EGFR (epidermal growth factor receptor) degradation agent and preparation method and application thereof

Abstract

The invention discloses an EGFR (epidermal growth factor receptor) degradation agent as well as a preparation The invention relates to a bifunctional chimeric heterocyclic compound of a targeted epidermal growth factor receptor (EGFR) as shown in a formula (I) and a medicinal composition, a preparation method and application thereof, and the bifunctional chimeric heterocyclic compound is used for promoting ubiquitination of the EGFR and degradation of the EGFR by proteasomes by recruiting ubiquitin ligase to the EGFR. Research results show that the compounds show good EGFR degradation activity and can be used for treating EGFR-mediated diseases. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry, and specifically relates to a novel bifunctional compound capable of inhibiting and degrading EGFR or its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates, and pharmaceutical compositions, preparation methods and uses thereof. Background Art

[0002] Cancer is one of the most important diseases that threaten human life and health. With the development of targeted drugs, certain progress has been made in the field of cancer treatment. For example, small molecule inhibitors targeting epidermal growth factor receptor (EGFR) can selectively block the binding of EGFR to ATP, thereby inhibiting the activation of EGFR and downstream signaling pathways, leading to stagnation of cell growth, proliferation and metastasis, and then apoptosis, achieving effective control of EGFR-mediated tumors. Unfortunately, acquired drug resistance is easy to occur after the clinical use of EGFR inhibitors. The main way is that EGFR has point mutations, which causes small molecules to be unable to effectively bind to it, resulting in a decrease or even disappearance of the inhibitory effect, such as the most common T790M mutation. In response to this situation, researchers have gradually developed a new generation of inhibitors that can effectively overcome the drug resistance problem of the previous generation. At present, the third-generation EGFR inhibitors (such as osimertinib, ametinib, etc.) can effectively overcome the T790M mutation, and have weak activity against wild-type EGFR, reducing the toxic side effects of the second-generation drugs. However, drug resistance to osimertinib has already emerged (Nature Medicine, 2015, 21, 560-562), and its main mechanism is that the cysteine ​​residue at position 797 of EGFR mutates to a serine residue (C797S), which leads to the disappearance of the covalent bond between Cys and the inhibitor and the emergence of drug resistance. Therefore, the development of the fourth-generation EGFR therapeutic drug that can overcome the C797S mutation is of great significance and clinical value.

[0003] PROTAC (proteolysis targeting chimera) molecules are a class of bifunctional compounds that can simultaneously bind to targeted proteins and E3 ubiquitin ligases. Such compounds can be recognized by the proteasome of the cell, causing the degradation of the targeted protein, and can effectively reduce the content of the targeted protein in the cell. By introducing ligands that can bind to different targeted proteins in PROTAC molecules, it is possible to apply PROTAC technology to the treatment of various diseases. In recent years, some patents (WO2019149922A1, WO2021127561A1, WO2022194269A1, WO222012622A1, WO2022228547A, WO2022251539A2, WO2021127561A1, etc.) have reported that a series of PROTAC-type compounds can overcome the drug resistance problem of C797S by degrading EGFR protein, becoming a new research direction. Although some progress has been made in EGFR allosteric inhibitors and EGFR degraders, the clinical demand for the treatment of EGFR protein-related diseases has not yet been met. Therefore, the development of new PROTAC drugs that bind to EGFR protein and E3 ubiquitin ligase for the treatment of EGFR protein-related diseases will be full of application prospects. Summary of the invention

[0004] The object of the present invention is to provide a novel bifunctional compound capable of inhibiting and degrading EGFR, or its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates, and pharmaceutical compositions, preparation methods and uses for treating EGFR-related diseases.

[0005] The first aspect of the present invention provides a compound represented by the following formula (I) or its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates:

[0006]

[0007] in,

[0008] Ring A is selected from: 6-12 membered aryl, 5-12 membered heteroaryl, said aryl, heteroaryl may be substituted by 1-4 R a1 replace;

[0009] R a1 are independently selected from: hydrogen, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, 6-12 membered aryl, 5-12 membered heteroaryl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8Cycloalkyl, 3-8 membered heterocyclyl, 6-12 membered aryl, 5-12 membered heteroaryl may be substituted by halogen;

[0010] Each R 1 are independently selected from: hydrogen, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, 6-12 membered aryl, 5-12 membered heteroaryl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, 6-12 membered aryl, 5-12 membered heteroaryl may be substituted by halogen;

[0011] Each R 2 are independently selected from: hydrogen, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups may be substituted by halogen;

[0012] Each R 3 are independently selected from: hydrogen, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, 6-12 membered aryl, 5-12 membered heteroaryl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, 6-12 membered aryl, 5-12 membered heteroaryl may be substituted by halogen;

[0013] Each R 4 are independently selected from: hydrogen, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, the C 1-6 Alkyl, C 1-6 The carbon atoms in the haloalkyl group may be independently replaced by one or more heteroatoms;

[0014] m, n, k or q are independently selected from: 0, 1 or 2;

[0015] L represents a connecting chain, and L is selected from -L 1 -L 2 -L 3 -L 4 -,in,

[0016] L 1 Selected from 3-12 membered heterocyclic diyl or C 3-10 Cycloalkanediyl, the heterocyclic diyl or cycloalkanediyl is optionally substituted by 1 to 4 halogen, hydroxyl, amino, -OR L1 、-N(R L1 )(R L1’ ) substituted, wherein R L1 , R L1’ are independently selected from hydrogen or C 1-6 alkyl;

[0017] L 2 , L 3 and L 4 are independently selected from a bond, C 1-6 Alkylene, 3-12 membered heterocyclic diyl, C 3-12 Cycloalkanediyl, C 2-6 Alkenylene, C 2-6 Alkyne, -C(O)-, -C(O)-N(R L2 )-、-O-、-N(R L2 )-, -S-, -C(S)-, -C(O)-O-, -C(S)-O-, -S(O) 2 -、-S(O)(R L2 )=N-、-S(O) 2 NH- or -C=N-; wherein the C 3-12 The cycloalkanediyl and 3-12 membered heterocyclic diyl may be optionally each independently substituted with one or more R L3 Replacement; said C 1-6 Alkylene, C 2-6 Alkenylene and C 2-6 The alkynylene group may be optionally each independently substituted with one or more R L4 replace;

[0018] R L2 Selected from hydrogen or C 1-6 alkyl;

[0019] Each R L3 Each independently selected from oxo, hydroxyl, -OC 1-6 Alkyl, halogen, nitro, cyano, amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 1-6 A haloalkyl group or a 3-12 membered heterocyclic group;

[0020] Each R L4 Each independently selected from halogen, oxo, cyano, hydroxyl, C1-6 Alkyl, C 3-8 Cycloalkyl or -OC 1-6 Alkyl; wherein the C 1-6 Alkyl, C 3-8 Cycloalkyl or -OC 1-6 The alkyl group may be substituted by 1-3 F atoms;

[0021] Ring B is selected from: saturated or partially saturated 5-8 membered heterocyclic group; the saturated or partially saturated 5-8 membered heterocyclic group may be independently substituted by one or more halogens, oxo groups;

[0022] X is selected from: absent, -NH-, -O- or -S-;

[0023] Y is selected from: -NH-, -O- or -S-;

[0024] Z is selected from: N or CR z1 ;

[0025] R Z1 Selected from: hydrogen, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, -OC 1-6 Alkyl, -N(R Z2 )-C 1-6 Alkyl, the C 1-6 Alkyl, -OC 1-6 Alkyl, -N(R Z2 )-C 1-6 The alkyl group can be hydrogen, halogen, hydroxyl, amino, nitro, cyano, -OR Z3 、-SR Z3 、-N(R Z3 ) 2 、-S(O) 2 R Z3 、-S(O) 2 N(R Z3 ) 2 、-S(O)R Z3 、-S(O)(NR Z3 )R Z3 、-P(O)(OR Z3 ) 2 、-P(O)(N(R Z3 ) 2 ) 2 , -CF 2 (R Z3 ),-CF 3 ,-C(R Z3 ) 2 (OR Z3 )、-C(R Z3 ) 2 (N(RZ3 ) 2 )、-C(O)R Z3 、-C(O)OR Z3 、-C(O)N(R Z3 ) 2 、-C(O)N(R Z3 )OR Z3 、-OC(O)R Z3 、-OC(O)N(R Z3 ) 2 、-N(R Z3 )C(O)OR Z3 、-N(R Z3 )C(O)R Z3 、-N(R Z3 )C(O)N(R Z3 ) 2 、-N(R Z3 )S(O) 2 R Z3 , C 3-7 Cycloalkyl, 3-8 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl substituted;

[0026] R Z2 Selected from: hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl;

[0027] Each R Z3 Each independently selected from: hydrogen, C 1-6 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, phenyl, C 4-7 Cycloalkyl, C 3-6 Cycloalkenyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl;

[0028] The heterocyclic group or heteroaryl group contains 1-4 heteroatoms independently selected from N, O and S.

[0029] In some embodiments of the present invention, the compound of formula (I) is selected from the following compounds of formula (II) or their stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, and solvates:

[0030]

[0031] in,

[0032] X is selected from: absent, -NH-, -O- or -S-;

[0033] Y is selected from: -NH-, -O- or -S-;

[0034] Z is selected from: N, COH, COC 1-3 Alkyl or COC 1-3 Alkylene-4-6 membered heterocyclic group;

[0035] W is selected from: N or CH;

[0036] R 1 Selected from: hydrogen, halogen, hydroxy, amino, cyano or C 1-3 alkyl;

[0037] R 2 Selected from: hydrogen, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl or C 1-6 Alkoxy;

[0038] R 3 Selected from: hydrogen, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl or C 1-6 Alkoxy;

[0039] R 4 Selected from: hydrogen, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, the C 1-6 Alkyl, C 1-6 The carbon atoms in the haloalkyl group may be independently replaced by one or more heteroatoms;

[0040] L represents a connecting chain, and L is selected from -L 1 -L 2 -L 3 -L 4 -,in,

[0041] L 1 Selected from 3-12 membered heterocyclic diyl or C 3-10 Cycloalkanediyl, the heterocyclic diyl or cycloalkanediyl is optionally substituted by 1 to 4 halogen, hydroxyl, amino, -OR L1 、-N(R L1 )(R L1’ ) substituted, wherein R L1 , R L1’ are independently selected from hydrogen or C 1-6 alkyl;

[0042] L 2 , L 3 and L 4 are independently selected from a bond, C 1-6 Alkylene, 3-12 membered heterocyclic diyl, C 3-12 Cycloalkanediyl, C 2-6 Alkenylene, C 2-6 Alkyne, -C(O)-, -C(O)-N(RL2 )-、-O-、-N(R L2 )-, -S-, -C(S)-, -C(O)-O-, -C(S)-O-, -S(O) 2 -、-S(O)(R L2 )=N-、-S(O) 2 NH- or -C=N-; wherein the C 3-12 The cycloalkanediyl and 3-12 membered heterocyclic diyl may be optionally each independently substituted with one or more R L3 Replacement; said C 1-6 Alkylene, C 2-6 Alkenylene and C 2-6 The alkynylene group may be optionally each independently substituted with one or more R L4 replace;

[0043] R L2 Selected from hydrogen or C 1-6 alkyl;

[0044] Each R L3 Each independently selected from oxo, hydroxyl, -OC 1-6 Alkyl, halogen, nitro, cyano, amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 1-6 A haloalkyl group or a 3-12 membered heterocyclic group;

[0045] Each R L4 Each independently selected from halogen, oxo, cyano, hydroxyl, C 1-6 Alkyl, C 3-8 Cycloalkyl or -OC 1-6 Alkyl; wherein the C 1-6 Alkyl, C 3-8 Cycloalkyl or -OC 1-6 The alkyl group may be substituted by 1-3 F atoms;

[0046] The heterocyclic group or heteroaryl group contains 1-4 heteroatoms selected from N, O and S.

[0047] In some embodiments of the present invention, R 1 Selected from: hydrogen, halogen, hydroxy, amino, cyano, methyl or ethyl.

[0048] In some embodiments of the present invention, R 1 Selected from: hydrogen, F, Cl, Br, hydroxyl or methyl;

[0049] R 2 Selected from: hydrogen;

[0050] R3 Selected from: hydrogen;

[0051] R 4 Selected from: hydrogen;

[0052] X is selected from: absent or -NH-;

[0053] Y is selected from: -NH-, -O- or -S-;

[0054] Z is selected from: N or C-OH;

[0055] W is selected from: N or CH.

[0056] In some embodiments of the present invention, the L is selected from -L 1 -L 2 -L 3 -L 4 -,in,

[0057] L 1 is selected from a 4-7 membered monoheterocyclic diyl or a 7-11 membered heterospirocyclic diyl, wherein the 4-7 membered monoheterocyclic diyl or the 7-11 membered heterospirocyclic diyl may be substituted by one to four halogens, hydroxyls, aminos, -OR L1 、-N(R L1 )(R L1’ ) substituted, wherein R L1 , R L1’ are independently selected from hydrogen or C 1-3 alkyl;

[0058] L 2 , L 3 and L 4 are independently selected from: a bond, C 1-3 Alkylene, 4-7 membered monoheterocyclic diyl, C 2-6 Alkenylene, C 2-4 Alkyne, -C(O)-, -C(O)-N(R L2 )-or-N(R L2 )-; wherein the monoheterocyclic diradical may be optionally substituted by hydroxyl, C 1-3 Alkyl or C 1-3 Alkoxy substituted; R L2 Selected from hydrogen or C 1-3 alkyl.

[0059] In some embodiments of the present invention, the L is selected from -L 1 -L 2 -L 3 -L 4 -,in,

[0060] L 1is selected from 7-11 membered heterospirocyclic diyl, wherein the 7-11 membered heterospirocyclic diyl may be substituted by one to four halogens, hydroxyls, aminos, -OR L1 、-N(R L1 )(R L1’ ) substituted, wherein R L1 , R L1’ are independently selected from hydrogen or C 1-3 alkyl;

[0061] L 2 , L 3 and L 4 Each independently selected from: C 1-3 Alkylene, 4-7 membered monoheterocyclic diyl, C 2-6 Alkenylene, C 2-4 Alkyne, -C(O)-, -C(O)-N(R L2 )-or-N(R L2 )-; wherein the monoheterocyclic diradical may be optionally substituted by hydroxyl, C 1-3 Alkyl or C 1-3 Alkoxy substituted; R L2 Selected from hydrogen or C 1-3 alkyl.

[0062] In some embodiments of the present invention, the L is selected from -L 1 -L 2 -L 3 -,in,

[0063] L 1 is selected from 7-11 membered heterospirocyclic groups;

[0064] L 2 and L 3 are independently selected from: a bond, C 1-3 Alkylene, -C(O)-, -C(O)-N(R L2 )-or-N(R L2 )-.

[0065] In some embodiments of the present invention, the L is selected from -L 1 -L 2 -L 3 -,in,

[0066] L 1 is selected from 7-11 membered heterospirocyclic diyl;

[0067] L 2 and L 3 Each is independently selected from: methylene, ethylene or -C(O)-.

[0068] In some embodiments of the present invention, L is selected from: *-7-11 membered heterospirocyclodiyl-C(O)-CH2 -** or *-7-11 membered heterospirocyclodiyl-C(O)-CH 2 -CH 2 -**; the * end is connected to the benzene ring.

[0069] In some embodiments of the present invention, L is selected from:

[0070]

[0071] The * end is connected to the benzene ring.

[0072] In some embodiments of the present invention, L is selected from:

[0073] The * end is connected to the benzene ring.

[0074] In some embodiments of the present invention, the compound of formula (I) is selected from the following compound of formula (III) or its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates:

[0075]

[0076] Among them, X, Y, Z, W, R 1 and L are as described above for the compound of formula (I) or (II).

[0077] In a second aspect, the present invention provides a compound having the following structure, and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, and solvates thereof:

[0078] Table 1

[0079]

[0080]

[0081]

[0082] The present invention also provides a pharmaceutical composition, which comprises the compound of the present invention, or its stereoisomer, optical isomer, pharmaceutically acceptable salt, prodrug, solvate, and optionally further comprises a pharmaceutically acceptable carrier.

[0083] The purpose of the present invention also includes providing the use of the compound shown in the present invention, or its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates, or pharmaceutical compositions containing the compound shown in the present invention, or its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates in the preparation of drugs for treating diseases mediated by EGFR.

[0084] The purpose of the present invention also includes providing the use of the compound shown in the present invention, or its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates, or pharmaceutical compositions comprising the compound shown in the present invention, or its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates in the preparation of drugs for treating cancer.

[0085] The cancer described in the present invention is selected from squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, liver cancer, kidney cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, head and neck cancer, nasopharyngeal cancer, oral cancer, salivary gland cancer, kidney cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, leukemia, lymphoma, glioma, neuroblastoma, melanoma, sarcoma, endometrial cancer, testicular cancer and thyroid cancer; more preferably, lung cancer; more preferably, non-small cell lung cancer.

[0086] The present invention also aims to provide a method for degrading and / or inhibiting EGFR protein kinase in a patient or a biological sample, comprising administering the patient, or contacting the biological sample with the compound of the present invention or a pharmaceutical composition thereof.

[0087] The compound described in the present invention, or its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates are used in the preparation of drugs for treating diseases mediated by EGFR, which can be administered in combination with other drugs.

[0088] The purpose of the present invention also includes providing a method for preventing and / or treating diseases mediated by EGFR, which comprises administering to a patient a therapeutically effective dose of the compound of the present invention, or its stereoisomer, optical isomer, pharmaceutically acceptable salt, prodrug, solvate or pharmaceutical composition of the present invention.

[0089] The purpose of the present invention also includes providing a method for preventing and / or treating cancer, which comprises administering to a patient a therapeutically effective dose of the compound of the present invention, or its stereoisomer, optical isomer, pharmaceutically acceptable salt, prodrug, solvate or pharmaceutical composition of the present invention.

[0090] The present invention also provides the following general preparation method of the compound of the present invention:

[0091] Synthesis scheme

[0092]

[0093] Ⅰ) Compound 1-a1 undergoes chemical transformation to obtain compound 1-a2;

[0094] For example, compound 1-a1 is used as a basic raw material to obtain compound 1-a2 through substitution reaction;

[0095] II) Compound 1-b1 undergoes chemical transformation to obtain compound 1-b2;

[0096] For example, compound 1-b2 is obtained by coupling reaction using compound 1-b1 as a basic raw material;

[0097] III) Compound 1-b2 undergoes chemical transformation to obtain compound (I);

[0098] For example, compound (I) is obtained by condensation reaction using compounds 1-b2, I-a2, etc. as basic raw materials. The present invention also provides a compound represented by formula (IV) and its salt:

[0099]

[0100] Among them, R 1 , R 2 , m and n are as described above for the compound of formula (I);

[0101] R 5 Selected from: -OH or CH 3 CH 2 O-;

[0102] R 6 Selected from:

[0103] The present invention also provides the following compounds and salts thereof:

[0104]

[0105] Explanation of terms

[0106] The terms "optional", "optionally", "optionally" or "arbitrarily" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0107] Unless otherwise specified, the term "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group, a straight or branched chain group containing 1 to 20 carbon atoms, for example, "C 1-12 Alkyl", "C 1-10 Alkyl", "C 1-8 Alkyl", "C 1-6 Alkyl", "C 1-3 "Alkyl" means that the group is an alkyl group, and the number of carbon atoms on the carbon chain is between 1-10, 1-6, and 1-3, respectively. It includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl, etc.

[0108] Unless otherwise specified, the term "cycloalkyl" refers to a monocyclic, bicyclic or polycyclic saturated or partially saturated aliphatic hydrocarbon group having a specific number of carbon atoms. Unless otherwise specified, the present application includes all possible monocyclic and condensed rings (including fused in the form of bis, spiro or bridge), including C 3-15 Cycloalkyl (3-15 membered cycloalkyl), preferably C 3-12 Cycloalkyl (3-12 membered cycloalkyl), preferably C 3-11 Cycloalkyl (3-11 membered cycloalkyl), more preferably C 3-9 Cycloalkyl (3-9 membered cycloalkyl), more preferably C 3-8 Cycloalkyl (3-8 membered cycloalkyl), more preferably C 3-7 Cycloalkyl (3-7 membered cycloalkyl), further preferably C 3-6 Cycloalkyl (3-6 membered cycloalkyl); preferably C 4-12 Cycloalkyl (4-12 membered cycloalkyl), preferably C 4-8 Cycloalkyl (4-8 membered cycloalkyl), more preferably C 5-7 Cycloalkyl (5-7 membered cycloalkyl), or C 4-6 Cycloalkyl (4-6 membered cycloalkyl). Monocyclic cycloalkyl usually refers to preferably C 3-12 Monocycloalkyl (3-12 membered monocycloalkyl), more preferably C 3-10 Monocycloalkyl (3-10 membered monocycloalkyl), more preferably C 3-8 Monocycloalkyl (3-8 membered monocycloalkyl), C 3-7 Monocycloalkyl (3-7 membered monocycloalkyl), C 4-7 Monocycloalkyl (4-7 membered monocycloalkyl), C 3-6 Monocyclic alkyl (3-6 membered monocyclic alkyl), examples of which include but are not limited to: cyclopropyl, cyclohexyl, methylcyclopropyl, 2-ethyl-cyclopentyl, dimethylcyclobutyl, etc. Condensed ring cycloalkyl includes spirocyclic alkyl, paracyclic alkyl, bridged cycloalkyl. Spirocyclic alkyl can be 7-12 membered spirocyclic alkyl, preferably 7-11 membered spirocyclic alkyl, further preferably 7-9 membered spirocyclic alkyl, examples of which include but are not limited to:

[0109] The cycloalkyl group may be a 6-11-membered cycloalkyl group, preferably a 7-10-membered cycloalkyl group, more preferably an 8-10-membered cycloalkyl group, and further preferably a 9-10-membered cycloalkyl group, and representative examples thereof include but are not limited to Preferred examples of partially saturated cycloalkyl groups include, but are not limited to The bridged cycloalkyl group may be a 6-10 membered bridged cycloalkyl group, preferably a 7-10 membered bridged cycloalkyl group, examples of which include but are not limited to:

[0111]

[0112] Unless otherwise specified, the term "heterocyclyl" or "heterocycle" refers to a saturated or partially saturated monocyclic or polycyclic non-aromatic substituent having ring carbon atoms and 1 to more ring heteroatoms, containing 3-20 ring atoms ("3-20 membered heterocyclyl"), wherein 1, 2, 3 or more ring atoms are selected from N, O or S, and the remaining ring atoms are C, and the heteroatoms are preferably 1-5 (i.e., 1, 2, 3, 4 or 5), more preferably 1-4, further preferably 1-3, and even more preferably 1-2. It preferably contains 3-14 ring atoms (“3-14-membered heterocyclyl”), further preferably contains 3-12 ring atoms (“3-12-membered heterocyclyl”), further preferably contains 4-11 ring atoms (“4-11-membered heterocyclyl”), or further preferably contains 3-8 ring atoms (“3-8-membered heterocyclyl”), further preferably contains 4-7 ring atoms (“4-7-membered heterocyclyl”), further preferably contains 5-10 ring atoms (“5-10-membered heterocyclyl”), further preferably contains 5-6 ring atoms (“5-6-membered heterocyclyl”); the number of heteroatoms is preferably 1, 2 or 3. "Heterocyclyl" may be a monocyclic ("monocyclic heterocyclyl" or "monoheterocyclyl") or a fused ("fused heterocyclyl" or "heterofused cyclyl"), bridged ("heterobridged cyclyl" or "bridged heterocyclyl") or spiro-fused ("heterospirocyclyl" or "spiroheterocyclyl") ring system, such as a bicyclic system ("bicyclic heterocyclyl"), and may be saturated or partially unsaturated. The monoheterocyclyl includes 3-9 membered monoheterocyclyls, preferably 3-7 membered monoheterocyclyls, more preferably 4-7 membered monoheterocyclyls, and further preferably 4-6 membered monoheterocyclyls. The heterospirocyclyl includes saturated or partially saturated heterospirocyclyls, including 7-11 membered heterospirocyclyls, preferably 7-9 membered heterospirocyclyls, more preferably 7-8 membered heterospirocyclyls, and further preferably 7 membered heterospirocyclyls. The hetero-bridged cyclic group includes a saturated or partially saturated hetero-bridged cyclic group, preferably a 7-9-membered hetero-bridged cyclic group, more preferably a 7-8-membered hetero-bridged cyclic group, and further preferably a 7-membered hetero-bridged cyclic group. The heterocyclic bicyclic system can include one or more heteroatoms in one or both rings. "Heterocyclic group" also includes a ring system in which the heterocyclic ring as defined above is fused with one or more carbocyclic or heteroaryl groups, or a ring system in which the heterocyclic ring as defined above is fused with one or more aryl or heteroaryl groups, and in such cases, the number of ring members continues to indicate the number of ring members in the heterocyclic ring system. In certain embodiments, each example of a heterocyclic group is independently optionally substituted, for example, unsubstituted (a "unsubstituted heterocyclic group") or substituted with one or more substituents (a "substituted heterocyclic group").

[0113] Exemplary 3-membered heterocyclic radicals containing 1 heteroatom include, but are not limited to aziridine, oxiranyl and thiorenyl. Exemplary 4-membered heterocyclic radicals containing 1 heteroatom include, but are not limited to azetidinyl, oxetanyl and thiidine. Exemplary 5-membered heterocyclic radicals containing 1 heteroatom include, but are not limited to tetrahydrofuranyl, dihydrofuranyl, tetrahydrophenylthio, dihydrophenylthio, pyrrolidinyl, dihydropyrrole and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic radicals containing 2 heteroatoms include, but are not limited to imidazolidinyl, dioxolane, oxathiolanyl, dithiolanyl and oxazolidin-2-one. Exemplary 5-membered heterocyclic radicals containing 3 heteroatoms include, but are not limited to triazolinyl, oxadiazolinyl and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to piperidinyl, tetrahydropyranyl, dihydropyridinyl and thianyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, but are not limited to piperazinyl, morpholinyl, dithianyl and dioxanyl. Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include, but are not limited to triazacyclohexane, oxadiazine, thiadiazine, oxathiazine and dioxazine. Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to azepanyl, oxanyl and thianyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to azooctanyl, oxanyl and thianyl. Fused to a C 6 Exemplary 5-membered heterocyclyl groups on an aryl ring (also referred to herein as a 5,6-bicyclic heterocycle) include, but are not limited to, dihydroindolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocycle) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. Exemplary structures of heterobridged ring groups include, but are not limited to, the following structures: Exemplary heterospirocyclic structures include, but are not limited to, the following structures:

[0115] Unless otherwise specified, the term "aryl" or "aromatic ring group" refers to a group containing 6 to 16 carbon atoms (C 6-16 aryl or 6-16 membered aryl), or 6-14 carbon atoms (C 6-14 aryl or 6-14 membered aryl), or 6-12 carbon atoms (C 6-12 aryl or 6-12 membered aryl), or 6-10 carbon atoms (C 6-10 aryl or 6-10 membered aryl) or 6-8 carbon atoms (C6-8 The term "aryl" can be used interchangeably with the term "aromatic ring". Examples of aryl groups may include phenyl, naphthyl, anthracenyl, phenanthrenyl or pyrenyl.

[0116] Unless otherwise specified, the term "heteroaryl" or "heteroaromatic ring group" means an aromatic monocyclic or polycyclic ring system containing a 5-14 membered structure (5-14 membered heteroaryl), or a 5-12 membered structure (5-12 membered heteroaryl), or a 5-10 membered structure (or 5-10 membered heteroaryl), preferably a 5-8 membered structure (5-8 membered heteroaryl), and more preferably a 5-6 membered structure (5-6 membered heteroaryl), wherein at least one ring atom is a heteroatom and the remaining atoms are carbon, the heteroatoms are independently selected from O, N or S, and the number of heteroatoms is preferably 1, 2 or 3. Examples of heteroaryl groups include furanyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiodiazolyl, triazinyl, phthalazinyl, quinolyl, isoquinolyl, pteridinyl, purinyl, indolyl, isoindolyl, indazolyl, benzofuranyl, benzothiophenyl, benzopyridinyl, benzopyrimidinyl, benzopyrazinyl 1,2-b]pyridinyl, [1,2,4]triazolo[4,3-b]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridinyl, etc.

[0117] Unless otherwise specified, the term "alkenyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one double bond. The alkenyl group may contain 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms (i.e., C 2-12 alkenyl), preferably containing 2 to 10 carbon atoms (i.e., C 2-10 Alkenyl), further preferably containing 2-8 carbon atoms (i.e. C 2-8 Alkenyl), more preferably containing 2 to 6 carbon atoms (i.e., C 2-6 alkenyl), 2-5 carbon atoms (i.e. C 2-5 alkenyl), 2-4 carbon atoms (i.e. C 2-4 alkenyl), 2-3 carbon atoms (i.e. C 2-3 alkenyl), 2 carbon atoms (i.e. C 2 alkenyl), such as "C 2-6"Alkenyl" means that the group is an alkenyl group, and the number of carbon atoms in the carbon chain is between 2 and 6 (specifically 2, 3, 4, 5 or 6). Non-limiting examples of alkenyl include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl and 1,3-butadienyl, etc.

[0118] Unless otherwise specified, the term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one triple bond. The alkynyl group may contain 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms (i.e., C 2-12 Alkynyl), preferably containing 2 to 10 carbon atoms (i.e., C 2-10 Alkynyl), further preferably containing 2 to 8 carbon atoms (i.e. C 2-8 Alkynyl), more preferably containing 2 to 6 carbon atoms (i.e. C 2-6 Alkynyl), 2-5 carbon atoms (i.e. C 2-5 Alkynyl), 2-4 carbon atoms (i.e. C 2-4 Alkynyl), 2-3 carbon atoms (i.e. C 2-3 Alkynyl), 2 carbon atoms (i.e. C 2 Alkynyl), such as "C 2-6 "Alkynyl" means that the group is an alkynyl group, and the number of carbon atoms in the carbon chain is between 2 and 6 (specifically 2, 3, 4, 5 or 6). Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl and 1-butynyl, etc.

[0119] Unless otherwise specified, the term "alkylene" (which is used interchangeably with "alkylene chain"), used alone or in combination, refers to a straight or branched divalent saturated hydrocarbon group consisting of carbon and hydrogen atoms. The term "Cx-y alkylene" (x and y are each an integer) refers to a straight or branched alkylene group containing x to y carbon atoms, including C 1-30 Alkylene, preferably C 1-15 Alkylene, C 1-12 Alkylene, C 1-8 Alkylene, C 1-7 Alkylene, C 1-6 Alkylene, C 1-5 Alkylene, C 1-4 Alkylene, C 1-3Representative examples include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, tert-butylene, pentylene, isopentylene, neopentylene, tert-pentylene, hexylene, heptylene, octylene, nonylene, decylene, undecylene, dodecylene, tridecylene, tetradecylene, pentadecylene, hexadecylene, heptadecylene, octadecylene, nonadecylene, eicosylene, heneicosylene, docosylene, tricosylene, tetracosylene, pentacosylene, hexacosylene, heptacosylene, octacosylene, nonacosylene, and triacontylene.

[0120] Unless otherwise specified, the "alkylene" group is optionally substituted, and the substituent is preferably one or more selected from hydroxy, amino, mercapto, halogen, cyano, C 1-3 Alkyl, C 1-3 The substituent may be an alkoxy group, a trifluoromethyl group, a heterocyclic group or a combination thereof.

[0121] Unless otherwise specified, the term "alkynylene", used alone or in combination, refers to a group consisting of 2 to 12 carbon atoms having one or more carbon-carbon triple bonds. 2-12 alkynylene), preferably 2 to 8 (C 2-8 alkynylene), preferably 2 to 6 (C 2-6 alkynylene), more preferably 2 to 4 (C 2-4 Examples of preferred alkynylene groups include, but are not limited to, ethynylene, 1-propynylene, 1-butynylene, and 1,3-diynylene.

[0122] Unless otherwise specified, the term "alkenylene", used alone or in combination, refers to an alkylene group having 2 to 12 carbon atoms and one or more carbon-carbon double bonds. 2-12 alkenylene), preferably 2 to 8 (C 2-8 alkenylene), preferably 2 to 6 (C 2-6 Alkenylene), more preferably 2 to 4 (C 2-4 Examples of preferred alkenylene groups include, but are not limited to, vinylene (e.g., -CH=CH-), 1-propyleneene, and 1-butyleneene.

[0123] Unless otherwise specified, the term "halogen" or "halo" refers to F (fluorine), Cl (chlorine), Br (bromine), I (iodine). The term "haloalkyl" refers to an alkyl group as defined above in which one, two or more hydrogen atoms or all hydrogen atoms are replaced by halogen. Representative examples of haloalkyl groups include CCl 3 CF 3 , CHCl 2 , CH 2 Cl, CH2 Br, CH 2 I. CH 2 CF 3 CF 2 CF 3 wait.

[0124] Unless otherwise specified, the term "alkoxy" refers to -O-alkyl, the alkyl being as defined above. Preferably, it has 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms. Representative examples include methoxy, ethoxy, propoxy, tert-butoxy, pentyloxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, and the like.

[0125] Unless otherwise specified, "cycloalkenyl" refers to a subgroup consisting of monocyclic hydrocarbon rings, bicyclic hydrocarbon rings and spiro-hydrocarbon rings, however, the system is unsaturated, i.e., there is at least one CC double bond but no aromatic system. Preferably, it contains 3-12 carbon atoms (i.e., C 3-12 cycloalkenyl), more preferably containing 3 to 10 carbon atoms (C 3-10 cycloalkenyl), preferably 3 to 6 carbon atoms (C 3-6 Cycloalkenyl), 4-6 carbon atoms (C 4-6 Cycloalkenyl), 5-6 carbon atoms (C 5-6 cycloalkenyl).

[0126] In this article, "diyl" is also used to describe the divalent group of the cyclic group, such as heterocyclic diyl, cycloalkane diyl, heterospirocyclic diyl, cyclobutane diyl, piperidine diyl, piperazine diyl. "Diyl" refers to a group formed by the corresponding ring losing two hydrogen atoms, and the two hydrogen atoms can be on the same ring atom or on two different reducing subatoms.

[0127] Unless otherwise specified, the terms "pharmaceutically acceptable salt" and "pharmaceutically acceptable salt" refer to salts that are suitable for contact with mammalian tissues, especially human tissues, within the scope of reasonable medical judgment without excessive toxicity, irritation, allergic response, etc. and are commensurate with a reasonable benefit / risk ratio. For example, medically acceptable salts of amines, carboxylic acids and other types of compounds are well known in the art.

[0128] Unless otherwise specified, the term "salt" encompasses salts derived from inorganic acids as well as salts prepared from organic acids. If the compound of the present invention is acidic, pharmaceutically acceptable non-toxic bases include salts prepared from inorganic bases and organic bases.

[0129] Unless otherwise specified, the term "solvate" means a physical association of a compound of the invention with one or more solvent molecules, whether organic or inorganic. The physical association includes hydrogen bonding. In certain cases, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate will be able to be separated. The solvent molecules in the solvate may exist in a regular arrangement and / or a disordered arrangement. The solvate may contain stoichiometric or non-stoichiometric amounts of solvent molecules. "Solvate" encompasses solution phase and separable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

[0130] Unless otherwise specified, the term "optical isomers" refers to substances with exactly the same molecular structure, similar physical and chemical properties, but different optical rotations.

[0131] Unless otherwise specified, the term "stereoisomer" refers to compounds with the same chemical constitution but different arrangements of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis / trans) isomers, atropisomers, etc. Any resulting mixture of stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, for example, by chromatography and / or fractional crystallization based on the differences in the physical and chemical properties of the components.

[0132] Unless otherwise indicated, the structural formulas described in the present invention include all isomeric forms (such as enantiomers, diastereomers, and geometric isomers (or conformational isomers)): for example, R, S configurations containing asymmetric centers, (Z), (E) isomers of double bonds, and (Z), (E) conformational isomers. Therefore, single stereochemical isomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers, or geometric isomers (or conformational isomers) are all within the scope of the present invention.

[0133] Unless otherwise specified, the term "prodrug" refers to a drug that is converted into the parent drug in vivo. Prodrugs are often useful because, in certain circumstances, they may be easier to administer than the parent drug. For example, they may be bioavailable by oral administration, whereas the parent drug is not. Prodrugs also have improved solubility in pharmaceutical compositions compared to the parent drug. An example of a prodrug, but not limited to, would be any compound of formula (I) or formula (III) administered as an ester ("prodrug") to facilitate transport across cell membranes, where water solubility is detrimental to mobility, but once inside the cell water solubility is beneficial, which is then metabolically hydrolyzed to the carboxylic acid, the active entity. Another example of a prodrug would be a short peptide (polyamino acid) conjugated to an acid group, where the peptide is metabolized to reveal the active moiety.

[0134] Unless otherwise specified, the terms "isotopically labeled analogues" and "isotopic derivatives" refer to molecules in a compound that are isotopically labeled to provide isotopically labeled analogues that may have improved pharmacological activity. The isotopes commonly used as isotopic labels are: Hydrogen isotopes: Deuterium ( 2 H) and tritium ( 3 H); Carbon isotope: 11 C, 13 C and 14 C; Chlorine isotope: 35 Cl and 37 Cl; Fluorine isotope: 18 F; Iodine isotope: 123 I and 125 I; Nitrogen isotopes: 13 N and 15 N; oxygen isotope: 15 O, 17 O and 18 O and sulfur isotopes 35 These isotope-labeled compounds can be used to study the distribution of drug molecules in tissues. 13 C, because they are easy to label and detect, they are more widely used. Some heavy isotopes, such as deuterium ( 2 H), the substitution can enhance metabolic stability, prolong half-life, thereby achieving the purpose of reducing dosage and providing therapeutic advantages. The compounds of the present invention include their isotopic derivatives, such as deuterated compounds and deuterated compounds.

[0135] Unless otherwise specified, the term "optionally substituted" means that the hydrogen at the substitutable position of the group is not replaced, or is replaced by one or more substituents, the substituents being preferably selected from the following group: halogen, hydroxyl, thiol, cyano, nitro, amino, azido, oxo, carboxyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl, C 1-6 alkoxy, 3-10 membered cycloalkyl, 3-10 membered cycloalkylsulfonyl, 3-12 membered heterocyclic group, 6-14 membered aryl or 5-10 membered heteroaromatic ring group, wherein the C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl, C 1-6 The alkoxy, 3-10 membered cycloalkyl, 3-10 membered cycloalkylsulfonyl, 3-12 membered heterocyclic group, 6-14 membered aryl or 5-10 membered heteroaromatic ring group may be optionally selected from halogen, hydroxyl, amino, cyano, C 1-6 Alkyl or C 1-6 The present invention is substituted by one or more alkoxy groups.

[0136] The beneficial effects of the present invention are:

[0137] The present invention provides a novel PROTAC bifunctional compound that binds to EGFR protein and E3 ubiquitin ligase and its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, and solvates. The test results show that these compounds have obvious proliferation inhibition activity on BaF3-EGFR-L858R / T790M / C797S cells, and have a significant degradation effect on EGFR-L858R / T790M / C797S, and are well absorbed in mice, and can be used to treat diseases mediated by EGFR. DETAILED DESCRIPTION

[0138] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples that do not specify specific conditions are usually performed under conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise defined, all professional and scientific terms used in the text have the same meanings as those familiar to professionals in the field. In addition, any method and material similar or equivalent to the described content can be applied to the method of the present invention. The preferred implementation methods and materials shown in the text are for demonstration purposes only.

[0139] The structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or / and liquid chromatography-mass spectrometry (LC-MS) or / and liquid chromatography (HPLC). The instrument used for NMR determination is BrukerAVANCE III 600MHz, the instrument used for LC-MS is Waters arc / QDa; the instrument used for HPLC is Waters e2695_2998.

[0140] The starting materials in the examples of the present invention are known and commercially available, or can be synthesized according to methods known in the art.

[0141] The abbreviations used in the Preparation Examples, Examples, Test Examples and elsewhere herein are:

[0142] DCM Dichloromethane

[0143] TEA Triethylamine

[0144] DIPEA N,N-Diisopropylethylamine

[0145] DMF N,N-Dimethylformamide

[0146] EtOAc Ethyl acetate

[0147] H Hour

[0148] mL milliliters

[0149] MeOH Methanol

[0150] NaH Sodium hydride

[0151] TFA Trifluoroacetic acid

[0152] NBS N-Bromosuccinimide

[0153] NIS N-iodosuccinimide

[0154] THF Tetrahydrofuran

[0155] Pd(dppf)Cl 2 [1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride

[0156] DMSO-d 6 Deuterated dimethyl sulfoxide

[0157] Toluene

[0158] CDI N,N'-Carbonyldiimidazole

[0159] BPO Benzoyl Peroxide

[0160] Dioxane 1,4-Dioxane

[0161] Boc: tert-butyloxycarbonyl

[0162] Intermediate Preparation Example 1: Synthesis of 2-((4aS)-8-((2,6-dioxopiperidin-3-yl)amino)-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-3(4H)-yl)acetic acid (Intermediate 1)

[0163]

[0164] Step 1: Synthesis of (S)-tert-butyl 4-(2-fluoro-4-nitrophenyl)-3-(hydroxymethyl)piperazine-1-carboxylate

[0165] 1,2-difluoro-4-nitrobenzene (5.00 g, 31.43 mmol), (S)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (7.50 g, 34.68 mmol), DMSO (50 mL) and DIPEA (8.20 g, 63.44 mmol) were added to the reaction flask in sequence, and the reaction solution was heated to 120 ° C for 8 h. LCMS detection showed that the reaction was complete, and water (100 mL) was added to the reaction solution. Solids precipitated and filtered to obtain a filter cake. The filter cake was purified by silica gel column chromatography (PE: EA = 3: 1) to obtain the product (9.9 g). ESI-MS (m / z): 356.15 [M+H]+ .

[0166] Step 2: Synthesis of tert-butyl (S)-8-nitro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylate

[0167] Add (S)-4-(2-fluoro-4-nitrophenyl)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (9.5 g, 26.76 mmol) and DMF (55 mL) to the reaction bottle in sequence, cool the reaction solution to below 0°C, slowly add 60% NaH (1.3 g, 51.17 mmol), and after the addition is complete, return to room temperature for reaction for 0.5 h. After LCMS shows that the reaction is complete, slowly add water (100 mL) to the reaction solution to quench the reaction, then extract with ethyl acetate (200 mL), separate the liquids, collect the organic phase, wash it once with water and saturated sodium chloride aqueous solution, and concentrate the organic phase to dryness under reduced pressure to obtain the product (9.20 g). ESI-MS (m / z): 336.15 [M+H] + .

[0168] Step 3: Synthesis of tert-butyl (S)-8-amino-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylate

[0169] (S)-8-nitro-1,2,4a,5-tetrahydrobenzo[b]pyrazine[1,2-d][1,4]oxazine-3(4H)-carboxylic acid tert-butyl ester (5.0 g, 14.92 mmol), methanol (50 mL) and Pd / C (2 g) were added to the reaction flask in sequence. The reaction solution was stirred at 25 ° C and hydrogen atmosphere (pressure 20 psi) for 8 hours. After LCMS showed that the reaction was complete, the reaction solution was filtered through diatomaceous earth, the filter cake was rinsed with ethyl acetate (100 mL), and the filtrate was concentrated to dryness under reduced pressure to obtain the product (4.7 g). ESI-MS (m / z): 306.17 [M+H] + .

[0170] Step 4: Synthesis of tert-butyl (4aS)-8-((2,6-dioxopiperidin-3-yl)amino)-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylate

[0171] (S)-8-amino-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylic acid tert-butyl ester (2.72 g, 8.8 mmol), 3-bromopiperidine-2,6-dione (1.71 g, 8.8 mmol), DIPEA (6.93 g, 53.0 mmol) and DMF (20 mL) were added to the reaction bottle in sequence, and the mixture was reacted at 80°C for 16 h. LCMS showed that the reaction was complete, and the mixture was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (PE:EA=1:1) to obtain the product (1.12 g, 2.6 mmol). ESI-MS (m / z): 417.21 [M+H] + .

[0172] Step 5: Synthesis of 3-(((S)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)amino)piperidine-2,6-dione hydrochloride

[0173] (4aS)-8-((2,6-dioxopiperidin-3-yl)amino)-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-tert-butylcarboxylate (0.54 g, 1.30 mmol) and 1,4-dioxane hydrochloride (6 mL) were added to the reaction flask. The reaction solution was reacted at 25°C for 3 h. After LCMS detection, the reaction was concentrated under reduced pressure to obtain a crude product of 3-(((S)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)amino)piperidine-2,6-dione hydrochloride (0.41 g). ESI-MS (m / z): 317.25 [M+H] + .

[0174] Step 6: Synthesis of tert-butyl 2-((4aS)-8-((2,6-dioxopiperidin-3-yl)amino)-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-3(4H)-yl)acetate

[0175] 3-(((S)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazine[1,2-d][1,4]oxazin-8-yl)amino)piperidine-2,6-dione hydrochloride (0.41 g), tert-butyl 2-bromoacetate (0.34 g, 1.7 mmol), DIPEA (0.68 g, 5.3 mmol) and acetonitrile (20 mL) were added to the reaction bottle. The reaction solution was reacted at 70°C for 8 h. After the reaction was completed by LCMS, it was concentrated under reduced pressure and the concentrate was purified by silica gel column chromatography (DCM:MeOH=92:8) to obtain the product (0.47 g, 1.1 mmol). ESI-MS (m / z): 431.46 [M+H]+ .

[0176] Step 7: Synthesis of 2-((4aS)-8-((2,6-dioxopiperidin-3-yl)amino)-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-3(4H)-yl)acetic acid

[0177] Add tert-butyl 2-((4S)-8-((2,6-dioxopiperidin-3-yl)amino)-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-yl)acetate (0.10 g, 0.2 mmol), trifluoroacetic acid (2 mL), and dichloromethane (2 mL) into the reaction flask. The reaction solution was reacted at 25°C for 3 h. After the reaction was completed by LCMS, the product was concentrated under reduced pressure to obtain a crude product (0.09 g). ESI-MS (m / z): 375.16 [M+H] + .

[0178] Intermediate Preparation Example 2: Synthesis of 2-((4aR)-8-((2,6-dioxopiperidin-3-yl)amino)-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-3(4H)-yl)acetic acid (Intermediate 2)

[0179]

[0180] Referring to the preparation method of Intermediate Preparation Example 1, only (S)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester in step 1 was replaced with (R)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester to obtain a crude product (0.23 g). ESI-MS (m / z): 375.16 [M+H] + .

[0181] Intermediate Preparation Example 3: Synthesis of (S)-2-(8-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-3(4H)-yl)acetic acid (Intermediate 3)

[0182]

[0183] Steps 1-3 are the same as Steps 1-3 in the above Intermediate Preparation Example 1.

[0184] Step 4: Synthesis of (S)-3-((3-(tert-butylcarbonyl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)amino)propanoic acid

[0185] Add (S)-8-amino-1,2,4a,5-tetrahydrobenzo[b]pyrazine[1,2-d][1,4]oxazine-3(4H)-carboxylic acid tert-butyl ester (4.7 g, 15.40 mmol) and toluene (50 mL) to the reaction flask, and then add acrylic acid (1.25 g, 17.36 mmol). Heat the reaction solution to 110 ° C and stir for 8 hours. After LCMS shows that the reaction is complete, the reaction solution is directly concentrated to dryness under reduced pressure to obtain a crude product (6.9 g). ESI-MS (m / z): 378.20 [M+H] + .

[0186] Step 5: Synthesis of (S)-1-(3-acetyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0187] Add (S)-3-((3-(tert-butyloxycarbonyl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazine[1,2-d][1,4]oxazin-8-yl)amino)propanoic acid (6.50 g), urea (3.2 g) and acetic acid (60 mL) to the reaction flask. The reaction solution was stirred at 120°C for 12 hours. LCMS showed that the reaction was complete. The reaction solution was concentrated to dryness under reduced pressure, and the concentrate was purified by column chromatography (DCM:MeOH=20:1) to obtain the product (3.4 g). ESI-MS (m / z): 345.15 [M+H] + .

[0188] Step 6: Synthesis of (S)-1-(1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0189] (S)-1-(3-acetyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazine[1,2-d][1,4]oxazine-8-yl)dihydropyrimidine-2,4(1H,3H)-dione (3.4 g, 9.88 mmol) and HCl (20 mL, 3N) were added to the reaction flask, and the reaction solution was stirred at 50°C for 8 h. LCMS showed that the reaction was complete, and the reaction solution was concentrated to dryness under reduced pressure to obtain a crude product (2.9 g). ESI-MS (m / z): 303.14 [M+H] + .

[0190] Step 7: Synthesis of tert-butyl (S)-2-(8-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-3(4H)-yl)acetate

[0191] Add crude (S)-1-(1,2,3,4,4a,5-hexahydrobenzo[b]pyrazine[1,2-d][1,4]oxazine-8-yl)dihydropyrimidine-2,4(1H,3H)-dione (2.0 g), tert-butyl 2-bromoacetate (1.55 g, 7.95 mmol), acetonitrile (50 mL) and DIPEA (4.28 g, 33.1 mmol) into the reaction flask. The reaction solution was reacted at 80°C for 3 h. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure by LCMS, and the concentrate was purified by silica gel column chromatography (DCM:MeOH=30:1) to obtain the product (1.44 g). ESI-MS (m / z): 417.21 [M+H] + .

[0192] Step 8: Synthesis of (S)-2-(8-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-3(4H)-yl)acetic acid

[0193] Add (S)-2-(8-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1,2,4a,5-tetrahydrobenzo[b]pyrazine[1,2-d][1,4]oxazine-3-(4H)-yl)acetate (1.44 g, 3.46 mmol), trifluoroacetic acid (10 mL) and dichloromethane (10 mL) into the reaction flask. The reaction solution was reacted at 25°C for 2 h. After the reaction was completed by LCMS, the reaction solution was concentrated to dryness under reduced pressure to obtain a crude product (1.52 g). ESI-MS (m / z): 361.14 [M+H] + .

[0194] Intermediate Preparation Example 4: Synthesis of (R)-2-(8-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-3(4H)-yl)acetic acid (Intermediate 4)

[0195]

[0196] Referring to the preparation method of Intermediate Preparation Example 3, only (S)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester in step 1 was replaced with (R)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester to obtain a crude product (1.52 g). ESI-MS (m / z): 361.14 [M+H] + .

[0197] Intermediate Preparation Example 5: Synthesis of 5-bromo-2-(bromomethyl)-3-fluorobenzoic acid methyl ester (Intermediate 5)

[0198]

[0199] Methyl 5-bromo-3-fluoro-2-methylbenzoate (5 g, 20.24 mmol) was added to chloroform (50 mL), followed by NBS (3.96 g, 22.26 mmol), and then BPO (980.43 mg, 4.05 mmol) was slowly added. After the addition was completed, the temperature of the reaction system was raised to 80°C and the reaction was carried out for 12 hours. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE:EA=5:1) to obtain the product (5.43 g).

[0200] Intermediate Preparation Example 6: Synthesis of tert-butyl 6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (Intermediate 6)

[0201]

[0202] Step 1: Synthesis of tert-butyl 6-(4-bromophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0203] 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester oxalate (5 g, 17.34 mmol) and 4-bromophenylboronic acid (6.97 g, 34.69 mmol) were dissolved in DCM (150 mL), followed by the addition of 4A molecular sieves (5 g), Cu(OAc) 2 (6.30g, 34.69mmol) and TEA (7.02g, 69.37mmol), the reaction solution was stirred at 25°C for 16 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain a crude product of tert-butyl 6-(4-bromophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate. The crude product was purified by silica gel column chromatography (PE:EA=5:1) to obtain the product (2g). ESI-MS (m / z): 353.08 / 355.08 [M+H] + .

[0204] Step 2: Synthesis of tert-butyl 6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0205] 6-(4-Bromophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (4 g, 11.32 mmol) and biboronic acid pinacol ester (4.31 g, 16.98 mmol) were dissolved in 1,4-dioxane (40 mL), followed by the addition of potassium acetate (3.33 g, 33.97 mmol) and Pd(dppf)Cl2 ·CH 2 Cl 2 (924.70mg, 1.13mmol), the reaction system was replaced with nitrogen 3 times, and the reaction solution was heated to 100℃ and stirred for 16 hours. After the reaction was completed by LCMS, water (200mL) was added to the reaction solution to quench the reaction, and the reaction solution was extracted with ethyl acetate (3×200mL), and the organic phase was collected. The organic phase was washed with saturated sodium chloride aqueous solution (100mL), dried over anhydrous sodium sulfate, and the organic phase was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE:EA=3:1) to obtain the product (3.4g). ESI-MS (m / z): 401.25 [M+H] + .

[0206] Intermediate Preparation Example 7: Synthesis of 2-(6-(4-(2,6-diazaspiro[3.3]heptane-2-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide (Intermediate 7)

[0207]

[0208] Step 1: Synthesis of tert-butyl (S)-2-(1H-imidazole-1-carbonyl)pyrrolidine-1-carboxylate

[0209] Add Boc-L-proline (23.7 g, 110.11 mmol) to THF (150 mL), then add CDI (16.23 g, 100.10 mmol), and stir the mixture at 20 ° C for 2 h. LCMS detected that the reaction was complete. Add 50 mL of THF to the reaction solution to obtain the product (29.2 g, 0.5 M) as a yellow solution. ESI-MS (m / z): 266.14 [M+H] + .

[0210] Step 2: Synthesis of tert-butyl (S)-2-(3-ethoxy-3-oxopropanoyl)pyrrolidine-1-carboxylate

[0211] Dissolve ethyl malonate potassium salt (28.1 g, 165.10 mmol) in THF (200 mL) and add MgCl 2(10.48g, 110.06mmol), the reaction system was stirred at 50℃ for 2h, then cooled to 0℃, and (S)-2-(1H-imidazole-1-carbonyl)pyrrolidine-1-carboxylic acid tert-butyl ester (29.2g, 0.5M) was added dropwise to the reaction system. The reaction solution was stirred at 20℃ for 48h. LCMS detected that the reaction was complete, and a saturated aqueous solution of sodium bisulfate (200mL) was added to the reaction solution to quench the reaction, and ethyl acetate (3×500mL) was used for extraction. The organic phase was collected, washed with a saturated aqueous sodium carbonate solution (500mL×2), dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to obtain a crude product of (S)-2-(3-ethoxy-3-oxopropionyl)pyrrolidine-1-carboxylic acid tert-butyl ester, which was purified by silica gel column chromatography (PE:EA=2:1) to obtain the product (25g). ESI-MS (m / z): 286.16 [M+H] + .

[0212] Step 3: Synthesis of (S)-ethyl 3-oxo-3-(pyrrolidin-2-yl)propanoate

[0213] Dissolve (S)-2-(3-ethoxy-3-oxopropanoyl)pyrrolidine-1-carboxylic acid tert-butyl ester (20 g, 70.09 mmol) in ethyl acetate (20 mL), then add HCl / dioxane (100 mL, 4 M), and stir the mixture at room temperature for 1 h. LCMS detected that the reaction was complete. The reaction solution was concentrated to dryness under reduced pressure to obtain a crude product (16 g). ESI-MS (m / z): 186.11 [M+H] + .

[0214] Step 4: Synthesis of ethyl 2-(3-thioloxy-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetate

[0215] (S)-3-oxo-3-(pyrrolidin-2-yl)propionic acid ethyl ester (16g) was added to EtOH (100mL), and then KSCN (7.36g, 75.78mmol) was added, and the mixture was stirred at 80°C for 2h. LCMS detected that the reaction was complete. After the reaction solution was concentrated to dryness under reduced pressure, the residue was dissolved in ethyl acetate (200mL) and water (200mL), and saturated sodium bicarbonate solution was added, and ethyl acetate (3×500mL) was used for extraction. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain a crude product (13.5g). ESI-MS (m / z): 227.08 [M+H] + .

[0216] Step 5: Synthesis of ethyl 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate

[0217] Ethyl 2-(3-thioloxy-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetate (13.5 g) was added to AcOH (130 mL), and H 2 O 2 (23.77g, 209.65mmol, 20.14mL, 30% purity), the mixture was stirred at 20℃ for 1h. LCMS detected that the reaction was complete. Saturated aqueous sodium sulfite solution (200mL) was added to the reaction solution to quench the reaction, and the pH was adjusted to 8 with 4N NaOH aqueous solution (500mL). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated to dryness under reduced pressure to obtain a crude product (13.5g). ESI-MS (m / z): 195.11 [M+H] + .

[0218] Step 6: Synthesis of ethyl 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxoacetate

[0219] Ethyl 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate (13.5 g) was added to 1,4-dioxane (120 mL), followed by SeO 2 (412.49 g, 112.60 mmol), the mixture was stirred at 80 ° C for 3 h. LCMS detected that the reaction was complete. The reaction solution was concentrated to dryness under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (EA) to obtain the product (5.8 g). ESI-MS (m / z): 209.08 [M+H] + .

[0220] Step 7: Synthesis of ethyl (Z)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(hydroxyimino)acetate

[0221] Ethyl 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxoacetate (1.2 g) was added to EtOH (10 mL), and then NH 2 OH H 2 O (440.55 mg, 6.34 mmol) and NaOEt (784.39 mg, 11.53 mmol), the mixture was stirred at 80 ° C for 3 h. LCMS detected that the reaction was complete, the reaction system was cooled to room temperature, 50 mL of DCM was added to the reaction solution, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain a crude product (650 mg). ESI-MS (m / z): 224.10 [M+H] + .

[0222] Step 8: Synthesis of ethyl 2-amino-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate

[0223] Ethyl (Z)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(hydroxyimino)acetate (600 mg) was dissolved in AcOH (6 mL), and Zn (480 mg, 7.34 mmol) was added. The reaction solution was stirred at 20 °C for 48 h. LCMS detected that the reaction was complete. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. Ethyl acetate (5 mL) and HCl / EA (5 mL, 4 M) were added and stirred for 30 min. After filtration, the filter cake was rinsed with ethyl acetate 3 times, and the mother liquor was concentrated to dryness under reduced pressure to obtain the product (1 g). ESI-MS (m / z): 210.12 [M+H] + .

[0224] Step 9: Synthesis of ethyl 2-(6-bromo-4-fluoro-1-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate

[0225] Ethyl 2-amino-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate (100 mg) was dissolved in DMF (0.5 mL), and then TEA (164.73 mg, 1.63 mmol) and methyl 5-bromo-2-(bromomethyl)-3-fluorobenzoate (Intermediate 5) (106.13 mg, 325.59 μmol) were added. The mixture was stirred at 20 ° C for 0.5 h, and then the reaction system was heated to 80 ° C and stirred for 4 h. LCMS detected that the reaction was complete. Ethyl acetate (5 mL) was added to the reaction solution, and then washed with saturated sodium carbonate aqueous solution (3×5 mL) and saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by prep-TLC (DCM:MeOH=10:1) to obtain the product (59 mg). ESI-MS(m / z):422.04 / 424.04[M+H] + .

[0226] Step 10: Synthesis of tert-butyl 6-(4-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-ethoxy-2-oxoethyl)-7-fluoro-3-oxoisoindolin-5-yl)phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0227] Ethyl 2-(6-bromo-4-fluoro-1-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate (59 mg, 139.73 μmol) and tert-butyl 6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (Intermediate 6) (67.12 mg, 167.67 μmol) were added to 1,4-dioxane (0.4 mL) and H 2 O (0.4 mL), and then Na 2 CO 3 (7.36g, 75.78mmol), tBuXphos (11.87mg, 27.95μmol) and Pd(dppf)Cl 2 (10.22 mg, 13.97 μmol), the reaction system was stirred at 80°C for 4 h under nitrogen protection. LCMS detected that the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by prep-TLC (DCM: MeOH = 10: 1) to obtain the product (30 mg). ESI-MS (m / z): 616.29 [M+H] + .

[0228] Step 11: Synthesis of 2-(6-(4-(6-(tert-butoxycarbonyl)-2,6-diazaspiro[3.3]heptane-2-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid

[0229] 6-(4-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-ethoxy-2-oxoethyl)-7-fluoro-3-oxoisoindolin-5-yl)phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (30 mg, 48.73 μmol) was added to EtOH (0.3 mL), and LiOH solution (1 M, 58.47 μL) was added at 0°C. The reaction solution was stirred at room temperature for 4 h. LCMS detected that the reaction was complete. The reaction solution was concentrated to dryness under reduced pressure to obtain a crude product (40 mg). ESI-MS (m / z): 588.25 [M+H] + .

[0230] Step 12: Synthesis of tert-butyl 6-(4-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-7-fluoro-3-oxoisoindolin-5-yl)phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0231] 2-(6-(4-(6-(tert-butoxycarbonyl)-2,6-diazaspiro[3.3]heptane-2-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid (40 mg) was added to DMF (0.5 mL), and then HATU (38.43 mg, 101.08 μmol) was added to the mixture. The mixture was stirred at 20° C. for 30 min, and then DIEA (26.13 mg, 202.17 μmol) and thiazole-2-amine (8.10 mg, 80.87 μmol) were added. The reaction system was stirred at 20° C. for 1.5 h. LCMS detected that the reaction was complete. Saturated sodium bicarbonate aqueous solution (1 mL) was added to the reaction solution, and then extracted with ethyl acetate (3×1 mL). The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by prep-TLC (DCM: MeOH = 10: 1) to obtain the product (40 mg). ESI-MS (m / z): 670.25 [M+H] +

[0232] Step 13: Synthesis of 2-(6-(4-(2,6-diazaspiro[3.3]heptane-2-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide

[0233] 6-(4-(2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl)-7-fluoro-3-oxoisoindolin-5-yl)phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (40 mg, 59.72 μmol) was added to DCM (0.4 mL), and then TFA (0.1 mL) was added, and the mixture was stirred at 20°C for 2 h. LCMS detected that the reaction was complete. The reaction solution was added dropwise to the stirred MTBE (2 mL), and solid precipitated. It was filtered and the filter cake was dried to obtain the product (4.5 mg). ESI-MS (m / z): 570.20 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ: 12.77(s,1H),8.67-8.54(m,2H),7.82-7.72(m,2H),7.65(br d,J=8.6Hz,2H),7.52(d,J=3.5Hz,1H),7.31(d,J=3.5Hz,1H),6.55(d,J=8. 8Hz,2H),6.37-6.23(m,1H),4.81-4.72(m,1H),4.44-4.36(m,1H),4.18(br t,J=6.0Hz,7H),4.04(s,4H),2.95-2.76(m,4H).

[0234] Example 1: Synthesis of 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(6-(2-((S)-8-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1,2,4a,5-tetrahydrobenzo[b]pyrazin[1,2-d][1,4]oxazin-3(4H)-yl]acetyl)-2,6-diazaspiro[3,3]heptane-2-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide (Compound 1)

[0235]

[0236] The crude product (S)-2-(8-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)yl)acetic acid (Intermediate 3) (0.04 g) and N,N-dimethylformamide (10 mL) were added to the reaction flask. 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.04 g, 0.1 mmol) and N,N-diisopropylethylamine (0.04 g, 0.3 mmol) were added at 0°C. After half an hour of reaction, 2-(6-(4-(2,6-diazaspiro[3.3]heptane-2-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide (Intermediate 7) (0.05 g, 0.1 mmol) was added. The reaction solution was reacted at 25°C for 2 hours. LCMS detected that the reaction was complete, water and ethyl acetate were added to the reaction solution for extraction, the organic phase was collected, and the organic phase was concentrated to dryness under reduced pressure. The residue was separated by silica gel column chromatography (DCM:MeOH=92:8) to obtain the product (0.02 g). ESI-MS (m / z): 912.41 [M+H] + ; 1 H NMR (600 MHz, DMSO-d 6)δ: 12.53(s,1H),10.24(s,1H),7.74(s,1H),7.70(d,J=10.2Hz,1H),7.64(d,J=8.4Hz,2H),7.49(d,J=3.6Hz,1H),7.26(d,J=3. 6Hz,1H),6.86(d,J=8.8Hz,1H),6.75(dd,J=8.6,2.5Hz,1H),6.70(d,J=2.4Hz,1H),6.53(d,J=8.3Hz,2H),6.15(s,1H),4.79(d, J=17.6Hz,1H),4.41(s,2H),4.29–4.19(m,2H),4.10(s,2H),4.02–3.86(m,4H),3.74(d,J=12.7Hz,1H),3.70–3.59(m,2H),3.16 –3.10(m,4H),3.03–2.87(m,2H),2.80–2.61(m,4H),2.71–2.63(m,2H),2.47–2.42(m,2H),2.39–2.15(m,2H),2.09–1.82(m,2H).

[0237] Example 2: Synthesis of 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(6-(2-((4aS)-8-((2,6-dioxopiperidin-3-yl)amino)-1,2,4a,5-tetrahydrobenzo[b]pyrazin[1,2-d][1,4]oxazin-3(4H)-yl)acetyl)-2,6-diazaspiro[3,3]heptane-2-yl)phenyl)-4-fluoro-1-oxoisoindol-2-yl)-N-(thiazol-2-yl)acetamide (Compound 2)

[0238]

[0239] Referring to the preparation method of Example 1, only the crude (S)-2-(8-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-yl)acetic acid (Intermediate 3) in the step was replaced with the crude 2-((4aS)-8-((2,6-dioxopiperidin-3-yl)amino)-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-yl)acetic acid (Intermediate 1) to obtain the product (0.02 g). ESI-MS (m / z): 926.35 [M+H] + ; 1 H NMR (600 MHz, DMSO-d 6)δ: 12.48(s,1H),10.73(s,1H),7.72(s,1H),7.69(d,J=10.7Hz,1H),7.63(d,J=8.5Hz,2H),7.60(s,1H),7.48(d,J=3.6Hz,1H),7.28(d,J=3. 6Hz,1H),6.62(d,J=8.8Hz,1H),6.52(d,J=8.4Hz,2H),6.19(d,J=8.8Hz,1H),6.14(s,2H),5.31–5.27(m,2H),4.92(d,J=17.6Hz,1H),4.40(s, 2H),4.19(d,J=17.5Hz,1H),4.16(d,J=9.9Hz,2H),4.08(s,2H),3.98–3.92(m,2H),3.83(t,J=9.8Hz,1H),3.59–3.47(m,2H),3.28–3.23(m,2 H),3.00(q,J=15.2Hz,2H),2.93–2.75(m,4H),2.78–2.65(m,2H),2.64 –2.54(m,2H),2.30–2.21(m,2H),2.12–1.94(m,2H),1.90–1.76(m,2H).

[0240] Example 3: Synthesis of 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(6-(2-((4aR)-8-((2,6-dioxopiperidin-3-yl)amino)-1,2,4a,5-tetrahydrobenzo[b]pyrazin[1,2-d][1,4]oxazin-3(4H)-yl)acetyl)-2,6-diazaspiro[3,3]heptane-2-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide (Compound 3)

[0241]

[0242] Referring to the preparation method of Example 1, only the crude (S)-2-(8-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-yl)acetic acid (Intermediate 3) in the step was replaced with the crude 2-((4aR)-8-((2,6-dioxopiperidin-3-yl)amino)-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-yl)acetic acid (Intermediate 2) to obtain the product (0.03 g). ESI-MS (m / z): 926.35 [M+H] + ; 1H NMR (600 MHz, DMSO-d 6 )δ: 12.51(s,1H),10.73(s,1H),7.73(s,1H),7.70(d,J=10.7Hz,1H),7.63(d,J=8.5Hz,2H),7.61(s,1H),7.48(d,J=3.6Hz,1H),7.25(d,J=3. 6Hz,1H),6.63(d,J=8.8Hz,1H),6.53(d,J=8.4Hz,2H),6.19(d,J=8.8Hz,1H),6.14(s,2H),5.31–5.27(m,2H),4.79(d,J=17.6Hz,1H),4.41(s, 2H),4.21(d,J=17.5Hz,1H),4.16(d,J=9.9Hz,2H),4.08(s,2H),3.99–3.93(m,2H),3.83(t,J=9.8Hz,1H),3.59–3.48(m,2H),3.29–3.23(m,2 H),3.03(q,J=15.2Hz,2H),2.93–2.77(m,4H),2.79–2.65(m,2H),2.64 –2.55(m,2H),2.31–2.22(m,2H),2.12–1.94(m,2H),1.91–1.74(m,2H).

[0243] Example 4: Synthesis of 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(6-(2-((R)-8-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2d][1,4]oxazin-3(4H)-yl)acetyl)-2,6-diazaspiro[3.3]heptane-2-yl)phenyl)-4-fluoro-1-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide (Compound 4)

[0244]

[0245] Referring to the preparation method of Example 1, only the crude (S)-2-(8-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)yl)acetic acid (Intermediate 3) in the step was replaced with the crude (R)-2-(8-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)yl)acetic acid (Intermediate 4) to obtain the product (0.01 g). ESI-MS (m / z): 912.41 [M+H] + , 1 H NMR (600 MHz, DMSO-d 6 )δ: 12.52(s,1H),10.25(s,1H),7.74(s,1H),7.70(d,J=10.6Hz,1H),7.64(d,J=8.4Hz,2H),7.49(d,J=3.5Hz,1H),7.26(d,J=3.4Hz,1H),6. 85(d,J=8.8Hz,1H),6.74(dd,J=8.6,2.0Hz,1H),6.69(d,J=2.1Hz,1H),6.54(d,J=8.4Hz,2H),6.15(s,1H),4.79(d,J=17.6Hz,1H),4.42(s, 2H),4.24(dd,J=26.5,13.1Hz,2H),4.09(s,2H),4.06–3.94(m,7H),3.93–3.86(m,1H),3.74–3.64(m,4H),3.06(dd,J=30.7,14.5Hz,3H),2. 94(d,J=10.5Hz,1H),2.88(d,J=9.8Hz,1H),2.77(dd,J=16.9,8.1Hz,2H),2.72–2.63(m,4H),2.29(t,J=10.2Hz,1H),1.90(t,J=10.5Hz,1H).

[0246] Example 5-24: Compound 5-24 was prepared by referring to the preparation method of Example 1.

[0247]

[0248]

[0249]

[0250]

[0251] Biological Activity Test Example 1. EGFR Protein Degradation Test in BaF3-LTC Cells Based on Western Blot Method 1. Cell Line

[0252] Cell line source: Nanjing Kebai Biotechnology Co., Ltd. Cell type: BaF3-EGFR-L858R / T790M / C797S (BaF3-LTC).

[0253] 2. Reagents, consumables and instruments

[0254]

[0255]

[0256] 3. Test methods

[0257] Protein sample preparation: Collect cells, adjust the cell suspension to an appropriate concentration with complete culture medium (RPMI1640 + 10% FBS), and then plate on a 6-well plate. Incubate at 37°C, 5% CO 2 The cells were incubated overnight in an incubator. The next day, 100 nM of the test compound was added and a DMSO control well was set up. The DMSO concentration in all wells was 0.1%. The 6-well plate was placed at 37°C and 5% CO 2 After 48 hours of culture in an incubator, the cells were collected and lysed on ice by adding 50 μL of RIPA lysis buffer containing protease inhibitors and phosphatase inhibitors. The cells were centrifuged at 4°C and 12,000 rpm to collect the protein supernatant, and the protein was quantified by the BCA method to prepare the protein samples for Western Blot detection.

[0258] Western detection: Add an appropriate amount of protein sample to each well, perform polyacrylamide gel electrophoresis and transfer to the membrane. After transfer, transfer the membrane to a 5% BSA blocking buffer. After blocking for 2 hours, transfer it to a hybridization bag and add diluted anti-EGFR antibody or β-actin antibody accordingly, and incubate overnight at 4°C. Transfer the membrane to an elution buffer (containing TBST) and elute 4 times. After washing the membrane, add diluted goat anti-rabbit or goat anti-mouse antibodies, incubate at room temperature for 2 hours, transfer the membrane to an elution buffer and elute 4 times. Place the membrane in the exposure cassette of the gel imaging system, add the substrate working solution (ECL working solution), expose it, and save the exposure image.

[0259] The degradation rate of the compound at a concentration of 100 nM was calculated according to the following formula, where EGFR 化合物 is the gray value of EGFR protein after compound incubation, EGFR vehicle is the gray value of EGFR protein in the DMSO control group.

[0260] Degradation rate (%) = [1-(EGFR 化合物 / β-actin 化合物 ) / (EGFR vehicle / β-actin vehicle )]×100%

[0261] 4. Test results: The results of exemplary compounds are shown in Table 1:

[0262] Table 1 Effects on EGFR protein degradation activity in BaF3-LTC cells

[0263] Compound No. BaF3-LTC cells (EGFR degradation rate, %) 1 64 4 95

[0264] The results show that the compounds of the present invention have a good degradation effect on the EGFR protein of BaF3-EGFR-L858R / T790M / C797S cells.

[0265] Experimental Example 2: Degradation test of H1975-EGFR-L858R / T790M / C797S cells based on HiBiT method

[0266] 1. Cell lines

[0267] Cell line source: Shanghai Runnuo Biotechnology Co., Ltd.

[0268] Cell type: H1975-EGFR-L858R / T790M / C797S-HiBiT

[0269] 2. Test methods

[0270] Collect cells, resuspend them in complete medium (RPMI-1640 + 10% FBS + 1% P / S), count and plate on 384-well plates. Add compounds at different concentrations, and set up a control group with cells plus DMSO and a blank control group with cell culture medium. The concentration of DMSO is 0.1%. Place the cell culture plate at 37°C and 5% CO 2 Incubate in an incubator for 24 hours. Prepare Nano-Glo HiBiT detection solution by mixing Nano-Glo HiBiT Lytic Buffer: Substate: Protein at a ratio of 100:2:1; add 20 μL / well of Nano-Glo HiBiT detection solution, shake at 300 rpm to mix, and incubate at room temperature in the dark for 10 minutes. Detect on an Envision microplate reader and calculate the protein degradation rate.

[0271] The test results show that the compound of the present invention has a good EGFR protein degradation effect on H1975-EGFR-L858R / T790M / C797S cells.

[0272] Experimental Example 3: Proliferation inhibition test of BaF3-LTC cells and A431 cells (EGFR-WT) based on MTT method

[0273] 1. Cell lines

[0274] Cell line source: Nanjing Kebai Biotechnology Co., Ltd.

[0275] Cell type: BaF3-EGFR-L858R / T790M / C797S (BaF3-LTC), A431 cells (EGFR-WT)

[0276] 2. Reagents, consumables and instruments

[0277] name Part Number / Model factory RPMI Medium 1640 C1187550013T Gibco DMEM medium C11995500BT Gibco Puromycin A11138-03 Gibco Fetal bovine serum 10099-141C Gibco MTT 298-93-1 Shanghai Tebo Chemical Technology Co., Ltd. DMSO #D8371 Solarbio 96-well culture plate 3599 Costar Fluorescence microplate reader Varioskan Flash Thermo Scientific

[0278] 3. Test methods

[0279] Collect cells, resuspend them in complete medium (RPMI1640+10% FBS or DMEM+15% FBS), count and plate on 96-well plates. Add test compounds at concentrations of 10000nM, 2500nM, 625nM, 156.25nM, 39.06nM, 9.77nM, 2.44nM, and 0.61nM, respectively, and set up a control group of cells plus DMSO and a blank control group of cell culture medium. The concentration of DMSO is 0.1%. Place the cell culture plate at 37°C and 5% CO 2 After the culture was completed, the cell culture plate was removed, 20 μL / well of MTT was added, and the cells were incubated at 37°C and 5% CO 2 The cells were cultured in an incubator for 4 hours, the supernatant was discarded, DMSO 150 μL / well was added, the mixture was shaken and the OD value was detected by a microplate reader at 550 nM. The cell proliferation inhibition rate data were processed using the following formula to calculate the inhibition rate corresponding to different concentrations of the compound, where OD 化合物 is the OD value detected after compound incubation, OD 空白孔 is the OD value detected in the cell culture medium well, OD DMSO对照孔 The OD value of the control wells with DMSO added to the cells was measured. The inhibition rate curve was plotted using GraphPad Prism software and the IC was calculated using SPSS software. 50 value.

[0280] Inhibition Rate (Inh%) = (OD 化合物 -OD 空白孔 ) / (OD DMSO对照孔 -OD 空白孔 )×100%

[0281] 4. Test results: The results are shown in Table 2:

[0282] Table 2 Proliferation inhibition activity of the compounds of the present invention on BaF3-LTC cells and A431 cells

[0283]

[0284] The results showed that the compound of the present invention had obvious selective proliferation inhibition activity on BaF3-EGFR-L858R / T790M / C797S cells.

[0285] Test Example 4: Pharmacokinetics test in mice

[0286] 1. Experimental Animals

[0287] ICR mice, SPF grade, female, 20-30 g, were purchased from Beijing Weitonglihua Experimental Animal Technology Co., Ltd.

[0288] 2. Test methods

[0289] Animals were fasted but not watered for 12 hours one day before administration. On the day of the experiment, ICR mice were randomly divided into groups according to body weight, with 3 mice in each group, and the compound was administered orally at 10 mpk or intravenously at 1 mpk.

[0290] Sample collection: 100 μL of blood was collected from the orbital venous plexus of mice in the intravenous injection group (G2 and G4) before administration (0) and 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 8h, and 24h after administration, respectively, and placed in sodium heparin anticoagulant tubes; 100 μL of blood was collected from the orbital venous plexus of mice in the oral gavage group (G1 and G3) before administration (0) and 0.25h, 0.5h, 1h, 2h, 4h, 8h, and 24h after administration, respectively, and placed in sodium heparin anticoagulant tubes. The plasma was separated by centrifugation and transferred to a 1.5mL centrifuge tube and stored in a -80℃ refrigerator. The drug concentration in plasma was determined by LC-MS / MS method.

[0291] 3. Test results: The results are shown in Table 3:

[0292] Table 3 Pharmacokinetic test of the compounds of the present invention in mice

[0293]

[0294] Note: Solvent for oral gavage group and intravenous group: 20% PEG400 + 80% (20% HP-β-CD);

[0295] The results show that the compound of the present invention has good oral absorption in mice.

Claims

1. A compound represented by formula (II) or its stereoisomer, optical isomer, pharmaceutically acceptable salt, prodrug, solvate: in, X is selected from: absent, -NH-, -O- or -S-; Y is selected from: -NH-, -O- or -S-; Z is selected from: N, C-OH, COC 1-3 Alkyl or COC 1-3 Alkylene-4-6 membered heterocyclic diyl; W is selected from: N or CH; R 1 Selected from: hydrogen, halogen, hydroxy, amino, cyano or C 1-3 alkyl; R 2 Selected from: hydrogen, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl or C 1-6 Alkoxy; R 3 Selected from: hydrogen, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl or C 1-6 Alkoxy; R 4 Selected from: hydrogen, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, the C 1-6 Alkyl, C 1-6 The carbon atoms in the haloalkyl group may be independently replaced by one or more heteroatoms; L represents a connecting chain, and L is selected from -L1-L2-L3-L4-, wherein, L1 is selected from 7-11 membered heterospirocyclic diyl, wherein the 7-11 membered heterospirocyclic diyl may be substituted by one to four halogens, hydroxyls, aminos, -OR L1 、-N(R L1 )(R L1’ ) substituted, wherein R L1 , R L1’ are independently selected from hydrogen or C 1-3 alkyl; L2, L3 and L4 are independently selected from: 1-3 Alkylene, 4-7 membered monoheterocyclic diyl, C 2-6 Alkenylene, C 2-4 Alkyne, -C(O)-, -C(O)-N(R L2 )-or-N(R L2 )-; wherein the monocyclic heterocyclic diradical may be optionally substituted by hydroxyl, C 1-3 Alkyl or C 1-3 Alkoxy substituted; R L2 Selected from hydrogen or C 1-3 alkyl.

2. The compound according to claim 1 or its stereoisomer, optical isomer, pharmaceutically acceptable salt, prodrug, solvate, wherein: R 1 Selected from: hydrogen, F, Cl, Br, hydroxyl or methyl; R 2 Selected from: hydrogen; R 3 Selected from: hydrogen; R 4 Selected from: hydrogen; X is selected from: absent or -NH-; Y is selected from: -NH-, -O- or -S-; Z is selected from: N or C-OH; W is selected from: N or CH.

3. The compound according to claim 1 or 2, or its stereoisomer, optical isomer, pharmaceutically acceptable salt, prodrug, solvate, wherein: The L is selected from -L1-L2-L3-, wherein L1 is selected from 7-11 membered heterospirocyclic diyl; L2 and L3 are independently selected from: methylene, ethylene or -C(O)-; L is preferably *-7-11 membered heterospirocyclodiyl-C(O)-CH2-** or *-7-11 membered heterospirocyclodiyl-C(O)-CH2-CH2-**.

4. The compound according to claim 3 or its stereoisomer, optical isomer, pharmaceutically acceptable salt, prodrug, solvate, wherein: The L is selected from: The * end is connected to the benzene ring.

5. The compound according to any one of claims 1 to 4 is represented by formula (III) or its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates: in, R 1 Selected from: hydrogen, F, Cl, Br, hydroxyl or methyl; X is selected from: absent or -NH-; Y is selected from: -NH-, -O- or -S-; Z is selected from: N or C-OH; L is selected from: The * end is connected to the benzene ring.

6. The compound according to any one of claims 1 to 5 or its stereoisomer, optical isomer, pharmaceutically acceptable salt, prodrug, solvate, wherein: The compounds are as follows:

7. A pharmaceutical composition comprising the compound according to any one of claims 1 to 6 or its stereoisomer, optical isomer, pharmaceutically acceptable salt, prodrug, solvate, and optionally further comprising a pharmaceutically acceptable carrier.

8. Use of the compound according to any one of claims 1 to 6, or its stereoisomer, optical isomer, pharmaceutically acceptable salt, prodrug, solvate or the composition according to claim 7 in the preparation of a medicament for treating a disease mediated by EGFR.

9. Use of the compound of claims 1 to 6, or its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates, or the composition of claim 7 in the preparation of a medicament for treating cancer; the cancer is preferably squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, liver cancer, kidney cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, head and neck cancer, nasopharyngeal cancer, oral cancer, salivary gland cancer, kidney cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, leukemia, lymphoma, glioma, neuroblastoma, melanoma, sarcoma, endometrial cancer, testicular cancer and thyroid cancer; more preferably lung cancer; more preferably non-small cell lung cancer.

10. The use according to any one of claims 8 to 9, wherein The compound, or its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates may be administered in combination with other drugs.

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