was collected in EP tubes, centrifuged, and the supernatant was discarded. An appropriate amount of SDS protein lysis buffer was added, and the cells and lysis buffer were thoroughly mixed. The cells were then denatured in a 98°C metal bath for 10 min. Denatured proteins were separated by 10% SDS-PAGE electrophoresis (upper gel 80V, 40 min; lower gel 120V, 80 min). The proteins were then transferred to a PVDF membrane using wet transfer (250mA, 150 min). The membrane was blocked with 5% skim milk for 2 h, incubated overnight at 4°C with primary antibody (SOS1 (CST, 12409S) and β-tubulin (CST, 2146S), washed three times with TBST buffer (10 min each time), incubated at room temperature with secondary antibody (Millipore, 401315) for 2 h, washed three times with TBST buffer (10 min each time), and developed after incubation with enhanced chemiluminescent horseradish peroxidase substrate (ThermoFisher Scientific, 32106).

[0428] Figure 50 The negative control A11-NC showed that it did not affect intracellular SOS1 degradation and PERK phosphorylation; the compound A11 prepared in Example 13 showed a sustained inhibitory effect on SOS1 signaling after elution, and its inhibitory effect on SOS1 degradation and ERK phosphorylation was still significant after elution for 72 h; after elution of the small molecule compound BI3406 for 72 h, ERK phosphorylation had returned to the level of the untreated group.

[0429] Example 52

[0430] Pharmacokinetic properties of compound A11 prepared in mice according to the most preferred example 13

[0431] Male ICR mice, aged 6-8 weeks and weighing approximately 25g, were used. Compound A11 was administered intravenously (2 mg / kg), intraperitoneally (10 mg / kg), and orally (10 mg / kg), with three animals in each group. Blood samples were collected from mice at 0, 0.083, 0.25, 0.50, 1.00, 2.00, 4.00, 8.00, and 24.00 h. Plasma samples were collected after centrifugation at 5000 rpm for 10 min at 4°C. All samples were stored at -80°C before analysis. Drug concentrations in the samples were determined using liquid chromatography-mass spectrometry (LC-MS / MS). All studies were conducted in accordance with the animal use protocol approved by the Institutional Animal Care and Use Committee. See Table 3 for details.

[0432] Table 3. Pharmacokinetic parameters of the most preferred embodiment 13 (A11) in mice.

[0433]

[0434] Note: "--" indicates that it is not applicable.

[0435] As shown in Table 3, A11 is partially absorbed orally in male ICR mice, and exhibits good pharmacokinetic properties when administered intravenously or intraperitoneally.

[0436] Example 53

[0437] Example 13: Inhibitory activity of compound A11 prepared against the growth of human pancreatic cancer MIA PaCa-2 xenografts in nude mice.

[0438] BALB / c female nude mice, 6-7 weeks old, were purchased from Beijing Huafukang Biotechnology Co., Ltd. Human MIAPaCa-2 pancreatic cancer cells were introduced at a concentration of 7.0 × 10⁻⁶. 6 Cells / mouse were subcutaneously inoculated into the right axilla of each mouse. Mice were monitored daily, and measurements were taken with calipers when tumors became visible. The width (W) and length (L) of each tumor were measured using calipers, and the equation V = (L × W) / (L × W) was used. 2 Calculate the tumor volume using 1 / 2. Wait until the tumor grows to approximately 100 mm. 3Mice were then randomly divided into groups (n=5). One group received intraperitoneal injection of compound A11 (20 mg / kg or 40 mg / kg) prepared in Example 13 once daily, or gavage administered BI3406 (50 mg / kg). The control group received an equal volume of solvent via gavage daily. Tumor volume and mouse weight were measured every three days. The tumor inhibition index was the tumor volume inhibition rate: TGI% = (1 - relative tumor volume of the treatment group / relative tumor volume of the control group) * 100%. The use and welfare of these laboratory animals were conducted in accordance with the regulations of the Committee on Evaluation and Accreditation of Laboratory Animals (AAALAC). The health status and mortality of the animals were monitored daily, and routine checks included observing the effects of the test substance and drug on the animals' daily behavior, such as activity levels, weight changes, and physical appearance.

[0439] Compound A11, prepared in Example 13 of this invention, showed a significant inhibitory effect on the growth of subcutaneous xenografts of human MIA PaCa-2 pancreatic cancer in mice when used alone. Figure 51 As shown, on day 24, the TGI (%) of the A11 20mg / kg group and the 40mg / kg group were 45.9% and 81.3% respectively (P<0.01), and the TGI (%) of the BI3406 50mg / kg group was 62.0% (P<0.05).

[0440] The above embodiments are merely illustrative of the principles and effects of the present invention and are not intended to limit this application. Any person skilled in the art can modify or alter the above embodiments without departing from the spirit and scope of this application. Therefore, all equivalent modifications or alterations made by those skilled in the art without departing from the spirit and technical concept disclosed in this invention should still be covered by the claims of this application.

Claims

1. A compound or pharmaceutically acceptable salt, characterized in that, The compound is selected from the group consisting of:

2. A pharmaceutical composition comprising the compound of claim 1, further comprising a pharmaceutically acceptable carrier, adjuvant or excipient.

3. The pharmaceutical composition of claim 2, wherein Further comprising other drugs selected from the group consisting of a combination of one or more of KRAS G12C inhibitors, MEK inhibitors, EGFR wild type or mutant inhibitors, PI3K inhibitors, SHP2 inhibitors, AKT inhibitors, mTOR inhibitors, TOP1 inhibitors, HER2 wild type or mutant inhibitors, ALK wild type or mutant inhibitors, BCR-ABL mutant inhibitors, c-MET mutant inhibitors, taxanes, platinums, CDK4 or CDK6 inhibitors, metabolic antineoplastic drugs, PD-1 or PD-L1 mAbs, CTLA-4 mAbs, anti-angiogenic drugs, apoptosis drugs, PARP inhibitors, epigenetic drugs; The KRAS G12C inhibitor is selected from the group consisting of a combination of one or more of Sotorasib, Adagrasib, JDQ-443, GF-105, GDC-6036; The MEK inhibitor is selected from the group consisting of a combination of one or more of Trametinib, Selumetinib, Cobimetinib, Binimetinib, Binimetinib; The EGFR wild type or mutant inhibitor is selected from the group consisting of a combination of one or more of Erlotinib, Gefitinib, Afatinib, Amivantamab, Olmutinib, Mobociclib, Eflomithine, Osimertinib, Panitumumab, Nintedanib, Cetuximab, and Necitumumab; The PI3K inhibitor is selected from the group consisting of a combination of one or more of Duvelumbo, Alpelisib, Copanlisib, Idelalisib, BAY-84-1236; The SHP2 inhibitor is selected from the group consisting of a combination of one or more of JAB-3068, BR-790, BBP-398, JAB-3312, RMC-4630, TNO-155; The AKT inhibitor is selected from the group consisting of a combination of one or more of Ipatasertib Dihydrochloride, Afuresertib, Capivasertib, TIC-10; The mTOR inhibitor is selected from the group consisting of a combination of one or more of Sirolimus, Temsirolimus, Everolimus, and Deforolimus; The TOP1 inhibitor is selected from the group consisting of a combination of one or more of Irinotecan, Topotecan, Belotecan, Aclarubicin, and Camptothecin; The HER2 wild type or mutant inhibitor is selected from the group consisting of a combination of one or more of Lapatinib, Trastuzumab, and Pertuzumab; The ALK wild type or mutant inhibitor is selected from the group consisting of a combination of one or more of Lorlatinib, Alectinib, Ceritinib, Entospletinib, Brigatinib, and Crizotinib; The BCR-ABL mutant inhibitor is selected from the group consisting of a combination of one or more of Imatinib, Dasatinib, and Nilotinib; The c-MET mutant inhibitor is selected from the group consisting of a combination of one or more of Tivantinib, Savolitinib, and Capmatinib; and the taxane is selected from the group consisting of Paclitaxel or Docetaxel. the platinum is selected from a combination of one or more of cisplatin, carboplatin and oxaliplatin; the CDK4 or CDK6 inhibitor is selected from a combination of one or more of abemaciclib, ribociclib, libenziclib, and trilaciclib; the metabolic anti-neoplastic agent is selected from a combination of one or more of 5-fluorouracil, capecitabine, and gemcitabine; the PD-1 or PD-L1 mAb is selected from a combination of one or more of BMS-936559, Nivolumab, Cemiplimab, Toripalimab, Camrelizumab, Tislelizumab, Sintilimab, Pemarizumab, Knobs- out, Knobs-in, Dostarlimab, Enavatuzumab, Durvalumab, Toripalimab, Avelumab, and Sugemalimab; the CTLA-4 mAb is selected from a combination of one or more of Ipilimumab, Tremelimumab, and Knobs-out; the anti-angiogenic agent is selected from bevacizumab or nintedanib; the apoptosis agent is selected from a combination of one or more of Venetoclax, Lisaftoclax, LP-168, BGB-11417, FCN-338, FCN-011, and Pelcitoclax; the PARP inhibitor is selected from a combination of one or more of Olaparib, Niraparib, Rucaparib, and Talazoparib; the epigenetic agent is selected from a combination of one or more of Azacitidine, Vorinostat, Romidepsin, Chidamide, Epigenetide, and Taselisib.

4. Use of a compound of claim 1 or a pharmaceutical composition of claim 2 or 3 in the manufacture of a SOS1 -related genetic disease or cancer product.

5. The use according to claim 4, wherein the compound is ###0002### the genetic disease is selected from a combination of one or more of neurofibromatosis type I, gingival fibromatosis, and Noonan syndrome; and / or, the cancer is selected from a combination of one or more of non-melanoma skin cancer, breast cancer, lung cancer, colorectal cancer, prostate cancer, gastric cancer, liver cancer, cervical cancer, esophageal cancer, thyroid cancer, bladder cancer, non-Hodgkin's lymphoma, pancreatic cancer, leukemia, renal cancer, endometrial cancer, lip / oral cancer, melanoma, ovarian cancer, brain and central nervous system tumor, laryngeal cancer, multiple myeloma, nasopharyngeal cancer, gallbladder cancer, bile duct cancer, oropharyngeal cancer, hypopharyngeal cancer, Hodgkin's lymphoma, testicular cancer, salivary gland cancer, vulvar cancer, penile cancer, Kaposi's sarcoma, mesothelioma, and vaginal cancer.

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