GSPT1 degradation agent and application thereof

Abstract

The invention belongs to the field of medical chemistry, and particularly relates to compounds serving as GSPT1 degradation agents or pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs of the compounds, preparation methods of the compounds, pharmaceutical compositions containing the compounds and application of the compounds or the compositions to treatment of diseases beneficial to GSPT1 degradation, such as cancers. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and specifically relates to compounds serving as GSPT1 degraders or their pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs, methods for preparing the same, pharmaceutical compositions containing the same, and the use of the same for treating diseases, such as cancer, in which degradation of GSPT1 is beneficial. Background Art

[0002] Cereblon (CRBN) is a protein encoded by the CRBN gene. Cereblon forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1), Cullin-4A (CUL4A), and regulator of cullins 1 (ROC1). This complex ubiquitinates many other proteins.

[0003] Cereblon, a component of the DDB1-CUL4a-Roc1 ubiquitin ligase complex, is a molecular target for immunomodulatory agents such as thalidomide, lenalidomide, and pomalidomide. Inhibition of CRBN ubiquitination by these drugs leads to CRBN accumulation, resulting in increased degradation of target proteins mediated by the cullin-4RING E3 ligase. Cereblon E3 ligase inhibitors have a well-defined mechanism of action in the treatment of tumor-related diseases.

[0004] GSPT1 (G1 to S phase transition 1, also known as eRF3a) plays an important role in inhibiting cell proliferation by mediating stop codon recognition and the release of nascent proteins from ribosomes through interaction with the release factor eRF1. Studies have shown that GSPT1, as a new substrate of CRBN, can be effectively degraded by CRBN protein regulators, resulting in significant inhibition of leukemia cell proliferation. It has also been reported that GSPT1 is a cause of off-target effects of PTOTAC molecules that recruit CRBN. As a target of molecular glue, GSPT1 plays an important role in the protein translation process. Its degradation can lead to abnormal protein synthesis, thereby affecting the proliferation and survival of tumor cells. At the same time, as a GTPase, GSPT1 is difficult to target because the GTP concentration in the cell is very high and the GTP binding pocket binds strongly to the GTPase.

[0005] Safe and effective GSPT1 degraders need to be developed to meet clinical needs. Summary of the Invention

[0006] One object of the present invention is to provide a class of compounds having GSPT1 degradation activity represented by general formula (I) or pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs thereof,

[0007]

[0008] Another object of the present invention is to provide a method for preparing the compound of general formula (I) of the present invention or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof.

[0009] Another object of the present invention is to provide a composition comprising a compound of the general formula (I) of the present invention or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof and a pharmaceutically acceptable carrier, as well as a composition comprising a compound of the general formula (I) of the present invention or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof and one or more other drugs.

[0010] Another object of the present invention is to provide a method for treating GSPT1-related diseases such as cancer using a compound of the general formula (I) of the present invention or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, as well as use of a compound of the general formula (I) of the present invention or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof in the preparation of a medicament for treating GSPT1-related diseases such as cancer.

[0011] In view of the above-mentioned invention objectives, the present invention provides the following technical solutions:

[0012] In a first aspect, the present invention provides a compound represented by general formula (I) or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof,

[0013]

[0014] in:

[0015] Ring A and Ring B are each independently selected from cycloalkyl and heterocycloalkyl;

[0016] Ring C is selected from aryl, heteroaryl, cycloalkyl and heterocycloalkyl, which is optionally substituted with one or more groups selected from halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl, dialkylamino and oxo;

[0017] X is selected from -CH- and -N-;

[0018] L is selected from -CH2-O-, -CH2-, -O-, -NH-, -O-CH2- and

[0019] R1 and R2 are each independently selected from hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl, dialkylamino, oxo, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;

[0020] R3 and R4 are each independently selected from hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl, dialkylamino; and

[0021] m, n, p, q are each independently selected from 1, 2, 3 and 4.

[0022] In some embodiments, the compound of the above general formula (I) according to the present invention or its pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug, wherein:

[0023] Ring A and Ring B are each independently selected from C 3-8 Cycloalkyl and 3-8 membered heterocycloalkyl, wherein the heteroatom is selected from N, O and S;

[0024] Ring C is selected from 6-12 membered aryl, 5-12 membered heteroaryl, C 3-10 Cycloalkyl and 4-10 membered heterocycloalkyl, which are optionally selected from halogen, hydroxy, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, nitro, carboxyl, cyano, amino, mono C 1-6 Alkylamino, C 1-6 Alkyl acylamino, C 1-6 Alkyl acyl, amino acyl, C 1-6 Alkylaminoacyl, di-C 1-6 substituted with one or more of an alkylamino group and an oxo group;

[0025] L is selected from -CH2-O-, -O- and

[0026] R1 and R2 are each independently selected from halogen, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6Alkoxy, nitro, carboxyl, cyano, amino, mono C 1-6 Alkylamino, C 1-6 Alkyl acylamino, C 1-6 Alkyl acyl, amino acyl, C 1-6 Alkylaminoacyl, di-C 1-6 Alkylamino, oxo, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 6-12 membered aryl, and 5-12 membered heteroaryl;

[0027] R3 and R4 are each independently selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, nitro, carboxyl, cyano, amino, mono C 1-6 Alkylamino, C 1-6 Alkyl acylamino, C 1-6 Alkyl acyl, amino acyl, C 1-6 Alkylaminoacyl and di-C 1-6 Alkylamino; and

[0028] m, n, p, q are each independently selected from 1, 2 and 3.

[0029] In some embodiments, the compound of the above general formula (I) according to the present invention or its pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug, wherein:

[0030] Ring A and Ring B are each independently selected from C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl, wherein the heteroatom is selected from N and O;

[0031] Ring C is selected from 5-10 membered aryl and 5-10 membered heteroaryl, which is optionally selected from halogen, hydroxy, C 1-3 Alkyl, halogenated C 1-3 Alkyl, hydroxyl C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, hydroxy C 1-3 Alkoxy, nitro, carboxyl, cyano, amino, mono C 1-3 Alkylamino, C 1-3 Alkyl acylamino, C 1-3 Alkyl acyl, amino acyl, C 1-3 Alkylaminoacyl, di-C 1-3 substituted with one or more of an alkylamino group and an oxo group;

[0032] L is selected from -CH2-O-, -O- and

[0033] R1 and R2 are each independently selected from halogen, hydroxyl, C 1-3 Alkyl, halogenated C 1-3 Alkyl, hydroxyl C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, hydroxy C 1-3 Alkoxy, nitro, carboxyl, cyano, amino, mono C 1-3 Alkylamino, C 1-3 Alkyl acylamino, C 1-3 Alkyl acyl, amino acyl, C 1-3 Alkylaminoacyl, di-C 1-3 Alkylamino, oxo, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered aryl and 5-10 membered heteroaryl;

[0034] R3 and R4 are each independently selected from hydrogen, halogen, hydroxyl, C 1-3 Alkyl, halogenated C 1-3 Alkyl, hydroxyl C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, hydroxy C 1-3 Alkoxy, nitro, carboxyl, cyano, amino, mono C 1-3 Alkylamino, C 1-3 Alkyl acylamino, C 1-3 Alkyl acyl, amino acyl, C 1-3 Alkylaminoacyl and di-C 1-3 Alkylamino; and

[0035] m, n, p, q are each independently selected from 1, 2 and 3.

[0036] In some embodiments, the compound of the above general formula (I) according to the present invention or its pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug, wherein:

[0037] Ring C is selected from phenyl, pyridyl, imidazolyl, pyrrolyl, furyl, thienyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, indolyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, isoindolyl, 2,3-dihydro-1H-isoindolyl, benzopyrazolyl, benzimidazolyl, benzofuranyl, benzopyranyl, benzothiazolyl, phenyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, quinoxalinyl, benzoxazinyl, benzothiazinyl, imidazopyridinyl, pyrimidopyrazolyl, pyrimidoimidazolyl, dihydrobenzofuranyl, cyclopentenylpyridinyl, dihydropyranopyridinyl, chromanyl, which is optionally selected from halogen, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, nitro, carboxyl, cyano, amino, mono C 1-6 Alkylamino, C 1-6 Alkyl acylamino, C 1-6 Alkyl acyl, amino acyl, C 1-6 Alkylaminoacyl, di-C 1-6 One or more groups selected from halogen, hydroxyl, C 1-3 Alkyl, halogenated C 1-3 Alkyl, hydroxyl C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, hydroxy C 1-3 Alkoxy, nitro, carboxyl, cyano, amino, mono C 1-3 Alkylamino, C 1-3 Alkyl acylamino, C 1-3 Alkyl acyl, amino acyl, C 1-3 Alkylaminoacyl, di-C 1-3 substituted with one or more of an alkylamino group and an oxo group;

[0038] L is selected from -CH2-O-, -O- and

[0039] R1 and R2 are each independently selected from halogen, hydroxyl, C 1-3 Alkyl, halogenated C 1-3 Alkyl, hydroxyl C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, hydroxy C 1-3 Alkoxy, nitro, carboxyl, cyano, amino, mono C1-3 Alkylamino, C 1-3 Alkyl acylamino, C 1-3 Alkyl acyl, amino acyl, C 1-3 Alkylaminoacyl, di-C 1-3 Alkylamino, oxo, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered aryl and 5-10 membered heteroaryl;

[0040] R3 and R4 are each independently selected from hydrogen, halogen, hydroxyl, C 1-3 Alkyl, halogenated C 1-3 Alkyl, hydroxyl C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, hydroxy C 1-3 Alkoxy, nitro, carboxyl, cyano, amino, mono C 1-3 Alkylamino, C 1-3 Alkyl acylamino, C 1-3 Alkyl acyl, amino acyl, C 1-3 Alkylaminoacyl and di-C 1-3 Alkylamino; and

[0041] m, n, p, q are each independently selected from 1, 2 and 3.

[0042] In some specific embodiments, according to the present invention, the compound of the above general formula (I) or its pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug, wherein Selected from and R1 and R2 are each independently selected from fluorine, chlorine, bromine, hydroxy, methyl, ethyl, propyl, halo 1-3 Alkyl, hydroxyl C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, hydroxy C 1-3 Alkoxy, nitro, carboxyl, cyano, amino, mono C 1-3 Alkylamino, C 1-3 Alkyl acylamino, C 1-3 Alkyl acyl, amino acyl, C 1-3 Alkylaminoacyl, di-C 1-3 Alkylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3-8 membered heterocycloalkyl, 5-10 membered aryl and 5-10 membered heteroaryl, R3 is selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, methyl, ethyl, propyl, halo C 1-3 Alkyl, hydroxyl C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, hydroxy C 1-3Alkoxy, nitro, carboxyl, cyano, amino, mono C 1-3 Alkylamino, C 1-3 Alkyl acylamino, C 1-3 Alkyl acyl, amino acyl, C 1-3 Alkylaminoacyl and di-C 1-3 Alkylamino, m, n, p are each independently selected from 1, 2 and 3.

[0043] In some specific embodiments, according to the present invention, the compound of the above general formula (I) or its pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug, wherein Selected from

[0044] In some specific embodiments, according to the compound of the general formula (I) above of the present invention or its pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug, wherein R1 and R2 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, methyl, ethyl, propyl, isopropyl, halogenated C 1-3 Alkyl, hydroxyl C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, hydroxy C 1-3 Alkoxy, nitro, carboxyl, cyano, amino, mono C 1-3 Alkylamino, C 1-3 Alkyl acylamino, C 1-3 Alkyl acyl, amino acyl, C 1-3 Alkylaminoacyl and di-C 1-3 Alkylamino.

[0045] In some specific embodiments, according to the above compounds of general formula (I) of the present invention or pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs thereof, wherein ring C is selected from It is optionally selected from halogen, hydroxy, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, nitro, carboxyl, cyano, amino, mono C 1-6 Alkylamino, C 1-6 Alkyl acylamino, C 1-6 Alkyl acyl, amino acyl, C 1-6 Alkylaminoacyl, di-C 1-6 One or more groups in the alkylamino group are substituted.

[0046] In some specific embodiments, according to the above compounds of general formula (I) of the present invention or pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs thereof, wherein ring C is It is optionally selected from halogen, hydroxy, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, nitro, carboxyl, cyano, amino, mono C 1-6 Alkylamino, C 1-6 Alkyl acylamino, C 1-6 Alkyl acyl, amino acyl, C 1-6 Alkylaminoacyl, di-C 1-6 One or more groups in the alkylamino group are substituted; and L is selected from -CH2-O- and -O-.

[0047] In some specific embodiments, according to the above compounds of general formula (I) of the present invention or pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs thereof, wherein ring C is It is optionally selected from fluorine, chlorine, bromine, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, nitro, carboxyl, cyano, amino, mono C 1-6 Alkylamino, C 1-6 Alkyl acylamino, C 1-6 Alkyl acyl, amino acyl, C 1-6 Alkylaminoacyl, di-C 1-6 One or more groups in the alkylamino group are substituted; and L is

[0048] The present invention provides the following specific compounds or pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs thereof:

[0049]

[0050]

[0051] In a second aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof.

[0052] In some embodiments, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, and a pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, for use in treating GSPT1-related diseases such as cancer.

[0053] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof and a pharmaceutically acceptable carrier.

[0054] The compound of the present invention or its pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug can be mixed with a pharmaceutically acceptable carrier, diluent or excipient to prepare a pharmaceutical preparation, so as to be suitable for oral or parenteral administration. Methods of administration include, but are not limited to intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal and oral routes. The preparation can be applied by any route, for example, by infusion or push injection, by the route of absorption through the epithelium or mucocutaneous membrane (such as oral mucosa or rectum, etc.). Administration can be systemic or local. Examples of oral administration preparations include solid or liquid dosage forms, specifically, tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions, etc. The preparation can be prepared by methods known in the art and include carriers, diluents or excipients conventionally used in the field of pharmaceutical preparations.

[0055] In a third aspect, the present invention provides a method for treating GSPT1-related diseases using a compound represented by formula (I) of the present invention or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, or a pharmaceutical composition comprising the same, as well as use of the compound in the preparation of a medicament for treating GSPT1-related diseases.

[0056] In some preferred embodiments, the present invention provides a method for treating GSPT1-related diseases such as cancer using a compound represented by formula (I) of the present invention or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, or a pharmaceutical composition comprising the same, as well as use in the preparation of a medicament for treating GSPT1-related diseases such as cancer.

[0057] In some preferred embodiments, the present invention provides a compound represented by general formula (I) of the present invention or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, or a pharmaceutical composition comprising the same for use in a method for treating cancer and in the preparation of a drug for treating cancer, wherein the cancer includes but is not limited to: non-small cell lung cancer, lung adenocarcinoma, lung cancer, large cell lung cancer, non-small cell lung cancer, lung squamous cell carcinoma, small cell lung cancer, melanoma, desmoplastic melanoma, uveal melanoma, ovarian small cell carcinoma, ovarian rhabdoid tumor, skin squamous cell carcinoma, glioma, uterine cancer, endometrial cancer, ovarian serous cystadenocarcinoma, bladder urothelial carcinoma, primary central nervous system lymphoma, esophageal cancer, bladder cancer, gastric adenocarcinoma, adenoid cystic carcinoma, lymphoid tumor diffuse large B-cell lymphoma, pancreatic cancer, colorectal adenocarcinoma, bile duct cancer, sarcoma , head and neck cancer, cervical cancer and endocervical cancer, medulloblastoma, cutaneous T-cell lymphoma, hepatocellular carcinoma, renal papillary cell carcinoma, breast cancer, mantle cell lymphoma, gallbladder cancer, testicular germ cell cancer, clear cell renal cell carcinoma, prostate cancer, pediatric Ewing sarcoma, thymoma, chromophobe renal cell carcinoma, non-clear cell renal carcinoma, pheochromocytoma and paraganglioma, thyroid cancer, malignant peripheral nerve sheath tumor, neuroendocrine prostate cancer, head and neck squamous cell carcinoma, adrenal cortical carcinoma, cervical cancer and endocervical cancer, cutaneous squamous cell carcinoma, testicular germ cell cancer, glioblastoma, glioblastoma multiforme, Ewing sarcoma, clear cell renal cell carcinoma, neuroblastoma, diffuse large B-cell lymphoma, acute myeloid leukemia, chronic lymphocytic leukemia, multiple myeloma, malignant rhabdoid tumor, epithelioid sarcoma, renal medullary carcinoma, synovial sarcoma, meningioma, and soft tissue sarcoma.

[0058] In some specific embodiments, the compound represented by the general formula (I) of the present invention or its pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug is used to treat a condition caused by accumulation of GSPT1 protein, such as non-Hodgkin's lymphoma, leukemia and / or solid tumors. The non-Hodgkin's lymphoma is selected from one or more of diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma, mucosa-associated lymphoid tissue lymphoma and T-cell lymphoma. The leukemia includes one or more of chronic lymphocytic leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, and acute myeloid leukemia. The solid tumor includes one or more of lung cancer, liver cancer, breast cancer, and brain glioma.

[0059] Definition of terms

[0060] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0061] The "hydrogen", "carbon" and "oxygen" in the compounds of the present invention include all isotopes thereof. Isotopes should be understood to include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include protium, tritium and deuterium, and isotopes of carbon include 12 C. 13 C and 14 C, oxygen isotopes include 16 O and 18 O etc.

[0062] "Isomers" in the present invention refer to molecules with identical atomic composition and bonding patterns but different three-dimensional arrangements, including but not limited to diastereomers, enantiomers, cis-trans isomers, and mixtures thereof, such as racemic mixtures. Many organic compounds exist in optically active forms, meaning they have the ability to rotate the plane of plane-polarized light. When describing optically active compounds, the prefixes D, L, R, or S are used to indicate the absolute configuration of the chiral center of the molecule. The prefixes D, L, or (+), (-) are used to designate the sign of rotation of plane-polarized light in the compound, with (-) or L indicating that the compound is levorotatory and the prefix (+) or D indicating that the compound is dextrorotatory. These stereoisomers have the same chemical structure but different stereostructures. Specific stereoisomers can be enantiomers, and a mixture of isomers is often referred to as an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may result in a lack of stereoselectivity or stereospecificity during chemical reactions. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers, devoid of optical activity.

[0063] Depending on the choice of starting materials and process, the compounds of the present invention may exist as one of the possible isomers or as a mixture thereof, such as a racemate and a diastereomeric mixture (depending on the number of asymmetric carbon atoms). Optically active (R)- or (S)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.

[0064] Any resulting mixture of stereoisomers can be separated into the pure or substantially pure geometric isomers, enantiomers, and diastereomers on the basis of the differences in the constituent physicochemical properties, for example, by chromatography and / or fractional crystallization.

[0065] The term "halogen" in the present invention refers to fluorine, chlorine, bromine, or iodine. The term "halo" in the present invention refers to substitution with fluorine, chlorine, bromine, or iodine.

[0066] The "alkyl" of the present invention refers to a straight-chain or branched saturated aliphatic hydrocarbon group, preferably a straight-chain or branched group containing 1 to 6 carbon atoms, more preferably a straight-chain or branched group containing 1 to 3 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, etc. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be at any available point of attachment.

[0067] The -C(O)- group of the present invention refers to a "carbonyl group".

[0068] The -S(O)2- group of the present invention means a "sulfonyl group".

[0069] The "haloalkyl group" of the present invention refers to an alkyl group substituted with at least one halogen.

[0070] The "hydroxyalkyl group" of the present invention refers to an alkyl group substituted with at least one hydroxy group.

[0071] "Alkoxy" herein refers to -O-alkyl. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, n-propoxy, isopropoxy, isobutoxy, sec-butoxy, and the like. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituent may be at any available point of attachment.

[0072] "Cycloalkyl" herein refers to a cyclic, saturated hydrocarbon group. "Cycloalkyl" herein may also be a partially unsaturated alkyl ring system, such as a monocyclic, fused bicyclic, bridged bicyclic, or spirobicyclic ring. Suitable cycloalkyl groups may be substituted or unsubstituted monocyclic, bicyclic, or tricyclic saturated hydrocarbon groups having 3 to 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0073] The present invention " heterocycloalkyl " refers to a cyclic alkyl group containing 1 or 2 heteroatoms such as nitrogen, oxygen or sulfur, preferably consisting of 3-12 atoms. This heterocycloalkyl group can be saturated or partially saturated and unsubstituted or substituted, and can be monocyclic or bicyclic. The heterocycloalkyl group includes but is not limited to azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiopyranyl, dihydropyranyl, tetrahydropyranyl, 1,3-dioxolane, 1,4-dioxanyl, 1,4-oxacycloalkyl, 1,4-dithiopyranyl, 1,3-dioxanyl, 1,3-dithianyl, piperazinyl, thiomorpholinyl, piperidinyl, morpholinyl, azabicyclo [2.2.1] hept-5-yl, 8-oxa-3-azabicyclo [3.2.1] oct-3-yl.

[0074] The term "aryl" herein refers to an aromatic system that may comprise a monocyclic or fused polycyclic ring, preferably a monocyclic or fused bicyclic ring, containing 6 to 12 carbon atoms, preferably about 6 to about 10 carbon atoms. Suitable aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, fluorenyl, and indanyl. The aryl group may be optionally substituted or unsubstituted, and when substituted, the substituent may be at any available point of attachment.

[0075] The "heteroaryl" of the present invention refers to an aryl group in which at least one carbon atom is replaced by a heteroatom, preferably composed of 5-12 atoms (5-12 membered heteroaryl), more preferably composed of 5-10 atoms (5-10 membered heteroaryl), wherein the heteroatom is O, S, or N. The "heteroaryl" of the present invention includes a fully or partially aromatic ring system in the form of a monocyclic or fused bicyclic ring. The heteroaryl groups include, but are not limited to, imidazolyl, pyrrolyl, furyl, thienyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, indolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, isoindolyl, benzopyrazolyl, benzimidazolyl, benzofuranyl, benzopyranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, quinolyl, isoquinolyl, quinazolinyl, cinnolinyl, quinoxalinyl, benzoxazinyl, benzothiazinyl, imidazopyridinyl, pyrimidopyrazolyl, pyrimidoimidazolyl, dihydrobenzofuranyl, cyclopentenylpyridinyl, dihydropyranopyridinyl, chromanyl, and the like. Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents may be at any available point of attachment.

[0076] The "pharmaceutically acceptable salts" of the present invention refer to salts of the compounds of the present invention, which are safe and effective when used in mammals and have the desired biological activity.

[0077] In the present invention, "solvate" refers to a complex formed by the combination of a solute (e.g., an active compound, a salt of an active compound) and a solvent (e.g., water). The solvent is any solvent known or readily identified by one skilled in the art. If the solvate is water, the solvate is typically referred to as a hydrate, such as a hemihydrate, monohydrate, dihydrate, trihydrate, or alternatives thereof.

[0078] The in vivo effects of the compound of formula (I) can be exerted in part by one or more metabolites formed in the human or animal body after administration of the compound of formula (I). As mentioned above, the in vivo effects of the compound of formula (I) can also be exerted via the metabolism of a precursor compound ("prodrug"). "Prodrug" of the present invention refers to a compound that is converted into a compound of the present invention under physiological conditions in an organism due to reaction with an enzyme, gastric acid, etc., i.e., a compound that is converted into a compound of the present invention by oxidation, reduction, hydrolysis, etc. of an enzyme and / or a compound that is converted into a compound of the present invention by a hydrolysis reaction of gastric acid, etc.

[0079] The term "crystalline" in the present invention refers to a solid whose internal structure is formed by regularly repeating constituent atoms (or groups thereof) in three dimensions, as distinguished from an amorphous solid that does not have such a regular internal structure.

[0080] A "pharmaceutical composition" of the present invention refers to a mixture comprising any of the compounds described herein, including corresponding isomers, prodrugs, solvates, pharmaceutically acceptable salts, or chemically protected forms thereof, and one or more pharmaceutically acceptable carriers and / or one or more additional drugs. The purpose of a pharmaceutical composition is to facilitate administration of the compound to an organism. Such compositions are typically used to prepare medicaments for treating and / or preventing diseases mediated by one or more kinases.

[0081] The term "pharmaceutically acceptable carrier" as used herein refers to a carrier that does not significantly irritate an organism and does not interfere with the biological activity and properties of the administered compound, and includes all solvents, diluents or other excipients, dispersants, surfactants, isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants, and the like. This excludes any conventional carrier medium that is incompatible with the compound of the invention. Examples of pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, cellulose, and cellulose acetate; malt, gelatin, and the like.

[0082] The "excipient" of the present invention refers to an inert substance added to a pharmaceutical composition to further facilitate administration of a compound. Excipients may include calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols. DETAILED DESCRIPTION

[0083] The present invention will be further described in detail below with reference to the following examples, but the present invention is not limited to these examples. Unless otherwise specified, the materials used in the following examples were all commercially available.

[0084] Example 1: (2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl(1'-cyclopropyl-4,4,7'-trifluoro-2'-oxospiro[cyclohexane-1,3'-indolin]-5'-yl)carbamate

[0085]

[0086] Step 1: Preparation of phenyl (1'-cyclopropyl-4,4,7'-trifluoro-2'-oxospiro [cyclohexane-1,3'-indoline] -5'-yl) carbamate

[0087]

[0088] 5'-Amino-1'-cyclopropyl-4,4,7'-trifluorospiro[cyclohexane-1,3'-indolin]-2'-one (230 mg, 0.74 mmol) was added to a single-necked flask, followed by dichloromethane (5 mL) and sodium bicarbonate (125 mg, 1.48 mmol). Phenyl chloroformate (139 mg, 0.89 mmol) was added dropwise at 0°C and allowed to react at room temperature for 1 h. After completion of the reaction, the reaction solution was concentrated and column chromatography was performed to obtain the title product. ESI-MS m / z: 431.1 [M+H] + .

[0089] Step 2: Preparation of (2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl(1'-cyclopropyl-4,4,7'-trifluoro-2'-oxospiro[cyclohexane-1,3'-indolin]-5'-yl)carbamate

[0090]

[0091] 3-(6-(Hydroxymethyl)-1-oxoisoindol-2-yl)piperidine-2,6-dione (0.051 g, 0.186 mmol) was added to a single-necked flask, followed by 5 mL of dimethylacetamide. Sodium hydride (15 mg, 0.372 mmol) and phenyl(1'-cyclopropyl-4,4,7'-trifluoro-2'-oxospiro[cyclohexane-1,3'-indoline]-5'-yl)carbamate (0.08 g, 0.186 mmol) were then added at 0°C and allowed to react for 0.5 h at room temperature. After completion of the reaction, saturated ammonium chloride solution was added to quench the reaction, followed by extraction with ethyl acetate, washing with saturated sodium chloride solution, drying over anhydrous sodium sulfate, and concentration under reduced pressure to obtain the title product. ESI-MS m / z: 609.2 [MH] - .

[0092] 1H NMR(400MHz,DMSO-d6)δ11.00(s,1H),9.89(s,1H),7.79(s,1H),7.72-7.61( m,2H),7.41-7.23(m,2H),5.28(s,2H),5.18-5.09(m,1H),4.52-4.44(m,1H) ,4.39-4.31(m,1H),2.98-2.82(m,2H),2.65-2.57(m,1H),2.47-2.30(m,3H) ,2.12-1.94(m,3H),1.92-1.70(m,4H),0.98-0.90(m,2H),0.89-0.81(m,2H).

[0093] Example 2: (2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl(4,4,7'-trifluoro-1'-methyl-2'-oxospiro[cyclohexane-1,3'-indolin]-5'-yl)carbamate

[0094]

[0095] Step 1: Preparation of 5'-bromo-4,4,7'-trifluorospiro[cyclohexane-1,3'-indole]

[0096]

[0097] A mixture of (4-bromo-2-fluorophenyl)hydrazine hydrochloride (700 mg, 2.9 mmol) and 4,4-difluorocyclohexane-1-carbaldehyde (1.0 g, 6.25 mmol) was dissolved in acetic acid (10 mL) under ice-cooling conditions. The mixture was stirred in an oil bath at 60°C for 3 h. The reaction was quenched with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated to afford the title product. ESI-MS m / z: 318.0 [M+H] + .

[0098] Step 2: Preparation of 5'-bromo-4,4,7'-trifluorospiro[cyclohexane-1,3'-indoline]-2'-one

[0099]

[0100] Dissolve 5'-bromo-4,4,7'-trifluorospiro[cyclohexane]-1,3'-indole (1.1 g, 3.46 mmol) in 10 mL of tetrahydrofuran, add 2-methyl-2-butene (243 mg, 3.46 mmol) and sodium chlorite (1.29 g, 17.3 mmol), and stir at room temperature for 10 minutes. Then, add 5.19 mL of 1N aqueous sodium dihydrogen phosphate and stir for 1 hour. After the reaction is complete, quench with water, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate to obtain the title product, which is directly used in the next step. ESI-MS m / z: 332.0 [MH] - .

[0101] Step 3: Preparation of 6-bromo-3,3,8-trifluoro-9-methyl-2,3,4,9-tetrahydro-1H-carbazole

[0102]

[0103] Under ice-cooling conditions, 5'-bromo-4,4,7'-trifluorospiro[cyclohexane-1,3'-indolin]-2'-one (1.07 g, 3.2 mmol) was dissolved in 10 mL of tetrahydrofuran and placed in a single-necked flask. Sodium hydride (192 mg, 4.8 mmol) was added and stirred for 5 minutes. Methyl iodide (454 mg, 3.2 mmol) was then added and stirred in an oil bath at 60°C for 1 hour. After completion of the reaction, the mixture was quenched with water and extracted with ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated to yield the title product, which was used directly in the next step. ESI-MS m / z: 348.0 [M+H] + .

[0104] Step 4: Preparation of tert-butyl (4,4,7'-trifluoro-1'-methyl-2'-oxospiro[cyclohexane-1,3'-indoline]-5'-yl) carbamate

[0105]

[0106] 6-Bromo-3,3,8-trifluoro-9-methyl-2,3,4,9-tetrahydro-1H-carbazole (1.2 g, 3.45 mmol), tert-butyl carbamate (808 mg, 6.9 mmol), tris(dibenzylideneacetone)dipalladium (316 mg, 0.345 mmol), 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (370 mg, 0.69 mmol), and cesium carbonate (3.37 g, 10.35 mmol) were placed in a two-necked flask. The atmosphere was replaced with argon. 20 mL of 1,4-dioxane was added to dissolve the mixture. The mixture was heated to 100°C and reacted for 1.5 h. Extraction was performed three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography to obtain the title product. ESI-MS m / z: 385.1 [M+H] + .

[0107] Step 5: Preparation of 5'-amino-4,4,7'-trifluoro-1'-methylspiro[cyclohexane-1,3'-indolin]-2'-one

[0108]

[0109] Dissolve (tert-butyl(4,4,7'-trifluoro-1'-methyl-2'-oxospiro[cyclohexane-1,3'-indoline]-5'-yl)carbamate (552 mg, 1.43 mmol) in 6 mL of dichloromethane, add 2 mL of trifluoroacetic acid, and stir at room temperature for 1 hour. After completion of the reaction, quench with saturated sodium bicarbonate aqueous solution, extract with dichloromethane, dry over anhydrous sodium sulfate, and concentrate to obtain the desired product, which is directly used in the next step. ESI-MS m / z: 285.1 [M+H] + .

[0110] Step 6: Preparation of phenyl (4,4,7'-trifluoro-1'-methyl-2'-oxospiro [cyclohexane-1,3'-indoline] -5'-yl) carbamate

[0111]

[0112] 5'-Amino-4,4,7'-trifluoro-1'-methylspiro[cyclohexane-1,3'-indolin]-2'-one (332 mg, 1.13 mmol) was added to a single-necked flask, followed by dichloromethane (5 mL) and sodium bicarbonate (212 mg, 1.37 mmol). Phenyl chloroformate (190 mg, 2.26 mmol) was added dropwise at 0°C and allowed to react at room temperature for 1 h. After completion of the reaction, the reaction solution was concentrated and column chromatography was performed to obtain the title product. ESI-MS m / z: 404.9 [M+H] + .

[0113] Step 7: Preparation of (2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl(4,4,7'-trifluoro-1'-methyl-2'-oxospiro[cyclohexane-1,3'-indolin]-5'-yl)carbamate

[0114]

[0115] 3-(6-(Hydroxymethyl)-1-oxoisoindol-2-yl)piperidine-2,6-dione (0.075 g, 0.272 mmol) was added to a single-necked flask, followed by 5 mL of dimethylacetamide. Sodium hydride (22 mg, 0.544 mmol) and phenyl(4,4,7'-trifluoro-1'-methyl-2'-oxospiro[cyclohexane-1,3'-indoline]-5'-yl)carbamate (0.11 g, 0.272 mmol) were then added at 0°C and allowed to react for 0.5 h at room temperature. After completion of the reaction, saturated ammonium chloride solution was added to quench the reaction, followed by extraction with ethyl acetate, washing with saturated sodium chloride solution, drying over anhydrous sodium sulfate, and concentration under reduced pressure to obtain the title product. ESI-MS m / z: 583.2 [MH] - .

[0116] 1 H NMR (400MHz, DMSO-d6) δ10.99(s,1H),9.90(s,1H),7.79(s,1H),7.71-7.61(m,2H),7.40-7.27(m,2H),5.28(s,2H),5.18-5.07(m,1H),4.52- 4.43(m,1H),4.39-4.30(m,1H),3.27(d,3H),2.98-2.85(m,1H),2.66- 2.56(m,1H),2.46-2.35(m,2H),2.08-2.00(m,4H),1.92-1.74(m,4H).

[0117] Example 3: 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3,5-difluorophenyl)azetidin-3-yl(4,4,7'-trifluoro-1'-methyl-2'-oxospiro[cyclohexane-1,3'-indoline]-5'-yl)carbamate

[0118]

[0119] 1-(2,6-difluoro-4-(3-hydroxyazetidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (0.094 g, 0.317 mmol) was added to a single-necked flask, followed by 5 mL of dimethylacetamide. Sodium hydride (25 mg, 0.643 mmol) and phenyl(4,4,7'-trifluoro-1'-methyl-2'-oxospiro[cyclohexane-1,3'-indoline]-5'-yl)carbamate (0.128 g, 0.317 mmol) were then added at 0°C and allowed to react for 0.5 h at room temperature. After completion of the reaction, saturated ammonium chloride solution was added to quench the reaction, followed by extraction with ethyl acetate, washing with saturated sodium chloride solution, drying over anhydrous sodium sulfate, and concentration under reduced pressure to obtain the title product. ESI-MS m / z: 608.2 [M+H] + .

[0120] 1 H NMR (400MHz, DMSO-d6) δ10.50(s,1H),9.99(s,1H),7.39-7.27(m,2H),6.31(d,J=10.1Hz,2H),5.34-5.23(m,1H),4.31-4.19(m,2H),3.92- 3.79(m,2H),3.59(t,J=6.6Hz,2H),3.28(d,J=2.0Hz,3H),2.68(t,J=6.6Hz,2H),2.48-2.35(m,2H),2.11-2.03(m,2H),1.94-1.73(m,4H).

[0121] Example 4: 1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl-(2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)carbamate

[0122]

[0123] Step 1: Preparation of phenyl (2'-oxospiro [cyclopropane-1,3'-indoline] -5'-yl) carbamate

[0124]

[0125] 5'-Aminospiro[cyclopropane-1,3'-indolin]-2'-one (250 mg, 1.44 mmol) was added to a two-necked flask, followed by dichloromethane (10 mL) and sodium bicarbonate (145 mg, 1.73 mmol). The mixture was cooled to 0°C under an inert gas atmosphere, followed by phenyl chloroformate (451 mg, 2.88 mmol). The reaction was allowed to react at room temperature for 2 h. After completion of the reaction, the mixture was quenched with water, extracted with dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography to obtain the title product. ESI-MS m / z: 295.2 [M+H] + .

[0126] Step 2: Preparation of 1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl(2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)carbamate

[0127]

[0128] 3-(2,6-difluoro-4-(3-hydroxyazetidin-1-yl)phenyl)piperidine-2,6-dione (131 mg, 0.442 mmol) was added to a single-necked flask, and N,N-dimethylformamide (10 mL) was added to dissolve the mixture. The mixture was cooled to 0°C in an ice bath, and sodium hydride (35 mg, 0.884 mmol) and phenyl(2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)carbamate (130 mg, 0.442 mmol) were added. The mixture was allowed to react at room temperature for 2 h. After completion of the reaction, saturated ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the organic phase was concentrated and purified by column chromatography to obtain the title product. ESI-MS m / z: 497.2 [M+H] + .

[0129] 1 H NMR(400MHz,DMSO-d6)δ10.87(s,1H),10.46(s,1H),9.70(s,1H),7.18-7.07(m ,2H),6.83(d,J=8.3Hz,1H),6.22(d,J=11.0Hz,2H),5.28-5.21(m,1H),4.25-4. 18(m,2H),4.05(dd,J=12.5,5.1Hz,1H),3.81(dd,J=9.0,3.7Hz,2H),2.84-2.7 3(m,1H),2.57-2.52(m,1H),2.14-2.03(m,1H),1.98-1.91(m,1H),1.47(s,4H).

[0130] Example 5: 2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl(7-fluoro-1-methyl-2-oxo-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-5-yl)carbamate

[0131]

[0132] Step 1: Preparation of 5-bromo-7-fluoro-2',3',5',6'-tetrahydrospiro[indole-3,4'-pyran]

[0133]

[0134] A mixture of (4-bromo-2-fluorophenyl)hydrazine hydrochloride (2 g, 8.28 mmol) and tetrahydro-2H-pyran-4-carbaldehyde (945 mg, 8.28 mmol) was dissolved in acetic acid (20 mL) under ice-cooling conditions. The mixture was stirred in an oil bath at 60°C for 3 h. After concentration, the reaction was quenched with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated to yield the title product. ESI-MS m / z: 284.1 [M+H] + .

[0135] Step 2: Preparation of 5-bromo-7-fluoro-2',3',5',6'-tetrahydrospiro[indole-3,4'-pyran]-2-one

[0136]

[0137] Dissolve 5-bromo-7-fluoro-2',3',5',6'-tetrahydrospiro[indole-3,4'-pyran] (5.5 g, 19.36 mmol) in 10 mL of tetrahydrofuran, add 2-methyl-2-butene (1.35 g, 19.36 mmol) and sodium chlorite (8.7 g, 96.8 mmol), and stir at room temperature for 10 minutes. Then, add 29 mL of 1N aqueous sodium dihydrogen phosphate and stir for 1 hour. After completion of the reaction, quench with water, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate to obtain the title product, which is directly used in the next step. ESI-MS m / z: 300.0 [M+H] + .

[0138] Step 3: Preparation of 5-bromo-7-fluoro-1-methyl-2',3',5',6'-tetrahydrospiro[indole-3,4'-pyran]-2-one

[0139]

[0140] Under ice-cooling conditions, 5-bromo-7-fluoro-2',3',5',6'-tetrahydrospiro[indole-3,4'-pyran]-2-one (4.6 g, 15.33 mmol) was dissolved in 50 mL of tetrahydrofuran and placed in a single-necked flask. Sodium hydride (920 mg, 23 mmol) was added and stirred for 5 minutes. Methyl iodide (2.18 g, 15.33 mmol) was then added and stirred in an oil bath at 60°C for 1 hour. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to yield the title product. ESI-MS m / z: 314.0 [M+H] + .

[0141] Step 4: Preparation of tert-butyl (7-fluoro-1-methyl-2-oxo-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-5-yl)carbamate

[0142]

[0143] 5-Bromo-7-fluoro-1-methyl-2',3',5',6'-tetrahydrospiro[indole-3,4'-pyran]-2-one (500 mg, 1.59 mmol), tert-butyl carbamate (373 mg, 3.2 mmol), tris(dibenzylideneacetone)dipalladium (146 mg, 0.159 mmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (171 mg, 0.318 mmol), and cesium carbonate (1.55 g, 4.77 mmol) were placed in a two-necked flask. The atmosphere was replaced with argon. 10 mL of 1,4-dioxane was added to dissolve the mixture. The mixture was heated to 100°C and reacted for 6 h. Extraction was performed three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography to obtain the title product. ESI-MS m / z:351.1[M+H] + .

[0144] Step 5: Preparation of 5-amino-7-fluoro-1-methyl-2',3',5',6'-tetrahydrospiro[indole-3,4'-pyran]-2-one

[0145]

[0146] Dissolve tert-butyl (7-fluoro-1-methyl-2-oxo-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-5-yl)carbamate (380 mg, 1.09 mmol) in 6 mL of dichloromethane, add 2 mL of trifluoroacetic acid, and stir at room temperature for 1 hour. After completion of the reaction, quench with saturated aqueous sodium bicarbonate, extract with dichloromethane, dry over anhydrous sodium sulfate, and concentrate to obtain the title product, which is directly used in the next step. ESI-MS m / z: 251.1 [M+H] + .

[0147] Step 6: Preparation of phenyl (7-fluoro-1-methyl-2-oxo-2', 3', 5', 6'-tetrahydrospiro [indoline-3, 4'-pyran] -5-yl) carbamate

[0148]

[0149] 5-Amino-7-fluoro-1-methyl-2',3',5',6'-tetrahydrospiro[indole-3,4'-pyran]-2-one (320 mg, 1.27 mmol) was added to a single-necked flask, followed by dichloromethane (6 mL) and sodium bicarbonate (213 mg, 2.54 mmol). Phenyl chloroformate (239 mg, 1.52 mmol) was added dropwise at 0°C and allowed to react at room temperature for 1 h. After completion of the reaction, the reaction solution was concentrated and column chromatography was performed to obtain the title product. ESI-MS m / z: 371.1 [M+H] + .

[0150] Step 7: Preparation of 2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl(7-fluoro-1-methyl-2-oxo-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-5-yl)carbamate

[0151]

[0152] 3-(6-(Hydroxymethyl)-1-oxoisoindol-2-yl)piperidine-2,6-dione (0.074 g, 0.27 mmol) was added to a single-necked flask, followed by 5 mL of dimethylacetamide. Sodium hydride (22 mg, 0.544 mmol) and phenyl(7-fluoro-1-methyl-2-oxo-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-5-yl)carbamate (0.10 g, 0.27 mmol) were then added at 0°C and allowed to react for 0.5 h at room temperature. After completion of the reaction, saturated ammonium chloride solution was added to quench the reaction, followed by extraction with ethyl acetate, washing with saturated sodium chloride solution, drying over anhydrous sodium sulfate, and concentration under reduced pressure to obtain the title product. ESI-MS m / z: 549.2 [MH] - .

[0153] 1 H NMR (400MHz, DMSO-d6) δ10.99(s,1H),9.92(s,1H),7.79(s,1H),7.71-7.62(m,2H),7.45(s,1H),7.35(d,J=13.3 Hz,1H),5.28(s,2H),5.16-5.09(m,1H),4.52-4.43(m,1H),4.38-4.31(m,1H),4.08-3.99(m,2H),3.81-3.72(m,2 H), 3.27 (d, J = 2.5 Hz, 3H), 2.97-2.86 (m, 1H), 2.64-2.56 (m, 1H), 2.44-2.35 (m, 1H), 2.05-1.96 (m, 1H), 1.82-1.70 (m, 2H), 1.70-1.60 (m, 2H). Example 6: (2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl (2'-oxospiro[cyclopropane-1,3'-indolin]-5'-yl)carbamate

[0154]

[0155] Step 1: Preparation of phenyl (2'-oxospiro [cyclopropane-1,3'-indoline] -5'-yl) carbamate

[0156]

[0157] 5'-Aminospiro[cyclopropane-1,3'-indolin]-2'-one (250 mg, 1.44 mmol) was added to a two-necked flask, followed by dichloromethane (10 mL) and sodium bicarbonate (145 mg, 1.73 mmol). The mixture was cooled to 0°C under an inert gas atmosphere, followed by phenyl chloroformate (451 mg, 2.88 mmol). The reaction was allowed to react at room temperature for 2 h. After completion of the reaction, the mixture was quenched with water, extracted with dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography to obtain the title product. ESI-MS m / z: 295.2 [M+H] + .

[0158] Step 2: Preparation of (2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl(2'-oxospiro[cyclopropane-1,3'-indolin]-5'-yl)carbamate

[0159]

[0160] 3-(6-(Hydroxymethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (132 mg, 0.48 mmol) was added to a single-necked flask, and N,N-dimethylformamide (10 mL) was added to dissolve the mixture. The mixture was cooled to 0°C in an ice bath, and sodium hydride (38 mg, 0.96 mmol) and phenyl(2'-oxospiro[cyclopropane-1,3'-indolin]-5'-yl)carbamate (140 mg, 0.48 mmol) were added. The mixture was allowed to react at room temperature for 2 h. After completion of the reaction, saturated ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the organic phase was concentrated and purified by column chromatography to obtain the title product. ESI-MS m / z: 475.2 [M+H] + .

[0161] 1 H NMR(400MHz,DMSO-d6)δ11.00(s,1H),10.45(s,1H),9.61(s,1H),7.78(s,1H), 7.68-7.61(m,2H),7.17-7.09(m,2H),6.82(d,J=8.3Hz,1H),5.24(s,2H),5.13 (dd,J=13.3,5.1Hz,1H),4.50-4.41(m,1H),4.38-4.31(m,1H),2.95-2.88(m,1 H),2.64-2.58(m,1H),2.44-2.38(m,1H),2.04-1.99(m,1H),1.52-1.42(m,4H).

[0162] Example 7: 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3,5-difluorophenyl)azetidin-3-yl(7-fluoro-1-methyl-2',3',5',6'-tetrahydrospiro[indole-3,4'-pyran]-5-yl)carbamate

[0163]

[0164] 1-(2,6-difluoro-4-(3-hydroxyazetidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (0.113 g, 0.38 mmol) was added to a single-necked flask, followed by 5 mL of dimethylacetamide. Sodium hydride (30 mg, 0.76 mmol) and phenyl(7-fluoro-1-methyl-2-oxo-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-5-yl)carbamate (0.14 g, 0.38 mmol) were then added at 0°C and allowed to react for 0.5 h at room temperature. After completion of the reaction, saturated ammonium chloride solution was added to quench the reaction, followed by extraction with ethyl acetate, washing with saturated sodium chloride solution, drying over anhydrous sodium sulfate, and concentration under reduced pressure to obtain the title product. ESI-MS m / z: 574.2 [M+H] + .

[0165] 1 H NMR (400MHz, DMSO-d6) δ10.51(s,1H),10.02(s,1H),7.47(s,1H),7.32(d,J=13 .5Hz,1H),6.33(s,1H),6.30(s,1H),5.34-5.26(m,1H),4.30-4.22(m,2H),4.09 -4.00(m,2H),3.91-3.84(m,2H),3.82-3.72(m,2H),3.60(t,J=6.7Hz,2H),3.2 8(d,J=2.6Hz,3H),2.69(t,J=6.7Hz,2H),1.82-1.72(m,2H),1.70-1.61(m,2H).

[0166] Example 8: 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3,5-difluorophenyl)azetidin-3-yl(2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)carbamate

[0167]

[0168] Step 1: Preparation of phenyl (2'-oxospiro [cyclopropane-1,3'-indoline] -5'-yl) carbamate

[0169]

[0170] 5'-Aminospiro[cyclopropane-1,3'-indolin]-2'-one (300 mg, 1.72 mmol) was added to a two-necked flask, followed by dichloromethane (10 mL) and sodium bicarbonate (173 mg, 2.06 mmol). The mixture was cooled to 0°C under an inert gas atmosphere, followed by phenyl chloroformate (539 mg, 3.44 mmol). The reaction was allowed to react at room temperature for 3 h. After completion of the reaction, the mixture was quenched with water, extracted with dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography to obtain the title product. ESI-MS m / z: 295.1 [M+H] + .

[0171] Step 2: Preparation of 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3,5-difluorophenyl)azetidin-3-yl(2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)carbamate

[0172]

[0173] 1-(2,6-difluoro-4-(3-hydroxyazetidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (140 mg, 0.47 mmol) was added to a single-necked flask, and N,N-dimethylformamide (10 mL) was added to dissolve the mixture. The mixture was cooled to 0°C in an ice bath, and sodium hydride (38 mg, 0.94 mmol) and phenyl(2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)carbamate (170 mg, 0.56 mmol) were added. The mixture was allowed to react at room temperature for 2 h. After completion of the reaction, saturated ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the organic phase was concentrated and purified by column chromatography to obtain the title product. ESI-MS m / z: 498.1 [M+H] + .

[0174] 1 H NMR (400MHz, DMSO-d6) δ10.50(s,1H),10.46(s,1H),9.70(s,1H),7.16-7.07(m,2H),6.82(d,J=8.3Hz,1H),6.30(d,J=10.2Hz,2H),5 .27-5.22(m,1H),4.23(dd,J=9.0,6.7Hz,2H),3.83(dd,J=9.2,3.8Hz,2H),3.59(t,J=6.7Hz,2H),2.68(t,J=6.7Hz,2H),1.46(s,4H).

[0175] Example 9: (2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl(4,4,7'-trifluoro-2'-oxospiro[cyclohexane-1,3'-indolin]-5'-yl)carbamate

[0176]

[0177] Step 1: Preparation of 5'-bromo-4,4,7'-trifluorospiro[cyclohexane-1,3'-indoline]

[0178]

[0179] A mixture of (4-bromo-2-fluorophenyl)hydrazine hydrochloride (700 mg, 2.9 mmol) and 4,4-difluorocyclohexane-1-carbaldehyde (1.0 g, 6.25 mmol) was dissolved in acetic acid (10 mL) under ice-cooling conditions. The mixture was stirred in an oil bath at 60°C for 3 h. The reaction was quenched with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated to afford the title product. ESI-MS m / z: 318.0 [M+H] + .

[0180] Step 2: Preparation of 5'-bromo-4,4,7'-trifluorospiro[cyclohexane-1,3'-indoline]-2'-one

[0181]

[0182] Dissolve 5'-bromo-4,4,7'-trifluorospiro[cyclohexane]-1,3'-indole (1.1 g, 3.46 mmol) in 10 mL of tetrahydrofuran, add 2-methyl-2-butene (243 mg, 3.46 mmol) and sodium chlorite (1.29 g, 17.3 mmol), and stir at room temperature for 10 min. Then, add 5.19 mL of 1N aqueous sodium dihydrogen phosphate and stir for 1 h. Add water, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate to obtain the title product, which is directly used in the next step. ESI-MS m / z: 332.0 [MH] - .

[0183] Step 3: Preparation of tert-butyl (4,4,7'-trifluoro-2'-oxospiro[cyclohexane-1,3'-indoline]-5'-yl)carbamate

[0184]

[0185] 5'-Bromo-4,4,7'-trifluorospiro[cyclohexane-1,3'-indolin]-2'-one (800 mg, 2.4 mmol), tert-butyl carbamate (562 mg, 4.8 mmol), tris(dibenzylideneacetone)dipalladium (220 mg, 0.24 mmol), 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (258 mg, 0.48 mmol), and cesium carbonate (2.3 g, 7.2 mmol) were placed in a two-necked flask. The atmosphere was purged with argon, and 20 mL of 1,4-dioxane was added to dissolve the mixture. The mixture was heated to 100°C and allowed to react for 12 h. After the reaction, the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography to obtain the title product. ESI-MS m / z: 371.1 [M+H] + .

[0186] Step 4: Preparation of 5'-amino-4,4,7'-trifluorospiro[cyclohexane-1,3'-indoline]-2'-one

[0187]

[0188] Dissolve tert-butyl (4,4,7'-trifluoro-2'-oxospiro[cyclohexane-1,3'-indoline]-5'-yl)carbamate (340 mg, 0.92 mmol) in 6 mL of dichloromethane, add 2 mL of trifluoroacetic acid, and stir at room temperature for 1 hour. After completion, quench the reaction with saturated aqueous sodium bicarbonate, extract with dichloromethane, dry over anhydrous sodium sulfate, and concentrate to obtain the title product, which is directly used in the next step. ESI-MS m / z: 271.1 [M+H] + .

[0189] Step 5: Preparation of phenyl (4,4,7'-trifluoro-2'-oxospiro [cyclohexane-1,3'-indoline] -5'-yl) carbamate

[0190]

[0191] 5'-Amino-4,4,7'-trifluorospiro[cyclohexane-1,3'-indolin]-2'-one (43 mg, 0.16 mmol) was added to a single-necked flask, followed by dichloromethane (5 mL) and sodium bicarbonate (27 mg, 0.32 mmol). Phenyl chloroformate (30 mg, 0.192 mmol) was added dropwise at 0°C and allowed to react at room temperature for 1 h. After completion of the reaction, the reaction solution was concentrated and column chromatography was performed to obtain the title product. ESI-MS m / z: 391.1 [M+H] + .

[0192] Step 6: Preparation of (2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl(4,4,7'-trifluoro-2'-oxospiro[cyclohexane-1,3'-indolin]-5'-yl)carbamate

[0193]

[0194] 3-(6-(Hydroxymethyl)-1-oxoisoindol-2-yl)piperidine-2,6-dione (0.041 g, 0.149 mmol) was added to a single-necked flask, followed by 1 mL of dimethylacetamide. Sodium hydride (12 mg, 0.298 mmol) and phenyl(4,4,7'-trifluoro-2'-oxospiro[cyclohexane-1,3'-indoline]-5'-yl)carbamate (0.58 mg, 0.149 mmol) were then added at 0°C and allowed to react for 0.5 h at room temperature. After completion of the reaction, saturated ammonium chloride solution was added to quench the reaction, followed by extraction with ethyl acetate, washing with saturated sodium chloride solution, drying over anhydrous sodium sulfate, and concentration under reduced pressure to obtain the title product. ESI-MS m / z: 571.2 [M+H] + .

[0195] 1 H NMR(400MHz,DMSO-d6)δ11.00(s,1H),10.91(s,1H),9.85(s,1H),7.79(s,1 H),7.71-7.61(m,2H),7.36-7.26(m,2H),5.28(s,2H),5.17-5.10(m,1H),4 .51-4.44(m,1H),4.38-4.32(m,1H),2.98-2.86(m,1H),2.65-2.57(m,1H), 2.48-2.32(m,3H),2.15-1.97(m,3H),1.95-1.85(m,2H),1.84-1.73(m,2H).

[0196] Example 10: (2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl(1'-methyl-2'-oxospiro[cyclopropane-1,3'-indolin]-5'-yl)carbamate

[0197]

[0198] Step 1: Preparation of 5'-bromo-1'-methylspiro[cyclopropane-1,3'-indolin]-2'-one

[0199]

[0200] Under ice-cooling conditions, 5'-bromospiro[cyclopropane-1,3'-indolin]-2'-one (980 mg, 4.12 mmol) was dissolved in 20 mL of tetrahydrofuran and placed in a single-necked flask. Sodium hydride (247 mg, 6.18 mmol) was added and stirred for 5 minutes. Methyl iodide (585 mg, 4.12 mmol) was then added and stirred in an oil bath at 60°C for 1 hour. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to yield the title product. ESI-MS m / z: 252.0 [M+H] + .

[0201] Step 2: Preparation of tert-butyl (1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)carbamate

[0202]

[0203] 5'-Bromo-1'-methylspiro[cyclopropane-1,3'-indolin]-2'-one (500 mg, 2 mmol), tert-butyl carbamate (469 mg, 4 mmol), tris(dibenzylideneacetone)dipalladium (183 mg, 0.2 mmol), 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (215 mg, 0.4 mmol), and cesium carbonate (2.1 g, 6 mmol) were weighed into a two-necked flask. The atmosphere was purged with argon, and 10 mL of 1,4-dioxane was added to dissolve the mixture. The mixture was heated to 100°C and reacted for 6 h. After completion of the reaction, the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography to obtain the title product. ESI-MS m / z: 289.1 [M+H] + .

[0204] Step 3: Preparation of 5'-amino-1'-methylspiro[cyclopropane-1,3'-indolin]-2'-one

[0205]

[0206] Dissolve tert-butyl (1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)carbamate (500 mg, 1.74 mmol) in 6 mL of dichloromethane, add 2 mL of trifluoroacetic acid, and stir at room temperature for 1 hour. After completion, quench the reaction with saturated aqueous sodium bicarbonate, extract with dichloromethane, dry over anhydrous sodium sulfate, and concentrate to obtain the title product, which is directly used in the next step. ESI-MS m / z: 189.1 [M+H] + .

[0207] Step 4: Preparation of phenyl (1'-methyl-2'-oxospiro [cyclopropane-1,3'-indoline] -5'-yl) carbamate

[0208]

[0209] 5'-Amino-1'-methylspiro[cyclopropane-1,3'-indolin]-2'-one (340 mg, 1.8 mmol) was added to a single-necked flask, followed by dichloromethane (6 mL) and sodium bicarbonate (302 mg, 3.6 mmol). Phenyl chloroformate (338 mg, 2.16 mmol) was added dropwise at 0°C and allowed to react at room temperature for 1 h. After completion of the reaction, the reaction solution was concentrated and column chromatography was performed to obtain the title product. ESI-MS m / z: 309.1 [M+H] + .

[0210] Step 5: Preparation of (2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl(1'-methyl-2'-oxospiro[cyclopropane-1,3'-indolin]-5'-yl)carbamate

[0211]

[0212] 3-(6-(Hydroxymethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (0.134 g, 0.49 mmol) was added to a single-necked flask, followed by 5 mL of dimethylacetamide. Sodium hydride (39 mg, 0.98 mmol) and phenyl(1'-methyl-2'-oxospiro[cyclopropane-1,3'-indolin]-5'-yl)carbamate (0.15 g, 0.49 mmol) were then added at 0°C and allowed to react for 0.5 h at room temperature. After completion of the reaction, saturated ammonium chloride solution was added to quench the reaction, followed by extraction with ethyl acetate, washing with saturated sodium chloride solution, drying over anhydrous sodium sulfate, and concentration under reduced pressure to obtain the title product. ESI-MS m / z: 489.2 [M+H] + .

[0213] 1H NMR(400MHz,DMSO-d6)δ10.99(s,1H),9.67(s,1H),7.78(s,1H),7.70-7.60(m,2 H),7.25(d,J=7.9Hz,1H),7.16(s,1H),6.99(d,J=8.4Hz,1H),5.25(s,2H),5.17 -5.09(m,1H),4.53-4.43(m,1H),4.39-4.29(m,1H),3.18(s,3H),2.98-2.84(m, 1H),2.65-2.56(m,1H),2.46-2.34(m,1H),2.06-1.96(m,1H),1.60-1.41(m,4H).

[0214] Example 11: 1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl(1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)carbamate

[0215]

[0216] 3-(6-(Hydroxymethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (0.077 g, 0.26 mmol) was added to a single-necked flask, followed by 5 mL of dimethylacetamide. Sodium hydride (21 mg, 0.52 mmol) and phenyl(1'-methyl-2'-oxospiro[cyclopropane-1,3'-indolin]-5'-yl)carbamate (0.080 g, 0.26 mmol) were then added at 0°C and allowed to react for 0.5 h at room temperature. After completion of the reaction, saturated ammonium chloride solution was added to quench the reaction, followed by extraction with ethyl acetate, washing with saturated sodium chloride solution, drying over anhydrous sodium sulfate, and concentration under reduced pressure. Preparative separation yielded the title product. ESI-MS m / z: 511.2 [M+H] + .

[0217] 1H NMR (400MHz, DMSO-d6) δ10.86 (s, 1H), 9.75 (s, 1H), 7.23 (d, J = 8.4Hz, 1H), 7.16 ( s,1H),7.00(d,J=8.4Hz,1H),6.23(s,1H),6.20(s,1H),5.29-5.21(m,1H),4.28 -4.15(m,2H),4.09-4.00(m,1H),3.87-3.76(m,2H),3.18(s,3H),2.84-2.71(m, 1H),2.55-2.51(m,1H),2.15-2.01(m,1H),2.00-1.89(m,1H),1.59-1.41(m,4H).

[0218] Example 12: 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3,5-difluorophenyl)azetidin-3-yl(1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)carbamate

[0219]

[0220] 1-(2,6-difluoro-4-(3-hydroxyazetidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (68 mg, 0.23 mmol) was added to a single-necked flask, and N,N-dimethylformamide (5 mL) was added to dissolve the mixture. The mixture was cooled to 0°C in an ice bath, and sodium hydride (18 mg, 0.46 mmol) and phenyl(1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)carbamate (70 mg, 0.23 mmol) were added. The mixture was allowed to react at room temperature for 2 h. After completion of the reaction, saturated ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the organic phase was concentrated and purified by column chromatography to obtain the title product. ESI-MS m / z: 512.2 [M+H] + .

[0221] 1H NMR (400MHz, DMSO-d6) δ10.51(s,1H),9.77(s,1H),7.24(d,J=8.1Hz,1H),7.17(s,1H),7.00(d,J=8.4Hz,1H),6.31(d,J=10.2Hz,2H),5.29-5 .24(m,1H),4.24(dd,J=8.9,6.7Hz,2H),3.85(dd,J=9.2,3.8Hz,2H),3.60(t,J=6.7Hz,2H),3.19(s,3H),2.69(t,J=6.7Hz,2H),1.52(s,4H).

[0222] Example 13: (2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl(2'-oxospiro[cyclopropane-1,3'-indolin]-6'-yl)carbamate

[0223]

[0224] Step 1: Preparation of phenyl (2'-oxospiro [cyclopropane-1,3'-indoline] -6'-yl) carbamate

[0225]

[0226] 6'-Aminospiro[cyclopropane-1,3'-indolin]-2'-one (100 mg, 0.57 mmol) was added to a two-necked flask, followed by dichloromethane (5 mL) and sodium bicarbonate (96 mg, 1.14 mmol). The mixture was cooled to 0°C under an inert gas atmosphere, followed by phenyl chloroformate (106 mg, 0.68 mmol). The reaction was allowed to react at room temperature for 2 h. After completion of the reaction, the mixture was quenched with water, extracted with dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography to obtain the title product. ESI-MS m / z: 295.1 [M+H] + .

[0227] Step 2: Preparation of (2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl(2'-oxospiro[cyclopropane-1,3'-indolin]-6'-yl)carbamate

[0228]

[0229] 3-(6-(Hydroxymethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (79 mg, 0.29 mmol) was added to a single-necked flask, and N,N-dimethylformamide (5 mL) was added to dissolve the mixture. The mixture was cooled to 0°C in an ice bath, and sodium hydride (23 mg, 0.58 mmol) and phenyl(2'-oxospiro[cyclopropane-1,3'-indolin]-6'-yl)carbamate (85 mg, 0.29 mmol) were added. The mixture was allowed to react at room temperature for 1 h. After completion of the reaction, saturated ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the organic phase was concentrated and purified by column chromatography to obtain the title product. ESI-MS m / z: 475.1 [M+H] + .

[0230] 1 H NMR (400MHz, DMSO-d6) δ10.99(s,1H),10.50(s,1H),9.79(s,1H),7.81(s,1H),7.67(dd,J= 20.2,7.8Hz,2H),7.25(s,1H),6.96(d,J=8.0Hz,1H),6.84(d,J=8.1Hz,1H),5.27(s,2H),5 .13(dd,J=13.2,5.0Hz,1H),4.51-4.42(m,1H),4.39-4.31(m,1H),2.96-2.88(m,1H),2.64 -2.58(m,1H),2.44-2.37(m,1H),2.05-1.98(m,1H),1.50-1.44(m,2H),1.42-1.37(m,2H).

[0231] Example 14: 1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl(2'-oxospiro[cyclopropane-1,3'-indoline]-6'-yl)carbamate

[0232]

[0233] Step 1: Preparation of phenyl (2'-oxospiro [cyclopropane-1,3'-indoline] -6'-yl) carbamate

[0234]

[0235] 6'-Aminospiro[cyclopropane-1,3'-indolin]-2'-one (130 mg, 0.75 mmol) was added to a two-necked flask, followed by dichloromethane (5 mL) and sodium bicarbonate (126 mg, 1.50 mmol). The mixture was cooled to 0°C under an inert gas atmosphere, followed by phenyl chloroformate (141 mg, 0.90 mmol). The reaction was allowed to react at room temperature for 2 h. After completion of the reaction, the mixture was quenched with water, extracted with dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography to obtain the title product. ESI-MS m / z: 295.1 [M+H] + .

[0236] Step 2: Preparation of 1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl(2'-oxospiro[cyclopropane-1,3'-indoline]-6'-yl)carbamate

[0237]

[0238] 3-(2,6-difluoro-4-(3-hydroxyazetidin-1-yl)phenyl)piperidine-2,6-dione (101 mg, 0.34 mmol) was added to a single-necked flask, and N,N-dimethylformamide (10 mL) was added to dissolve the mixture. The mixture was cooled to 0°C in an ice bath, and sodium hydride (27 mg, 0.68 mmol) and phenyl(2'-oxospiro[cyclopropane-1,3'-indoline]-6'-yl)carbamate (120 mg, 0.41 mmol) were added. The mixture was allowed to react at room temperature for 2 h. After completion of the reaction, saturated ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the organic phase was concentrated and purified by column chromatography to obtain the title product. ESI-MS m / z: 497.2 [M+H] + .

[0239] 1 H NMR(400MHz,DMSO-d6)δ10.87(s,1H),10.52(s,1H),9.87(s,1H),7.21(s,1H),6.99-6.9 5(m,1H),6.85(d,J=8.1Hz,1H),6.23(d,J=11.0Hz,2H),5.31-5.25(m,1H),4.26-4.19(m, 2H),4.05(dd,J=12.6,4.8Hz,1H),3.84(dd,J=9.1,3.6Hz,2H),2.82-2.74(m,1H),2.58- 2.53(m,1H),2.12-2.04(m,1H),1.99-1.93(m,1H),1.50-1.44(m,2H),1.43-1.37(m,2H).

[0240] Example 15: 1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl(1'-oxo-2',3'-dihydro-1'-H-spiro[cyclopropane-4'-isoquinolin]-6'-yl)carbamate

[0241]

[0242] Step 1: Preparation of methyl 4-bromo-2-(1-cyanocyclopropyl)benzoate

[0243]

[0244] Methyl 4-bromo-2-(cyanomethyl)benzoate (2 g, 7.87 mmol) was dissolved in 20 mL of dimethyl sulfoxide (DMSO) in a single-necked flask. Sodium hydride (630 mg, 15.74 mmol) was added and stirred for 1 hour. 1,2-dibromoethane (2.2 g, 11.8 mmol) was then added and stirred at room temperature for 2 hours. The reaction was quenched with saturated ammonium chloride and extracted three times with ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, concentrated, and column chromatographed to yield the title product. ESI-MS m / z: 279.9 [M+H] + .

[0245] Step 2: Preparation of 6'-bromo-2',3'-dihydro-1'-H-spiro[cyclopropane-1,4'-isoquinolin]-1'-one

[0246]

[0247] Dissolve methyl 4-bromo-2-(1-cyanocyclopropyl)benzoate (1.1 g, 3.9 mmol) in 20 mL of methanol, add cobalt dichloride (1.01 g, 7.8 mmol), cool to 0°C, add 2M lithium borohydride (9.75 mL, 19.5 mmol), and stir at room temperature for 3 hours. After the reaction is complete, concentrate under reduced pressure and perform column chromatography to obtain the title product. ESI-MS m / z: 252.1 [M+H] + .

[0248] Step 3: Preparation of tert-butyl (1'-oxo-2',3'-dihydro-1'-H-spiro[cyclopropane-1,4'-isoquinolinyl]-6'-yl)carbamate

[0249]

[0250] 6'-Bromo-2',3'-dihydro-1'-H-spiro[cyclopropane-1,4'-isoquinolin]-1'-one (618 mg, 2.45 mmol), tert-butyl carbamate (574 mg, 4.9 mmol), tris(dibenzylideneacetone)dipalladium (224 mg, 0.245 mmol), 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (263 mg, 0.49 mmol), and cesium carbonate (2.4 g, 7.35 mmol) were weighed and placed in a two-necked flask. The atmosphere was replaced with argon. 12 mL of 1,4-dioxane was added to dissolve the mixture. The mixture was heated to 100°C and reacted for 12 h. After completion of the reaction, the mixture was quenched with water and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography to obtain the title product. ESI-MS m / z:289.2[M+H] + .

[0251] Step 4: Preparation of 6'-amino-2'-,3'-dihydro-1'-H-spiro[cyclopropane-1,4'-isoquinolinyl]-1'-one

[0252]

[0253] Dissolve tert-butyl (1'-oxo-2',3'-dihydro-1'-H-spiro[cyclopropane-1,4'-isoquinolinyl]-6'-yl)carbamate (150 mg, 0.52 mmol) in 3 mL of dichloromethane, add 1 mL of trifluoroacetic acid, and stir at room temperature for 1 hour. After completion, quench the reaction with saturated aqueous sodium bicarbonate, extract with dichloromethane, dry over anhydrous sodium sulfate, and concentrate to obtain the title product, which is directly used in the next step. ESI-MS m / z: 189.1 [M+H] + .

[0254] Step 5: Preparation of phenyl (1'-oxo-2', 3'-dihydro-1'-H-spiro [cyclopropane-1, 4'-isoquinolinyl] -6'-yl) carbamate

[0255]

[0256] 6'-Amino-2',3'-dihydro-1'-H-spiro[cyclopropane-1,4'-isoquinolin]-1'-one (40 mg, 0.213 mmol) was added to a single-necked flask, followed by dichloromethane (4 mL) and sodium bicarbonate (36 mg, 0.426 mol). Phenyl chloroformate (50 mg, 0.32 mmol) was added dropwise at 0°C and allowed to react at room temperature for 1 h. After completion of the reaction, the reaction solution was concentrated and column chromatography was performed to obtain the title product. ESI-MS m / z: 309.1 [M+H] + .

[0257] Step 6: Preparation of 1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl(1'-oxo-2'-,3'-dihydro-1'-H-spiro[cyclopropane-4'-isoquinoline]-6'-yl)carbamate

[0258]

[0259] 3-(6-(Hydroxymethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (0.07 g, 0.236 mmol) was added to a single-necked flask, followed by 2 mL of dimethylacetamide. Sodium hydride (19 mg, 0.236 mmol) and phenyl(1'-oxo-2'-,3'-dihydro-1'-H-spiro[cyclopropane-1,4'-isoquinolin]-6'-yl)carbamate (0.070 g, 0.472 mmol) were then added at 0°C and allowed to react for 0.5 h at room temperature. After completion of the reaction, saturated ammonium chloride solution was added to quench the reaction, followed by extraction with ethyl acetate, washing with saturated sodium chloride solution, drying over anhydrous sodium sulfate, and concentration under reduced pressure to obtain the title product. ESI-MS m / z: 511.2 [M+H] + .

[0260] 1 H NMR (400MHz, DMSO-d6) δ10.87(s,1H),10.12(s,1H),7.85(s,1H),7.80(d,J=8.5Hz,1H),7.4 1-7.32(m,1H),7.13(d,J=1.4Hz,1H),6.23(d,J=11.0Hz,2H),5.34-5.24(m,1H),4.29-4.15 (m,2H),4.09-4.01(m,1H),3.91-3.78(m,2H),3.21(d,J=2.4Hz,2H),2.85-2.72(m,1H),2.5 5-2.52(m,1H),2.15-2.00(m,1H),2.00-1.89(m,1H),1.04-0.96(m,2H),0.93-0.85(m,2H).

[0261] Example 16: 1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)carbamate

[0262]

[0263] Step 1: Preparation of 5-bromo-7-chloroindol-2-one

[0264]

[0265] 7-Chloroindole-2-one (2.0 g, 11.9 mmol) was added to a single-necked flask and trifluoroacetic acid (20 mL) was added to dissolve it. N-bromosuccinimide (2.12 g, 11.9 mmol) was then added and reacted at 0°C for 6 h. After the reaction, the reaction solution was concentrated and the residual trifluoroacetic acid was quenched with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and column chromatography to obtain the title product. ESI-MS m / z: 245.9 [M+H] + .

[0266] Step 2: Preparation of 5'-bromo-7'-chlorospiro[cyclopropane-1,3'-indolin]-2'-one

[0267]

[0268] 5-Bromo-7-chloroindol-2-one (1.0 g, 4.08 mmol) was added to a single-necked flask. N,N-dimethylformamide (15 mL) was added to dissolve the mixture. 1,8-Diazabisspiro[5.4.0]undec-7-ene (1.86 g, 12.24 mmol), zinc trifluoromethanesulfonate (1.48 g, 4.08 mmol), and diphenyl(vinyl)sulfonium trifluoromethanesulfonate (1.78 g, 4.90 mmol) were then added. The mixture was allowed to react at room temperature for 2 h. After completion of the reaction, the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography to yield the title product. ESI-MS m / z: 271.9 [M+H] + .

[0269] Step 3: Preparation of tert-butyl (7'-chloro-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)carbamate

[0270]

[0271] 5'-Bromo-7'-chlorospiro[cyclopropane-1,3'-indolin]-2'-one (500 mg, 1.85 mmol) was added to a single-necked flask, and 1,4-dioxane (20 mL) was added to dissolve it. Then, tert-butyl carbamate (650 mg, 5.55 mmol), tris(dibenzylideneacetone)dipalladium (169 mg, 0.185 mmol), 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (298 mg, 0.555 mmol), and cesium carbonate (1.81 g, 5.55 mmol) were added. The mixture was reacted at 100°C overnight under inert gas. After completion of the reaction, the reaction solution was concentrated and column chromatography was performed to obtain the title product. ESI-MS m / z: 309.1 [M+H] + .

[0272] Step 4: Preparation of 5'-amino-7'-chlorospiro[cyclopropane-1,3'-indolin]-2'-one

[0273]

[0274] tert-Butyl (7'-chloro-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)carbamate (120 mg, 0.39 mmol) was added to a single-necked flask and dissolved in dichloromethane (5 mL). Trifluoroacetic acid (1 mL) was then added and allowed to react at room temperature for 3 h. After completion of the reaction, the residual trifluoroacetic acid was quenched with saturated sodium bicarbonate solution, extracted with dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography to obtain the title product. ESI-MS m / z: 209.1 [M+H] + .

[0275] Step 5: Preparation of phenyl (7'-chloro-2'-oxospiro [cyclopropane-1,3'-indoline] -5'-yl) carbamate

[0276]

[0277] 5'-Amino-7'-chlorospiro[cyclopropane-1,3'-indolin]-2'-one (80 mg, 0.38 mmol) was added to a two-necked flask. Dichloromethane (6 mL) and N,N-dimethylacetamide (2 mL) were added to dissolve the mixture. Then, sodium bicarbonate (64 mg, 0.76 mmol) was added. Under inert gas protection, phenyl chloroformate (72 mg, 0.46 mmol) was added and the mixture was allowed to react at room temperature for 1 h. After completion of the reaction, the mixture was quenched with water, extracted with dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography to obtain the title product. ESI-MS m / z: 329.0 [M+H] + .

[0278] Step 6: Preparation of 1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)carbamate

[0279]

[0280] 3-(2,6-difluoro-4-(3-hydroxyazetidin-1-yl)phenyl)piperidine-2,6-dione (151 mg, 0.51 mmol) was added to a single-necked flask, and N,N-dimethylformamide (5 mL) was added to dissolve the mixture. The mixture was cooled to 0°C in an ice bath, and sodium hydride (37 mg, 0.92 mmol) was added. Phenyl(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)carbamate (150 mg, 0.46 mmol) was then added and allowed to react at room temperature for 2 h. After completion of the reaction, saturated ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the organic phase was concentrated and purified by column chromatography to obtain the title product. ESI-MS m / z: 531.1 [M+H] + .

[0281] 1 H NMR(400MHz,DMSO-d6)δ10.91(s,1H),10.87(s,1H),9.87(s,1H),7.27(s,1H),7.04(s,1H),6.2 3(s,1H),6.20(s,1H),5.29-5.21(m,1H),4.27-4.15(m,2H),4.09-4.01(m,1H),3.87-3.75(m,2H ), 2.85-2.70 (m, 1H), 2.56-2.52 (m, 1H), 2.11-2.02 (m, 1H), 1.99-1.89 (m, 1H), 1.62-1.44 (m, 4H). Example 17: (2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl (1'-cyclopropyl-2'-oxospiro[cyclopropane-1,3'-indolin]-5'-yl)carbamate

[0282]

[0283] Step 1: Preparation of 5'-bromo-1'-cyclopropylspiro[cyclopropane-1,3'-indolin]-2'-one

[0284]

[0285] Dissolve 5'-bromospiro[cyclopropane-1,3'-indolin]-2'-one (1 g, 4.2 mmol) in 20 mL of tert-butanol. Add cyclopropylboronic acid (1.08 g, 12.6 mmol), copper acetate (838 mg, 4.2 mmol), 4-dimethylaminopyridine (1.54 g, 12.6 mmol), and 1 M potassium bis(trimethylsilyl)amide (4.2 mL, 4.2 mmol). Replace the atmosphere with oxygen and heat to 90°C with stirring. Concentrate and column chromatography to obtain the title product. ESI-MS m / z: 278.0 [M+H] + .

[0286] Step 2: Preparation of tert-butyl (1'-cyclopropyl-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)carbamate

[0287]

[0288] 5'-Bromo-1'-cyclopropylspiro[cyclopropane-1,3'-indolin]-2'-one (780 mg, 2.8 mmol), tert-butyl carbamate (656 mg, 5.6 mmol), tris(dibenzylideneacetone)dipalladium (256 mg, 0.28 mmol), 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (300 mg, 0.56 mmol), and cesium carbonate (2.7 g, 8.4 mmol) were weighed and placed in a two-necked flask. The atmosphere was replaced with argon. 20 mL of 1,4-dioxane was added to dissolve the mixture. The mixture was heated to 100°C and reacted for 12 h. The mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography to obtain the title product. ESI-MS m / z: 315.2 [M+H] + .

[0289] Step 3: Preparation of 5'-amino-1'-cyclopropylspiro[cyclopropane-1,3'-indolin]-2'-one

[0290]

[0291] Dissolve tert-butyl (1'-cyclopropyl-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)carbamate (500 mg) in 9 mL of dichloromethane, add 3 mL of trifluoroacetic acid, and stir at room temperature for 1 hour. After completion of the reaction, quench with saturated aqueous sodium bicarbonate, extract with dichloromethane, dry over anhydrous sodium sulfate, and concentrate to obtain the title product, which is directly used in the next step. ESI-MS m / z: 215.2 [M+H] + .

[0292] Step 4: Preparation of phenyl (1'-cyclopropyl-2'-oxospiro [cyclopropane-1,3'-indoline] -5'-yl) carbamate

[0293]

[0294] 5'-Amino-1'-cyclopropylspiro[cyclopropane-1,3'-indolin]-2'-one (350 mg, 1.6 mmol) was added to a single-necked flask, followed by dichloromethane (7 mL) and sodium bicarbonate (274 mg, 3.3 mmol). Phenyl chloroformate (383 mg, 2.45 mmol) was added dropwise at 0°C and allowed to react at room temperature for 1 h. After completion of the reaction, the reaction solution was concentrated and column chromatography was performed to obtain the title product. ESI-MS m / z: 335.1 [M+H] + .

[0295] Step 5: Preparation of (2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl(1'-cyclopropyl-2'-oxospiro[cyclopropane-1,3'-indolin]-5'-yl)carbamate

[0296]

[0297] 3-(6-(Hydroxymethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (0.082 g, 0.3 mmol) was added to a single-necked flask, followed by 5 mL of dimethylacetamide. Sodium hydride (24 mg, 0.6 mmol) and phenyl(1'-cyclopropyl-2'-oxospiro[cyclopropane-1,3'-indolin]-5'-yl)carbamate (0.1 g, 0.3 mmol) were then added at 0°C and allowed to react for 0.5 h at room temperature. After completion of the reaction, saturated ammonium chloride solution was added to quench the reaction, followed by extraction with ethyl acetate, washing with saturated sodium chloride solution, drying over anhydrous sodium sulfate, and concentration under reduced pressure to obtain the title product. ESI-MS m / z: 515.1 [M+H] + .

[0298] 1H NMR(400MHz,DMSO-d6)δ11.00(s,1H),9.67(s,1H),7.88-7.75(m,1H),7.71-7.58(m,2H), 7.26(d,J=7.7Hz,1H),7.11(s,2H),5.25(s,2H),5.18-5.08(m,1H),4.48(d,J=17.4Hz,1H) ,4.34(d,J=17.4Hz,1H),3.00-2.86(m,1H),2.77-2.66(m,1H),2.65-2.56(m,1H),2.43-2. 31(m,1H),2.07-1.95(m,1H),1.61-1.34(m,4H),0.99(d,J=5.2Hz,2H),0.86-0.72(m,2H).

[0299] Example 18: 1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl(1'-cyclopropyl-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)carbamate

[0300]

[0301] 3-(2,6-difluoro-4-(3-hydroxyazetidin-1-yl)phenyl)piperidine-2,6-dione (0.089 g, 0.3 mmol) was added to a single-necked flask, followed by 5 mL of dimethylacetamide. Sodium hydride (24 mg, 0.6 mmol) and phenyl(1'-cyclopropyl-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)carbamate (0.1 g, 0.3 mmol) were added at 0°C. The reaction was allowed to react at room temperature for 0.5 h and monitored by LCMS. After completion of the reaction, saturated ammonium chloride solution was added to quench the reaction, followed by extraction with ethyl acetate, washing with saturated sodium chloride solution, drying over anhydrous sodium sulfate, and concentration under reduced pressure to obtain the title product. ESI-MS m / z: 537.2 [M+H] + .

[0302] 1H NMR (400MHz, DMSO-d6) δ10.87 (s, 1H), 9.75 (s, 1H), 7.25 (d, J = 8.3Hz, 1H), 7.18-7. 07(m,2H),6.24(s,1H),6.21(s,1H),5.29-5.22(m,1H),4.26-4.17(m,2H),4.09-4 .00(m,1H),3.87-3.78(m,2H),2.86-2.66(m,2H),2.52-2.52(m,1H),2.11-2.05(m ,1H),1.99-1.89(m,1H),1.58-1.40(m,4H),1.03-0.96(m,2H),0.83-0.76(m,2H).

[0303] Example 19: 1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl(1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-yl)carbamate

[0304]

[0305] Step 1: Preparation of 6'-bromospiro[cyclopropane-1,3'-indolin]-2'-one

[0306]

[0307] 6-Bromoindol-2-one (1.0 g, 4.3 mmol) was added to a single-necked flask and dissolved in N,N-dimethylformamide (20 mL). 1,8-Diazabisspiro[5.4.0]undec-7-ene (1.96 g, 12.9 mmol), zinc trifluoromethanesulfonate (1.56 g, 4.3 mmol), and diphenyl(vinyl)sulfonium trifluoromethanesulfonate (1.87 g, 5.16 mmol) were then added. The reaction was allowed to proceed at room temperature for 2 h. After completion of the reaction, the mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain the title product. ESI-MS m / z: 237.9 [M+H] + .

[0308] Step 2: Preparation of 6'-bromo-1'-methylspiro[cyclopropane-1,3'-indolin]-2'-one

[0309]

[0310] 6'-Bromospiro[cyclopropane-1,3'-indolin]-2'-one (1.1 g, 4.6 mmol) was added to a single-necked flask and dissolved in tetrahydrofuran (30 mL). Sodium hydride (276 mg, 6.9 mmol) and iodomethane (653 mg, 4.6 mmol) were then added and allowed to react at 60°C for 1 h. After completion of the reaction, the reaction solution was concentrated and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain the title product. ESI-MS m / z: 252.0 [M+H] + .

[0311] Step 3: Preparation of tert-butyl (1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-yl)carbamate

[0312]

[0313] 6'-Bromo-1'-methylspiro[cyclopropane-1,3'-indolin]-2'-one (958 mg, 3.80 mmol) was added to a single-necked flask, and 1,4-dioxane (20 mL) was added to dissolve the mixture. Then, tert-butyl carbamate (890 mg, 7.60 mmol), tris(dibenzylideneacetone)dipalladium (348 mg, 0.38 mmol), 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (408 mg, 0.76 mmol), and cesium carbonate (3.71 g, 11.4 mmol) were added. The mixture was reacted at 100°C under inert gas for 5 h. After completion of the reaction, the reaction solution was concentrated and column chromatography was performed to obtain the title product. ESI-MS m / z: 289.1 [M+H] + .

[0314] Step 4: Preparation of 6'-amino-1'-methylspiro[cyclopropane-1,3'-indolin]-2'-one

[0315]

[0316] tert-Butyl (1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-yl)carbamate (1.1 g, 3.82 mmol) was added to a single-necked flask and dissolved in dichloromethane (12 mL). Trifluoroacetic acid (3 mL) was then added and allowed to react at room temperature for 6 h. After completion of the reaction, the residual trifluoroacetic acid was quenched with saturated sodium bicarbonate solution, and the mixture was extracted with dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography to obtain the title product. ESI-MS m / z: 189.1 [M+H] + .

[0317] Step 5: Preparation of phenyl (1'-methyl-2'-oxospiro [cyclopropane-1,3'-indoline] -6'-yl) carbamate

[0318]

[0319] 6'-Amino-1'-methylspiro[cyclopropane-1,3'-indolin]-2'-one (1.40 g, 7.43 mmol) was added to a two-necked flask. Dichloromethane (8 mL) and N,N-dimethylacetamide (4 mL) were added to dissolve the mixture. Then, sodium bicarbonate (1.25 g, 14.9 mmol) was added. Under inert gas protection, phenyl chloroformate (1.40 g, 8.92 mmol) was added and the mixture was allowed to react at room temperature for 1 h. After completion of the reaction, the mixture was extracted with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography to obtain the title product. ESI-MS m / z: 309.1 [M+H] + .

[0320] Step 6: Preparation of 1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl(1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-yl)carbamate

[0321]

[0322] 3-(2,6-difluoro-4-(3-hydroxyazetidin-1-yl)phenyl)piperidine-2,6-dione (130 mg, 0.44 mmol) was added to a single-necked flask, and N,N-dimethylformamide (10 mL) was added to dissolve it. Sodium hydride (35 mg, 0.88 mmol) was added, followed by phenyl(1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-yl)carbamate (203 mg, 0.66 mmol). The reaction was allowed to react at room temperature for 2 h. After completion of the reaction, saturated ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the organic phase was concentrated and purified by column chromatography to obtain the title product. ESI-MS m / z: 511.2 [M+H] + .

[0323] 1H NMR (400MHz, DMSO-d6) δ10.87(s,1H),9.96(s,1H),7.30(s,1H),7.01(dd,J=8.1,1.3Hz,1H ),6.92(d,J=8.0Hz,1H),6.23(d,J=11.0Hz,2H),5.32-5.26(m,1H),4.27-4.20(m,2H),4.0 5(dd,J=12.5,4.9Hz,1H),3.85(dd,J=9.0,3.4Hz,2H),3.17(s,3H),2.84-2.74(m,1H),2.5 6-2.52(m,1H),2.14-2.03(m,1H),1.98-1.92(m,1H),1.56-1.50(m,2H),1.49-1.44(m,2H).

[0324] Example 20: (2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl(1'-methyl-2'-oxospiro[cyclopropane-1,3'-indolin]-6'-yl)carbamate

[0325]

[0326] 3-(6-(Hydroxymethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (120 mg, 0.44 mmol) was added to a single-necked flask, and N,N-dimethylformamide (10 mL) was added to dissolve it. Sodium hydride (35 mg, 0.88 mmol) was added, followed by phenyl(1'-methyl-2'-oxospiro[cyclopropane-1,3'-indolin]-6'-yl)carbamate (203 mg, 0.66 mmol). The reaction was allowed to react at room temperature for 2 h. After completion of the reaction, saturated ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the organic phase was concentrated and subjected to preparative separation to obtain the title product. ESI-MS m / z: 489.2 [M+H] + .

[0327] 1H NMR (400MHz, DMSO-d6) δ11.00(s,1H),9.87(s,1H),7.81(s,1H),7.70(dd,J=7.8,1.5Hz,1H),7.6 5(d,J=7.8Hz,1H),7.31(s,1H),7.02(dd,J=8.0,1.4Hz,1H),6.92(d,J=8.1Hz,1H),5.29(s,2H),5 .13(dd,J=13.3,5.1Hz,1H),4.51-4.42(m,1H),4.37-4.32(m,1H),3.17(s,3H),2.97-2.88(m,1H ),2.66-2.61(m,1H),2.45-2.35(m,1H),2.05-1.98(m,1H),1.57-1.50(m,2H),1.49-1.42(m,2H).

[0328] Example 21: (2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl(6'-fluoro-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indolin]-5'-yl)carbamate

[0329]

[0330] Step 1: Preparation of 5-bromo-6-fluoroindol-2-one

[0331]

[0332] 6-Fluoroindole-2-one (1 g, 4.2 mmol) was added to a single-necked flask and dissolved in acetonitrile (70 mL). N-bromosuccinimide (2.8 g, 15.9 mmol) was added at 0°C and stirred at room temperature for 1 hour. The mixture was concentrated and purified by column chromatography to obtain the title product. ESI-MS m / z: 230.0 [M+H] + .

[0333] Step 2: Preparation of 5'-bromo-6'-fluorospiro[cyclopropane-1,3'-indolin]-2'-one

[0334]

[0335] 5-Bromo-6-fluoroindol-2-one (1.0 g, 4.35 mmol) was added to a single-necked flask and dissolved in N,N-dimethylformamide (30 mL). 1,8-Diazabisspiro[5.4.0]undec-7-ene (1.99 g, 13.25 mmol), zinc trifluoromethanesulfonate (1.58 g, 4.35 mmol), and diphenyl(vinyl)sulfonium trifluoromethanesulfonate (1.89 g, 5.22 mmol) were then added. The reaction was allowed to proceed at room temperature for 2 h. After completion of the reaction, the mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography to yield the title product. ESI-MS m / z: 256.0 [M+H] + .

[0336] Step 3: Preparation of 5'-bromo-6'-fluoro-1'-methylspiro[cyclopropane-1,3'-indolin]-2'-one

[0337]

[0338] 5'-Bromo-6'-fluorospiro[cyclopropane-1,3'-indolin]-2'-one (786 mg, 3.1 mmol) was added to a single-necked flask and dissolved in tetrahydrofuran (20 mL). Sodium hydride (184 mg, 4.6 mmol) and iodomethane (436 mg, 3.1 mmol) were then added and allowed to react at 60°C for 1 h. After completion of the reaction, the reaction solution was concentrated and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain the title product. ESI-MS m / z: 270.0 [M+H] + .

[0339] Step 4: Preparation of tert-butyl (6'-fluoro-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)carbamate

[0340]

[0341] 5'-Bromo-6'-fluoro-1'-methylspiro[cyclopropane-1,3'-indolin]-2'-one (820 mg, 3.0 mmol) was added to a two-necked flask, and 1,4-dioxane (20 mL) was added to dissolve the mixture. Then, tert-butyl carbamate (712 mg, 6.1 mmol), tris(dibenzylideneacetone)dipalladium (278 mg, 0.30 mmol), 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (326 mg, 0.61 mmol), and cesium carbonate (2.97 g, 9.1 mmol) were added. The atmosphere was replaced with argon and the reaction was carried out at 100°C for 12 h. After completion of the reaction, the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography to obtain the title product. ESI-MS m / z:307.1[M+H] + .

[0342] Step 5: Preparation of 5'-amino-6'-fluoro-1'-methylspiro[cyclopropane-1,3'-indolin]-2'-one

[0343]

[0344] tert-Butyl (6'-fluoro-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)carbamate (520 mg) was added to a single-necked flask and dissolved in dichloromethane (9 mL). Trifluoroacetic acid (3 mL) was then added and stirred at room temperature for 1 hour. After completion of the reaction, saturated aqueous sodium bicarbonate was added to quench the reaction. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated to obtain the title product, which was directly used in the next step. ESI-MS m / z: 207.1 [M+H] + .

[0345] Step 6: Preparation of phenyl (6'-fluoro-1'-methyl-2'-oxospiro [cyclopropane-1,3'-indoline] -5'-yl) carbamate

[0346]

[0347] 5'-Amino-6'-fluoro-1'-methylspiro[cyclopropane-1,3'-indolin]-2'-one (300 mg, 1.5 mmol) was added to a single-necked flask and dissolved in dichloromethane (6 mL). Sodium bicarbonate (244 mg, 2.9 mmol) was added dropwise. Phenyl chloroformate (341 mg, 2.18 mmol) was added dropwise at 0°C and allowed to react at room temperature for 1 h. After completion of the reaction, the reaction solution was concentrated and column chromatography was performed to obtain the title product. ESI-MS m / z: 327.1 [M+H] + .

[0348] Step 7: Preparation of (2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl(6'-fluoro-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indolin]-5'-yl)carbamate

[0349]

[0350] 3-(6-(Hydroxymethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (0.085 g, 0.3 mmol) was added to a single-necked flask and dissolved in N,N-dimethylacetamide (5 mL). Sodium hydride (25 ml, 0.6 mmol) and phenyl(6'-fluoro-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indolin]-5'-yl)carbamate (0.1 g, 0.3 mmol) were added at 0°C and allowed to react at room temperature for 0.5 h. After completion of the reaction, saturated ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title product. ESI-MS m / z: 507.1 [M+H] + .

[0351] 1 H NMR(400MHz,DMSO-d6)δ11.00(s,1H),9.28(s,1H),7.78(s,1H),7.69-7.60 (m,2H),7.21-7.07(m,2H),5.24(s,2H),5.17-5.09(m,1H),4.52-4.44(m,1 H),4.39-4.31(m,1H),3.19(s,3H),2.99-2.86(m,1H),2.67-2.57(m,1H),2 .44-2.35(m,1H),2.06-1.95(m,1H),1.63-1.55(m,2H),1.52-1.44(m,2H).

[0352] Example 22: 1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl(6'-fluoro-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)carbamate

[0353]

[0354] Step 1: Preparation of 5-bromo-6-fluoroindol-2-one

[0355]

[0356] 6-Fluoroindole-2-one (1 g, 4.2 mmol) was added to a single-necked flask and dissolved in acetonitrile (70 mL). N-bromosuccinimide (2.8 g, 15.9 mmol) was added at 0°C and stirred at room temperature for 1 hour. The mixture was concentrated and purified by column chromatography to obtain the title product. ESI-MS m / z: 230.0 [M+H] + .

[0357] Step 2: Preparation of 5'-bromo-6'-fluorospiro[cyclopropane-1,3'-indolin]-2'-one

[0358]

[0359] 5-Bromo-6-fluoroindol-2-one (1.0 g, 4.35 mmol) was added to a single-necked flask and dissolved in N,N-dimethylformamide (30 mL). 1,8-Diazabisspiro[5.4.0]undec-7-ene (1.99 g, 13.25 mmol), zinc trifluoromethanesulfonate (1.58 g, 4.35 mmol), and diphenyl(vinyl)sulfonium trifluoromethanesulfonate (1.89 g, 5.22 mmol) were then added. The reaction was allowed to proceed at room temperature for 2 h. After completion of the reaction, the mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography to yield the title product. ESI-MS m / z: 256.0 [M+H] + .

[0360] Step 3: Preparation of 5'-bromo-6'-fluoro-1'-methylspiro[cyclopropane-1,3'-indolin]-2'-one

[0361]

[0362] 5'-Bromo-6'-fluorospiro[cyclopropane-1,3'-indolin]-2'-one (786 mg, 3.1 mmol) was added to a single-necked flask and dissolved in tetrahydrofuran (20 mL). Sodium hydride (184 mg, 4.6 mmol) and iodomethane (436 mg, 3.1 mmol) were then added and allowed to react at 60°C for 1 h. After completion of the reaction, the reaction solution was concentrated and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain the title product. ESI-MS m / z: 270.0 [M+H] + .

[0363] Step 4: Preparation of tert-butyl (6'-fluoro-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)carbamate

[0364]

[0365] 5'-Bromo-6'-fluoro-1'-methylspiro[cyclopropane-1,3'-indolin]-2'-one (820 mg, 3.0 mmol) was added to a two-necked flask, and 1,4-dioxane (20 mL) was added to dissolve the mixture. Then, tert-butyl carbamate (712 mg, 6.1 mmol), tris(dibenzylideneacetone)dipalladium (278 mg, 0.30 mmol), 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (326 mg, 0.61 mmol), and cesium carbonate (2.97 g, 9.1 mmol) were added. The atmosphere was replaced with argon and the reaction was carried out at 100°C for 12 h. After completion of the reaction, the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography to obtain the title product. ESI-MS m / z:307.1[M+H] + .

[0366] Step 5: Preparation of 5'-amino-6'-fluoro-1'-methylspiro[cyclopropane-1,3'-indolin]-2'-one

[0367]

[0368] tert-Butyl (6'-fluoro-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)carbamate (520 mg) was added to a single-necked flask and dissolved in dichloromethane (9 mL). Trifluoroacetic acid (3 mL) was then added and stirred at room temperature for 1 hour. After completion of the reaction, saturated aqueous sodium bicarbonate was added to quench the reaction. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated to obtain the title product, which was directly used in the next step. ESI-MS m / z: 207.1 [M+H] + .

[0369] Step 6: Preparation of phenyl (6'-fluoro-1'-methyl-2'-oxospiro [cyclopropane-1,3'-indoline] -5'-yl) carbamate

[0370]

[0371] 5'-Amino-6'-fluoro-1'-methylspiro[cyclopropane-1,3'-indolin]-2'-one (300 mg, 1.5 mmol) was added to a single-necked flask and dissolved in dichloromethane (6 mL). Sodium bicarbonate (244 mg, 2.9 mmol) was added dropwise. Phenyl chloroformate (341 mg, 2.18 mmol) was added dropwise at 0°C and allowed to react at room temperature for 1 h. After completion of the reaction, the reaction solution was concentrated and column chromatography was performed to obtain the title product. ESI-MS m / z: 327.1 [M+H] + .

[0372] Step 7: Preparation of 1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl(6'-fluoro-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)carbamate

[0373]

[0374] 3-(2,6-difluoro-4-(3-hydroxyazetidin-1-yl)phenyl)piperidine-2,6-dione (0.092 g, 0.3 mmol) was added to a one-necked flask and N,N-dimethylacetamide (5 mL) was added to dissolve the mixture. Sodium hydride (25 mg, 0.6 mmol) and phenyl(6'-fluoro-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)carbamate (0.1 g, 0.3 mmol) were added at 0°C and allowed to react at room temperature for 0.5 h. After completion of the reaction, saturated ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title product. ESI-MS m / z: 529.1 [M+H] + .

[0375] 1 H NMR(400MHz,DMSO-d6)δ10.87(s,1H),9.37(s,1H),7.12(d,J=10.6Hz,2H), 6.22(d,J=11.0Hz,2H),5.29-5.19(m,1H),4.29-4.13(m,2H),4.09-4.00(m, 1H),3.92-3.67(m,2H),3.20(s,3H),2.86-2.72(m,1H),2.58-2.52(m,1H), 2.16-2.01(m,1H),2.00-1.89(m,1H),1.65-1.54(m,2H),1.53-1.42(m,2H).

[0376] The compound of Example 23 was synthesized using different raw materials according to the synthesis method of Examples 1-22 of the present invention. The characterization parameters of Example 23 are shown in Table 1.

[0377] Table 1

[0378]

[0379] Experimental Example 1: Evaluation of compound in vitro cell activity

[0380] 1. Experimental Materials

[0381] Test compounds: The compounds of the present invention prepared in the above examples, each compound was prepared into a 10 mM stock solution with DMSO and finally diluted to 10 concentrations for detection. The final concentrations of the compounds in the NCI-H1155 cell experiment were 20000 nM, 4000 nM, 800 nM, 160 nM, 32 nM, 6.4 nM, 1.28 nM, 0.26 nM, 0.051 nM / 30000 nM, 7500 nM, 1875 nM, 468.75 nM, 117.19 nM, 29.30 nM, 7.32 nM, 1.83 nM, 0.46 nM, and 0.11 nM.

[0382] Human lung cancer cells NCI-H1155 cells (highly expressing MYC): ATCC.

[0383] Reagent: TrypLE TM Express Enzyme (1X), no phenol red, product number is Gibco 12604-021; Celltiter Glo assay kit (CTG), product number is Promega G7573.

[0384] 2. Experimental Methods

[0385] 2.1 Cell culture and passaging

[0386] (1) All cells were cultured according to the method recommended by ATCC, and the cells were cultured during the exponential growth phase.

[0387] (2) Cell culture medium:

[0388] NCI-H1155 cells: mulated Leibovitz's L-15 medium, 10% FBS, 1% penicillin-streptomycin.

[0389] (3) Cell culture conditions: 37°C, 5% CO2, 95% air

[0390] (4) Depending on the cell growth, the culture medium should be changed every 2-3 days or the cells should be subcultured.

[0391] 2.2 Cell plating

[0392] Remove cells from the cell culture flask and resuspend in fresh culture medium. Inoculate 40 μL of the cell suspension into a 384-well culture plate.

[0393] 2.3 Administration

[0394] NCI-H1155 cells were cultured in 40 μL of the original culture medium. 40 nL of drugs at different concentrations were added to the drug group, and 40 nL of DMSO was added to the DMSO group. Two replicates were set for each concentration group and the cells were cultured in a 5% CO2 incubator for 3 days. The compound was prepared as follows: 1-2 mg of the compound was weighed in advance and prepared into a 10 mM stock solution using DMSO. The drug was diluted with DMSO, starting at 10 mM and then diluted to 10 concentration gradients in a 1:4 gradient. The final concentrations were: 30,000 nM, 7,500 nM, 1,875 nM, 468.75 nM, 117.19 nM, 29.30 nM, 7.32 nM, 1.83 nM, 0.46 nM, and 0.11 nM.

[0395] 2.4 Detection

[0396] After 3 days of drug treatment, the Celltiter Glo assay kit was taken out 30 minutes in advance and equilibrated to room temperature. Then 40 μL of Celltiter-Glo reagent was added to the PC well, the dosing well, and the DMSO well, and shaken for 2 minutes. After incubation in the dark at room temperature for 28 minutes, the luminescence signal was detected. According to the LUM value, the inhibition rate of each well relative to the solvent control well was calculated: Inhibition% = (Ave_H-Sample) / (Ave_H-Ave_L) X 100, Note: H = Ave (DMSO), L = Ave (Medium). According to different drug concentrations and their corresponding inhibition rates, IC was performed using GraphicPad 5.0 software. 50 Draw curves, analyze data, and obtain the final IC 50 The experimental results are shown in Table 2.

[0397] Table 2 Inhibition of tumor cell growth by compounds

[0398]

[0399]

[0400] The experimental results show that the compound of the present invention has a strong inhibitory effect on human lung cancer cells NCI-H1155 cells (highly expressing MYC).

[0401] Experimental Example 2: Evaluation of the ability of compounds to degrade GSPT1 protein

[0402] 1. Experimental Materials

[0403] Test compounds: Compounds of the present invention prepared in the above examples. Each compound was prepared in DMSO to a 10 mM stock solution and finally diluted to 9 concentrations for detection. The final compound concentrations in the HEK293-GSPT1-HiBiT reporter assay were 1000 nM, 333.333 nM, 111.111 nM, 37.037 nM, 12.346 nM, 4.115 nM, 1.372 nM, 0.457 nM, and 0.152 nM.

[0404] HEK293 GSPT1 HiBiT KI cells were obtained from Beijing Aisiyipu Technology Co., Ltd.

[0405] Reagents: HiBiT Lytic Detection System, Promega, Cat. No. N3040.

[0406] 2. Experimental Methods

[0407] 1) Culture HEK293 GSPT1 HiBiT KI cells in DMEM containing 10% FBS and 1% anti-antibody. When the cell density reaches 80-90%, trypsinize and resuspend the cells into single cells.

[0408] 2) The digested cells were then plated at 1×10 4 Add 40 μL of the solution into each well of a 384-well plate and continue culturing in a 37°C carbon dioxide incubator.

[0409] 3) After the cells adhered, the compound of the present invention was added, starting at 1 μM and diluted 3-fold for a total of 9 steps, and then continued to be cultured in a 37°C carbon dioxide incubator for 24 hours;

[0410] 4) Return Nano-Glo HiBiT to room temperature, then dilute LgBiT protein 1:100 and Nano-Glo HiBiT cleavage substrate 1:2 into an appropriate volume of Nano-Glo HiBiT lysis buffer, add to a new EP tube, and invert to mix thoroughly;

[0411] 5) Equilibrate the cell culture plate at room temperature for 10 minutes;

[0412] 6) Add 40 μL of Nano-Glo HiBiT lysis buffer to the plate and shake at 300 rpm for 3 minutes in the dark;

[0413] 7) Read the luminescence value using BMG PHERAstar FSX;

[0414] 8) Calculate the DC50 of the compound using the following formula:

[0415] Y=Bottom+(Top-Bottom) / (1+10^((LogDC50-X)x HillSlope))

[0416] X: compound concentration; Y: %Protein remain; Top and Bottom: Plateausin same units as Y; logDC50: same log units as X; HillSlope: Slope factor or Hillslope

[0417] DC50: half degradation concentration; Dmax: maximum degradation level.

[0418] 3. Experimental Results

[0419] Table 3 Degradation of GSPT1 (eRF3) by compounds

[0420] Compound <![CDATA[DC 50 (nM)]]> Dmax(%) Example 4 4.58 95.16 Example 11 4.38 96.66 Example 12 9.19 95.38 Example 13 1.21 95.29

[0421] The experimental results show that the compound of the present invention exhibits excellent protein degradation ability in the GSPT1 (eRF3) protein degradation experiment.

[0422] Although the present invention has been described in detail above, it will be appreciated by those skilled in the art that various modifications and variations may be made to the present invention without departing from the spirit and scope of the present invention. The scope of the present invention is not limited to the detailed description above, but rather to the claims.

Claims

1. A compound represented by general formula (I) or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, in: Ring A and Ring B are each independently selected from cycloalkyl and heterocycloalkyl; Ring C is selected from aryl, heteroaryl, cycloalkyl and heterocycloalkyl, which is optionally substituted with one or more groups selected from halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl, dialkylamino and oxo; X is selected from -CH- and -N-; L is selected from -CH2-O-, -CH2-, -O-, -NH-, -O-CH2- and R1 and R2 are each independently selected from hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl, dialkylamino, oxo, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; R3 and R4 are each independently selected from hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl, dialkylamino; and m, n, p, q are each independently selected from 1, 2, 3 and 4.

2. The compound according to claim 1 or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein: Ring A and Ring B are each independently selected from C 3-8 Cycloalkyl and 3-8 membered heterocycloalkyl, wherein the heteroatom is selected from N, O and S; Ring C is selected from 6-12 membered aryl, 5-12 membered heteroaryl, C 3-10 Cycloalkyl and 4-10 membered heterocycloalkyl, which are optionally selected from halogen, hydroxy, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, nitro, carboxyl, cyano, amino, mono C 1-6 Alkylamino, C 1-6 Alkyl acylamino, C 1-6 Alkyl acyl, amino acyl, C 1-6 Alkylaminoacyl, di-C 1-6 substituted with one or more of an alkylamino group and an oxo group; L is selected from -CH2-O-, -O- and R1 and R2 are each independently selected from halogen, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, nitro, carboxyl, cyano, amino, mono C 1-6 Alkylamino, C 1-6 Alkyl acylamino, C 1-6 Alkyl acyl, amino acyl, C 1-6 Alkylaminoacyl, di-C 1-6 Alkylamino, oxo, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 6-12 membered aryl, and 5-12 membered heteroaryl; R3 and R4 are each independently selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, nitro, carboxyl, cyano, amino, mono C 1-6 Alkylamino, C 1-6 Alkyl acylamino, C 1-6 Alkyl acyl, amino acyl, C 1-6 Alkylaminoacyl and di-C 1-6 Alkylamino; and m, n, p, q are each independently selected from 1, 2 and 3.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein: Ring A and Ring B are each independently selected from C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl, wherein the heteroatom is selected from N and O; Ring C is selected from 5-10 membered aryl and 5-10 membered heteroaryl, which is optionally selected from halogen, hydroxy, C 1-3 Alkyl, halogenated C 1-3 Alkyl, hydroxyl C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, hydroxy C 1-3 Alkoxy, nitro, carboxyl, cyano, amino, mono C 1-3 Alkylamino, C 1-3 Alkyl acylamino, C 1-3 Alkyl acyl, amino acyl, C 1-3 Alkylaminoacyl, di-C 1-3 substituted with one or more of an alkylamino group and an oxo group; L is selected from -CH2-O-, -O- and R1 and R2 are each independently selected from halogen, hydroxyl, C 1-3 Alkyl, halogenated C 1-3 Alkyl, hydroxyl C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, hydroxy C 1-3 Alkoxy, nitro, carboxyl, cyano, amino, mono C 1-3 Alkylamino, C 1-3 Alkyl acylamino, C 1-3 Alkyl acyl, amino acyl, C 1-3 Alkylaminoacyl, di-C 1-3 Alkylamino, oxo, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered aryl and 5-10 membered heteroaryl; R3 and R4 are each independently selected from hydrogen, halogen, hydroxyl, C 1-3 Alkyl, halogenated C 1-3 Alkyl, hydroxyl C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, hydroxy C 1-3 Alkoxy, nitro, carboxyl, cyano, amino, mono C 1-3 Alkylamino, C 1-3 Alkyl acylamino, C 1-3 Alkyl acyl, amino acyl, C 1-3 Alkylaminoacyl and di-C 1-3 Alkylamino; and m, n, p, q are each independently selected from 1, 2 and 3.

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein Selected from R1 and R2 are each independently selected from fluorine, chlorine, bromine, hydroxy, methyl, ethyl, propyl, halo 1-3 Alkyl, hydroxyl C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, hydroxy C 1-3 Alkoxy, nitro, carboxyl, cyano, amino, mono C 1-3 Alkylamino, C 1-3 Alkyl acylamino, C 1-3 Alkyl acyl, amino acyl, C 1-3 Alkylaminoacyl, di-C 1-3 Alkylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3-8 membered heterocycloalkyl, 5-10 membered aryl and 5-10 membered heteroaryl, R3 is selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, methyl, ethyl, propyl, halo C 1-3 Alkyl, hydroxyl C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, hydroxy C 1-3 Alkoxy, nitro, carboxyl, cyano, amino, mono C 1-3 Alkylamino, C 1-3 Alkyl acylamino, C 1-3 Alkyl acyl, amino acyl, C 1-3 Alkylaminoacyl and di-C 1-3 Alkylamino, m, n, p are each independently selected from 1, 2 and 3.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein R1 and R2 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, methyl, ethyl, propyl, isopropyl, halogenated C 1-3 Alkyl, hydroxyl C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, hydroxy C 1-3 Alkoxy, nitro, carboxyl, cyano, amino, mono C 1-3 Alkylamino, C 1-3 Alkyl acylamino, C 1-3 Alkyl acyl, amino acyl, C 1-3 Alkylaminoacyl and di-C 1-3 Alkylamino.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein ring C is selected from phenyl, pyridyl, imidazolyl, pyrrolyl, furyl, thienyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, indolyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, isoindolyl, 2,3-dihydro-1H-isoindolyl, benzopyrazolyl, benzothiazolyl ... oxazolyl, benzimidazolyl, benzofuranyl, benzopyranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, quinoxalinyl, benzoxazinyl, benzothiazinyl, imidazopyridinyl, pyrimidopyrazolyl, pyrimidoimidazolyl, dihydrobenzofuranyl, cyclopentenylpyridinyl, dihydropyranopyridinyl and chromanyl, which are optionally selected from halogen, hydroxy, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, nitro, carboxyl, cyano, amino, mono C 1-6 Alkylamino, C 1-6 Alkyl acylamino, C 1-6 Alkyl acyl, amino acyl, C 1-6 Alkylaminoacyl, di-C 1-6 One or more of the alkylamino and oxo groups are substituted.

7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein ring C is selected from It is optionally selected from halogen, hydroxy, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, nitro, carboxyl, cyano, amino, mono C 1-6 Alkylamino, C 1-6 Alkyl acylamino, C 1-6 Alkyl acyl, amino acyl, C 1-6 Alkylaminoacyl and di-C 1-6 One or more groups in the alkylamino group are substituted.

8. The compound according to claim 1 or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein the compound is selected from the following:

9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof and a pharmaceutically acceptable carrier.

10. Use of the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, or the pharmaceutical composition according to claim 9 in the preparation of a medicament for treating cancer.

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