Benzyl or thienylmethylene substituted aminoquinazoline derivatives and their use as sos1 degraders

Abstract

The application discloses a kind of SOS1 degrader and its application.The application provides a kind of compound as shown in formula (I), and / or its stereoisomer, enantiomer, diastereoisomer, deuterated compound, hydrate, solvate, prodrug and / or its pharmaceutically acceptable salt.The compound of the application can be used as SOS1 degrader.

Description

[0001] This application claims priority to Chinese patent application 2022112963993, filed on October 21, 2022. This application incorporates the entirety of the aforementioned Chinese patent application. TECHNICAL FIELD

[0002] The present application belongs to the technical field of medicine, and specifically, the present application relates to a SOS1 degrader, and its use as a therapeutic agent for preventing and / or treating cancer. BACKGROUND

[0003] SOS1 (son of sevenless homolog 1) protein is a regulatory protein widely expressed in cells. As a key protein in the signal pathway, SOS1 plays an important regulatory role in many signal transduction pathways in cells, such as participating in the regulation of Ras and Rac signal pathways. SOS1 is composed of 1333 amino acids, and contains a proline-rich domain (PxxP) at its C-terminus. The domain can bind to growth factor receptor-bound protein 2 (Grb2) in the Ras pathway, forming a Grb2 and SOS1 complex, thereby bringing SOS1 to the vicinity of the cell membrane Ras protein. SOS1 catalyzes the binding of Ras to GTP, promotes the activation of Ras, and in turn activates multiple downstream signal pathways, such as Ras-Raf-Mek-Erk, Ras-PI3K-AKT-mTOR. PxxP can also bind to the SH3 (Src homology 3) domain of proteins such as E3B1 in the Rac pathway, forming an EPS8-E3B1-SOS1 complex. The EPS8-E3B1-SOS1 complex connects actin filaments through EPS8, causing GTP to be converted, thereby activating Rac, and subsequently activating signal pathways such as JNK and MAPK.

[0004] Ras mutant genes are considered to be the main oncogenes with high incidence in human cancers. Studies have shown that 20-30% of tumor patients have mutations in Ras, of which KRas mutations account for 85%, NRas and HRas account for 12% and 3%, respectively. However, due to the picomolar affinity of GTP to its binding site, and the smooth surface of the Ras protein lacking other suitable binding pockets, it is considered extremely challenging to directly act on Ras to inhibit its activity.

[0005] Abnormal expression or mutation of SOS1 is also closely related to the occurrence of clinical diseases. Studies have shown that mutations of SOS1 exist in NS patients and CFC patients, HGF1 is a rare autosomal dominant genetic disease, and the cause thereof is also related to mutations of PxxP domains of SOS1. In addition, abnormal expression or mutation of SOS1 is also related to the occurrence of cancer.

[0006] WO2018172250A1, WO2020173935A1, WO2019201848A1, WO2020180768A1, WO2020180770A1, WO2019122129A1 and EP3558979A1 disclose several types of SOS1 inhibitors, but so far, there is no related report on SOS1 degrading agents. Proteolysis targeting chimeria (PROTAC) is a technology different from traditional small molecule inhibitors, which usually need to act on the active site of the target protein to inhibit its activity. PROTAC is a hetero-bifunctional molecule, one end of which is a small molecule inhibitor that can recognize the target protein, and the other end is an E3 ubiquitin ligase ligand that can recognize the E3 ubiquitin ligase. This bifunctional molecule recognizes the target protein and the E3 ubiquitin ligase in vivo, and pulls the target protein and the E3 ubiquitin ligase close to form a ternary complex, ubiquitinates the target protein, and then degrades the target protein through the ubiquitin-proteasome pathway in vivo. Compared with traditional small molecule inhibitors, on the one hand, PROTAC only needs to pull the target protein and the E3 ubiquitin ligase close to degrade the substrate, and this mode of action makes this technology applicable to some undruggable targets; on the other hand, since the target protein is degraded, the PROTAC molecule can also be released to continue to participate in the degradation process of the next protein, so this catalytic degradation effect makes a small amount of PROTAC drug dosage can achieve efficient degradation; on the other hand, the resistance of traditional small molecule inhibitors is often caused by point mutations, which makes the small molecule inhibitors lose the inhibitory effect on the target, and PROTAC can directly degrade the target protein, which can avoid the resistance caused by point mutations to a certain extent. Therefore, compared with traditional small molecule inhibitors, the use of PROTAC technology for new drug small molecule research and development has high advantages and feasibility. SUMMARY

[0007] In order to solve the technical problem of lack of SOS1 protein degrading agent in the prior art, the present application provides a new SOS1 protein degrading agent and its application. The SOS1 protein degrading agent described in the present application can effectively bind to or produce an inhibitory effect on the SOS1 target protein, and further effectively degrade the SOS1 protein.

[0008] The present invention solves the above-mentioned technical problems by means of the following method.

[0009] This invention provides a compound of Formula I, its stereoisomers, enantiomers, diastereomers, deuterated derivatives, hydrates, solvates, prodrugs, or pharmaceutically acceptable salts thereof:

[0010] SLE

[0011] I

[0012] Where S is

[0013] L is L is connected to S via A or B;

[0014] E is

[0015] In a preferred embodiment of the present invention, certain groups in the compound of Formula I, its stereoisomers, enantiomers, diastereomers, deuterates, hydrates, solvates, prodrugs, or pharmaceutically acceptable salts thereof have the following definitions, and the definitions of groups not mentioned are as described in any of the preceding embodiments (hereinafter referred to as "in a preferred embodiment of the present invention"):

[0016] In a preferred embodiment of the present invention, S is... L is

[0017] In a preferred embodiment of the present invention, S is...

[0018] L is

[0019] In a preferred embodiment of the present invention, S is...

[0020] L is

[0021] In a preferred embodiment of the present invention, S is...

[0022] L is

[0023] In a preferred embodiment of the present invention, S is...

[0024] L is

[0025] In a preferred embodiment of the application, S is

[0026] L is

[0027] In a preferred embodiment of the application, S is L is

[0028] In a preferred embodiment of the application, S is

[0029] L is

[0030] In a preferred embodiment of the application, S is L is

[0031] In a preferred embodiment of the application, S is

[0032] E is

[0033] In a preferred embodiment of the application, S is

[0034] E is

[0035] In a preferred embodiment of the application, S is

[0036] E is

[0037] In a preferred embodiment of the application, S is

[0038] E is

[0039] In a preferred embodiment of the application, S is

[0040] E is

[0041] In a preferred embodiment of the application, S is

[0042] E is

[0043] In a preferred embodiment of the application, S is

[0044] E is

[0045] In a preferred embodiment of the application, S is

[0046] E is

[0047] In a preferred embodiment of the application, S is E is

[0048] In a preferred embodiment of the application, L is E is

[0049] In a preferred embodiment of the application, L is E is

[0050] In a preferred embodiment of the application, L is E is

[0051] In a preferred embodiment of the application, L is E is

[0052] In a preferred embodiment of the application, L is E is

[0053] In a preferred embodiment of the application, L is E is

[0054] In a preferred embodiment of the application, L is E is

[0055] In a preferred embodiment of the application, L is E is

[0056] In a preferred embodiment of the application, L is E is

[0057] In a preferred embodiment of the application, L is E is

[0058] In a preferred embodiment of the present invention, L is... E is

[0059] In a preferred embodiment of the present invention, L is... E is

[0060] In a preferred embodiment of the present invention, L is... E is

[0061] In a preferred embodiment of the present invention, L is... E is

[0062] In a preferred embodiment of the present invention, L is... E is

[0063] In a preferred embodiment of the present invention, L is... E is

[0064] In a preferred embodiment of the present invention, S is... L is E is

[0065] In a preferred embodiment of the present invention, S is... L is E is

[0066] In a preferred embodiment of the present invention, S is... L is E is

[0067] In a preferred embodiment of the present invention, S is... L is E is

[0068] In a preferred embodiment of the present invention, S is... L is E is

[0069] In a preferred embodiment of the present invention, S is... L is E is

[0070] In a preferred embodiment of the present application, S is L is E is

[0071] In a preferred embodiment of the present application, S is L is E is

[0072] In a preferred embodiment of the present application, S is L is E is

[0073] In a preferred embodiment of the present application, A in L is connected to S.

[0074] In a preferred embodiment of the present application, the compound of Formula I is any one of the following compounds:

[0075]

[0076]

[0077]

[0078]

[0079]

[0080] The present application also provides a pharmaceutical composition comprising G and a pharmaceutically acceptable carrier, diluent, or excipient, wherein G is a compound described above, a stereoisomer, an enantiomer, a diastereomer, a deuterated compound, a hydrate, a solvate, a prodrug, or a pharmaceutically acceptable salt thereof.

[0081] The present application provides a method of degrading SOS1 protein, comprising contacting SOS1 protein with a compound described above, a stereoisomer, an enantiomer, a diastereomer, a deuterated compound, a hydrate, a solvate, a metabolite, a prodrug, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described above.

[0082] The present application provides a compound described above, a stereoisomer, an enantiomer, a diastereomer, a deuterated compound, a hydrate, a solvate, a metabolite, a prodrug, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described above for use as a medicament for treating or preventing a SOS1-mediated disease or disorder.

[0083] The present application provides use of a compound described above, stereoisomer, enantiomer, diastereomer, deuterated compound, hydrate, solvate, metabolite, prodrug, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described above as a drug for treating or preventing a disease or disorder (cancer) caused by SOS1 and Ras (e.g. KRAS) or SOS1 and Rac (e.g. KRAS) interaction.

[0084] The present application provides use of a compound described above, stereoisomer, enantiomer, diastereomer, deuterated compound, hydrate, solvate, metabolite, prodrug, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described above in the preparation of a drug for treating or preventing a SOS1 mediated disease or disorder (e.g. cancer).

[0085] The present application provides use of a compound described above, stereoisomer, enantiomer, diastereomer, deuterated compound, hydrate, solvate, metabolite, prodrug, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described above in the preparation of a drug for treating or preventing a disease or disorder (e.g. cancer) caused by SOS1 and Ras (e.g. KRAS) or SOS1 and Rac (e.g. KRAS) interaction.

[0086] The present application provides use of a compound described above, stereoisomer, enantiomer, diastereomer, deuterated compound, hydrate, solvate, metabolite, prodrug, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described above in the preparation of a drug for treating or preventing a cancer.

[0087] In any embodiment of the present application, the cancer can be pancreatic cancer, lung cancer, colorectal cancer, cholangiocyte cancer, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer, or sarcoma.

[0088] The present application provides use of a compound described above, stereoisomer, enantiomer, diastereomer, deuterated compound, hydrate, solvate, metabolite, prodrug, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described above in the preparation of a drug for treating or preventing pancreatic cancer, lung cancer, colorectal cancer, cholangiocyte cancer, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer, and sarcoma.

[0089] The present application provides a use of the above-mentioned compound, stereoisomer, enantiomer, diastereomer, deuterated compound, hydrate, solvate, metabolite, prodrug, or pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition in the preparation of a medicament for treating or preventing neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Noonan syndrome with multiple lentigines (NSML), capillary malformation-arteriovenous malformation syndrome (CM-AVM), Costello syndrome (CS), cardio-facio-cutaneous syndrome (CFC), Legius syndrome, and hereditary gingival fibromatosis.

[0090] In any embodiment of the present application, the SOS1-mediated disease or disorder can be cancer, neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Noonan syndrome with multiple lentigines (NSML), capillary malformation-arteriovenous malformation syndrome (CM-AVM), Costello syndrome (CS), cardio-facio-cutaneous syndrome (CFC), Legius syndrome, or hereditary gingival fibromatosis; wherein the cancer can be any cancer described in any aspect of the present application.

[0091] The present application provides a method for treating or preventing a SOS1-mediated disease or disorder, comprising administering to a patient in need thereof a therapeutically effective amount of the above-mentioned compound, stereoisomer, enantiomer, diastereomer, deuterated compound, hydrate, solvate, metabolite, prodrug, or pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition.

[0092] The present application provides a method for treating or preventing a disease or disorder (e.g., cancer) regulated by SOS1 and Ras (e.g., KRAS) or SOS1 and Rac (e.g., KRAS) interaction, comprising administering to a patient in need thereof a therapeutically effective amount of the above-mentioned compound, or stereoisomer, enantiomer, diastereomer, deuterated compound, hydrate, solvate, metabolite, prodrug, or pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition.

[0093] In some embodiments of the present application, the cancer can be selected from the group consisting of:

[0094] Heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma group;

[0095] Lung: bronchogenic carcinoma (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar carcinoma (bronchiolar carcinoma), bronchial adenoma, sarcoma, lymphoma, chondroma hamartoma, mesothelioma;

[0096] Gastrointestinal esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vasoactive intestinal peptide tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma);

[0097] Urogenital system: kidney (adenocarcinoma, nephroblastoma, lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma);

[0098] Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma;

[0099] Biliary tract: gallbladder carcinoma, ampullary carcinoma, cholangiocarcinoma;

[0100] Bone: osteosarcoma (osteogenic sarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, chondroma (osteocartilaginous exostosis), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor;

[0101] Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, glioma), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma);

[0102] Gynecology: uterus (endometrial carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, carcinoma undifferentiated), granulosa-thecal cell tumors, Sertoli-Leydig's tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma)), fallopian tubes (carcinoma);

[0103] Hematology: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disease, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma);

[0104] Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis;

[0105] Adrenal gland: neuroblastoma.

[0106] In some embodiments of the present application, the cancer can be selected from the group consisting of pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer, and sarcoma.

[0107] The present application also provides a use of a compound described above, or a stereoisomer, an enantiomer, a diastereomer, a deuterated compound, a hydrate, a solvate, a metabolite, a prodrug, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the foregoing, in the manufacture of a medicament for treating and / or preventing a KRAS-mediated disease or disorder.

[0108] The present application also provides a method of treating and / or preventing a KRAS-mediated disease or disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a compound described above, or a stereoisomer, an enantiomer, a diastereomer, a deuterated compound, a hydrate, a solvate, a metabolite, a prodrug, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0109] In some embodiments of the present application, the KRAS can be a mutant KRAS. The mutant KRAS is preferably one or more of KRAS G12C, KRAS G12D, KRAS G13D, and KRAS G12V.

[0110] Detailed description: Unless otherwise indicated, the following terms used in the specification and claims have the following meanings.

[0111] "Pharmaceutical composition" means a mixture of one or more compounds described herein or physiologically / pharmaceutically acceptable salts or prodrugs thereof with other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism and absorption of the active ingredient(s) to elicit a biological activity.

[0112] The present application also provides pharmaceutically acceptable salts of the compounds of Formula (I). The term "pharmaceutically acceptable salt" means either an acid addition salt or a base addition salt which are relatively non-toxic. The acid addition salts are salts of the compounds of Formula (I) with such organic or inorganic acids which are known to form relatively non-toxic acid addition salts. The acid addition salts can be prepared from the free base of the compounds of Formula (I) by contacting the free base with the appropriate inorganic or organic acid in its acid form, or by reacting a purified compound of Formula (I) in its free base form with an appropriate inorganic or organic acid in its acid form. Representative salts include the hydrochloride, hydrobromide, sulfate, bisulfate, sulfite, acetate, oxalate, valerate, oleate, palmitate, stearate, pamoate, borate, benzoate, lactate, phosphate, hydrogen phosphate, carbonate, bicarbonate, toluene sulfonate, citrate, maleate, fumarate, succinate, benzoate, tartrate, methanesulfonate, p-toluenesulfonate, gluconate, lactobionate, and laurylsulfonate salts, and the like. The base addition salts are salts of the compounds of Formula (I) with such organic or inorganic bases which are known to form relatively non-toxic base addition salts. The base addition salts can be prepared from the free acid of the compounds of Formula (I) by contacting the free acid with the appropriate inorganic or organic base in its base form, or by reacting a purified compound of Formula (I) in its free acid form with an appropriate inorganic or organic base in its base form. Representative bases include alkali metal, alkaline earth metal, and quaternary ammonium hydroxides, including sodium, lithium, potassium, calcium, magnesium, tetramethylammonium hydroxide, tetraethylammonium hydroxide, and the like; and amine bases including ammonia, primary, secondary, and tertiary amines, such as methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.

[0113] The compounds of the present application, or their pharmaceutically acceptable salts, can be administered to mammals including humans, orally, rectally, parenterally (intravenous, intramuscular, or subcutaneous), topically (powders, ointments or drops), or intralesionally.

[0114] The compounds of the present application can be administered in a dose of about 0.05 to 300 mg / kg body weight per day, preferably 10 to 300 mg / kg body weight per day, more preferably 10 to 200 mg / kg body weight per day.

[0115] The compounds of the present application, or their pharmaceutically acceptable salts, can be formulated into solid dosage forms for oral administration such as, but not limited to, capsules, tablets, pills, powders, and granules. In these solid dosage forms, the compounds of Formula (I) of the present application as the active ingredient are mixed with at least one conventional inert excipient (or carrier) such as sodium citrate or dicalcium phosphate, or with ingredients such as (1) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, and the like; (2) binders such as hydroxymethylcellulose, alginic acid, gelatin, polyvinylpyrrolidone, sucrose, and acacia, and the like; (3) humectants such as glycerol and the like; (4) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate, and the like; (5) solution retarders such as paraffin, and the like; (6) absorption accelerators such as quaternary ammonium compounds, and the like; (7) wetting agents such as cetyl alcohol and glycerol monostearate, and the like; (8) absorbents such as kaolin and the like; and (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and the like, or mixtures thereof. Buffers, preservatives, flavoring agents, coloring agents, and the like, can also be incorporated.

[0116] The solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other well-known coatings and shells as is well known in the art. They can contain opacifying agents, and can be of a composition that they release the active ingredient(s) only, or otherwise over a period of time, in a certain part of the intestinal tract, in a such a manner as to not release the active ingredient(s) in the stomach and / or proximal portion of the intestinal tract. Examples of embedding compositions that can be used are polymeric substances and waxes. The active ingredient(s) can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.

[0117] The compounds of the present application, or their pharmaceutically acceptable salts, can be formulated into liquid dosage forms for oral administration such as, but not limited to, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the compounds of Formula (I) or their pharmaceutically acceptable salts as the active ingredient, the liquid dosage forms can contain inert diluents such as water and other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and the like, or mixtures thereof, and the like. Except insofar as any conventional diluent is incompatible with the compounds of Formula (I) or their pharmaceutically acceptable salts, such as those having a pKa value that is substantially different from that of the active ingredient, other conventional diluents, such as those described above, can be employed. Supplementary active ingredients can also be incorporated into the compositions.

[0118] The suspending agents include, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan, microcrystalline cellulose, aluminum metahydroxide, and agar-agar, and the like or mixtures thereof.

[0119] The compounds of the present application, or their pharmaceutically acceptable salts, can be formulated into dosage forms for parenteral injection by dissolution or suspension in a physiologically acceptable diluent. Suitable diluents and solvents include water, ethanol, polyols, glycol and

[0120] The compounds of the present application, or their pharmaceutically acceptable salts, can also be formulated into dosage forms for topical administration including, for example, ointments, powders, suppositories, drops, sprays, and inhalers. The compounds of the present application, or their pharmaceutically acceptable salts, as active ingredients, are mixed under sterile conditions with a physiologically acceptable carrier and optionally an preservative, buffer, or propellant, as required.

[0121] The present application also provides pharmaceutical compositions comprising a compound of the present application, or a pharmaceutically acceptable salt thereof, as an active ingredient, in combination with a pharmaceutically acceptable carrier, excipient, or diluent. In making the pharmaceutical compositions that include a compound of the present application, or a pharmaceutically acceptable salt thereof, the compound is usually mixed with an excipient, carrier, or diluent at the concentration dictated by the solubility and chemical properties of the drug substance.

[0122] The compositions described herein can be formulated into conventional pharmaceutical compositions by conventional methods. For example, tablets, pills, capsules, powders, granules, emulsions, suspensions, solutions, syrups, elixirs, ointments, drops, suppositories, inhalers, sprays, and the like.

[0123] The compounds described herein, or their pharmaceutically acceptable salts, can be administered alone or, if desired, in combination with other pharmaceutically acceptable therapeutic agents, such as other anti-tumor agents. The components to be combined can be administered simultaneously or sequentially, in either order, in separate compositions or in a unitary composition. The combinations described herein can include combinations of a compound of the present application and one other active agent, as well as combinations of a compound of the present application and two or more other active agents.

[0124] In the present application, other pharmaceutically acceptable therapeutic agents that can be used together or in combination with the SOS1 degrader compound of formula (I) can be: EGFR and / or its mutant inhibitor, ErbB2 (Her2) and / or its mutant inhibitor, ALK and / or its mutant inhibitor, MEK and / or its mutant inhibitor, Kras and / or its mutant inhibitor, BCR-ABL and / or its mutant inhibitor, FGFR1 / FGFR2 / FGFR3 and / or its mutant inhibitor, ROS1 and / or its mutant inhibitor, c-MET and / or its mutant inhibitor, AXL and / or its mutant inhibitor, NTRK1 and / or its mutant inhibitor, RET and / or its mutant inhibitor, taxane, platinum-containing compound, antimetabolite, mitotic kinase inhibitor, immunotherapeutic agent, anti-angiogenic drug, topoisomerase inhibitor, A-Raf / B-Raf / C-RAf and / or its mutant inhibitor, ERK and / or its mutant inhibitor, apoptosis inhibitor, mTOR inhibitor, epigenetic regulator, IGF1 / 2 and / or IGF1-R inhibitor, Ras GEF and / or its mutant inhibitor, PI3K and / or its mutant inhibitor.

[0125] In the present application, other pharmaceutically acceptable therapeutic agents that can be used together or in combination with the SOS1 degrader compound of formula (I) can be: afatinib, erlotinib, gefitinib, lapatinib, cetuximab, panitumumab, osimertinib, olmutinib, EGF-816, trastuzumab, pertuzumab, crizotinib, alectinib, entrectinib, brigatinib, trametinib, cobimetinib, binimetinib, selumetinib, refametinib, imatinib, dasatinib, nilotinib, nintedanib, crizotinib, lorlatinib, ceritinib, merestinib, paclitaxel, nab-paclitaxel, docetaxel, cisplatin, carboplatin, oxaliplatin, 5-fluorouracil, capecitabine, floxuridine, cytarabine, gemcitabine, the combination of trifluridine and tipiracil (= TAS102), palbociclib, ribociclib, abemaciclib, ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, pidilizumab, PDR-001 (= spartalizumab), bevacizumab, irinotecan, liposomal irinotecan, topotecan, ulixertinib, rapamycin, temsirolimus, everolimus,Ridaforolimus, JQ-1, GSK525762, OTX 015 (= MK8628), CPI 0610, TEN-010 (= RO 6870810), xentuzumab (antibody 60833 in WO 2010 / 066868) or MEDI-573 (= dusigitumab).

[0126] On the basis of common general knowledge in the art, the above-mentioned preferred conditions can be combined arbitrarily, i.e. to obtain preferred embodiments of the present application.

[0127] The reagents and starting materials used in the present application are commercially available.

[0128] The positive progress effect of the present application is that the compound of formula I can effectively bind to or produce inhibitory effect on SOS1 target protein, and further effectively degrade SOS1 protein, thereby achieving the effect of preventing or treating diseases or disorders caused by SOS1 or the interaction of SOS1 with Ras or SOS1 with Rac. DETAILED DESCRIPTION

[0129] The present application will be further described by way of examples, but the present application is not limited to the scope of the examples. The experimental methods in the following examples, if not otherwise specified, are selected according to the conventional methods and conditions, or according to the product instructions.

[0130] Intermediate 1: 1-(2-chloro-5-(4-((2-(piperidin-4-yl)ethoxy)methyl-d2)piperidine-1- carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0131] Step 1: Preparation of 4-(2-((1-(tert-butoxycarbonyl)piperidin-4-yl)methoxy-d2)ethyl)piperidine-1- carboxylate

[0132]

[0133] Dissolve 4-(hydroxymethyl-d2)piperidine-1-carboxylic acid tert-butyl ester (600 mg, 2.76 mmol) in anhydrous THF (20 mL), add NaH (60%, 133 mg, 3.31 mmol) at 0 °C and stir for 1 h, add 4-(2-(toluene sulfonyl)ethyl)piperidine-1-carboxylic acid benzyl ester (1.73 g, 4.14 mmol), warm the reaction to 65 °C and stir overnight. Slowly add water (30 mL) to the reaction, extract with ethyl acetate (50 mL x 3), wash the organic phase with saturated brine (100 mL), dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure. Purify the crude product by silica gel column chromatography (ethyl acetate: petroleum ether = 1:3) to obtain 4-(2-((1-(tert-butoxycarbonyl)piperidin-4-yl)methoxy-d2)ethyl)piperidine-1-carboxylic acid benzyl ester.

[0134] LC-MS: (ESI, m / z): [M+H] + = 463.2.

[0135] Step 2: Preparation of 4-(2-(piperidin-4-ylmethoxy-d2)ethyl)piperidine-1-carboxylic acid benzyl ester

[0136]

[0137] Dissolve 4-(2-((1-(tert-butoxycarbonyl)piperidin-4-yl)methoxy-d2)ethyl)piperidine-1-carboxylic acid benzyl ester (350 mg, 0.758 mmol) in dichloromethane (10 mL), then add trifluoroacetic acid (2 mL) and stir at room temperature for 2 h, directly concentrate the reaction under reduced pressure to obtain 4-(2-(piperidin-4-ylmethoxy-d2)ethyl)piperidine-1-carboxylic acid benzyl ester, which is used directly in the next reaction without purification.

[0138] LC-MS: (ESI, m / z): [M+H] + = 363.1.

[0139] Step 3: Preparation of 4-(2-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)methoxy-d2)ethyl)piperidine-1-carboxylic acid benzyl ester

[0140]

[0141] Benzyl 4-(2-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4- yl)methoxy-d2)ethyl)piperidine-1-carboxylate (300 mg, 0.489 mmol) was added to trifluoroacetic acid (5 mL), the reaction was warmed to 90 °C and stirred for 3 h, directly concentrated under reduced pressure, the residue was dissolved in dichloromethane (30 mL), then saturated sodium bicarbonate solution was slowly added until the solution pH = 8, the organic phase was separated, the aqueous phase was extracted with dichloromethane / methanol solution (10 / 1, 40 mL x 5), the combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give 1-(2-chloro-5-(4-((2-(piperidin-4-yl)ethoxy)methyl-d2)piperidin-1- ylcarbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione, which was used directly in the next reaction without purification.

[0142] LC-MS: (ESI, m / z): [M+H] + = 613.2.

[0143] Step 4: Preparation of 1-(2-chloro-5-(4-((2-(piperidin-4-yl)ethoxy)methyl-d2)piperidin-1- ylcarbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0144]

[0145] Benzyl 4-(2-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4- yl)methoxy-d2)ethyl)piperidine-1-carboxylate (300 mg, 0.489 mmol) was added to trifluoroacetic acid (5 mL), the reaction was warmed to 90 °C and stirred for 3 h, directly concentrated under reduced pressure, the residue was dissolved in dichloromethane (30 mL), then saturated sodium bicarbonate solution was slowly added until the solution pH = 8, the organic phase was separated, the aqueous phase was extracted with dichloromethane / methanol solution (10 / 1, 40 mL x 5), the combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give 1-(2-chloro-5-(4-((2-(piperidin-4-yl)ethoxy)methyl-d2)piperidin-1- ylcarbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione, which was used directly in the next reaction without purification.

[0146] LC-MS: (ESI, m / z): [M+H] + = 479.1.

[0147] Example 1: (1R,4R)-4-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7- methoxy-2-methylquinazolin-6-yl)-N-(3-(3-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)- yl)benzoyl)-3-azaspiro[5.5]undecan-9-yl)propyl)-N-methylcyclohexane-1-carboxamide

[0148] Step 1: Preparation of tert-butyl (E)-9-(3-ethoxy-3-oxoprop-1-en-1-yl)-3- azaspiro[5.5]undecane-3-carboxylate

[0149]

[0150] Phosphoryl acetic acid (1.27 g, 5.7 mmol) was dissolved in THF (50 mL), NaH (342 mg, 8.55 mmol, 60%) was added at 0 °C, stirred for 2 h, then 9-formyl-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (800 mg, 2.85 mmol) was added, continued to stir at room temperature for 2 h, the reaction solution was diluted with water (100 mL), extracted with ethyl acetate (100 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:10) to obtain (E)-9-(3-ethoxy-3-oxoprop-1-en-1-yl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester.

[0151] 1 H NMR (400 MHz, DMSO-d6) δ 6.86 (dd, J = 15.8, 6.9 Hz, 1H), 5.80 (dd, J = 15.8, 1.1 Hz, 1H), 4.15-4.02 (m, 2H), 3.30-3.22 (m, 4H), 2.23-2.05 (m, 1H), 1.72-1.60 (m, 2H), 1.57-1.49 (m, 2H), 1.46-1.34 (m, 13H), 1.32 (s, 1H), 1.28 (s, 1H), 1.25-1.19 (m, 5H).

[0152] Step 2: Preparation of tert-butyl 9-(3-ethoxy-3-oxopropyl)-3-azaspiro[5.5]undecane-3- carboxylate

[0153]

[0154] (E)-9-(3-ethoxy-3-oxoprop-1-en-1-yl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (740 mg, 2.1 mmol) was dissolved in EtOH (30 mL), Pd / C (100 mg) was added under hydrogen atmosphere, the reaction was stirred at room temperature for 1 h, filtered through celite, the filtrate was directly concentrated under reduced pressure to give 9-(3-ethoxy-3-oxopropyl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester.

[0155] 1 H NMR (400 MHz, DMSO-d6) δ 4.05 (dq, J = 14.2, 7.2 Hz, 2H), 3.30 - 3.20 (m, 4H), 2.27 (t, J = 7.7 Hz, 2H), 1.66 - 1.55 (m, 2H), 1.51 - 1.41 (m, 4H), 1.40 - 1.32 (m, 11H), 1.25 - 1.12 (m, 6H), 1.08 - 0.97 (m, 4H).

[0156] Step 3: Preparation of 9-(3-hydroxypropyl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester

[0157]

[0158] 9-(3-ethoxy-3-oxopropyl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (700 mg, 1.98 mmol) was added to THF (30 mL), a solution of LiBH4(174 mg, 7.92 mmol) in THF was added dropwise at 0 °C, the reaction was heated to 80 °C and stirred for 16 h. The reaction was diluted with water (40 mL), extracted with ethyl acetate (40 mL x 3), the organic phase was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, the crude product was purified by silica gel column chromatography (PE:EA = 4:1) to give 9-(3-hydroxypropyl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester.

[0159] 1 H NMR (400 MHz, DMSO-d6) δ 4.32 (t, J = 5.1 Hz, 1H), 3.37 - 3.32 (m, 2H), 3.29 - 3.15 (m, 4H), 1.69 - 1.62 (m, 2H), 1.54 - 1.32 (m, 15H), 1.26 - 1.10 (m, 6H), 1.09 - 0.98 (m, 3H).

[0160] Step 4: Preparation of 9-(3-oxopropyl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester

[0161]

[0162] Step 4: Preparation of tert-butyl 9-(3-oxopropyl)-3-azaspiro[5.5]undecane-3- carboxylate tert-Butyl 9-(3-hydroxypropyl)-3-azaspiro[5.5]undecane-3-carboxylate (400 mg, 1.29 mmol) and PCC (660 mg, 2.58 mmol) were added into EA (20 mL), stirred at room temperature for 2 h, filtered by diatomite, the filtrate was directly concentrated under reduced pressure, the crude product was purified by silica gel column chromatography (PE:EA = 5:1) to give tert-butyl 9-(3-oxopropyl)-3-azaspiro[5.5]undecane-3-carboxylate.

[0163] 1 H NMR (400 MHz, DMSO-d6) δ 9.66 (s, 1H), 3.30-3.19 (m, 4H), 2.46-2.35 (m, 2H), 1.66-1.57 (m, 2H), 1.49-1.42 (m, 4H), 1.42-1.33 (m, 11H), 1.22-1.17 (m, 3H), 1.06-0.99 (m, 4H).

[0164] Step 5: Preparation of tert-butyl 9-(3-(benzyl(methyl)amino)propyl)-3- azaspiro[5.5]undecane-3-carboxylate

[0165]

[0166] Step 4: Preparation of tert-butyl 9-(3-oxopropyl)-3-azaspiro[5.5]undecane-3- carboxylate tert-Butyl 9-(3-hydroxypropyl)-3-azaspiro[5.5]undecane-3-carboxylate (400 mg, 1.29 mmol) and PCC (660 mg, 2.58 mmol) were added into EA (20 mL), stirred at room temperature for 2 h, filtered by diatomite, the filtrate was directly concentrated under reduced pressure, the crude product was purified by silica gel column chromatography (PE:EA = 5:1) to give tert-butyl 9-(3-oxopropyl)-3-azaspiro[5.5]undecane-3-carboxylate.

[0167] LC-MS: (ESI, m / z): [M+H] + = 415.3.

[0168] Step 6: Preparation of tert-butyl 9-(3-(methylamino)propyl)-3-azaspiro[5.5]undecane- 3-carboxylate

[0169]

[0170] tert-Butyl 9-(3-(methylamino)propyl)-3-azaspiro[5.5]undecane-3-carboxylate was prepared according to the procedure described in Example 1, Step 2.

[0171] LC-MS: (ESI, m / z): [M+H] = 325.3. +

[0172] Step 7: Preparation of tert-Butyl 9-(3-((1R,4R)-4-(4-(((R)-1-(3-((tert- butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2- methylquinazolin-6-yl)-N-methylcyclohexane-1-carboxamido)propyl)-3-azaspiro[5.5]undecane-3-carboxylate

[0173]

[0174] (1R,4R)-4-(4-(((R)-1-(3-((tert-butoxycarbonyl)amino)-5- (trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1- carboxylic acid (200 mg, 0.33 mmol), HATU (152 mg, 0.40 mmol) and DIEA (128 mg, 0.99 mmol) were added into DMF (30 mL), stirred at room temperature for 10 min, then tert-butyl 9-(3- (methylamino)propyl)-3-azaspiro[5.5]undecane-3-carboxylate (130 mg, 0.40 mmol) was added, and the stirring was continued for 1 hour. The reaction solution was diluted with water (40 mL), extracted with ethyl acetate (40 mL x 3), the organic phase was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 10:1) to obtain tert-butyl 9-(3-((1R,4R)-4-(4-(((R)-1-(3-((tert-butoxycarbonyl)amino)-5- (trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)-N- methylcyclohexane-1-carboxamido)propyl)-3-azaspiro[5.5]undecane-3-carboxylate.

[0175] LC-MS: (ESI, m / z): [M+H] = 909.5. +

[0176] ​​Step 8: Preparation of (1R,4R)-N-(3-(3-azaspiro[5.5]undecan-9-yl)propyl)-4-(4-(((R)-1-(3-amino-5- (trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)-N- methylcyclohexane-1-carboxamide

[0177]

[0178] Step 8: Preparation of (1R,4R)-N-(3-(3-azaspiro[5.5]undecan-9-yl)propyl)-4-(4-(((R)-1-(3-amino-5- (trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)-N- methylcyclohexane-1-carboxamide

[0179] Step 9: Preparation of (1R,4R)-4-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7- methoxy-2-methylquinazolin-6-yl)-N-(3-(3-(4-chloro-3-(2,4-dioxotetrahydropyrimidin- 1(2H)-yl)benzoyl)-3-azaspiro[5.5]undecan-9-yl)propyl)-N-methylcyclohexane-1- carboxamide

[0180]

[0181] To a solution of (1R,4R)-N-(3-(3-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)-3- azaspiro[5.5]undec-9-yl)propyl)-N-methylcyclohexane-1-carboxamide (120 mg, 0.17 mmol) in DMSO (10 mL) was added 4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoic acid pentafluoro phenyl ester (73.6 mg, 0.17 mmol), DIEA (65.8 mg, 0.51 mmol) and the reaction was stirred at room temperature for 30 min. The reaction was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by Prep-HPLC to give (1R,4R)-4-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2- methylquinazolin-6-yl)-N-(3-(3-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)-3- azaspiro[5.5]undec-9-yl)propyl)-N-methylcyclohexane-1-carboxamide.

[0182] 1 H NMR (400 MHz, DMSO-d6) δ 10.51 (s, 1H), 8.12 (s, 1H), 8.05 (d, J = 6.8 Hz, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.54 (s, 1H), 7.38 (d, J = 5.5 Hz, 1H), 6.99 (s, 1H), 6.88 (s, 1H), 6.85 (s, 1H), 6.70 (s, 1H), 5.66-5.40 (m, 3H), 3.89 (s, 3H), 3.79-3.70 (m, 1H), 3.66-3.46 (m, 4H), 3.28-3.22 (m, 2H), 3.10-2.86 (m, 4H), 2.90-2.55 (m, 5H), 2.36 (s, 3H), 1.9-1.75 (m, 4H), 1.72-1.39 (m, 14H), 1.35-0.96 (m, 9H).

[0183] Example 2: 1-(2-chloro-5-(4-((2-(1-((1R,4R)-4-(7-methoxy-2-methyl-4-(((R)-1-(4-(2-((methylamino)methyl)phenyl)thien-2-yl)ethyl)amino)quinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)ethoxy)methyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0184] Step 1: Preparation of tert-butyl 4-(2-(pyridin-4-ylmethoxy)ethyl)piperidine-1- carboxylate

[0185]

[0186] Tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate (2.00 g, 8.72 mmol) was dissolved in DMF (25 mL) solution, cooled to 0-5 °C. NaH (1.74 g, 43.6 mmol, 60%) was added portionwise, then stirred at room temperature for 30 min, the mixture was stirred at 0-5 °C for 30 min, then 4-(bromomethyl)pyridine hydrobromide (2.64 g, 10.46 mmol) was added and stirred at room temperature for 3 h. The mixture was diluted with aqueous NH4Cl (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure, the obtained crude was purified by silica gel column chromatography (PE:EtOAc = 50:1 ~ 1:1) to give tert-butyl 4-(2-(pyridin-4-ylmethoxy)ethyl)piperidine-1-carboxylate.

[0187] Step 2: Preparation of tert-butyl 4-(2-(piperidin-4-ylmethoxy)ethyl)piperidine-1- carboxylate

[0188]

[0189] To a solution of tert-butyl 4-(2-(pyridin-4-ylmethoxy)ethyl)piperidine-1-carboxylate (1.2 g, 3.74 mmol) in i-PrOH / H2O (20 mL / 20 mL) was added Pd / C (150 mg), and reacted at 65 °C overnight under the protection of hydrogen balloon. The reaction liquid was filtered through celite, and the filtrate was concentrated to give tert-butyl 4-(2-(piperidin-4-ylmethoxy)ethyl)piperidine-1-carboxylate.

[0190] LC-MS: (ESI, m / z): [M+H] + = 327.2.

[0191] Step 3: Preparation of tert-butyl 4-(2-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)- yl)benzoyl)piperidin-4-yl)methoxy)ethyl)piperidine-1-carboxylate

[0192]

[0193] To a solution of tert-butyl 4-(2-(piperidin-4-ylmethoxy)ethyl)piperidine-1- carboxylate (200 mg, 0.61 mmol) in DMSO (2 mL) was added 4-chloro-3-(2,4- dioxotetrahydropyrimidin-1 (2H)-yl)benzoic acid pentafluorophenyl ester (280 mg, 1.64 mmol) and DIEA (237 mg, 1.83 mmol), and the reaction was stirred at room temperature for 2 hours. Water (20 mL) was added to the reaction, which was extracted with ethyl acetate (20 mL x 2), and the combined organic phase was washed with saturated brine (30 mL x 3) and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate and purification by silica gel column chromatography (DCM:MeOH = 100:1 ~ 10:1) gave tert-butyl 4-(2-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1 (2H)-yl)benzoyl)piperidin-4-yl)methoxy)ethyl)piperidine-1-carboxylate.

[0194] LC-MS: (ESI, m / z): [M+Na] = 599.2. +

[0195] Step 4: Preparation of 1-(2-chloro-5-(4-((2-(piperidin-4-yl)ethoxy)methyl)piperidine-1- carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0196]

[0197] Tert-butyl 4-(2-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1 (2H)-yl)benzoyl)piperidin-4-yl)methoxy)ethyl)piperidine-1-carboxylate (250 mg, crude) was dissolved in DCM (4.5 mL), and TFA (1.5 mL) was added dropwise. The reaction was stirred at room temperature for 2 hours and concentrated to give 1-(2-chloro-5-(4-((2-(piperidin-4-yl)ethoxy)methyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione, which was used directly in the next reaction.

[0198] LC-MS: (ESI, m / z): [M+H] = 477.1. +

[0199] Step 5: Preparation of (2-(5-((R)-1-((6-((1R,4R)-4-(4-(2-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1 (2H)-yl)benzoyl)piperidin-4-yl)methoxy)ethyl)piperidine-1-carbonyl)cyclohexyl)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)thiophen-3-yl)benzyl)(methyl)carboxylate

[0200] LC-MS: (ESI, m / z): [M+H] = 477.1.​

[0201] To a solution of 1-(2-chloro-5-(4-((2-(1-((1R,4R)-4-(7-methoxy-2-methyl-4-(((R)-1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)quinolin-6-yl)cyclohexan-1-carbonyl)piperidin-4-yl)ethoxy)methyl)piperidin-1-yl)benzyl)carbamic acid tert-butyl ester (150 mg, 0.16 mmol) in DMSO (4 mL) was added (1R,4R)-4-(4-(((R)-1-(4-(2-(((tert-butoxycarbonyl)(methyl)amino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid (100 mg, 0.16 mmol) and DIEA (70 mg, 0.54 mmol). The reaction was stirred at room temperature for 2 hours. Water (20 mL) was added to the reaction, which was then extracted with ethyl acetate (20 mL x 2), the organic phases were combined and washed with saturated brine (30 mL x 3) and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate and purification of the resulting crude product by silica gel column chromatography (DCM:MeOH = 100:1 ~ 5:1) gave (2-(5-((R)-1-((6-((1R,4R)-4-(4-(2-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)methoxy)ethyl)piperidin-1-carbonyl)cyclohexyl)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)thiophen-3-yl)(methyl)carbamic acid tert-butyl ester.

[0202] LC-MS: (ESI, m / z): [(M-Boc) / 2 + H] + = 502.2.

[0203] Step 6: Preparation of 1-(2-chloro-5-(4-((2-(1-((1R,4R)-4-(7-methoxy-2-methyl-4-(((R)-1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)quinolin-6-yl)cyclohexan-1-carbonyl)piperidin-4-yl)ethoxy)methyl)piperidin-1-yl)benzyl)carbamic acid tert-butyl ester

[0204]

[0205] To a solution of tert-butyl (2-(5-((R)-1-((6-((1R,4R)-4-(4-(2-((1-(4-chloro-3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)methoxy)ethyl)piperidine-1- carbonyl)cyclohexyl)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)thiophen-3-yl)benzyl)(methyl)carboxylate (130 mg, crude) in DCM (3 mL) was added TFA (1 mL). The reaction was stirred at room temperature for 2 hours, the reaction was directly concentrated under reduced pressure, the crude was purified by pre-HPLC to give 1-(2-chloro-5-(4-((2-(1-((1R,4R)-4-(7-methoxy-2-methyl-4-(((R)-1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)quinolin-6-yl)cyclohexan-1-yl)piperidin-4-yl)ethoxy)methyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[0206] LC-MS: (ESI, m / z): [M / 2 + H] + = 502.2.

[0207] 1 H NMR (400 MHz, CD3OD) δ 7.99 (s, 1H), 7.67 - 7.59 (m, 1H), 7.55 - 7.26 (m, 6H), 7.22 - 7.11 (m, 2H), 7.01 (s, 1H), 6.06 (q, J = 6.5 Hz, 1H), 4.66 - 4.49 (m, 2H), 4.08 - 3.92 (m, 4H), 3.79 - 3.68 (m, 4H), 3.49 (t, J = 6.1 Hz, 2H), 3.18 - 3.01 (m, 3H), 2.91 - 2.48 (m, 8H), 2.21 (s, 3H), 2.01 - 1.49 (m, 20H), 1.38 - 1.11 (m, 6H).

[0208] Example 3: 2-(2,6-dioxopiperidin-3-yl)-5-(4-((2-(1-((1R,4R)-4-(7-methoxy-2-methyl-4-(((R)-1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)quinolin-6-yl)cyclohexan-1-yl)piperidin-4-yl)ethoxy)methyl)piperidin-1-yl)isoindoline-1,3-dione

[0209] Step 1: Preparation of tert-butyl 4-(2-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methoxy)ethyl)piperidine-1-carboxylate

[0210]

[0211] tert-Butyl 4-(2-(piperidin-4-ylmethoxy)ethyl)piperidine-1-carboxylate (200 mg, 0.61 mmol) was dissolved in DMSO (4 mL), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (186 mg, 0.67 mmol) and DIEA (237 mg, 1.83 mmol) were added. The mixture was reacted at 70 °C for 16 hours. After cooling to room temperature, water (20 mL) was added to the reaction solution, which was extracted with ethyl acetate (20 mL x 2). The organic phases were combined and washed with saturated aqueous sodium chloride solution (30 mL x 3) and dried over anhydrous sodium sulfate. Filtration was performed, and the filtrate was concentrated. The obtained crude product was purified by silica gel column chromatography (DCM:MeOH = 100:1 ~ 20:1) to obtain tert-butyl 4-(2-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methoxy)ethyl)piperidine-1-carboxylate.

[0212] LC-MS: (ESI, m / z): [M-Boc+H] + = 483.1.

[0213] Step 2: Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-(4-((2-(piperidin-4-yl)ethoxy)methyl)piperidin-1-yl)isoindoline-1,3-dione

[0214]

[0215] tert-Butyl 4-(2-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methoxy)ethyl)piperidine-1-carboxylate (240 mg, crude) was dissolved in DCM (4.5 mL), and TFA (1.5 mL) was added. The obtained reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated to obtain 2-(2,6-dioxopiperidin-3-yl)-5-(4-((2-(piperidin-4-yl)ethoxy)methyl)piperidin-1-yl)isoindoline-1,3-dione.

[0216] LC-MS: (ESI, m / z): [M+H] + = 483.2.

[0217] Step 3: Preparation of tert-butyl (2-(5-((1R)-1-((6-((1R,4R)-4-(4-(2-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methoxy)ethyl)piperidine-1-carbonyl)cyclohexyl)-7-methoxy-2-methylquinolin-4-yl)amino)ethyl)thiophen-3-yl)benzyl)(methyl)carboxylate

[0218]

[0219] To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-(4-((2-(piperidin-4-yl)ethoxy)methyl)piperidin-1-yl)isoindoline-1,3-dione (150 mg, 0.31 mmol) in DMSO (4 mL) was added (1R,4R)-4-(4-(((R)-1-(4-(2-(((tert-butoxycarbonyl)(methyl)amino))methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinolin-6-yl)cyclohexane-1-carboxylic acid pentafluorophenyl ester (285 mg, 0.35 mmol) and DIEA (136 mg, 1.05 mmol). The mixture was stirred at room temperature for 2 hours. Water (20 mL) was added to the reaction solution, which was extracted with ethyl acetate (20 mL x 2), the organic phases were combined and washed with saturated brine (30 mL x 3), and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate, and purification of the obtained crude product by silica gel column chromatography (DCM:MeOH = 100:1 ~ 5:1) gave tert-butyl (2-(5-((1R)-1-((6-((1R,4R)-4-(4-(2-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methoxy)ethyl)piperidine-1-carbonyl)cyclohexyl)-7-methoxy-2-methylquinolin-4-yl)amino)ethyl)thiophen-3-yl)benzyl)(methyl)carboxylate.

[0220] LC-MS: (ESI, m / z): [M / 2 + H] + = 555.3.

[0221] Step 4: Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-(4-((2-(1-((1R,4R)-4-(7-methoxy-2-methyl-4-(((R)-1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)quinolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)ethoxy)methyl)piperidin-1-yl)isoindoline-1,3-dione

[0222]

[0223] tert-Butyl (2-(5-((1R)-1-((6-((1R,4R)-4-(4-(2-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methoxy)ethyl)piperidine-1-carbonyl)cyclohexyl)-7-methoxy-2-methylquinolin-4-yl)amino)ethyl)thiophen-3-yl)benzyl)(methyl)carboxylate (180 mg, crude) was dissolved in DCM (1 mL), and TFA (0.5 mL) was added. The mixture was stirred at room temperature for 2 hours, concentrated, and the resulting crude was purified by pre-HPLC to give 2-(2,6-dioxopiperidin-3-yl)-5-(4-((2-(1-((1R,4R)-4-(7-methoxy-2-methyl-4-(((R)-1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)quinolin-6-yl)cyclohexan-1-carbonyl)piperidin-4-yl)ethoxy)methyl)piperidin-1-yl)isoindoline-1,3-dione.

[0224] LC-MS: (ESI, m / z): [M+H] 1009.3. +

[0225] 1 H NMR (400 MHz, CD3OD) δ 8.12 (s, 1H), 7.67 - 7.60 (m, 1H), 7.57 - 7.52 (m, 1H), 7.46 - 7.38 (m, 3H), 7.32 (t, J = 2.2 Hz, 1H), 7.27 (s, 1H), 7.22 - 7.16 (m, 2H), 7.03 (s, 1H), 6.11 (q, J = 6.8 Hz, 1H), 4.64 - 4.46 (m, 4H), 4.21 (s, 2H), 4.05 (d, J = 13.2 Hz, 2H), 3.97 (s, 3H), 3.59 - 3.54 (m, 2H), 3.23 - 2.93 (m, 6H), 2.83 - 2.65 (m, 4H), 2.59 - 2.50 (m, 6H), 1.94 - 1.80 (m, 10H), 1.73 - 1.66 (m, 4H), 1.57 - 1.54 (m, 2H), 1.41 - 1.33 (m, 8H).

[0226] ​Example 4: 1-(2-chloro-5-(4-(4-(4-(4-((1R,4R)-4-(7-methoxy-2-methyl-4-(((R)-1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)quinazolin-6-yl)cyclohexane-1-carbonyl)piperazin-1-yl)butyl)piperidin-1-ylcarbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0227] Step 1: Preparation of 4-(pyridin-4-yl)butanal

[0228]

[0229] Step 1: Preparation of 4-(pyridin-4-yl)butanal

[0230] 1 H NMR (400 MHz, CDC13) δ 9.79 (s, 1H), 8.52 (d, J = 5.6 Hz, 2H), 7.13 (d, J = 5.6 Hz, 2H), 2.66 (t, J = 7.2 Hz, 2H), 2.50 (t, J = 7.2 Hz, 2H), 2.03 - 1.94 (m, 2H).

[0231] Step 2: Preparation of tert-butyl 4-(4-(pyridin-4-yl)butyl)piperazine-1-carboxylate

[0232]

[0233] To a solution of 4-(pyridin-4-yl)butanal (1.60 g, 10.73 mmol) and tert-butyl piperazine-1-carboxylate (3.00 g, 16.10 mmol) in 1,2-dichloroethane / methanol (28 mL / 14 mL) was added acetic acid (3 mL). The mixture was stirred at 30 °C for 1 h. NaBH(OAc)3(4.55 g, 21.48 mmol) was added at 0 °C and the reaction was stirred at room temperature for 16 h. The reaction was completed, H2O (10 mL) was added to the reaction mixture and extracted with ethyl acetate (30 ml x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude product was purified by silica gel column chromatography (DCM:MeOH = 20:1) to give tert-butyl 4-(4-(pyridin-4-yl)butyl)piperazine-1-carboxylate.

[0234] LC-MS: (ESI, m / z): [M+H] + = 320.2.

[0235] Step 3: Preparation of tert-butyl 4-(4-(piperidin-4-yl)butyl)piperazine-1-carboxylate

[0236]

[0237] To a solution of tert-butyl 4-(4-(pyridin-4-yl)butyl)piperazine-1-carboxylate (1.10 g, 3.44 mmol) in i-PrOH / H2O (20 mL / 20 mL) was added Pd / C (150 mg) and the reaction was stirred at 75 °C for 16 h under hydrogen balloon protection. The reaction was filtered through celite and the filtrate was concentrated to give tert-butyl 4-(4-(piperidin-4-yl)butyl)piperazine-1-carboxylate which was used directly in the next step.

[0238] LC-MS: (ESI, m / z): [M+H] + = 326.3.

[0239] Step 4: Preparation of tert-butyl 4-(4-(1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)- yl)benzoyl)piperidin-4-yl)butyl)piperazine-1-carboxylate

[0240]

[0241] To a solution of tert-butyl 4-(4-(piperidin-4-yl)butyl)piperazine-1-carboxylate (300 mg, 0.92 mmol) in DMSO (6 mL) was added 4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)- yl)benzoic acid pentafluorophenyl ester (401 mg, 0.92 mmol) and DIEA (238 mg, 1.84 mmol), the reaction was stirred at room temperature for 2 hours. Water (20 mL) was added to the reaction, extracted with ethyl acetate (20 mL x 2), the organic phases were combined and washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, the obtained crude was purified by silica gel column chromatography (DCM:MeOH = 100:1 ~ 10:1) to give tert-butyl 4-(4-(1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)- yl)benzoyl)piperidin-4-yl)butyl)piperazine-1-carboxylate.

[0242] LC-MS: (ESI, m / z): [M+H] + = 576.0.

[0243] Step 5: Preparation of 1-(2-chloro-5-(4-(4-(piperazin-1-yl)butyl)piperidine-1- carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0244]

[0245] Tert-butyl 4-(4-(1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)- yl)benzoyl)piperidin-4-yl)butyl)piperazine-1-carboxylate (150 mg, 0.315 mmol) was dissolved in DCM (3 mL), then TFA (1.5 mL) was added dropwise. The reaction was stirred at room temperature for 1 hour and concentrated to give 1-(2-chloro-5-(4-(4-(piperazin-1-yl)butyl)piperidine-1- carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione, which was used directly in the next step.

[0246] LC-MS: (ESI, m / z): [M+H] + = 476.0.

[0247] Step 6: Preparation of (2-(5-((R)-1-((6-((1R,4R)-4-(4-(4-(1-(4-chloro-3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)butyl)piperazine-1- carbonyl)cyclohexyl)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)thiophen-3- yl)benzyl)(methyl)carboxylate

[0248]

[0249] 1-(2-chloro-5-(4-(4-(piperazin-1-yl)n-butyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (280 mg, crude) was dissolved in DMSO (4 mL), and (1R,4R)-4-(4-((R)-1-(4-(2-((tert-butoxycarbonyl)(methyl)amino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazoline-6-yl)cyclohexane-1-carboxylic acid ester (255 mg, 0.315 mmol) and DIEA (203 mg, 1.575 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL x 2). The organic phases were combined and washed with saturated brine (30 mL x 3), and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated. The crude product was purified by silica gel column chromatography (DCM:MeOH = 100:1 to 5:1) to obtain (2-(5-((R)-1-((6-((1R,4R)-4-(4-(4-(1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)n-butyl)piperazine-1-carbonyl)cyclohexyl)-7-methoxy-2-methylquinazoline-4-yl)amino)ethyl)thiophene-3-yl)benzyl)(methyl)carboxylic acid tert-butyl ester.

[0250] LC-MS:(ESI,m / z):[M+H] + =1102.5.

[0251] Step 7: Preparation of 1-(2-chloro-5-(4-(4-(4-((1R,4R)-4-(7-methoxy-2-methyl-4-(((R)-1-(4-(2-((methylamino)methyl)phenyl)thiophene-2-yl)ethyl)amino)quinazolin-6-yl)cyclohexane-1-carbonyl)piperazin-1-yl)n-butyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0252]

[0253] To a solution of (2-(5-((R)-1-((6-((1R,4R)-4-(4-(4-(1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)butyl)piperazin-1-carbonyl)cyclohexyl)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)thiophen-3-yl)benzyl)(methyl)carboxylate (140 mg, 0.13 mmol) in dichloromethane (2.0 mL) was added trifluoroacetic acid (1.0 mL) and stirred at 30 °C for 1 h. After the reaction was completed, it was concentrated under reduced pressure. The crude product was purified by pre-HPLC to give 1-(2-chloro-5-(4-(4-(4-((1R,4R)-4-(7-methoxy-2-methyl-4-(((R)-1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)quinazolin-6-yl)cyclohexan-1-carbonyl)piperazin-1-yl)butyl)piperidin-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[0254] LC-MS: (ESI, m / z): [M+H] + = 1002.3.

[0255] 1 H NMR (400 MHz, CDCl3) δ 7.54 - 7.49 (m, 2H), 7.41 - 7.29 (m, 6H), 7.22 - 7.12 (m, 3H), 6.50-6.23 (m, 1H), 6.09 - 6.03 (m, 1H), 4.75 - 4.52 (s, 1H), 3.91 (s, 3H), 3.85 (s, 2H), 3.78 - 3.45 (m, 8H), 3.08 - 2.31 (m, 24H), 2.00 - 1.83 (m, 4H), 1.59 - 1.42 (m, 5H), 1.37 - 0.89 (m, 8H).

[0256] Example 5: 3-(4-(9-((4-((1R,4R)-4-(7-methoxy-2-methyl-4-(((R)-1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)quinazolin-6-yl)cyclohexan-1-carbonyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)piperidine-2,6-dione

[0257] Step 1: Preparation of 4-(2,6-di(benzyloxy)pyridin-3-yl)benzoic acid

[0258]

[0259] To a mixture of 2,6-bis(benzyloxy)-3-bromopyridine (2.80 g, 7.57 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (1.87 g, 11.35 mmol) in dioxane / H2O (50 mL / 10 ml) was added Pd(dppf)Cl2(262 mg, 0.36 mmol) and sodium carbonate (2.01 g, 18.92 mmol). The mixture was reacted at 80 °C for 16 h under nitrogen protection, cooled to room temperature, adjusted pH = 2 by adding 1 N aqueous HCl solution, extracted with ethyl acetate (30 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (DCM:MeOH = 100:1 ~ 2:1) to give 4-(2,6-di(benzyloxy)pyridin-3-yl)benzoic acid.

[0260] LC-MS: (ESI, m / z): [M+H] + = 412.1.

[0261] Step 2: Preparation of 4-(2,6-dioxopiperidin-3-yl)benzoic acid

[0262]

[0263] To a solution of 4-(2,6-di(benzyloxy)pyridin-3-yl)benzoic acid (0.50 g, 1.22 mmol) in i-PrOH (20 mL) was added Pd / C (0.2 mg), and reacted at 40 °C for 16 h under the protection of a hydrogen balloon. The reaction liquid was filtered through celite, and the filtrate was concentrated to give 4-(2,6-dioxopiperidin-3-yl)benzoic acid, which was directly used in the next reaction.

[0264] LC-MS: (ESI, m / z): [M-H] - = 231.9.

[0265] Step 3: Preparation of 4-((3-(4-(2,6-dioxopiperidin-3-yl)benzoyl)-3- azaspiro[5.5]undec-9-yl)methyl)piperazine-1-carboxylate benzyl ester

[0266]

[0267] benzyl 4-((3-(4-(2,6-dioxopiperidin-3-yl)benzoyl)-3-azaspiro[5.5]undecan-9- yl)methyl)piperazine-1-carboxylate (230 mg, 0.38 mmol) in i-PrOH (5 mL) was added Pd / C (0.2 mg) and stirred at room temperature for 2 h under the protection of hydrogen balloon. The reaction mixture was filtered through celite and the filtrate was concentrated to give 3-(4-(9-(piperazin-1-ylmethyl)-3-azaspiro[5.5]undecane-3- carbonyl)phenyl)piperidine-2,6-dione, which was used directly in the next step.

[0268] LC-MS: (ESI, m / z): [M+H] = 467.0. + LC-MS: (ESI, m / z): [M+H] = 467.0.

[0269] Step 4: Preparation of 3-(4-(9-(piperazin-1-ylmethyl)-3-azaspiro[5.5]undecane-3- carbonyl)phenyl)piperidine-2,6-dione

[0270]

[0271] benzyl 4-((3-(4-(2,6-dioxopiperidin-3-yl)benzoyl)-3-azaspiro[5.5]undecan-9- yl)methyl)piperazine-1-carboxylate (230 mg, 0.38 mmol) in i-PrOH (5 mL) was added Pd / C (0.2 mg) and stirred at room temperature for 2 h under the protection of hydrogen balloon. The reaction mixture was filtered through celite and the filtrate was concentrated to give 3-(4-(9-(piperazin-1-ylmethyl)-3-azaspiro[5.5]undecane-3- carbonyl)phenyl)piperidine-2,6-dione, which was used directly in the next step.

[0272] LC-MS: (ESI, m / z): [M+H] = 467.0. + LC-MS: (ESI, m / z): [M+H] = 467.0.

[0273] Step 5: Preparation of (2-(5-((1R)-1-((6-((1R,4R)-4-(4-((3-(4-(2,6-dioxopiperidin-3- yl)benzoyl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperazine-1-carbonyl)cyclohexyl)-7- methoxy-2-methylquinazolin-4-yl)amino)ethyl)thiophen-3-yl)benzyl)(methyl)carboxylate

[0274] LC-MS: (ESI, m / z): [M+H] = 467.0.

[0275] To a solution of 3-(4-(9-(piperazin-l-ylmethyl)-3-azaspiro[5.5]undecane-3- carbonyl)phenyl)piperidine-2,6-dione (250 mg, crude) in DMSO (2 mL) was added (1R,4R)-4-(4-((R)-l-(4-(2-((tert-butoxycarbonyl)(methyl)amino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-l- carboxylic acid pentafluorophenyl ester (308 mg, 0.38 mmol) and DIEA (245 mg, 1.90 mmol), the reaction was stirred at room temperature for 2 hours. Water (20 mL) was added to the reaction, which was then extracted with ethyl acetate (20 mL x 2), the organic phases were combined and washed with saturated brine (30 mL x 3) and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate gave crude (2-(5-((lR)-l-((6-((lR,4R)-4-(4-((3-(4-(2,6-dioxopiperidin-3-yl)benzoyl)-3- azaspiro[5.5]undec-9-yl)methyl)piperazine-l-carbonyl)cyclohexyl)-7-methoxy-2- methylquinazolin-4-yl)amino)ethyl)thiophen-3-yl)benzyl)(methyl)carboxylic acid tert-butyl ester.

[0276] LC-MS: (ESI, m / z): [M / 2 + H] + = 547.4.

[0277] Step 6: Preparation of 3-(4-(9-((4-((lR,4R)-4-(7-methoxy-2-methyl-4-(((R)-l-(4-(2- ((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)quinazolin-6-yl)cyclohexane-l- carbonyl)piperazin-l-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)piperidine-2,6- dione

[0278]

[0279] To a solution of tert-butyl (2-(5-((1R)-1-((6-((1R,4R)-4-(4-((3-(4-(2,6-dioxopiperidin-3-yl)benzoyl)-3- azaspiro[5.5]undec-9-yl)methyl)piperazine-1-carbonyl)cyclohexyl)-7-methoxy-2-methylquinolin-4- yl)amino)ethyl)thiophen-3-yl)benzyl)(methyl)carboxylate (160 mg, 0.15 mmol) in dichloromethane (2.0 mL) was added trifluoroacetic acid (1.0 mL) and stirred at 30 °C for 1 h. After the reaction was completed, it was concentrated under reduced pressure. The crude product was purified by pre-HPLC to give 3-(4-(9-((4-((1R,4R)-4-(7-methoxy-2-methyl-4-(((R)-1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)quinolin-6-yl)cyclohexane-1-carbonyl)piperazin-1-yl)methyl)-3- azaspiro[5.5]undecane-3-carbonyl)phenyl)piperidine-2,6-dione.

[0280] LC-MS: (ESI, m / z): [M / 2+H] + = 497.4.

[0281] 1 H NMR (400 MHz, CD3OD) δ 7.42 - 7.39 (m, 3H), 7.32 - 7.27 (m, 6H), 7.24 - 7.12 (m, 2H), 7.11 (s, 1H), 6.06 - 5.98 (m, 1H), 5.66 (d, J = 8.0 Hz, 1H), 3.92 (s, 3H), 3.83 - 3.79 (m, 1H), 3.75 - 3.68 (m, 3H), 3.65 - 3.59 (m, 2H), 3.56 - 3.48 (m, 2H), 3.42 - 3.26 (m, 2H), 3.14 - 3.02 (m, 1H), 2.78 - 2.12 (m, 17H), 2.05 - 1.70 (m, 14H), 1.54 - 1.10 (m, 13H).

[0282] Example 6: 1-(2-chloro-5-(4-(2-((1-((1R,4R)-4-(4-(((R)-1-(4-(2-chloro-6-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)methoxy)ethyl)piperazine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0283] Step 1: Preparation of tert-butyl 4-(2-((l-((lR,4R)-4-(4-(((R)-l-(4-(2-chloro-6- ((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2- methylquinazolin-6-yl)cyclohexan-l -carbonyl)piperidin-4-yl)methoxy)ethyl)piperazine- 1 -carboxylate

[0284]

[0285] (1R,4R)-4-(4-(((R)-l-(4-(2-chloro-6-((dimethylamino)methyl)phenyl)thiophen-2- yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-l -carboxylic acid (145 mg, 0.24 mmol) was dissolved in DMF (5 mL), then tert-butyl 4-(2-(piperidin-4- ylmethoxy)ethyl)piperazine-l-carboxylate (80 mg, 0.24 mmol), HATU (102 mg, 0.31 mmol) and DIEA (93 mg, 0.72 mmol) were added, and the reaction solution was stirred at room temperature overnight. The reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3), and the organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (methanol:dichloromethane = 1 :9) to obtain tert-butyl 4-(2-((l-((lR,4R)-4-(4-(((R)-l-(4-(2-chloro-6- ((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2- methylquinazolin-6-yl)cyclohexan-l-carbonyl)piperidin-4-yl)methoxy)ethyl)piperazine- 1 -carboxylate.

[0286] LC-MS: (ESI, m / z): [M+H] + = 902.5.

[0287] Step 2: Preparation of ((lR,4R)-4-(4-(((R)-l-(4-(2-chloro-6-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexyl)(4- ((2-(piperazin-l-yl)ethoxy)methyl)piperidin-l-yl)methanone

[0288]

[0289] 4-(2-((1-((1R,4R)-4-(4-(((R)-1-(4-(2-chloro-6-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinolin-6-yl)cyclohexan-1-carbonyl)piperidin-4-yl)methoxy)ethyl)piperazin-1-yl)acetic acid (120 mg, 0.13 mmol) was dissolved in dichloromethane (5 mL), then trifluoroacetic acid (1 mL) was added and stirred at room temperature for 2 hours, the reaction solution was directly concentrated under reduced pressure to obtain ((1R,4R)-4-(4-(((R)-1-(4-(2-chloro-6-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinolin-6-yl)cyclohexyl)(4-((2-(piperazin-1-yl)ethoxy)methyl)piperidin-1-yl)methanone, which was directly used in the next reaction without purification.

[0290] LC-MS: (ESI, m / z): [M+H] + = 802.4.

[0291] Step 3: Preparation of 1-(2-chloro-5-(4-(2-((1-((1R,4R)-4-(4-(((R)-1-(4-(2-chloro-6- ((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinolin-6- yl)cyclohexan-1-carbonyl)piperidin-4-yl)methoxy)ethyl)piperazin-1-ylcarbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0292]

[0293] ((1R,4R)-4-(4-(((R)-1-(4-(2-chloro-6-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexyl)(4-((2-(piperazin-1-yl)ethoxy)methyl)piperidin-1-yl)methanone (120 mg, 0.13 mmol) was dissolved with dimethyl sulfoxide (5 mL), 4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoic acid pentafluorophenyl ester (57 mg, 0.13 mmol) and DIEA (168 mg, 1.3 mmol) were added, the reaction was stirred at room temperature for 2 hours. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3), the organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by pre-HPLC to obtain 1-(2-chloro-5-(4-(2-((1-((1R,4R)-4-(4-(((R)-1-(4-(2-chloro-6-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexan-1-carbonyl)piperidin-4-yl)methoxy)ethyl)piperazin-1-yl)carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[0294] LC-MS: (ESI, m / z): [M+H] + = 1052.4.

[0295] 1 H NMR (400 MHz, DMSO-d6) δ 10.51 (s, 1H), 8.31 (d, J = 8.3 Hz, 1H), 8.05 (s, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.55 (s, 1H), 7.45 - 7.31 (m, 4H), 7.24 (s, 1H), 7.02 (s, 1H), 6.96 (s, 1H), 6.04 - 5.88 (m, 1H), 4.44 - 4.34 (m, 1H), 3.97 - 3.86 (m, 4H), 3.78 - 3.71 (m, 1H), 3.66 - 3.54 (m, 3H), 3.50 - 3.45 (m, 2H), 3.27 - 3.20 (m, 2H), 3.15 - 2.87 (m, 5H), 2.81 - 2.56 (m, 6H), 2.45 - 2.37 (m, 5H), 2.01 (s, 6H), 1.93 - 1.42 (m, 17H), 1.13 - 0.91 (m, 2H).

[0296] Example 7: 1-(5-(4-(3-(4-((1R,4R)-4-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexan-1-carbonyl)piperazin-1-yl)propyl)piperidin-1-yl)-2-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0297] Step 1: Preparation of 3-(1-(4-chloro-3-nitrophenyl)piperidin-4-yl)propan-1-ol

[0298]

[0299] DMSO (30 mL), then 3-(piperidin-4-yl)propan-1-ol (3.66 g, 25.57 mmol) and DIEA (6.59 g, 51.12 mmol) were added and warmed to 50 °C and stirred overnight. Water (200 mL) was added to the reaction solution, and ethyl acetate (100 mL x 3) was used for extraction. The organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:4) to obtain 3-(1-(4-chloro-3-nitrophenyl)piperidin-4-yl)propan-1-ol.

[0300] LC-MS: (ESI, m / z): [M+H] + = 299.1.

[0301] Step 2: Preparation of benzoic acid 3-(1-(4-chloro-3-nitrophenyl)piperidin-4-yl)propyl ester

[0302]

[0303] 3-(1-(4-chloro-3-nitrophenyl)piperidin-4-yl)propan-1-ol (200 mg, 0.67 mmol) was dissolved in tetrahydrofuran (10 mL), and then benzoyl chloride (122 mg, 0.8 mmol) and triethylamine (203 mg, 0.8 mmol) were added sequentially. The reaction solution was heated to 70 °C and stirred overnight. Water (50 mL) was added to the reaction solution, and ethyl acetate (50 mL x 3) was used for extraction. The organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:9) to obtain benzoic acid 3-(1-(4-chloro-3-nitrophenyl)piperidin-4-yl)propyl ester.

[0304] LC-MS: (ESI, m / z): [M+H] + = 403.2.

[0305] Step 3: Preparation of Benzoic acid 3-(l-(3-amino-4-chlorophenyl)piperidin-4- yl)propyl ester

[0306]

[0307] Benzoic acid 3-(l-(3-amino-4-chlorophenyl)piperidin-4-yl)propyl ester (900 mg, 2.42 mmol) and acrylic acid (1.74 g, 24.19 mmol) were added to H2O / AcOH (5 / 1, 12 mL) and the reaction was stirred at 110 °C overnight under nitrogen atmosphere. The reaction was directly concentrated under reduced pressure and the crude was purified by pre-HPLC (acetonitrile / formic acid water system) to give 3-((5-(4-(3-(benzoyloxy)propyl)piperidin-l-yl)-2-chlorophenyl)amino)propanoic acid.

[0308] LC-MS: (ESI, m / z): [M+H] + = 445.2.

[0309] Step 4: Preparation of 3-((5-(4-(3-(benzoyloxy)propyl)piperidin-l-yl)-2- chlorophenyl)amino)propanoic acid

[0310]

[0311] Benzoic acid 3-(l-(3-amino-4-chlorophenyl)piperidin-4-yl)propyl ester (900 mg, 2.42 mmol) and acrylic acid (1.74 g, 24.19 mmol) were added to H2O / AcOH (5 / 1, 12 mL) and the reaction was stirred at 110 °C overnight under nitrogen atmosphere. The reaction was directly concentrated under reduced pressure and the crude was purified by pre-HPLC (acetonitrile / formic acid water system) to give 3-((5-(4-(3-(benzoyloxy)propyl)piperidin-l-yl)-2-chlorophenyl)amino)propanoic acid.

[0312] LC-MS: (ESI, m / z): [M+H] + = 445.2.

[0313] Step 5: Preparation of Benzoic acid 3-(l-(4-chloro-3-(2,4-dioxotetrahydropyrimidin- l(2H)-yl)phenyl)piperidin-4-yl)propyl ester

[0314]

[0315] Dissolve 3-((5-(4-(3-(benzoyloxy)propyl)piperidin-1-yl)-2-chlorophenyl)amino)propanoic acid (850 mg, 1.91 mmol) with AcOH (8 mL), then add urea (1.19 g, 19.14 mmol), and stir the reaction solution at 110°C overnight. Add water (80 mL) to the reaction solution, extract with ethyl acetate (50 mL x 3), combine the organic phases, wash with saturated aqueous sodium chloride solution, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify the crude product by silica gel column chromatography (PE:EA = 2:1) to obtain 3-(1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)propanoic acid benzyl ester.

[0316] LC-MS: (ESI, m / z): [M+H] + = 470.1.

[0317] Step 6: Preparation of 1-(2-chloro-5-(4-(3-hydroxypropyl)piperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0318]

[0319] Dissolve 3-(1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)propanoic acid benzyl ester (500 mg, 1.06 mmol) with methanol / concentrated hydrochloric acid (1:1, 8 mL), and stir the reaction solution at 70°C overnight under a nitrogen atmosphere. Directly concentrate under reduced pressure, and purify the crude product by pre-HPLC (acetonitrile / formic acid water system) to obtain 1-(2-chloro-5-(4-(3-hydroxypropyl)piperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[0320] LC-MS: (ESI, m / z): [M+H] + = 366.1.

[0321] Step 7: Preparation of 3-(1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)propanal

[0322]

[0323] 1-(2-chloro-5-(4-(3-hydroxypropyl)piperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (200 mg, 0.55 mmol) was dissolved in dichloromethane (10 mL), Dess-Martin (466 mg, 1.10 mmol) was added and stirred at room temperature overnight. The reaction solution was directly concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain 3-(1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)propanal.

[0324] LC-MS: (ESI, m / z): [M+H] + = 364.0.

[0325] Step 8: Preparation of tert-butyl 4-(3-(1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)propyl)piperazine-1-carboxylate

[0326]

[0327] tert-Butyl 4-(3-(1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)propyl)piperazine-1-carboxylate (110 mg, 0.20 mmol) was dissolved in THF (10 mL), and sodium triacetoxyborohydride (95 mg, 0.45 mmol) was added and stirred at room temperature overnight. Water (50 mL) was added to the reaction solution, and ethyl acetate (50 mL x 3) was extracted. The combined organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 2:1) to obtain tert-butyl 4-(3-(1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)propyl)piperazine-1-carboxylate.

[0328] LC-MS: (ESI, m / z): [M+H] + = 534.2.

[0329] Step 9: Preparation of 1-(2-chloro-5-(4-(3-(piperazin-1-yl)propyl)piperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0330]

[0331] tert-Butyl 4-(3-(1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4- yl)propyl)piperazine-1-carboxylate (120 mg, 0.225 mmol) was dissolved with DCM / TFA (1:1, 8 mL) and stirred at room temperature for 1 hour, the reaction was concentrated under reduced pressure to give 1-(2-chloro-5-(4-(3-(piperazin-1-yl)propyl)piperidin-1-yl)phenyl)dihydropyrimidine- 2,4(1H,3H)-dione. Without purification, it was used directly in the next step.

[0332] LC-MS: (ESI, m / z): [M+H] = 434.2. +

[0333] Step 10: Preparation of tert-butyl (3-((R)-1-((6-((1R,4R)-4-(4-(3-(1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)propyl)piperazin-1- carbonyl)cyclohexyl)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)-5- (trifluoromethyl)phenyl)carboxylate

[0334]

[0335] tert-Butyl 4-(3-(1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4- yl)propyl)piperazine-1-carboxylate (120 mg, 0.225 mmol) was dissolved with DCM / TFA (1:1, 8 mL) and stirred at room temperature for 1 hour, the reaction was concentrated under reduced pressure to give 1-(2-chloro-5-(4-(3-(piperazin-1-yl)propyl)piperidin-1-yl)phenyl)dihydropyrimidine- 2,4(1H,3H)-dione. Without purification, it was used directly in the next step.

[0336] LC-MS: (ESI, m / z): [M+H] = 1018.4. + ​​

[0337] Step 11: Preparation of l-(5-(4-(3-(4-((lR,4R)-4-(4-(((R)-l-(3-amino-5- (trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-l- carbonyl)piperazin-l-yl)propyl)piperidin-l-yl)-2-chlorophenyl)dihydropyrimidine-2,4(lH,3H)- dione

[0338]

[0339] tert-Butyl (3-((R)-l-((6-((lR,4R)-4-(4-(3-(l-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-l(2H)- yl)phenyl)piperidin-4-yl)propyl)piperazine-l-carbonyl)cyclohexyl)-7-methoxy-2- methylquinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)carbamate (100 mg, 0.10 mmol) was dissolved with DCM / TFA (1 / 1, 8 mL) and stirred at room temperature for 1 hour, the reaction was directly concentrated under reduced pressure, the crude product was purified using pre-HPLC to give l-(5-(4-(3-(4-((lR,4R)-4-(4-(((R)-l-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-l-carbonyl)piperazin-l-yl)propyl)piperidin-l-yl)-2-chlorophenyl)dihydropyrimidine-2,4(lH,3H)-dione.

[0340] LC-MS: (ESI, m / z): [M+H] = 918.4. + = 918.4.

[0341] 1 H NMR (400 MHz, DMSO-d6) δ 10.39 (s, 1H), 8.20-8.00 (m, 2H), 7.30 (d, J = 8.8 Hz, 1H), 7.03 (s, 1H), 6.99 (s, 1H), 6.94-6.86 (m, 2H), 6.85 (s, 1H), 6.70 (s, 1H), 5.63-5.46 (m, 3H), 3.88 (s, 3H), 3.75-3.60 (m, 3H), 3.60-3.53 (m, 1H), 3.52-3.40 (m, 4H), 2.98-2.92 (m, 1H), 2.80-2.60 (m, 6H), 2.35-2.28 (m, 8H), 1.89-1.43 (m, 16H), 1.29-1.11 (m, 4H).

[0342] Example 8: 1-(2-chloro-5-(4-(3-((1-((1R,4R)-4-(4-(((R)-1-(4-(2-chloro-6-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)oxy)propyl)piperazine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0343] Step 1: Preparation of 4-(3-ethoxy-3-oxopropoxy)piperidine-1-carboxylate benzyl ester

[0344]

[0345] Benzyl 4-cyanopiperidine-1-carboxylate (5.0 g, 21.28 mmol) was dissolved in acetonitrile (100 mL), then methyl acrylate (4.256 g, 42.56 mmol) and cesium carbonate (13.87 g, 42.56 mmol) were added, and the reaction was stirred at room temperature overnight. Concentration under reduced pressure, the residue was added with water (100 mL), then extracted with ethyl acetate (100 mL x 3), the organic phase was washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:4) to obtain benzyl 4-(3-ethoxy-3-oxopropoxy)piperidine-1-carboxylate.

[0346] LC-MS: (ESI, m / z): [M+H] + = 336.1.

[0347] Step 2: Preparation of 4-(3-hydroxypropoxy)piperidine-1-carboxylate benzyl ester

[0348]

[0349] Benzyl 4-(3-ethoxy-3-oxopropoxy)piperidine-1-carboxylate (1.5 g, 4.47 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL), and a solution of borane tetrahydrofuran (45 mL, 45 mmol) was slowly added to the solution under a nitrogen atmosphere. The reaction was warmed to 50°C and stirred for 3 hours. After cooling to room temperature, methanol was slowly added dropwise until no gas bubbles were generated, and the reaction was directly concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (methanol:dichloromethane = 1:9) to obtain benzyl 4-(3-hydroxypropoxy)piperidine-1-carboxylate.

[0350] LC-MS: (ESI, m / z): [M+H] + = 294.1.

[0351] Step 3: Preparation of 4-(3-oxopropoxy)piperidine-1-carboxylate benzyl ester

[0352]

[0353] Benzyl 4-(3-hydroxypropoxy)piperidine-l-carboxylate (500 mg, 1.70 mmol) was dissolved with acetonitrile (15 mL), IBX (952 mg, 3.40 mmol) was added, and the reaction solution was heated to reflux for 2 hours. It was directly concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (methanol: dichloromethane = 1:9) to obtain benzyl 4-(3-oxopropoxy)piperidine-l-carboxylate.

[0354] LC-MS: (ESI, m / z): [M+H] + = 292.1.

[0355] Step 4: Preparation of tert-butyl 4-(3-((l-((benzyloxy)carbonyl)piperidin-4- yl)oxy)propyl)piperazine-l-carboxylate

[0356]

[0357] Benzyl 4-(3-hydroxypropoxy)piperidine-l-carboxylate (500 mg, 1.70 mmol) was dissolved with acetonitrile (15 mL), IBX (952 mg, 3.40 mmol) was added, and the reaction solution was heated to reflux for 2 hours. It was directly concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (methanol: dichloromethane = 1:9) to obtain benzyl 4-(3-oxopropoxy)piperidine-l-carboxylate.

[0358] LC-MS: (ESI, m / z): [M+H] + = 462.2.

[0359] Step 5: Preparation of tert-butyl 4-(3-(piperidin-4-yloxy)propyl)piperazine-l- carboxylate

[0360]

[0361] tert-Butyl 4-(3-(piperidin-4-yloxy)propyl)piperazine-1-carboxylate (110 mg, 0.34 mmol) was dissolved with DMF (5 mL), added (1R,4R)-4-(4-(((R)-1-(4-(2-chloro-6-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid (202 mg, 0.34 mmol), HATU (144 mg, 0.44 mmol) and DIEA (132 mg, 1.02 mmol) respectively, the reaction solution was stirred at room temperature overnight. Diluted with water (50 mL), extracted with dichloromethane (30 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, the crude product was purified by silica gel column chromatography (methanol:dichloromethane = 1:9) to obtain tert-butyl 4-(3-((1-((1R,4R)-4-(4-(((R)-1-(4-(2-chloro-6-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)oxy)propyl)piperazine-1-carboxylate.

[0362] LC-MS: (ESI, m / z): [M+H] + = 328.3.

[0363] Step 6: Preparation of tert-butyl 4-(3-((1-((1R,4R)-4-(4-(((R)-1-(4-(2-chloro-6-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)oxy)propyl)piperazine-1-carboxylate

[0364]

[0365] tert-Butyl 4-(3-(piperidin-4-yloxy)propyl)piperazine-1-carboxylate (110 mg, 0.34 mmol) was dissolved with DMF (5 mL), added (1R,4R)-4-(4-(((R)-1-(4-(2-chloro-6-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid (202 mg, 0.34 mmol), HATU (144 mg, 0.44 mmol) and DIEA (132 mg, 1.02 mmol) respectively, the reaction solution was stirred at room temperature overnight. Diluted with water (50 mL), extracted with dichloromethane (30 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, the crude product was purified by silica gel column chromatography (methanol:dichloromethane = 1:9) to obtain tert-butyl 4-(3-((1-((1R,4R)-4-(4-(((R)-1-(4-(2-chloro-6-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)oxy)propyl)piperazine-1-carboxylate.

[0366] LC-MS: (ESI, m / z): [M+H] + = 902.4.

[0367] Step 7: Preparation of ((1R,4R)-4-(4-(((R)-1-(4-(2-chloro-6- ((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2- methylquinazolin-6-yl)cyclohexyl)(4-(3-(piperazin-1-yl)propoxy)piperidin-1- yl)methanone

[0368]

[0369] tert-Butyl 4-(3-((1-((1R,4R)-4-(4-(((R)-1-(4-(2-chloro-6- ((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2- methylquinazolin-6-yl)cyclohexan-1-carbonyl)piperidin-4-yl)oxy)propyl)piperazine- 1-carboxylate (90 mg, 0.10 mmol) was dissolved with dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added and stirred at room temperature for 2 hours, the reaction solution was directly concentrated under reduced pressure to obtain ((1R,4R)-4-(4-(((R)-1-(4-(2-chloro-6- ((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2- methylquinazolin-6-yl)cyclohexyl)(4-(3-(piperazin-1-yl)propoxy)piperidin-1- yl)methanone, which was directly used in the next reaction without purification;

[0370] LC-MS: (ESI, m / z): [M+H] + = 802.4.

[0371] Step 8: Preparation of 1-(2-chloro-5-(4-(3-((1-((1R,4R)-4-(4-(((R)-1-(4-(2-chloro-6- ((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2- methylquinazolin-6-yl)cyclohexan-1-carbonyl)piperidin-4-yl)oxy)propyl)piperazine- 1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0372]

[0373] ((1R,4R)-4-(4-(((R)-1-(4-(2-chloro-6-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexyl)(4-(3-(piperazin-1-yl)propoxy)piperidin-1-yl)methanone (90 mg, 0.10 mmol) was dissolved with dimethyl sulfoxide (5 mL), 4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoic acid pentafluorophenyl ester (44 mg, 0.10 mmol) and DIEA (129 mg, 1.0 mmol) were added, the reaction was stirred at room temperature for 2 hours. The reaction was diluted with water (50 mL), extracted with dichloromethane (30 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by pre-HPLC to obtain 1-(2-chloro-5-(4-(3-((1-((1R,4R)-4-(4-(((R)-1-(4-(2-chloro-6-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexan-1-yl)carbonyl)piperidin-4-yl)oxy)propyl)piperazine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[0374] LC-MS: (ESI, m / z): [M+H] + = 1054.5.

[0375] 1 H NMR (400 MHz, DMSO-d6) δ 10.51 (s, 1H), 8.31 (d, J = 8.2 Hz, 1H), 8.05 (s, 1H), 7.65 (s, 1H), 7.63 (s, 1H), 7.56 (s, 1H), 7.46 - 7.31 (m, 4H), 7.24 (s, 1H), 7.02 (s, 1H), 6.96 (s, 1H), 6.05 - 5.86 (m, 1H), 3.89 (s, 3H), 3.87 - 3.80 (m, 1H), 3.79 - 3.56 (m, 6H), 3.52 - 3.42 (m, 4H), 3.16 - 3.06 (m, 3H), 2.98 - 2.89 (m, 1H), 2.77 - 2.60 (m, 5H), 2.44 - 2.32 (m, 8H), 2.01 (s, 6H), 1.89 - 1.75 (m, 6H), 1.74 - 1.68 (m, 3H), 1.68 - 1.48 (m, 6H), 1.44 - 1.26 (m, 2H).

[0376] Example 9: 3-((R)-1-((6-((1R,4R)-4-(4-((3-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)-3-azaspiro[5.5]undec-9-yl)methyl)piperazine-1-carbonyl)cyclohexyl)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)-2-methylbenzonitrile

[0377] Step 1: Preparation of tert-butyl 9-((4-((benzyloxy)carbonyl)piperazin-1-yl)methyl)-3- azaspiro[5.5]undecane-3-carboxylate

[0378]

[0379] tert-Butyl 9-((4-((benzyloxy)carbonyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3- carboxylate was prepared from tert-butyl 9-formyl-3-azaspiro[5.5]undecane-3-carboxylate (300 mg, 1.06 mmol) and benzyl piperazine-1-carboxylate (282 mg, 1.27 mmol) using sodium triacetoxyborohydride (674 mg, 3.18 mmol) in tetrahydrofuran (10 mL) at room temperature overnight. The reaction was diluted with water (50 mL) and extracted with dichloromethane (30 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (ethyl acetate: petroleum ether = 1:1) to give tert-butyl 9-((4-((benzyloxy)carbonyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carboxylate.

[0380] LC-MS: (ESI, m / z): [M+H] + = 486.3.

[0381] Step 2: Preparation of tert-butyl 9-(piperazin-1-ylmethyl)-3-azaspiro[5.5]undecane-3- carboxylate

[0382]

[0383] tert-Butyl 9-(piperazin-1-ylmethyl)-3-azaspiro[5.5]undecane-3-carboxylate was prepared from tert-butyl 9-((4-((benzyloxy)carbonyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3- carboxylate (200 mg, 0.41 mmol) using palladium hydroxide on carbon (20%, 100 mg) in ethyl acetate (15 mL) at 70 °C overnight. After the reaction was cooled to room temperature, it was filtered through celite and the filtrate was directly concentrated under reduced pressure to give tert-butyl 9-(piperazin-1-ylmethyl)-3-azaspiro[5.5]undecane-3-carboxylate, which was used directly in the next step without purification.

[0384] LC-MS: (ESI, m / z): [M+H] + = 352.4.

[0385] Step 3: Preparation of (1R,4R)-4-(4-(((R)-1-(3-cyano-2-methylphenyl)ethyl)amino)-7- methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid methyl ester

[0386]

[0387] Methyl (1R,4R)-4-(4-hydroxy-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1- carboxylate (200 mg, 0.61 mmol), BOP (344 mg, 0.78 mmol) and DBU (232 mg, 1.52 mmol) were dissolved with DMF (5 mL), after stirring at room temperature for 30 minutes, (R)-3-(1- aminoethyl)-2-methylbenzonitrile (154 mg, 0.78 mmol) was added, the reaction was warmed to 70 °C and stirred overnight. Cooled to room temperature, the reaction was diluted with water (50 mL), extracted with ethyl acetate (30 mL x 3), the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, the crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 9: 1) to obtain methyl (1R,4R)-4-(4-(((R)-1-(3-cyano-2-methylphenyl)ethyl)amino)-7- methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylate.

[0388] LC-MS: (ESI, m / z): [M+H] + = 473.2.

[0389] Step 4: Preparation of (1R,4R)-4-(4-(((R)-1-(3-cyano-2-methylphenyl)ethyl)amino)-7- methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid

[0390]

[0391] Methyl (1R,4R)-4-(4-(((R)-1-(3-cyano-2-methylphenyl)ethyl)amino)-7-methoxy-2- methylquinolin-6-yl)cyclohexane-1-carboxylate (130 mg, 0.27 mmol) was dissolved in a mixture of tetrahydrofuran / water (10 mL / 5 mL), lithium hydroxide (53 mg, 2.2 mmol) was added, the reaction was warmed to 50 °C and stirred overnight. Cooled to room temperature, the reaction was diluted with water (30 mL), the pH of the mixture was adjusted to neutral with saturated aqueous sodium citrate solution, extracted with ethyl acetate (30 mL x 3), the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give (1R,4R)-4-(4-(((R)-1-(3-cyano-2-methylphenyl)ethyl)amino)-7-methoxy-2- methylquinolin-6-yl)cyclohexane-1-carboxylic acid.

[0392] LC-MS: (ESI, m / z): [M+H] = 459.2. +

[0393] Step 5: Preparation of tert-butyl 9-((4-((1R,4R)-4-(4-(((R)-1-(3-cyano-2-methylphenyl)ethyl)amino)-7-methoxy-2-methylquinolin-6-yl)cyclohexane-1-carbonyl)piperazin-1-yl)methyl)-3- azaspiro[5.5]undecane-3-carboxylate

[0394]

[0395] (1R,4R)-4-(4-(((R)-1-(3-cyano-2-methylphenyl)ethyl)amino)-7-methoxy-2- methylquinolin-6-yl)cyclohexane-1-carboxylic acid (120 mg, 0.26 mmol) and tert-butyl 9-(piperazin-1-ylmethyl)-3-azaspiro[5.5]undecane-3-carboxylate (120 mg, 0.34 mmol) were dissolved in DMF (5 mL), then HATU (148 mg, 0.39 mmol) and N,N-diisopropylethylamine (100 mg, 0.78 mmol) were added, the reaction was stirred at room temperature for 2 hours. The reaction was diluted with water (50 mL), extracted with ethyl acetate (30 mL x 3), the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, the crude product was purified by silica gel column chromatography (methanol:dichloromethane = 1:9) to give tert-butyl 9-((4-((1R,4R)-4-(4-(((R)-1-(3-cyano-2-methylphenyl)ethyl)amino)-7-methoxy-2-methylquinolin-6-yl)cyclohexane-1-carbonyl)piperazin-1-yl)methyl)-3- azaspiro[5.5]undecane-3-carboxylate.​

[0396] LC-MS: (ESI, m / z): [M+H] + = 792.4.

[0397] Step 6: Preparation of 3-((R)-1-((6-((1R,4R)-4-(4-((3-azaspiro[5.5]undec-9-yl)methyl)piperazine-1-carbonyl)cyclohexyl)-7-methoxy-2-methylquinolin-4-yl)amino)ethyl)-2-methylbenzonitrile

[0398]

[0399] tert-Butyl 9-((4-((1R,4R)-4-(4-(((R)-1-(3-cyano-2-methylphenyl)ethyl)amino)-7-methoxy-2-methylquinolin-6-yl)cyclohexane-1-carbonyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carboxylate (160 mg, 0.20 mmol) was dissolved with dichloromethane (5 mL), trifluoroacetic acid (2 mL) was added and stirred at room temperature for 2 hours, the reaction solution was directly concentrated under reduced pressure to obtain 3-((R)-1-((6-((1R,4R)-4-(4-((3-azaspiro[5.5]undec-9-yl)methyl)piperazine-1-carbonyl)cyclohexyl)-7-methoxy-2-methylquinolin-4-yl)amino)ethyl)-2-methylbenzonitrile, which was directly used in the next reaction without purification.

[0400] LC-MS: (ESI, m / z): [M+H] + = 692.4.

[0401] Step 7: Preparation of 3-((R)-1-((6-((1R,4R)-4-(4-((3-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)-3-azaspiro[5.5]undec-9-yl)methyl)piperazine-1-carbonyl)cyclohexyl)-7-methoxy-2-methylquinolin-4-yl)amino)ethyl)-2-methylbenzonitrile

[0402]

[0403] Dissolve 3-((R)-1-((6-((1R,4R)-4-(4-((3-azaspiro[5.5]undec-9-yl)methyl)piperazine-1- carbonyl)cyclohexyl)-7-methoxy-2-methylquinolin-4-yl)amino)ethyl)-2-methylbenzonitrile (160 mg, TFA salt, 0.20 mmol) in dimethyl sulfoxide (3 mL), add 4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)- yl)benzoic acid pentafluorophenyl ester (95 mg, 0.22 mmol) and N,N-diisopropylethylamine (77 mg, 0.60 mmol) with stirring. Stir the reaction at room temperature overnight, add water (50 mL) to the reaction, filter, and purify the filter cake by pre-HPLC (CH3CN / 0.08% NH4HCO3 in water, 5% to 95%) to give 3-((R)-1-((6-((1R,4R)-4-(4-((3-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)- yl)benzoyl)-3-azaspiro[5.5]undec-9-yl)methyl)piperazine-1-carbonyl)cyclohexyl)-7- methoxy-2-methylquinolin-4-yl)amino)ethyl)-2-methylbenzonitrile.

[0404] LC-MS: (ESI, m / z): [M+H] + = 942.5.

[0405] 1 H NMR (400 MHz, DMSO-d6) δ 10.52 (s, 1H), 8.25 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.71 - 7.60 (m, 2H), 7.55 (s, 1H), 7.39 (t, J = 7.7 Hz, 2H), 7.02 (s, 1H), 5.78 - 5.68 (m, 1H), 3.91 (s, 3H), 3.81 - 3.38 (m, 8H), 3.3 - 3.25 (m, 2H), 3.01 - 2.93 (m, 1H), 2.80 - 2.63 (m, 7H), 2.48 - 2.21 (m, 7H), 1.90 - 1.77 (m, 4H), 1.75 - 1.20 (m, 18H), 1.16 - 0.92 (m, 4H).

[0406] Example 10: 1-(2-chloro-5-(4-((2-(1-((1R,4R)-4-(4-(((R)-1-(4-(2-chloro-6-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinolin-6-yl)cyclohexan-1- carbonyl)piperidin-4-yl)ethoxy)methyl-d2)piperidine-1-carbonyl)phenyl)dihydropyrimidine- 2,4(1H,3H)-dione

[0407]

[0408] To a solution of 1-(2-chloro-5-(4-((2-(piperidin-4-yl)ethoxy)methyl-d2)piperidine-1- carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (190 mg, 0.397 mmol) in DMF (5 mL) was added (1R,4R)-4-(4-(((R)-1-(4-(2-chloro-6-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid (85 mg, 0.143 mmol), DIEA (156 mg, 1.2 mmol) and PyBOP (250 mg, 0.48 mmol) respectively. The reaction was stirred at 60 °C for 16 h under N2. The reaction was diluted with water (40 mL) and extracted with ethyl acetate (40 mL x 4), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by pre-HPLC to give 1-(2-chloro-5-(4-((2-(1-((1R,4R)-4-(4-(((R)-1-(4-(2-chloro-6-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)ethoxy)methyl-d2)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[0409] LC-MS: (ESI, m / z): [M+H] + = 1053.4.

[0410] 1H NMR (400 MHz, MeOD) δ 8.01 (s, 1H), 7.64 (s, 1H), 7.62 (s, 1H), 7.52 (s, 1H), 7.44-7.35 (m, 3H), 7.30 (t, J = 7.8 Hz, 1H), 7.09 (d, J = 1.1 Hz, 1H), 7.01 (s, 1H), 6.95 (s, 1H), 6.06 (d, J = 6.8 Hz, 1H), 4.68-4.47 (m, 2H), 4.10-4.00 (m, 1H), 3.95 (s, 3H), 3.82-3.60 (m, 4H), 3.49 (t, J = 6.2 Hz, 2H), 3.27 (s, 2H), 3.17-3.02 (m, 3H), 2.91-2.80 (m, 3H), 2.75-2.67 (m, 1H), 2.66-2.55 (m, 1H), 2.52 (s, 3H), 2.05 (s, 6H), 2.00-1.58 (m, 19H), 1.58-1.49 (m, 2H), 1.32-1.29 (m, 2H).

[0411] Example 11: l-(5-(4-((2-(l-((lR,4R)-4-(4-(((R)-l-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexan-l- carbonyl)piperidin-4-yl)ethoxy)methyl-d2)piperidine-l-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(lH,3H)-dione

[0412] Step 1: Preparation of (lR,4R)-4-(4-(((R)-l-(3-((tert-butoxycarbonyl)amino)-5- (trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane- 1-carboxylic acid pentafluorophenyl ester

[0413]

[0414] (1R,4R)-4-(4-(((R)-1-(3-((tert-butoxycarbonyl)amino)-5- (trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane- 1-carboxylic acid (200 mg, 0.33 mmol) was dissolved with DMF (5 mL), 2,3,4,5,6- pentafluorophenol (74 mg, 0.40 mmol) and DCC (82 mg, 0.40 mmol) were added, the reaction was warmed to 70 °C and stirred for 2 h. The reaction was diluted with water (50 mL) and extracted with dichloromethane (50 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:1) to give (1R,4R)-4-(4-(((R)-1-(3-((tert-butoxycarbonyl)amino)-5- (trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane- 1-carboxylic acid pentafluorophenyl ester.

[0415] LC-MS: (ESI, m / z): [M+H] + = 769.4.

[0416] Step 2: Preparation of tert-butyl (3-((R)-1-((6-((1R,4R)-4-(4-(2-((1-(4-chloro-3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)methoxy-d2)ethyl)piperidine-1- carbonyl)cyclohexyl)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)-5- (trifluoromethyl)phenyl)carboxylate

[0417]

[0418] (1R,4R)-4-(4-(((R)-1-(3-(((tert-butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid pentafluorophenyl ester (200 mg, 0.26 mmol) was dissolved in dimethyl sulfoxide (5 mL), and 1-(2-chloro-5-(4-((2-(piperidin-4-yl)ethoxy)methyl-d2)piperidin-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (144 mg, 0.30 mmol) and DIEA (117 mg, 0.90 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with water (50 mL), extracted with dichloromethane (30 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (methanol:dichloromethane = 1:9) to obtain (3-((R)-1-((6-((1R,4R)-4-(4-(2-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)methoxy-d2)ethyl)piperidin-1-carbonyl)cyclohexyl)-7-methoxy-2-methylquinazoline-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)tert-butyl carboxylate.

[0419] LC-MS:(ESI,m / z):[M+H] + =1063.4.

[0420] Step 3: Preparation of 1-(5-(4-((2-(1-((1R,4R)-4-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazoline-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)ethoxy)methyl-d2)piperidin-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0421]

[0422] tert-Butyl (3-((R)-1-((6-((1R,4R)-4-(4-(2-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin- 1(2H)-yl)benzoyl)piperidin-4-yl)methoxy-d2)ethyl)piperidine-1-carbonyl)cyclohexyl)-7- methoxy-2-methylquinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)carboxylate (150 mg, 0.14 mmol) was dissolved in DCM (5 mL), TFA (1 mL) was added, stirred at room temperature for 1 hour, concentrated under reduced pressure, dissolved in MeOH / DCM (1 / 9, 10 mL), adjusted to neutral pH by adding one-fold diluted saturated aqueous sodium bicarbonate solution, stirred for 10 minutes, extracted with MeOH / DCM (1 / 9, 30 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by pre-HPLC to obtain 1-(5-(4-((2-(1-((1R,4R)-4-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7- methoxy-2-methylquinazolin-6-yl)cyclohexan-1-carbonyl)piperidin-4-yl)ethoxy)methyl-d2) piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[0423] LC-MS: (ESI, m / z): [M+H] + = 963.2

[0424] 1 H NMR (400 MHz, DMSO-d6) δ 10.52 (s, 1H), 8.12 (d, J = 8.1 Hz, 1H), 8.06 (s, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.54 (d, J = 2.0 Hz, 1H), 7.38 (dd, J = 8.2, 2.0 Hz, 1H), 6.99 (s, 1H), 6.88 (s, 1H), 6.85 (s, 1H), 6.70 (s, 1H), 5.62 - 5.51 (m, 3H), 4.54 - 4.30 (m, 2H), 3.96 - 3.83 (m, 4H), 3.80 - 3.51 (m, 3H), 3.40 (t, J = 6.4 Hz, 2H), 3.11 - 2.89 (m, 3H), 2.80 - 2.59 (m, 4H), 2.36 (s, 3H), 1.92 - 1.37 (m, 20H), 1.20 - 0.89 (m, 4H).

[0425] Example 12: 1-(2-chloro-5-(9-((4-((1R,4R)-4-(4-(((R)-1-(3-(difluoromethyl)-2- methylphenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1- carbonyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl) dihydropyrimidine-2,4(1H,3H)-dione

[0426] Step 1: Preparation of (1R,4R)-4-(4-(((R)-1-(3-(difluoromethyl)-2-methylphenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid methyl ester

[0427]

[0428] Methyl (1R,4R)-4-(4-hydroxy-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1- carboxylate (400 mg, 1.212 mmol) was dissolved with DMF (5 mL), BOP (696 mg, 1.576 mmol) and DBU (461 mg, 3.03 mmol) were added, after stirring at room temperature for 0.5 hours, (R)-1-(3-(difluoromethyl)-2-methylphenyl)ethyl-1-amine (244 mg, 1.33 mmol) was added, the reaction was warmed to 70 °C and stirred overnight. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3), the organic phase was washed with saturated aqueous sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 9:1) to obtain methyl (1R,4R)-4-(4-(((R)-1-(3-(difluoromethyl)-2-methylphenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylate.

[0429] LC-MS: (ESI, m / z): [M+H] + = 498.2.

[0430] Step 2: Preparation of (1R,4R)-4-(4-(((R)-1-(3-(difluoromethyl)-2-methylphenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid

[0431]

[0432] Methyl (1R,4R)-4-(4-(((R)-1-(3-(difluoromethyl)-2-methylphenyl)ethyl)amino)-7- methoxy-2-methylquinolin-6-yl)cyclohexane-1-carboxylate (178 mg, 0.36 mmol) was dissolved with THF (5 mL), LiOH (44 mg, 1.83 mmol) was added, the reaction was warmed to 50 °C and stirred for 2 hours. Water (50 mL) was added to dilute, the pH was adjusted to neutral with citric acid, extracted with ethyl acetate (30 mL x 3), the organic phase was washed with saturated aqueous sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (1R,4R)-4-(4-(((R)-1-(3-(difluoromethyl)-2-methylphenyl)ethyl)amino)-7-methoxy-2- methylquinolin-6-yl)cyclohexane-1-carboxylic acid, which was used directly in the next step without purification.

[0433] LC-MS: (ESI, m / z): [M+H] + = 484.2.

[0434] Step 3: Preparation of 1-(2-chloro-5-(9-((4-((1R,4R)-4-(4-(((R)-1-(3-(difluoromethyl)-2- methylphenyl)ethyl)amino)-7-methoxy-2-methylquinolin-6-yl)cyclohexane-1-carbonyl)piperazin- 1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0435]

[0436] (1R,4R)-4-(4-(((R)-1-(3-(difluoromethyl)-2-methylphenyl)ethyl)amino)-7- methoxy-2-methylquinolin-6-yl)cyclohexane-1-carboxylic acid (128 mg, 0.265 mmol) was dissolved with DMF (5 mL), 1-(2-chloro-5-(9-(piperazin-1-ylmethyl)-3- azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (133 mg, 0.265 mmol), DIEA (103 mg, 0.795 mmol) and HATU (141 mg, 0.307 mmol) were added respectively, the reaction was stirred at room temperature for 2 hours. Diluted with water (50 mL), extracted with ethyl acetate (30 mL x 3), the organic phase was washed with saturated aqueous sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, the crude product was purified by Prep-HPLC (CH3CN / 0.08% NH4HCO3 aqueous solution, 5%~95%) to give 1-(2-chloro-5-(9-((4-((1R,4R)-4-(4-(((R)-1-(3-(difluoromethyl)-2- methylphenyl)ethyl)amino)-7-methoxy-2-methylquinolin-6-yl)cyclohexane-1- carbonyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine- 2,4(1H,3H)-dione.

[0437] LC-MS: (ESI, m / z): [M+H] + = 967.3.

[0438] 1 H NMR (400 MHz, DMSO-d6) δ 10.51 (s, 1H), 8.23 (d, J = 7.3 Hz, 1H), 8.08 (s, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.55 (d, J = 1.9 Hz, 1H), 7.41 - 7.35 (m, 2H), 7.35 - 7.04 (m, 2H), 6.97 (s, 1H), 5.82 - 5.72 (m, 1H), 3.87 (s, 3H), 3.80 - 3.69 (m, 1H), 3.66 - 3.54 (m, 3H), 3.54 - 3.42 (m, 4H), 3.30 - 3.20 (m, 2H), 3.00 - 2.89 (m, 1H), 2.78 - 2.70 (m, 2H), 2.58 - 2.54 (m, 3H), 2.38 - 2.21 (m, 7H), 2.15 - 2.07 (m, 2H), 1.91 - 1.77 (m, 4H), 1.74 - 1.24 (m, 17H), 1.17 - 0.95 (m, 4H).

[0439] Example 13: l-(5-(4-(3-(4-((lR,4R)-4-(4-(((R)-l-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexan-l- carbonyl)piperazin-l-yl)propoxy)piperidine-l-carbonyl)-2-chlorophenyl)dihydropyrimidine- 2,4(lH,3H)-dione

[0440] Step 1: Preparation of tert-butyl (3-((R)-l-((6-((lR,4R)-4-(4-(3-((l-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-l(2H)- yl)benzoyl)piperidin-4-yl)oxy)propyl)piperazine-l-carbonyl)cyclohexyl)-7-methoxy-2- methylquinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)carboxylate

[0441]

[0442] To a solution of (lR,4R)-4-(4-(((R)-l-(3-((tert-butoxycarbonyl)amino)-5- (trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane- 1-carboxylic acid (80 mg, 0.16 mmol) in DMF (5 mL) was added l-(2-chloro-5-(4-(3- (piperazin-l-yl)propoxy)piperidine-l-carbonyl)phenyl)dihydropyrimidine-2,4(lH,3H)- dione (90 mg, 0.13 mmol), HATU (59 mg. 0.16 mmol) and DIEA (50 mg, 0.39 mmol), stirred at room temperature for 2 hours, added water (50 mL) and stirred, filtered, the filter cake was washed with water 3 times, then dissolved with dichloromethane (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to give the crude tert-butyl (3-((R)-l-((6-((lR,4R)-4-(4-(3-((l-(4-chloro-3-(2,4- dioxotetrahydropyrimidin-l(2H)-yl)benzoyl)piperidin-4-yl)oxy)propyl)piperazine-l- carbonyl)cyclohexyl)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)-5- (trifluoromethyl)phenyl)carboxylate.

[0443] LC-MS: (ESI, m / z): [M+H] + = 1062.5.

[0444] Step 2: Preparation of 1-(5-(4-(3-(4-((1R,4R)-4-(4-(((R)-1-(3-amino-5- (trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1- carbonyl)piperazin-1-yl)propoxy)piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine- 2,4(1H,3H)-dione

[0445]

[0446] tert-Butyl (3-((R)-1-((6-((1R,4R)-4-(4-(3-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin- 1(2H)-yl)benzoyl)piperidin-4-yl)oxy)propyl)piperazine-1-carbonyl)cyclohexyl)-7-methoxy- 2-methylquinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)carboxylate (130 mg, 0.12 mmol) was dissolved with dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, then the reaction was stirred at room temperature for 2 hours, concentrated under reduced pressure, the crude product was purified by reverse phase preparation to obtain 1-(5-(4-(3-(4-((1R,4R)-4-(4-(((R)-1-(3-amino-5- (trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1- carbonyl)piperazin-1-yl)propoxy)piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine- 2,4(1H,3H)-dione.

[0447] LC-MS: (ESI, m / z): [M+H] + = 962.5.

[0448] 1 H NMR (400 MHz, DMSO-d6) δ 10.51 (s, 1H), 8.17 - 7.98 (m, 2H), 7.67 - 7.50 (m, 2H), 7.47 - 7.34 (m, 1H), 6.99 (s, 1H), 6.88 (s, 1H), 6.85 (s, 1H), 6.70 (s, 1H), 5.64 - 5.46 (m, 3H), 3.88 (s, 4H), 3.74 (s, 1H), 3.62 (d, J = 5.7 Hz, 1H), 3.56 - 3.39 (m, 8H), 3.18 (s, 1H), 3.00 - 2.89 (m, 1H), 2.80 - 2.70 (m, 2H), 2.68 - 2.59 (m, 1H), 2.40 - 2.25 (m, 9H), 1.94 - 1.35 (m, 18H).

[0449] Example of biological activity test

[0450] Test Example 1: KRAS-G12C / SOS1 binding assay

[0451] The following method is used to determine the degree of inhibition of the preferred compounds of the present application on KRAS-G12C / SOS1 binding under in vitro conditions. This method uses the KRAS-G12C / SOS1 binding assay kit (Cisbio, 63ADK000CB16PEG) to determine the competitive inhibition of preferred compounds on KRAS-G12C / SOS1 binding using homogeneous time-resolved fluorescence technology (HTRF).

[0452] The experimental procedure is as follows (for detailed methods, refer to the kit instructions): The compounds in the present application are first dissolved in DMSO at a concentration of 20 mM, and gradient dilution is performed with the buffer in the kit, so that the final concentration of the test compound in the reaction system is in the range of 10000 nM-0.04 nM, and the final concentration of DMSO is 0.5%. 2 μL of the compound is incubated with 4 μL of 1x Tag1-SOS1, 4 μL of 1x Tag2-KRAS-G12C (containing 10 μM guanosine triphosphate, GTP) at 25°C for 15 min, and then 5 μL of 1x Anti-Tag1-Tb3+ and 5 μL of 1x Anti-Tag2-XL665 are added to the reaction system and incubated on ice for 3 h. After incubation, the fluorescence intensity of each well at an excitation wavelength of 337 nm and an emission wavelength of 620 nm and 665 nm is measured on an enzyme marker EnVision (PerkinElmer, 2105) in HTRF mode. The Ratio value is calculated using the formula Ratio=(665 nm / 620 nm) x 104. By comparing the fluorescence intensity ratio with the control group, the inhibition rate of the compound at each concentration is calculated, and then the IC50 value of the compound is obtained by nonlinear curve fitting of the logarithmic concentration-inhibition rate using GraphPad Prism 8, as shown in Table 1.

[0453] Test Example 2: SOS1 degradation assay

[0454] The degradation effect of the compound on SOS1 was investigated on KRAS G12C mutant human non-small cell lung cancer cells NCI-H358 (ATCC or Chinese Academy of Sciences Cell Bank), KRAS G12D mutant human lung cancer cells A-427 (ATCC), KRAS G12V mutant human colorectal adenocarcinoma cells SW-620 (ATCC), and KRAS G13D mutant human colorectal adenocarcinoma epithelial cells DLD-1 (ATCC). The specific method is as follows:

[0455] The cells were plated in 24-well cell culture plates at 0.95 mL per well with a cell density of 5 x 105per well; the cell plates were placed in a 5% CO2incubator at 37°C overnight. Then 50 μL of diluted compound solution was added to the corresponding wells with cells, so that the final concentration of the compound was in the range of 0.03-3000 nM. The final concentration of DMSO was 0.25%. After the administration, the cell plates were placed in a 5% CO2incubator at 37°C for 24 h. After removing the cell culture solution in the 24-well plates, the cells were washed twice with 1 x PBS, and the NCI-H358 cells adhering to the bottom of the cell culture plates were lysed by adding 180 μL of RIPA (strong) lysis solution (Bi Yun Tian, P0013B) supplemented with 1 mM phenylmethylsulfonyl fluoride, a protease inhibitor cocktail (Bi Yun Tian, P1008), and a protease phosphatase inhibitor cocktail (Bi Yun Tian, P1045), and then incubated on ice for 30 min. The protein lysate in each well was transferred to a 1.5 mL centrifuge tube, and centrifuged at 15000 g at 4°C for 20 min. The cell lysate supernatant after centrifugation was frozen at -80°C for testing, and used for WB method to detect the degradation level of SOS1 protein. The total protein concentration in the cell lysate supernatant was determined using a BCA protein quantification kit (Tian Gen, PA115-02).

[0456] Test Example 3: Human SOS1 protein immunoblotting test

[0457] The concentration of total protein in the cell lysate was detected by BCA, and adjusted to 0.5 μg / μL with PBS and 5x SDS-PAGE protein loading buffer (Bi Yun Tian, P0015L) at 100°C water bath for 15 min, then placed on ice for 5 min, 14000g, 4°C centrifugation for 1 min, mixed as the sample for WB. The precast gel (Kai Ji, KGMG010W15) was used for protein electrophoresis, and the loading amount was 10 μL (5 μg of total protein). After Tris-MOPS-SDS electrophoresis solution (Adamas, P1598253), 120V constant voltage electrophoresis for 55 min, after electrophoresis, the proteins on the gel strip were transferred to the PVDF membrane at a constant current of 250mA for 65 min. After the transfer, the membrane was placed in 1x QuickBlock blocking solution (Bi Yun Tian, P0235) and incubated at room temperature for 30 min. After blocking, the PVDF membrane was incubated with SOS1 primary antibody (Abeam, ab140621) at 4°C overnight, and the membrane was washed with TBST buffer (2.4g Tris, 8.8g NaCl, 1.5mL Tween 20, pH 7.4, constant volume to 1L) for 30 min (10 min / time). The secondary antibody (Abeam, ab205718) was incubated at room temperature for 2h, and the membrane was washed with TBST buffer for 30 min (10 min / time). Finally, Clarity Western ECL Substrate (BIO-RAD, 170-5061) was incubated for 5 min for color development, and the color development and protein map were photographed by ChemiScope 6200 Touch chemical luminescence imaging system. The protein map was analyzed by ChemiScope chemical luminescence analysis software. The gray correction value of each sample was calculated using the formula: gray correction value = (target protein gray value / corresponding internal reference gray value) x 103. The degradation rate was calculated by comparing the gray correction value of the control group. Further, the log concentration-inhibition rate was nonlinearly fitted by GraphPad Prism 8 to obtain the DC 50 and D max value of the compound.

[0458] Test Example 4: 3D cell proliferation inhibition test

[0459] The inhibitory effect of the compound on 3D cell proliferation was investigated on KRAS G12C mutant human non-small cell lung cancer cells NCI-H358 (ATCC or Chinese Academy of Sciences Cell Bank), KRAS G12D mutant human metastatic pancreatic adenocarcinoma cells AsPC-1 (ATCC), KRAS G12V mutant human lung adenocarcinoma cells NCI-H441 (ATCC), and KRAS G13D mutant human colorectal adenocarcinoma epithelial cells DLD-1 (ATCC). The specific method is as follows:

[0460] The 200nL compound gradient dilution solution was added into the corresponding microwells of the 384-well low-adsorption microwell plate (Corning, 3657) by the Echo acoustic liquid handling system (Labcyte, Echo 550), so that the final concentration of the test compound in the reaction system ranged from 20000nM to 0.008nM. Then 40μL of cells with a certain density were added into the corresponding microwell plate. In addition to the test compound test well, DMSO control wells and culture medium control wells were set up at the same time, the DMSO control wells contained DMSO and cells, and the culture medium wells only contained culture medium. After the addition was completed, the plate cover was covered, and the 384-well low-adsorption microwell plate was placed into a 5% carbon dioxide incubator at 37°C for 7 days of incubation. After 7 days, the microwell plate was taken out, 40μL of CTG reagent (Promega, G9683) was added to each well, and after incubation at room temperature for 30 minutes, the reading was performed on the EnVision enzyme label instrument using the chemiluminescence program. The inhibition rate of the compound at each concentration was calculated by the cell proliferation inhibition percentage calculation formula: inhibition rate % = (DMSO control group average value - single concentration reading value of compound) / (DMSO control group average value - culture medium control group average value) x 100, and then the IC 50 values of the compounds were obtained by non-linear curve fitting of the logarithmic concentration-inhibition rate using GraphPad Prism 8.

[0461] The experimental results are shown in Table 1:

[0462] Table 1

[0463]

[0464]

[0465] “-” represents not detected;

[0466] When DC 50 ≤50nM is A, when 50nM<DC 50 ≤100nM is B, when 100nM<DC 50 ≤500nM is C, when 500nM<DC 50 ≤1000nM is D; 1000nM<DC 50 ≤10μM is E;

[0467] When 80≤D max (%)≤100 is A, when 50≤D max (%)<80 is B, when 30≤D max (%)<50 is C, when D max (%)<30 is D;

[0468] When IC 50≤ 15 nM is A, when 15 nM < IC 50 ≤ 30 nM is B, when 30 nM < IC 50 ≤ 50 nM is C, when 50 nM < IC 50 ≤ 100 nM is D, when 100 nM < IC 50 ≤ 1000 nM is E.

[0469] Experimental conclusion: The compound can effectively bind to the SOS1 target protein or produce an inhibitory effect, and the compound can effectively and specifically degrade the SOS1 protein.

[0470] Although the specific embodiments of the present application are described above, those skilled in the art should understand that these are only illustrative, and various changes or modifications can be made to these embodiments without departing from the principles and essence of the present application. Therefore, the protection scope of the present application is defined by the appended claims.

Claims

1. A compound of Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: ； wherein, S is , , , , , , , , , or ; L is , , , , , , , , , , or , L is attached to S via A; E is , or ; the compound of Formula I is not any one of the following: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 and .

2. The compound of formula I as claimed in claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that, the compound of Formula I satisfies one or more of the following conditions: (1) S is , L is or ; (2) S is , L is , , , or ; (3) S is , L is , , , , , or ; (4) S is , L is or ; (5) S is , L is , , or ; (6) S is , L is ; (7) S is , L is ; (8) S is , E is ​ (9) S is , E is ; (10) S is , E is ; (11) S is , E is ; (12) S is , E is , or ; (13) S is , E is ; (14) S is , E is ; (15) L is , E is or ; (16) L is , E is ; (17) L is , E is ; (18) L is , E is ; (19) L is , E is : (20) L is , E is ; (21) L is , E is ; (22) L is , E is ; (23) L is , E is ; (24) L is , E is ; (25) L is , E is .

3. The compound of claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I satisfies one or more of the following conditions: (1) S is , L is or ; E is ; (2) S is , L is , , , or ; E is ; (3) S is , L is , , , , , or ; E is ; (4) S is , L is or ; E is ; (5) S is , L is , , or ; E is , or ; (6) S is , L is ; E is ; (7) S is , L is ; E is .

4. The compound of claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I is any one of the following: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 or .

5. A pharmaceutical composition comprising G and a pharmaceutically acceptable carrier, diluent, or excipient, the G being a compound of any one of claims 1-4, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

6. Use of a compound of any one of claims 1-4, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 5 in the manufacture of a medicament for treating or preventing a SOS1-mediated disease or disorder, or a disease or disorder caused by SOS1 interaction with Ras or SOS1 interaction with Rac.

7. Use according to claim 6, wherein the SOS1-mediated disease or disorder, or a disease or disorder caused by SOS1 interaction with Ras or SOS1 interaction with Rac is selected from: cardiac sarcoma, cardiac myxoma, cardiac rhabdomyoma, cardiac fibroma, cardiac lipoma, and cardiac teratoma; bronchial carcinoma, alveolar carcinoma, bronchial adenoma, pulmonary sarcoma, pulmonary lymphoma, pulmonary chondroma hamartoma, pulmonary mesothelioma; gastrointestinal esophageal squamous cell carcinoma, gastrointestinal esophageal adenocarcinoma, gastrointestinal esophageal leiomyosarcoma, gastrointestinal esophageal lymphoma; gastric carcinoma, gastric lymphoma, gastric leiomyosarcoma; pancreatic ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, pancreatic carcinoid tumor, vasoactive intestinal peptide tumor; small intestinal adenocarcinoma, small intestinal lymphoma, small intestinal carcinoid tumor, small intestinal Kaposi's sarcoma, small intestinal leiomyoma, small intestinal hemangioma, small intestinal lipoma, small intestinal neurofibroma, small intestinal fibroma; large intestinal adenocarcinoma, large intestinal tubular adenoma, large intestinal villous adenoma, large intestinal hamartoma, large intestinal leiomyoma; renal adenocarcinoma, nephroblastoma, renal lymphoma, renal leukemia; bladder squamous cell carcinoma, bladder transitional cell carcinoma, bladder adenocarcinoma, urethral squamous cell carcinoma, urethral transitional cell carcinoma, urethral adenocarcinoma; prostatic adenocarcinoma, prostatic sarcoma; seminoma, testicular teratoma, testicular embryonal carcinoma, testicular choriocarcinoma, testicular sarcoma, testicular interstitial cell carcinoma, testicular fibroma, testicular fibroadenoma, testicular adenomatoid tumor, testicular lipoma; hepatocellular carcinoma, bile duct carcinoma, hepatoblastoma, hepatic angiosarcoma, hepatocellular adenoma, hepatic hemangioma; gallbladder carcinoma, ampullary carcinoma, bile duct carcinoma; osteosarcoma, bone fibrosarcoma, malignant fibrous histiocytoma of bone, Ewing's sarcoma of bone, malignant lymphoma of bone, multiple myeloma, giant cell tumor of tendon sheath, chondroma, chondromyxofibroma, osteoid osteoma, giant cell tumor; skull osteoma, skull hemangioma, skull granuloma, skull xanthoma, skull osteitis deformans; meningioma; cerebral astrocytoma, cerebral medulloblastoma, cerebral glioma, cerebral ependymoma, cerebral blastoma, cerebral neurinoma, cerebral retinoblastoma, cerebral congenital tumor, cerebral neurofibroma, cerebral sarcoma; Endometrial carcinoma, uterine granulosa-theacell tumor, uterine supporting interstitial cell tumor, uterine anagynoma, uterine malignant teratoma; Vulvar squamous cell carcinoma, vulvar intraepithelial carcinoma, vulvar adenocarcinoma, vulvar fibrosarcoma, vulvar melanoma; Vaginal clear cell carcinoma, vaginal squamous cell carcinoma, vaginal grape-like sarcoma; Fallopian tube cancer; Myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disease, myelodysplastic syndrome, Hodgkin's disease, non-Hodgkin's lymphoma; Malignant melanoma of skin, basal cell carcinoma of skin, squamous cell carcinoma of skin, Kaposi's sarcoma of skin, nevus dysplastic nevus, lipoma of skin, hemangioma of skin, fibroma of skin, keloid of skin, psoriasis; Adrenal neuroblastoma.

8. Use according to claim 7, wherein the compound is ###00010### One or more of the following conditions are met: (1) the bronchogenic carcinoma is selected from the group consisting of bronchogenic squamous cell carcinoma, bronchogenic undifferentiated small cell carcinoma, bronchogenic undifferentiated large cell carcinoma and bronchogenic adenocarcinoma; (2) the alveolar carcinoma is bronchiolar carcinoma; (3) the bone malignant lymphoma is bone reticulum cell sarcoma; (4) the chondroma is selected from the group consisting of osteochondroxyphosis and chondroblastoma; (5) the cerebral germinoma is pinealoma; (6) the cerebral glioma is selected from the group consisting of cerebral pleomorphic glioblastoma and cerebral oligodendroglioblastoma; (7) the endometrial carcinoma is selected from the group consisting of endometrial serous cystadenocarcinoma, endometrial mucinous cystadenocarcinoma and endometrial carcinoma not classified; (8) the vaginal grape-like sarcoma is vaginal embryonal rhabdomyosarcoma; (9) the myeloid leukemia is selected from the group consisting of acute myeloid leukemia and chronic myeloid leukemia; (10) the non-Hodgkin's lymphoma is non-Hodgkin's malignant lymphoma.

9. The use according to claim 6, wherein the compound is ###00010### 8 or ###00011### The SOS1-mediated disease or disorder, or a disease or disorder caused by the interaction of SOS1 with Ras or SOS1 with Rac, is pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial carcinoma, gastric cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer or sarcoma.

10. Use according to claim 9, wherein, The SOS1-mediated disease or disorder, or a disease or disorder caused by the interaction of SOS1 with Ras or SOS1 with Rac, is endometrial carcinoma or cervical cancer.

11. Use according to claim 6, wherein The SOS1-mediated disease or disorder is cancer.

12. The use according to claim 6, wherein The SOS1-mediated disease or disorder is neurofibromatosis type 1, Noonan syndrome, Noonan syndrome with multiple lentigines, capillary malformation-arteriovenous malformation syndrome, Costello syndrome, cardio-facio-cutaneous syndrome, Legius syndrome or hereditary gingival fibromatosis.

13. Use of a compound of any one of claims 1-4, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 5 in the manufacture of a medicament for the treatment and / or prevention of a KRAS-mediated disease or disorder.

14. The use of claim 13, wherein, The KRAS is a mutant KRAS.

15. The use of claim 14, wherein, The mutant KRAS is selected from one or more of KRAS G12C, KRAS G12D, KRAS G13D, and KRAS G12V. The mutant KRAS is selected from one or more of KRAS G12C, KRAS G12D, KRAS G13D, and KRAS G12V. The mutant KRAS is selected from one or more

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