E3 ubiquitin ligase CRBN ligand and application thereof

Abstract

The invention discloses a CRBN ligand with a structure as shown in a formula (I) or a formula (II) and a derivative, a tautomer, a meracemate, a racemate, an enantiomer, a diastereoisomer, an isotope derivative or a pharmaceutically acceptable salt and a solvate of the CRBN ligand, and the CRBN ligand can be efficiently combined to CRBN and can also be used for preparing PROTACs or a molecular glue degradation agent. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technologies, and particularly to an E3 ubiquitin ligase CRBN ligand and its application. Background Art

[0002] The concept of the protein degradation targeting chimera (PROTACs) technology was proposed by the Crews research group at Yale University in 2001 (Proc. Natl. Acad. Sci. USA, 2001, 98, 8584). This technology can utilize the naturally occurring ubiquitin-proteasome protein clearance system in the body to reduce protein levels rather than inhibit protein function, thereby achieving the purpose of treating diseases. The molecular core of this technology involves bifunctional molecules that can simultaneously recruit E3 ubiquitin ligase (E3) and the target protein (POI). PROTACs bring the target protein and the intracellular E3 ubiquitin ligase closer together to form a ternary complex of target protein-PROTAC-E3. Subsequently, the E3 ubiquitin ligase labels the target protein with ubiquitinated protein tags, and the proteasome specifically degrades the target protein by recognizing the ubiquitination label, thereby inhibiting the corresponding protein signaling pathway (Cell Biochem Funct. 2019, 37, 21-30). Compared with traditional small molecule inhibitors, PROTACs exhibit unique advantages: 1. PROTACs do not need to bind to the target protein for a long time and with high intensity. As long as there is a ligand that can bind, it can play a role. Therefore, it can act on some targets that small molecules cannot bind to, and has the potential to treat undruggable targets; 2. The process of degrading the target protein by PROTACs is a catalytic reaction process, which can cyclically bind and degrade the target protein, thereby reducing the systemic exposure of the drug and reducing the occurrence of side effects; 3. Degrading the target protein shows a more efficient and lasting therapeutic effect than inhibiting its activity, and is expected to solve the problem of drug resistance.

[0003] Early PROTACs used polypeptides as ligands to recruit E3 ligases and successfully targeted targets such as MetAP-2, androgen receptor (AR), estrogen receptor α (Erα), etc. However, polypeptides have deficiencies such as poor cell permeability and stability, which have prompted people to focus on developing non-peptide ligands for E3 ligases; in 2008, small molecule PROTACs based on the MDM2 E3 ligase emerged; in 2010, Ito et al. discovered that thalidomide binds to the E3 ubiquitin ligase CUL4–RBX1–DDB1–CRBN (CRL4 CRBN) binds to the subunit CRBN, promotes the degradation of the transcription factor Sall4, thus producing teratogenic effects (Science 2010, 327, 1345), and thus small molecule CRBN ligands were discovered. In 2012, the Crews and Ciulli laboratories developed and continuously optimized a new type of VHL peptidomimetic ligand using a hydroxyproline core fragment, enabling the binding level of small molecule ligands to E3 ligases to reach the micromolar level, laying the foundation for the subsequent development of PROTACs.

[0004] Although a variety of PROTACs have been reported so far, most of the E3 ligase ligands used are limited to CRBN or VHL ligands. PROTACs based on CRBN ligands are in a more suitable chemical space for oral absorption compared to PROTACs based on VHL ligands. Multiple PROTACs based on CRBN ligands have entered clinical studies, including the two most well-known compounds ARV-110 and ARV-471, and ARV-471 has entered phase III clinical trials.

[0005] The CRBN ligands mainly used in PROTACs and molecular glues currently are still immunomodulators, such as Lenalidomide, Thalidomide, and Pomalidomide. The main degrader drugs approved for marketing currently are also molecular glue drugs represented by Lenalidomide, Thalidomide, and Pomalidomide. They are called cereblon (CRBN) E3 ligase modulators (CELMoD) or immunomodulatory drugs (IMiDs). They bind to CRBN, and CRBN forms an E3 ubiquitin ligase complex (CRL4) with DDB1 (damaged DNA binding protein 1), Cul4A (Cullin 4A), and ROC1. CRBN acts as a substrate receptor and binds to some proteins, promoting their ubiquitination and proteasome-dependent proteolysis, such as CK1-a and Ikaros (IKZF1) / Aiolos (IKZF3), etc. However, these compounds all have some defects, such as easy racemization and easy degradation of neosubstrate, etc. Therefore, people have been developing new CRBN ligands. For example, patents W02015160845, W02016197032, W02016105518, etc. have all disclosed CRBN ligands, aiming to improve the chemical stability of such compounds, enhance their activity and drug-likeness, and reduce the toxicity of such compounds. Summary of the Invention

[0006] The technical problem to be solved by the present invention is to provide a novel class of E3 ubiquitin ligase CRBN ligands in view of the drawbacks and deficiencies of the prior art. These ligands can efficiently bind to CRBN and are expected to be used in the synthesis of novel PROTACs and molecular glue degraders.

[0007] To solve the above technical problems, the present invention adopts the following technical solutions:

[0008] CRBN ligands having the structure shown in formula (I) or formula (II), and their derivatives, tautomers, meso forms, racemates, enantiomers, diastereoisomers, isotope derivatives, or pharmaceutically acceptable salts, solvates thereof,

[0009]

[0010] Wherein:

[0011] X and Y are each independently selected from -CR2R3- or -C(=O)-, wherein R2 and R3 are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 cycloalkyl;

[0012] R1 is selected from hydrogen, halogen, cyano, hydroxy, mercapto, carboxy, ester, amide, aldehyde; or R1 is selected from the following groups which are unsubstituted or substituted by one or more first substituents: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 cycloalkyl, C3-C6 cycloalkoxy, amino, C1-C6 alkylthio, C1-C6 alkenyl, C1-C6 alkynyl, C4-C10 heterocyclic group, aryl, C5-C10 heteroaryl, -NH-R4-NR5R6, -NH-R4-OR6, -NR7-R4-COOH, -O-NR5R6, -Ar-(C=O)-NR5R6, -O-R5-R 12 、-CO-R 13 ; wherein, R4 is C1-C6 alkyl, R5, R6 and R7 are each independently H or C1-C6 alkyl, R 12 is C3-C6 cycloalkyl, R 13 is C1-C6 alkyl; the first substituent is selected from deuterium, halogen, hydroxy, amino, carboxy, aldehyde, ester, amide, arylalkyl, halogen-substituted arylalkyl, carboxy-substituted arylalkyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 cycloalkyl, C1-C6 alkenyl, C1-C6 alkynyl, aryl, aryloxy or cyano.

[0013] In the present invention, Ar refers to a benzene ring.

[0014] In some embodiments, X is -C(=O)- and Y is -CH2-; or X is -CH2- and Y is -C(=O)-.

[0015] In some embodiments, R1 is selected from hydrogen, halogen, amino, cyano, hydroxy, mercapto, carboxyl, ester, aldehyde, amide.

[0016] In some embodiments, R1 is selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, halo-C1-C6 alkyl, halo-C1-C6 cycloalkyl, deuterated C1-C6 alkyl, halo-C1-C6 alkoxy, aryl-substituted C1-C6 alkoxy, C1-C6 cycloalkyl, C1-C6 cycloalkoxy or

[0017] In some embodiments, R1 is selected from methyl, methoxy, methylthio, trifluoromethyl, trifluoromethoxy, trideuteriomethyl, difluoromethoxy, difluoromethyl, dideuteriomethyl, cyclohexyl, cyclopentyloxy, phenyl-ring-substituted C1-C6 alkoxy, difluorocyclohexyl.

[0018] In some embodiments, R1 is selected from amino substituted with one or two C1-C6 alkyl groups, amino substituted with one or two arylalkyl groups, amino substituted with one aryl group, amino substituted with haloarylalkyl, amino substituted with aldehyde, C1-C6 alkyl substituted with amino, -NH-R4-OR6, -NH-R4-NR5R6, -O-NR5R6, R8-O-NR5R6; wherein R5 and R6 are each independently H or C1-C6 alkyl, and R8 is C1-C6 alkyl.

[0019] In some embodiments, R1 is selected from amino substituted with one or two C1-C6 alkyl groups, amino substituted with one or two arylalkyl groups, amino substituted with one aryl group, amino substituted with haloarylalkyl, amino substituted with aldehyde, C1-C6 alkyl substituted with amino, -NH-R4-OR6, -NH-R4-NR5R6, -O-NR5R6, R8-O-NR5R6; wherein R4 is C1-C6 alkyl, R5 and R6 are each independently H or C1-C6 alkyl, and R8 is C1-C6 alkyl.

[0020] In some embodiments, R1 is selected from CH3NH-, (CH3)2N-, (CH2CH3)2N-, NH2-(CH2) n -, Ar-CH2-NH-, Ar-NH-, R9-(C=O)NH-, X-Ar-CH2-NH-, (CH3)2N-O-, NH2-O-, -NH-CH2CH2O-CH3, -NHCH2CH2N(CH3)2; where n is 1, 2, or 3; R9 is C1-C6 alkyl; X is halogen.

[0021] In some embodiments, R1 is selected from the following groups which are unsubstituted or substituted by one or more first substituents: C4-C6 heterocyclic group, phenyl or C5-C8 heteroaryl; the C4-C6 heterocyclic group contains 1-2 heteroatoms selected from N or O; the C5-C8 heteroaryl contains 1-2 N atoms; the first substituent is selected from Ar-CH2-, halogen, COOH-Ar-CH2-, amide group, N(CH3)2(C=O)- or cyano.

[0022] In some embodiments, the C4-C6 heterocyclic group is selected from The C5-C8 heteroaryl is selected from

[0023] In some embodiments, R1 is selected from

[0024]

[0025] or phenyl.

[0026] In some embodiments, R1 is selected from -R 10 -COOH, -O-R 10 -COOR 11 , -S-R 10 -COOR 11 , -NR5-R 10 -COOH, -O-R 10 -CONH2, -S-R 10 -CONH2 or wherein R 10 is selected from C1-C6 alkylene, C3-C6 cycloalkylene, C2-C6 alkynylene which are unsubstituted or substituted by one or more deuterium, halogen; R 11 is selected from H or C1-C6 alkyl; R5 is selected from H or C1-C6 alkyl.

[0027] In some embodiments, R 10 is selected from C1-C6 alkylene, dideuterated C1-C6 alkylene, difluorinated C1-C6 alkylene, cyclopropylidene, ethynylene.

[0028] In some embodiments, R 11 is selected from H or methyl; R5 is selected from H or methyl.

[0029] In some embodiments, R1 is selected from C1-C6 alkenyl, halo C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 alkenyloxy, C1-C6 alkynyloxy, C1-C6 alkenylthio, C1-C6 alkynylthio, CN-R 13 -O-, CN-R 13 -S-, wherein R 13 is C1-C6 alkylene.

[0030] In some embodiments, R1 is selected from vinyl, ethynyl, CH2=CH-CH2-O-, CH2=CH-CH2-S-, CN-CH2-O-, CN-CH2-S-, CF2=CH-,

[0031] In some embodiments, the CRBN ligand is a compound selected from the following structures:

[0032]

[0033]

[0034]

[0035]

[0036]

[0037]

[0038]

[0039]

[0040]

[0041] The present invention also provides a pharmaceutical composition comprising the above CRBN ligand and its derivatives, tautomers, mesomers, racemates, enantiomers, diastereoisomers, isotope derivatives or pharmaceutically acceptable salts, solvates thereof.

[0042] The present invention also provides the use of the above-mentioned CRBN ligands and their derivatives, tautomers, mesomers, racemates, enantiomers, diastereomers, isotope derivatives or pharmaceutically acceptable salts and solvates thereof in the preparation of PROTACs or molecular glue degradants. Using the above-mentioned CRBN ligands and their derivatives as reaction raw materials, organic reactions are carried out with other raw materials to synthesize PROTACs or molecular glue degradants accordingly. For example, PROTAC molecules usually include three segments of CLM-L-PTM. Among them, CLM uses the above-mentioned CRBN ligands and their derivatives of the present invention, and reacting it with the linker molecule L and PTM can synthesize PROTACs.

[0043] Furthermore, the molecular glue degradant is selected from the GSPT1 molecular glue degradant, the CDK2 molecular glue degradant or the IKZF1 / 2 / 3 molecular glue degradant.

[0044] Due to the implementation of the above technical solutions, the present invention has the following advantages compared with the prior art:

[0045] The CRBN ligands and their derivatives of the present invention have a thiazole ring moiety, and compared with the existing conventional CRBN ligands, the CRBN ligands of the present invention have higher activity in binding to CRBN. The present invention provides a novel ligand that effectively binds to CRBN. Description of the Drawings

[0046] Figure 1-2 1H NMR spectrum of the target product in Example 1;

[0047] Figure 3 1H NMR spectrum of the target product in Example 2;

[0048] Figure 4-5 1H NMR spectrum of the target product in Example 3;

[0049] Figure 6 1H NMR spectrum of compound 4-2 in Example 4;

[0050] Figure 7 1H NMR spectrum of the target product in Example 5;

[0051] Figure 8 1H NMR spectrum of the target product in Example 7;

[0052] Figure 9 1H NMR spectrum of the target product in Example 8;

[0053] Figure 10 1H NMR spectrum of compound 9 in Example 9;

[0054] Figure 11 1H NMR spectrum of the target product compound 10 in Example 9. Detailed Embodiments

[0055] Definitions

[0056] In the compounds of the present invention, when any variable (e.g., R1, R2, etc.) appears more than once in any component, its definition at each occurrence is independent of its definition at each other occurrence. Similarly, combinations of substituents and variables are permitted, provided that the compounds are stable. A line from a substituent into a ring system indicates that the bond so indicated may be attached to any ring atom capable of substitution. In a broad aspect, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic carbon and heteroatom substituents of organic compounds. It is to be understood that one of ordinary skill in the art may select substituents and substitution patterns of the compounds of the present invention to provide compounds that are chemically stable and readily synthesized from readily available starting materials by techniques well known in the art and the methods set forth hereinafter. If a substituent itself is substituted by more than one group, it is to be understood that these groups may be on the same carbon atom or on different carbon atoms, provided that the structure is stable.

[0057] As used herein, "alkyl" means a branched and straight-chain saturated aliphatic hydrocarbon group having a specific number of carbon atoms. For example, the definition of "C1-6 alkyl" for "C1-6" includes groups having 1, 2, 3, 4, 5, or 6 carbon atoms arranged in a straight-chain or branched-chain configuration.

[0058] As used herein, the term "heteroatom" means an atom of any element other than carbon and hydrogen. Preferred heteroatoms are nitrogen, oxygen, phosphorus, and sulfur.

[0059] As used herein, "heteroalkyl" refers to a straight-chain or branched-chain aliphatic hydrocarbon chain containing 1 to 3 heteroatoms, and each carbon and heteroatom available in the heteroalkyl chain may each be optionally and independently substituted, and the heteroatoms are independently selected from O, N, P, PO, PO2, S, SO, and SO2 (e.g., dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl, diethylaminomethyl, diethylaminoethyl, diethylaminopropyl, 2-diisopropylaminoethyl, bis-2-methoxyethylamino, [2-(dimethylamino-ethyl)-ethyl-amino]-methyl, 3-[2-(dimethylamino-ethyl)-ethyl-amino]-propyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, methoxy, ethoxy, propoxy, methoxymethyl, 2-methoxyethyl).

[0060] As used herein, the term "halogenated hydrocarbon group" refers to a hydrocarbon group in which one or more hydrogen atoms are replaced by halogen atoms. The halogenated hydrocarbon group includes saturated alkyl groups, unsaturated alkenyl groups and alkynyl groups, such as -CF3, -CHF2, -CH2F, -CF2CF3, -CHFCF3, -CH2CF3, -CF2CH3, -CHFCH3, -CF2CF2CF3, -CF2CH2CH3, -CF=CF2, -CCl=CH2, -CBr=CH2, -CI=CH2, -C≡C-CF3, -CHFCH2CH3 and -CHFCH2CF3.

[0061] The alkenyl and alkynyl groups include straight-chain, branched-chain or cyclic olefins and alkynes.

[0062] As used herein, the term "cyclic hydrocarbon group" refers to a mono- or polycyclic aliphatic hydrocarbon group having a specific number of carbon atoms, wherein the ring system may be a saturated ring, an unsaturated, non-aromatic ring or a spiro compound, and may optionally contain a double bond, such as, for example, cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, norbornyl, norbornenyl, indanyl, adamantyl, spiroheptyl and spiro[4.2]heptyl. The term "cycloalkyl group" as used herein refers to a mono- or polycyclic aliphatic alkyl group having a specific number of carbon atoms. The cycloalkylalkyl group includes an acyclic alkyl group in which a hydrogen atom bonded to a carbon atom is replaced by a cycloalkyl group.

[0063] As used herein, "heterocycle" or "heterocyclic group" refers to a saturated or unsaturated, non-aromatic monocyclic, bicyclic or bridged polycyclic or spirocyclic compound, including 3 to 12 carbon atoms, and further bearing one or more carbon atoms replaced by heteroatoms selected from O, N, P and S. Further examples of "heterocyclic group" include, but are not limited to: imidazolyl, indolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinoxalinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, 1,4-dioxanyl, pyrrolidinyl, dihydroimidazolyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridyl, dihydropyrimidinyl, dihydropyrrolyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, tetrahydrofuryl, tetrahydrothienyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, dihydroindolyl, isoindolinyl, morpholinyl, thiomorpholinyl, homomorpholinyl, homopiperidinyl, homopiperazinyl, homothiomorpholinyl, thiomorpholinyl-S-oxide, thiomorpholinyl-S,S-dioxide, tetrahydropyranyl, tetrahydrothienyl, homothiomorpholinyl-S,S-dioxide, oxazolidinonyl, dihydrofuryl, dihydropyranyl, tetrahydrothienyl-S-oxide, tetrahydrothienyl-S,S-dioxide, homothiomorpholin 1-S-oxide, 2-oxa-5-azabicyclo[2.2.1]heptane, 8-oxa-3-azabicyclo[3.2.1]octane, 3,8-diazabicyclo[3.2.1]octane, 2,5-diazabicyclo[2.2.1]heptane, 3,8-diazabicyclo[3.2.1]octane, 3,9-diazabicyclo[4.2.1]nonane and 2,6-diazabicyclo[3.2.2]nonane, and their N-oxides. The connection of the heterocyclic substituent can be achieved through a carbon atom or through a heteroatom. Heterocycloalkylalkyl refers to an acyclic alkyl group in which a hydrogen atom bonded to a carbon atom is replaced by a heterocycloalkyl group.

[0064] As used herein, "heteroaryl" refers to a mono- or polycyclic ring containing one or more heteroatoms in place of one or more carbon atoms, said heteroatoms being the same or different and being, for example, N, O, S and P. Examples include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and triazinyl. Examples of bicyclic heteroaryls are indolyl, isoindolyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl, benzimidazolyl, indazolyl, isoquinolyl, quinolyl, quinoxalinyl, phthalazinyl, cinnolinyl, quinazolinyl and benzotriazinyl, indolizinyl, oxazolopyridyl, imidazolopyridyl, quinazolinyl, dihydroindolyl, isochromanyl, chromanyl, tetrahydroisoquinolyl, isoindolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl, benzoxazolyl, pyridopyridyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, benzazinyl, phenothiazinyl, pteridinyl, benzothiazolyl, imidazolopyridyl, imidazolothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl, dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, coumarinyl, isocoumarinyl, chromanone, pyridyl-N-oxide, tetrahydroquinolyl, dihydroquinolyl, dihydroquinolinone, dihydroisoquinolinone, dihydrocoumarinyl, dihydroisocoumarinyl, isoindolinone, benzodioxane, benzoxazolinone, pyrrolyl-N-oxide, pyrimidinyl-N-oxide, pyridazinyl-N-oxide, pyrazinyl-N-oxide, quinolyl-N-oxide, indolyl-N-oxide, dihydroindolyl-N-oxide, isoquinolyl-N-oxide, quinazolinyl-N-oxide, quinoxalinyl-N-oxide, cinnolinyl-N-oxide, imidazolyl-N-oxide, isoxazolyl-N-oxide, oxazolyl-N-oxide, thiazolyl-N-oxide, indolizinyl-N-oxide, indazolyl-N-oxide, benzothiazolyl-N-oxide, benzimidazolyl-N-oxide, pyrrolyl-N-oxide, oxadiazolyl-N-oxide, thiadiazolyl-N-oxide, triazolyl-N-oxide, tetrazolyl-N-oxide, benzothiopyranyl-S-oxide and benzothiopyranyl-S,S-dioxide. Heteroarylalkyl includes acyclic alkyl in which a hydrogen atom attached to a carbon atom is replaced by a heteroaryl.

[0065] As used herein, "halogen" means including chlorine, fluorine, bromine and iodine.

[0066] Unless otherwise defined, alkyl, cycloalkyl, aryl, and heterocyclic substituents may be unsubstituted or substituted. For example, (C1-C6) alkyl may be substituted with one, two, or three substituents selected from OH, halogen, alkoxy, dialkylamino, or heterocyclic groups such as morpholinyl, piperidinyl, and the like.

[0067] The term "substituted" refers to a moiety in which a hydrogen on one or more carbons of the backbone is replaced with a substituent. It should be understood that "substitution" or "substituted with" includes the implicit proviso that the substitution is in accordance with the allowable valences of the atoms being substituted and the substituents, and that the substitution results in a stable compound, e.g., one that does not spontaneously undergo transformations such as rearrangement, cyclization, elimination, etc. As used herein, the term "substituted" is intended to include all allowable substituents of organic compounds. In a broad sense, allowable substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. Allowable substituents may be one or more and may be the same or different for a suitable organic compound. For the purposes of the present invention, a heteroatom such as nitrogen may have a hydrogen substituent and / or any allowable substituent of the organic compounds described herein that satisfies the valence of the heteroatom. Substituents may include, for example, halogen, hydroxy, carbonyl (such as carboxy, alkoxycarbonyl, formyl or acyl), thiocarbonyl (such as thioester, thioacetate or thiocarboxylate), alkoxy, phosphoryl, phosphate, phosphonate, phosphite, amino, amido, amidine, imine, cyano, nitro, azide, mercapto, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclic, C6-16 aryl or aromatic or heteroaromatic moieties. Those skilled in the art will appreciate that, where appropriate, a substituted moiety on a hydrocarbon chain may itself be substituted. In the context of specific nomenclature, the substituent is generally placed before the group being substituted, e.g., "C1-3 alkoxy C3-8 cycloalkyl C1-6 alkyl" refers to a C1-6 alkyl that is substituted with a C3-8 cycloalkyl, which in turn is substituted with a C1-3 alkoxy. By way of example, the structural formula of methoxycyclobutylmethyl is:

[0068] This document includes the free forms of the compounds of Formula I or Formula II, as well as their pharmaceutically acceptable salts. As used herein, "free form" refers to the non-salt form. The pharmaceutically acceptable salts included herein not only include the exemplary salts of the specific compounds described herein, but also all typical pharmaceutically acceptable salts of the free forms of all compounds of Formula I. The free form of a specific salt of the compound can be isolated using techniques known in the art. For example, the free form can be regenerated by treating the salt with a dilute aqueous solution of a suitable base such as dilute aqueous sodium hydroxide, dilute aqueous potassium carbonate, dilute aqueous ammonia, and dilute aqueous sodium bicarbonate. The free form differs somewhat from its respective salt form in certain physical properties, such as solubility in polar solvents, but for the purposes of the invention, such acid salts and base salts are equivalent to their respective free forms in other pharmaceutical aspects.

[0069] This text includes that the pharmaceutically acceptable salts of the compounds of the present invention can be synthesized from the compounds of the present invention containing a basic moiety or an acidic moiety by conventional chemical methods. Generally, salts of basic compounds are prepared by ion exchange chromatography or by reacting the free base with a stoichiometric or excess amount of an inorganic or organic acid in the desired salt form in a suitable solvent or a combination of solvents. Similarly, salts of acidic compounds are formed by reaction with a suitable inorganic or organic base.

[0070] The pharmaceutically acceptable salts of the compounds of the present invention include conventional non-toxic salts of the compounds of the present invention formed by reacting basic compounds of the present invention with inorganic or organic acids. For example, conventional non-toxic salts include salts prepared from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc., and also include salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, fumaric acid, benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, 2-hydroxyethanesulfonic acid, trifluoroacetic acid, etc.

[0071] If the compound of the present invention is acidic, the appropriate "pharmaceutically acceptable salts" refer to salts prepared by reacting with pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum salts, ammonium salts, calcium salts, copper salts, iron salts, ferrous salts, lithium salts, magnesium salts, manganese salts, manganous salts, potassium salts, sodium salts, zinc salts, etc. Ammonium salts, calcium salts, magnesium salts, potassium salts and sodium salts are particularly preferred. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary amines, secondary amines and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, aminoglucose, histidine, hydroxocobalamin, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, pyrrolidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.

[0072] Obviously, the definition of any substituent or variable at a particular position in a molecule is independent of other positions in the molecule. It is readily understood that one of ordinary skill in the art can select the substituents or substitution forms of the compounds of the present invention by means of the prior art and the methods described in the present invention to provide compounds that are chemically stable and easy to synthesize.

[0073] The compounds of the present invention may contain one or more asymmetric centers and may thus give rise to diastereoisomers and optical isomers. The present invention includes all possible diastereoisomers and their racemic mixtures, their substantially pure separated enantiomers, all possible geometric isomers and their pharmaceutically acceptable salts.

[0074] The present invention includes all stereoisomers of the compounds of formula I or formula II and their pharmaceutically acceptable salts. Further, mixtures of stereoisomers and isolated specific stereoisomers are also included in the present invention. During the synthesis of such compounds, or during the use of racemization or epimerization methods known to those of ordinary skill in the art, the products obtained may be mixtures of stereoisomers.

[0075] When the compounds of formula I or formula II exist as tautomers, unless otherwise stated, the present invention includes any possible tautomers and their pharmaceutically acceptable salts, and mixtures thereof.

[0076] On the other hand, the compounds of the present invention include compounds of the present invention defined using various isotopic labels, for example, those in which radioactive isotopes are present, such as 3 H, 14 C and 18 F, or those in which non-radioactive isotopes are present, such as 2 H and 13 C.

[0077] When the compounds of formula I or formula II and their pharmaceutically acceptable salts are in the form of solvates or polymorphs, the present invention includes any possible solvates and polymorphs. The type of solvent forming the solvate is not particularly limited as long as the solvent is pharmaceutically acceptable. For example, solvents such as water, ethanol, propanol, acetone and the like can be used.

[0078]

[0079] Example 1: Synthesis of Compound 1

[0080] The synthesis steps are as follows:

[0081]

[0082] Synthesis of intermediate ethyl 5-(bromomethyl)thiazole-4-carboxylate (1-2)

[0083]

[0084] At room temperature, N-bromosuccinimide (2.18 g, 12.2 mmol) and azobisisobutyronitrile (191.8 mg, 1.16 mmol) were added to a solution of ethyl 5-methylthiazole-4-carboxylate (2 g, 11.6 mmol) in dichloroethane (20 ml). The reaction system was stirred at 75 °C for 4 hours. The reaction was monitored by LCMS until completion, and the reaction solution was concentrated under reduced pressure to obtain crude ethyl 5-(bromomethyl)thiazole-4-carboxylate (1-2, 1.44 g). The product was a brown oil and was directly used in the next step. LC_MS: (ES + ): m / z 251.35 [M+H] + .

[0085] Synthesis of intermediate 4-formamido-4-({[4-(ethoxycarbonyl)-1,3-thiazol-5-yl]methyl}amino)butanoic acid 2-methylpropan-2-yl ester (1-4)

[0086]

[0087] At room temperature, 4-amino-4-formamidobutanoic acid 2-methylpropan-2-yl ester hydrochloride (1.37 g, 5.77 mmol) and N,N-diisopropylethylamine (2.23 g, 17.3 mmol) were added to a solution of ethyl 5-(bromomethyl)thiazole-4-carboxylate (1.43 g, 5.77 mmol) in acetonitrile (30 ml). The reaction system was refluxed and stirred overnight. The reaction was monitored by LCMS until completion. The reaction solution was concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (DCM / MeOH = 20:1 to 15:1) to obtain 4-formamido-4-({[4-(ethoxycarbonyl)-1,3-thiazol-5-yl]methyl}amino)butanoic acid 2-methylpropan-2-yl ester (1-4, 1.27 g, overall yield of two steps 29%). The product was a brown oil. LC_MS: (ES + ): m / z 372.95 [M+H] + . 1HNMR (400 MHz, CDCl3): δ 8.68 (s, 1H), 6.78 - 6.77 (m, 1H), 5.51 - 5.49 (m, 1H), 4.45 - 4.40 (m, 2H), 4.28 (s, 2H), 3.24 - 3.21 (m, 1H), 2.46 - 2.32 (m, 2H), 2.04 - 2.01 (m, 1H), 1.90 - 1.84 (m, 1H), 1.45 - 1.41 (m, 12H).

[0088] Synthesis of intermediate 5-(((1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)amino)methyl)thiazole-4-carboxylic acid (1-5)

[0089]

[0090] Dissolve 2-methylpropyl 4-formamido-4-({[4-(ethoxycarbonyl)-1,3-thiazol-5-yl]methyl}amino)butanoate (1.27 g, 3.41 mmol) in a solvent system of tetrahydrofuran (20 ml) and water (5 ml), and add lithium hydroxide monohydrate (143.2 mg, 3.41 mmol). The reaction system was stirred at room temperature for 4 hours. LCMS showed that the reaction was complete. Dilute hydrochloric acid (1 N, 3.4 ml) was added to adjust the pH of the system to 2 - 3, and tetrahydrofuran was evaporated. The remaining aqueous phase was extracted with a mixed solvent of isopropanol / dichloromethane (1v / 1v) until no product was detected by TLC in the aqueous phase. The organic phases were combined and concentrated under reduced pressure to obtain 5-(((1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)amino)methyl)thiazole-4-carboxylic acid (1 - 5, 420.8 mg, yield 36%), and the product was a yellow solid. LC_MS: (ES + ): m / z 344.20 [M + H] + .

[0091] Synthesis of intermediate tert-butyl 5-amino-5-oxo-4-(4-oxo-4H-pyrrolo[3,4-d]thiazol-5(6H)-yl)pentanoate (1 - 6)

[0092]

[0093] At room temperature, triethylamine (36.9 mg, 3.6 mmol) was added to a solution of 5-(((1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)amino)methyl)thiazole-4-carboxylic acid (416 mg, 1.2 mmol) in dichloromethane (20 ml) and stirred for 2 minutes, then PyBOP (1.26 g, 2.4 mmol) was added, and the mixture was stirred at room temperature under nitrogen protection for 2 hours. LCMS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (DCM / MeOH = 100:1 to 80:1) to obtain tert-butyl 5-amino-5-oxo-4-(4-oxo-4H-pyrrolo[3,4-d]thiazol-5(6H)-yl)pentanoate (1 - 6, 233 mg, yield 39%), and the product was a pale yellow solid. LC_MS: (ES + ): m / z 326.30 [M + H] + . 1HNMR (400 MHz, CDCl3): δ 8.90 (s, 1H), 4.91 - 4.89 (m, 1H), 4.78 - 4.57 (m, 2H), 2.98 - 2.38 (m, 4H), 1.41 (s, 9H).

[0094] Synthetic compound 3-(4-oxo-4H-pyrrolo[3,4-d]thiazol-5(6H)-yl)piperidine-2,6-dione (1)

[0095]

[0096] A solution of tert-butyl 5-amino-5-oxo-4-(4-oxo-4H-pyrrolo[3,4-d]thiazol-5(6H)yl)pentanoate (230 mg, 0.71 mmol) and p-toluenesulfonic acid (243.3 mg, 1.41 mmol) in acetonitrile (10 ml) was stirred under reflux overnight. LCMS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure. 6 ml of acetonitrile was added to the obtained crude product, stirred for 10 minutes, filtered, the solid was collected, then 6 ml of water was added, stirred, and filtered to obtain 3-(4-oxo-4H-pyrrolo[3,4-d]thiazol-5(6H)-yl)piperidine-2,6-dione (1, 70.3 mg, yield 39%). The product was an off-white solid. LC_MS: (ES + ): m / z 251.80 [M+H] + . 1HNMR (400 MHz, DMSO-d6): δ 10.98 (s, 1H), 9.24 (s, 1H), 5.06 - 5.02 (m, 1H), 4.60 - 4.44 (m, 2H), 2.93 - 2.85 (m, 1H), 2.67 - 2.57 (m, 1H), 2.39 - 2.33 (m, 1H), 2.03 - 2.02 (m, 1H). The NMR spectrum was as shown in Figure 1-2 shown.

[0097] Example 2: Synthesis of compound 2 The synthesis steps are as follows:

[0098]

[0099] Synthesis of intermediate ethyl 4-(bromomethyl)-thiazole-5-carboxylate (2-2)

[0100]

[0101] At room temperature, ethyl 4-methylthiazole-5-carboxylate (5 g, 29 mmol), N-bromosuccinimide (5.45 g, 30.6 mmol) and azobisisobutyronitrile (476.2 mg, 2.9 mmol) were successively added to carbon tetrachloride (50 ml). The reaction system was stirred at 75 °C for 4 hours. LCMS monitored that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain the crude product of ethyl 4-(bromomethyl)-thiazole-5-carboxylate (2-2, 7.4 g). The product was a brown oil and was directly used in the next step of the reaction.

[0102] Synthetic intermediate 4-formamido-4-({[5-(ethoxycarbonyl)-1,3-thiazol-4-yl]methyl}amino)butyric acid 2-methylpropyl ester (2-4)

[0103]

[0104] At room temperature, 4-amino-4-formamidobutyric acid 2-methylpropyl ester hydrochloride (6.99 g, 29.3 mmol) and N,N-diisopropylethylamine (11.36 g, 87.4 mmol) were added to a solution of ethyl 4-(bromomethyl)thiazole-5-carboxylate (7.3 g, 29.3 mmol) in acetonitrile (80 mL). The reaction system was refluxed and stirred for 4 hours. The reaction was monitored by LCMS until completion. The reaction solution was concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (EtOAc / MeOH = 85:1) to obtain 4-formamido-4-({[5-(ethoxycarbonyl)-1,3-thiazol-4-yl]methyl}amino)butyric acid 2-methylpropyl ester (2-4, 1.83 g, 20% yield in two steps). The product was a brown oil. LC_MS: (ES + ): m / z 372.4 [M+H] + . Synthetic intermediate 4-(7-formamido-2,2-dimethyl-4-oxo-8-aza-3-oxanon-9-yl)-1,3-thiazole-5-carboxylic acid (2-5)

[0105]

[0106] 4-Formamido-4-({[5-(ethoxycarbonyl)-1,3-thiazol-4-yl]methyl}amino)butyric acid 2-methylpropyl ester (1.83 g, 49.2 mmol) was dissolved in tetrahydrofuran and water (v / v = 28 ml / 7 ml), and then lithium hydroxide monohydrate (205.6 mg, 49.2 mmol) was added. The reaction system was stirred at room temperature for 4 hours. LCMS showed that the reaction was complete. Dilute hydrochloric acid (1 N, 4.9 ml) was added to adjust the pH of the reaction system to 2-3. Tetrahydrofuran was evaporated, and the remaining aqueous phase was extracted with a mixed solvent of isopropanol / dichloromethane (1v / 1v) until no product was detected by TLC in the aqueous phase. The organic phases were combined and concentrated under reduced pressure to obtain 4-(7-formamido-2,2-dimethyl-4-oxo-8-aza-3-oxanon-9-yl)-1,3-thiazole-5-carboxylic acid (2-5, 954.6 mg, 56% yield). The product was a yellow oil. LC_MS: (ES + ): m / z 344.25 [M+H] +.Synthetic intermediate 2-methylpropyl 4-formamido-4-(6-oxo-5,6-dihydro-4H-pyrrolo[4,3-d][1,3]thiazepin-5-yl)butyrate (2-6)

[0107]

[0108] At room temperature, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (885.8 mg, 2.32 mmol) was added to a solution of 4-(7-formamido-2,2-dimethyl-4-oxo-8-aza-3-oxanon-9-yl)-1,3-thiazepine-5-carboxylic acid (400 mg, 1.16 mmol) and N,N-diisopropylethylamine (451.6 mg, 3.49 mmol) in dichloromethane (20 ml). The reaction mixture was stirred at room temperature under nitrogen protection for 1 hour. LCMS showed that the reaction was complete. The reaction solution was poured into water and extracted with dichloromethane three times. The combined organic phases were concentrated, and the resulting crude product was purified by column chromatography (DCM / MeOH = 100:1 to 60:1) to obtain 2-methylpropyl 4-formamido-4-(6-oxo-5,6-dihydro-4H-pyrrolo[4,3-d][1,3]thiazepin-5-yl)butyrate (2-6, 232 mg, 49%). The product was a pale yellow solid. LC_MS: (ES + ): m / z 326.40 [M+H] + . 1HNMR (400 MHz, d6-DMSO): δ 9.51 (s, 1H), 7.57 (s, 1H), 7.21 (s, 1H), 4.68 - 4.65 (m, 1H), 4.63 - 4.59 (m, 2H), 2.21 - 2.19 (m, 2H), 2.16 - 2.12 (m, 1H), 2.02 - 1.93 (m, 1H), 1.34 (s, 9H). Synthesis of compound 3-(6-oxo-5,6-dihydro-4H-pyrrolo[4,3-d][1,3]thiazepin-5-yl)hexahydropyridine-2,6-dione (2)

[0109]

[0110] A solution of 2-methylpropyl 4-formamido-4-(6-oxo-5,6-dihydro-4H-pyrrolo[4,3-d][1,3]thiazepin-5-yl)butyrate (222 mg, 0.68 mmol) and p-toluenesulfonic acid (234.4 mg, 1.36 mmol) in acetonitrile (10 ml) was refluxed overnight with stirring. LCMS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure. 6 ml of acetonitrile was added to the obtained crude product, and it was stirred for 10 minutes, filtered, and the solid was collected. Then 6 ml of water was added, stirred, and filtered to obtain 3-(6-oxo-5,6-dihydro-4H-pyrrolo[4,3-d][1,3]thiazepin-5-yl)hexahydropyridine-2,6-dione (2, 67.6 mg, yield 39%). The product was an off-white solid. LC_MS: (ES + ): m / z 251.90 [M+H] + . 1HNMR (400 MHz, d6-DMSO): δ 11.00 (s, 1H), 9.55 (s, 1H), 5.09 - 5.05 (m, 1H), 4.60 - 4.39 (m, 2H), 2.90 - 2.87 (m, 1H), 2.62 - 2.58 (m, 1H), 2.40 - 2.37 (m, 1H), 2.07 - 2.01 (m, 1H). The NMR spectrum of compound 2 is as shown in Figure 3 shown.

[0111] Example 3: Synthesis of compound 3

[0112] The synthesis steps are as follows:

[0113]

[0114] Synthesis of intermediate ethyl 2-bromo-4-(bromomethyl)-4H,5H-1,3-thiazepine-5-carboxylate (3-2)

[0115]

[0116] At room temperature, ethyl 2-bromo-4-methyl-1,3-thiazole-5-carboxylate (3 g, 12 mmol), N-bromosuccinimide (2.24 g, 12.6 mmol), and azobisisobutyronitrile (197 mg, 1.2 mmol) were successively added to dichloroethane (15 ml). The reaction system was stirred at 75 °C for 4 hours. LCMS monitored that the reaction was complete. The reaction solution was poured into 30 ml of water and extracted with dichloromethane (15 mL, 3 times). The organic phases were combined, dried, and concentrated under reduced pressure to obtain the crude product of ethyl 2-bromo-4-(bromomethyl)-4H,5H-1,3-thiazepine-5-carboxylate (3-2, 5.1 g), which was directly used in the next step. LC_MS: (ES +): m / z 329.55 [M+H] + .

[0117] Synthetic intermediate 4-({[2-bromo-5-(ethoxycarbonyl)-1,3-thiazol-4-yl]methyl}amino)-4-carbamoylbutyric acid 2-methylpropan-2-yl ester (3-4)

[0118]

[0119] (4S)-4-Amino-4-carbamoylbutyric acid 2-methylpropan-2-yl ester hydrochloride (2.83 g, 11.85 mmol), N,N-diisopropylethylamine (4.59 g, 35.6 mmol) and ethyl 2-bromo-4-methyl-4H,5H-1,3-thiazole-5-carboxylate (5.1 g, 11.85 mmol) were added to acetonitrile (30 ml), and the reaction system was stirred at 75 °C for 3 hours. The reaction was monitored by LCMS until completion. The reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by column chromatography (EtOAc / MeOH = 85:1) to give 4-({[2-bromo-5-(ethoxycarbonyl)-1,3-thiazol-4-yl]methyl}amino)-4-carbamoylbutyric acid 2-methylpropan-2-yl ester (3-4, 2.56 g, two-step yield 36%), and the product was a brown oil. LC_MS: (ES + ): m / z 451.8 [M+H] + . 1H NMR (400 MHz, DMSO-d6): δ 7.35 (s, 1H), 7.05 (s, 1H), 4.32 - 4.26 (m, 2H), 4.03 - 3.93 (m, 2H), 3.31 (s, 1H), 3.00 - 2.96 (m, 1H), 2.21 (t, J = 7.6 Hz, 2H), 1.78 - 1.59 (m, 2H), 1.37 (s, 9H), 1.29 (t, J = 7.2 Hz, 3H).

[0120] Synthetic intermediate 2-bromo-4-(7-carbamoyl-2,2-dimethyl-4-oxo-8-aza-3-oxanon-9-yl)-1,3-thiazole-5-carboxylic acid (3-5)

[0121]

[0122] 4-({[2-Bromo-5-(ethoxycarbonyl)-1,3-thiazol-4-yl]methyl}amino)-4-carbamoylbutyric acid 2-methylpropan-2-yl ester (500 mg, 1.11 mmol) and lithium hydroxide monohydrate (46.6 mg, 1.11 mmol) were successively added to a mixed solution of tetrahydrofuran / water / methanol (v / v / v = 10 mL / 2.5 mL / 2.5 mL), and the reaction system was stirred at room temperature for 2 hours. LCMS showed that the reaction was complete. Dilute hydrochloric acid (1 N, 11.1 mL) was added to adjust the pH of the reaction solution to 2 - 3. Stir at room temperature for 5 minutes, and a white precipitate was formed. Filtered, the solid was collected and dried to obtain 264 mg of a white solid, with a yield of 56%. LC_MS: (ES + ): m / z 423.85 [M+H] + . 1H NMR (400 MHz, DMSO-d6): δ 7.83 (s, 1H), 7.63 (s, 1H), 4.28 - 4.13 (m, 2H), 3.67 - 3.64 (m, 1H), 2.33 - 2.29 (m, 2H), 1.96 - 1.92 (m, 2H) 1.40 (s, 9H).

[0123] Synthesis of intermediate 4-(2-bromo-6-oxo-5,6-dihydro-4H-pyrrolo[4,3-d][1,3]thiazol-5-yl)-4-carbamoylbutyric acid 2-methylpropan-2-yl ester (3 - 6)

[0124]

[0125] At room temperature, 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (2.61 g, 13.7 mmol) was added to a solution of 2-bromo-4-(7-carbamoyl-2,2-dimethyl-4-oxo-8-aza-3-oxanon-9-yl)-1,3-thiazole-5-carboxylic acid (2.9 g, 6.86 mmol) and N,N-diisopropylethylamine (2.66 g, 20.6 mmol) in dichloromethane (90 mL), and the reaction system was stirred at room temperature for 30 minutes. LCMS showed that the reaction was complete. The reaction solution was washed with water (100 ml, 3 times) and saturated brine (50 mL) respectively. The organic phase was dried and concentrated to obtain a crude product, which was slurried with methyl tert-butyl ether and filtered to obtain 4-(2-bromo-6-oxo-5,6-dihydro-4H-pyrrolo[4,3-d][1,3]thiazol-5-yl)-4-carbamoylbutyric acid 2-methylpropan-2-yl ester (3 - 6, 2.26 g, yield 81%), and the product was a pale yellow solid. LC_MS: (ES + ): m / z 405.9 [M+H] +.1H NMR (400 MHz, DMSO-d6): δ 7.58 (s, 1H), 7.23 (s, 1H), 4.69 - 4.64 (m, 1H), 4.60 - 4.56 (m, 2H), 2.24 - 2.15 (m, 3H), 2.01 - 1.91 (m, 1H), 1.35 (s, 9H).

[0126] Synthesis of compound 3-(2-bromo-6-oxo-5,6-dihydro-4H-pyrrolo[4,3-d][1,3]thiazepin-5-yl)piperidine-2,6-dione (3)

[0127]

[0128] A solution of 4-(2-bromo-6-oxo-5,6-dihydro-4H-pyrrolo[4,3-d][1,3]thiazepin-5-yl)-4-carbamoylbutyric acid 2-methylpropan-2-yl ester (500 mg, 1.24 mmol) and p-toluenesulfonic acid (425.9 mg, 2.47 mmol) in acetonitrile (20 mL) was stirred overnight under reflux. LCMS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the obtained crude product was recrystallized from acetonitrile to give 3-(2-bromo-6-oxo-5,6-dihydro-4H-pyrrolo[4,3-d][1,3]thiazepin-5-yl)piperidine-2,6-dione (3, 301 mg, yield 73%), and the product was a light gray solid. LC_MS: (ES + ): m / z 331.7 [M + H] + .1H NMR (400 MHz, DMSO-d6): δ 11.00 (s, 1H), 5.08 - 5.04 (m, 1H), 4.61 - 4.41 (m, 2H), 2.94 - 2.85 (m, 1H), 2.68 - 2.58 (m, 1H), 2.43 - 2.32 (m, 1H), 2.08 - 2.01 (m, 1H). The NMR spectra are as shown in Figure 4 and Figure 5 wherein Figure 5 is a partial magnification.

[0129] Example 4: Synthesis of compound 4

[0130]

[0131] Synthesis of intermediate 4-[5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-pyrrolo[4,3-d][1,3]thiazepin-2-yl]piperazine-1-carboxylic acid 2-methylpropan-2-yl ester (4-1)

[0132]

[0133] A solution of 3-(2-bromo-6-oxo-5,6-dihydro-4H-pyrrolo[4,3-d][1,3]thiazepin-5-yl)hexahydropyridine-2,6-dione (50 mg, 0.15 mmol), 1-tert-butoxycarbonylpiperazine (33.8 mg, 0.18 mmol) and triethylamine (30.53 mg, 0.30 mmol) in N,N-dimethylformamide (1 mL) was stirred at 70 °C for 16 h. The reaction was monitored by LCMS until completion. The reaction mixture was diluted with ethyl acetate (10 mL) and washed successively with water and saturated brine. The organic phase was dried, concentrated, and the resulting crude product was purified by column chromatography (DCM / MeOH = 30 / 1) to give 4-[5-(2,6-dioxohexahydropyridin-3-yl)-6-oxo-5,6-dihydro-4H-pyrrolo[4,3-d][1,3]thiazepin-2-yl]piperazine-1-carboxylic acid 2-methylpropan-2-yl ester (4-1, 42 mg, yield 63%), and the product was a brown solid. LC_MS:(ES + ): m / z 436.40 [M+H] + . 1H NMR (400 MHz, d6-DMSO): δ 10.92 (s, 1H), 4.98 - 4.93 (m, 1H), 4.31 - 4.10 (m, 2H), 3.56 - 3.48 (m, 8H), 2.92 - 2.83 (m, 1H), 2.59 - 2.54 (m, 1H), 2.36 - 2.25 (m, 1H), 2.01 - 1.93 (m, 1H), 1.42 (s, 9H).

[0134] Synthesis of compound 3-[6-oxo-2-(piperazin-1-yl)-5,6-dihydro-4H-pyrrolo[4,3-d][1,3]thiazepin-5-yl]hexahydropyridine-2,6-dione salt (4-2)

[0135]

[0136] 4-[5-(2,6-Dioxohexahydropyridin-3-yl)-6-oxo-5,6-dihydro-4H-pyrrolo[4,3-d][1,3]thiazepin-2-yl]piperazine-1-carboxylic acid 2-methylpropan-2-yl ester (42 mg, 0.096 mol) was dissolved in HCl / 1,4-dioxane (4 M, 2 mL), and the reaction system was stirred at room temperature for 30 minutes. LCMS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the obtained crude product was slurried with 6 mL of methyl tert-butyl ether, filtered and dried to obtain 3-[6-oxo-2-(piperazin-1-yl)-5,6-dihydro-4H-pyrrolo[4,3-d][1,3]thiazepin-5-yl]hexahydropyridine-2,6-dione salt (4-2, 12 mg, yield 34%), a light gray solid. LC_MS: (ES + ): m / z 336.25 [M+H] + . 1HNMR (400 MHz, DMSO-d6): δ 10.93 (s, 1H), 9.42 (brs, 2H), 4.99 - 4.94 (m, 1H), 4.33 - 4.12 (m, 2H), 3.79 (brs, 4H), 3.25 (brs, 4H), 2.93 - 2.83 (m, 1H), 2.66 - 2.55 (m, 1H), 2.37 - 2.26 (m, 1H), 1.98 - 1.94 (m, 1H). The NMR spectrum is as shown in Figure 6 .

[0137] Synthesis of compound 3-[6-oxo-2-(piperazin-1-yl)-5,6-dihydro-4H-pyrrolo[4,3-d][1,3]thiazepin-5-yl]hexahydropyridine-2,6-dione (4)

[0138]

[0139] 3-[6-oxo-2-(piperazin-1-yl)-5,6-dihydro-4H-pyrrolo[4,3-d][1,3]thiazepin-5-yl]hexahydropyridine-2,6-dione salt (20 mg, 0.054 mol) was added to saturated sodium bicarbonate solution, stirred at room temperature for 2 hours, and extracted with MeOH / DCM (10%). The organic phase was collected, dried, and concentrated to obtain 3-[6-oxo-2-(piperazin-1-yl)-5,6-dihydro-4H-pyrrolo[4,3-d][1,3]thiazepin-5-yl]hexahydropyridine-2,6-dione (4, 16 mg).

[0140] Example 5: Synthesis of compound 5

[0141]

[0142] Synthetic compound 3-[2-(4-benzylpiperazin-1-yl)-6-oxo-5,6-dihydro-4H-pyrrolo[4,3-d][1,3]thiazepin-5-yl]hexahydropyridine-2,6-dione (5)

[0143]

[0144] At room temperature, acetic acid (28 mg, 0.7 mmol) was added to a solution of 3-[6-oxo-2-(piperazin-1-yl)-5,6-dihydro-4H-pyrrolo[4,3-d][1,3]thiazepin-5-yl]hexahydropyridine-2,6-dione (117 mg, 0.348 mmol) and benzaldehyde (29.5 mg, 0.278 mmol) in methanol (4 ml), and the mixture was stirred at room temperature for 30 minutes. Then sodium borohydride (43.8 mg, 0.7 mmol) was added, and the reaction system was stirred at room temperature overnight. LCMS showed that the reaction was complete. The reaction solution was concentrated, saturated sodium bicarbonate solution was added to the concentrate, and extraction was carried out with MeOH / DCM (10%). The organic phase was collected, dried, concentrated, and the obtained crude product was purified by preparative thin-layer chromatography (DCM / MeOH = 10 / 1) to obtain 3-[2-(4-benzylpiperazin-1-yl)-6-oxo-5,6-dihydro-4H-pyrrolo[4,3-d][1,3]thiazepin-5-yl]hexahydropyridine-2,6-dione (5, 52 mg, yield 35%), and the product was a white solid. LC_MS: (ES + ): m / z 426.55 [M+H] + . 1HNMR (400 MHz, DMSO-d6): δ 10.91 (s, 1H), 7.33 - 7.26 (m, 5H), 4.97 - 4.92 (m, 1H), 4.29 - 4.08 (m, 2H), 3.59 - 3.51 (m, 6H). 3.31 - 2.97 (m, 4H), 2.91 - 2.82 (m, 1H), 2.67 - 2.58 (m, 1H), 2.34 - 2.27 (m, 1H), 2.01 - 1.90 (m, 1H). The NMR spectrum is as shown in Figure 7 shown.

[0145] Example 6 Synthesis of Compound 6

[0146] The method for preparing the target compound is similar to that of 3-(2-bromo-6-oxo-5,6-dihydro-4H-pyrrolo[4,3-d][1,3]thiazepin-5-yl)hexahydropyridine-2,6-dione (3). Using ethyl 2-bromo-5-methylthiazole-4-carboxylate as the raw material, 3-(2-bromo-4-oxo-5,6-dihydro-4H-pyrrolo[3,4-d][1,3]thiazepin-5-yl)hexahydropyridine-2,6-dione (6) was synthesized. LC_MS: (ES+): m / z 329.65 [M+H] + .1HNMR(400MHz,DMSO-d6):δ11.00(s,1H),5.08 - 5.04(m,1H),4.61 - 4.41(m,2H),2.94 - 2.85(m,1H),2.61 - 2.57(m,1H),2.39 - 2.32(m,1H),2.05 - 2.04(m,1H).

[0147] Example 7: Synthesis of Compound 7

[0148]

[0149] Synthesis of 2-(2-bromo-4-oxo-5,6-dihydro-4H-pyrrolo[3,4-d][1,3]thiazepin-5-yl)-7,7-dimethyl-5-oxooctanamide (7-1)

[0150] The method for preparing the target compound is similar to that of 4-(2-bromo-6-oxo-5,6-dihydro-4H-pyrrolo[4,3-d][1,3]thiazepin-5-yl)-4-formamidobutanoic acid 2-methylpropan-2-yl ester (3-6). Using ethyl 2-bromo-5-methylthiazole-4-carboxylate as the raw material, 2-(2-bromo-4-oxo-5,6-dihydro-4H-pyrrolo[3,4-d][1,3]thiazepin-5-yl)-7,7-dimethyl-5-oxooctanamide (6-1) was synthesized.

[0151] Synthesis of 5-(1-formamido-6,6-dimethyl-4-oxoheptyl)-4-oxo-5,6-dihydro-4H-pyrrolo[3,4-d][1,3]thiazepine-2-carboxamide (7-2)

[0152] At room temperature, 2-(2-bromo-4-oxo-5,6-dihydro-4H-pyrrolo[3,4-d][1,3]thiazepin-5-yl)-7,7-dimethyl-5-oxooctanamide (7-1, 1 g, 2.47 mmol) and cuprous cyanide (265.8 mg, 2.97 mmol) were successively added to dimethyl sulfoxide (15 mL), and the mixture was stirred at 110 °C overnight. LCMS showed that the reaction was complete. The reaction solution was poured into 15 mL of water, filtered through diatomaceous earth, and the filtrate was extracted with ethyl acetate (10 mL × 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained crude product was purified by column chromatography (dichloromethane / methanol = 60:1 - 20:1) to obtain 5-(1-formamido-6,6-dimethyl-4-oxoheptyl)-4-oxo-5,6-dihydro-4H-pyrrolo[3,4-d][1,3]thiazepine-2-carboxamide (7-2, 318 mg, yield 37%), a white solid. LC_MS: (ES+): m / z 368.85 [M+H] + . Synthesis of compound 5-(2,6-dioxohexahydropyridin-3-yl)-4-oxo-5,6-dihydro-4H-pyrrolo[3,4-d][1,3]thiazepine-2-carboxamide (7)

[0153] 5-(1-Formamido-6,6-dimethyl-4-oxoheptyl)-4-oxo-5,6-dihydro-4H-pyrrolo[3,4-d][1,3]thiazepine-2-carboxamide (7-2, 318 mg, 0.84 mmol) and p-toluenesulfonic acid (289.7 mg, 1.68 mmol) were added to acetonitrile (15 mL), and the mixture was stirred at 90 °C overnight. The reaction was monitored by LCMS until completion. The reaction solution was concentrated under reduced pressure, and the obtained crude product was added to 10 mL of acetonitrile, stirred for 10 minutes, and the solid was collected by filtration. Then, 10 mL of water was added and stirred, and the solid was filtered and dried to obtain 5-(2,6-dioxohexahydropyridin-3-yl)-4-oxo-5,6-dihydro-4H-pyrrolo[3,4-d][1,3]thiazepine-2-carboxamide (7, 114 mg, yield 45%), a white solid. LC_MS: (ES+): m / z 294.75 [M+H] + . 1HNMR (400 MHz, DMSO-d6): δ 11.02 (s, 1H), 8.42 (s, 1H), 8.14 (s, 1H), 5.13 - 5.09 (m, 1H), 4.64 - 4.44 (m, 2H), 2.91 - 2.87 (m, 1H), 2.62 - 2.58 (m, 1H), 2.42 - 2.37 (m, 1H), 2.06 - 2.03 (m, 1H). The NMR spectrum is as shown Figure 8 as follows.

[0154] Example 8: Synthesis of compound 5-(2,6-dioxohexahydropyridin-3-yl)-4-oxo-5,6-dihydro-4H-pyrrolo[3,4-d][1,3]thiazepine-2-carbonitrile (8)

[0155]

[0156] At room temperature, 3-(2-bromo-4-oxo-5,6-dihydro-4H-pyrrolo[3,4-d][1,3]thiazepin-5-yl)hexahydropyridine-2,6-dione (6,710 mg, 2.15 mmol) and cuprous cyanide (232 mg, 2.59 mmol) were successively added to dry dimethyl sulfoxide (8 mL), and the mixture was stirred at 110 °C for 2.5 h, monitored by LCMS. The reaction solution was poured into 10 mL of water, filtered through diatomaceous earth, and the filtrate was extracted with ethyl acetate (10 mL × 2). The combined organic phases were washed twice with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (dichloromethane:methanol = 60:1 to 20:1) to obtain 5-(2,6-dioxohexahydropyridin-3-yl)-4-oxo-5,6-dihydro-4H-pyrrolo[3,4-d][1,3]thiazepine-2-carbonitrile (8, 204 mg, yield 34%), a white solid. LC_MS: (ES+): m / z 276.70 [M+H] + . 1HNMR (400 MHz, DMSO-d6): δ 11.04 (s, 1H), 5.15 - 5.10 (m, 1H), 4.71 - 4.52 (m, 2H), 3.32 - 2.86 (m, 1H), 2.86 - 2.50 (m, 1H), 2.41 - 2.37 (m, 1H), 2.06 - 2.04 (m, 1H). The NMR spectrum is as shown Figure 9 as follows.

[0157] Example 9: Synthesis of compound 3-[2-(aminomethyl)-4-oxo-5,6-dihydro-4H-pyrrolo[3,4-d][1,3]thiazepin-5-yl]hexahydropyridine-2,6-dione (10)

[0158]

[0159] At room temperature, Raney nickel (250 mg) was added to a system of 5-(2,6-dioxohexahydropyridin-3-yl)-4-oxo-5,6-dihydro-4H-pyrrolo[3,4-d][1,3]thiazepine-2-carbonitrile (8,150 mg, 0.54 mmol), (Boc)2O (177 mg, 0.815 mmol) and triethylamine (109.9 mg, 1.086 mmol) in tetrahydrofuran (5 mL). The reaction was carried out at room temperature for 3 hours under a hydrogen atmosphere. LCMS showed that the reaction was complete. The supernatant of the reaction was poured into 10 mL of water and extracted with ethyl acetate (8 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by column chromatography (dichloromethane:methanol = 80:1 to 40:1) to obtain compound 9 (9,59 mg, yield 29%), a white solid. LC_MS: (ES+): m / z 380.90 [M+H] + . 1H NMR (400 MHz, DMSO-d6): δ 7.94 (s, 1H), 5.30 - 5.29 (m, 1H), 5.15 - 5.10 (m, 1H), 4.70 - 4.66 (m, 2H), 4.49 - 4.32 (m, 2H), 2.96 - 2.78 (m, 2H), 2.37 - 2.25 (m, 2H), 1.47 (s, 9H). The NMR spectrum is as shown in Figure 10 the following figure.

[0160] Compound 9 (9,42 mg, 0.11 mmol) was added to dioxane hydrochloride (2 mL) and stirred at room temperature for 1 hour. LCMS showed that the reaction was complete. The reaction solution was directly concentrated under reduced pressure to obtain 3-[2-(aminomethyl)-4-oxo-5,6-dihydro-4H-pyrrolo[3,4-d][1,3]thiazepine-5-yl]hexahydropyridine-2,6-dione (10,33 mg, yield 94%), a white solid. LC_MS: (ES+): m / z 280.70 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 11.01 (s, 1H), 8.74 - 8.65 (m, 2H), 5.10 - 5.06 (m, 1H), 4.61 - 4.39 (m, 4H), 2.95 - 2.86 (m, 1H), 2.62 - 2.58 (m, 1H), 2.40 - 2.36 (m, 1H), 2.08 - 1.99 (m, 1H). The NMR spectrum is as shown in Figure 11 the following figure.

[0161] Example 10: Synthesis of compound 11

[0162]

[0163] Synthetic compound {[5-(2,6-dioxohexahydropyridin-3-yl)-4-oxo-5,6-dihydro-4H-pyrrolo[3,4-d][1,3]thiazepin-2-yl](methyl)amino}acetic acid 2-methylpropan-2-yl ester (11-1)

[0164] At room temperature, 3-(2-bromo-4-oxo-5,6-dihydro-4H-pyrrolo[3,4-d][1,3]thiazepin-5-yl)hexahydropyridine-2,6-dione (6,500 mg, 1.5 mmol), (methylamino)acetic acid 2-methylpropan-2-yl ester hydrochloride (363 mg, 0.118 mmol) and TEA (612 mg, 6.04 mmol) were successively dissolved in N,N-dimethylformamide (8 mL), and stirred at 90 °C for 3 hours. LCMS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain {[5-(2,6-dioxohexahydropyridin-3-yl)-4-oxo-5,6-dihydro-4H-pyrrolo[3,4-d][1,3]thiazepin-2-yl](methyl)amino}acetic acid 2-methylpropan-2-yl ester (11-1, 330 mg, yield 57%), a white solid. LC_MS: (ES+): m / z 394.95 [M+H] + . Synthetic compound N-[5-(2,6-dioxohexahydropyridin-3-yl)-4-oxo-5,6-dihydro-4H-pyrrolo[3,4-d][1,3]thiazepin-2-yl]-N-methylglycine (11)

[0165] At room temperature, {[5-(2,6-dioxohexahydropyridin-3-yl)-4-oxo-5,6-dihydro-4H-pyrrolo[3,4-d][1,3]thiazepin-2-yl](methyl)amino}acetic acid 2-methylpropan-2-yl ester (11-1, 320 mg, 1.5 mmol) was successively added to a single-necked flask, and 1,4-dioxane hydrochloride (5 mL) was added, and stirred at 30 °C overnight. The reaction was monitored by LCMS. The reaction solution was concentrated under reduced pressure to obtain N-[5-(2,6-dioxohexahydropyridin-3-yl)-4-oxo-5,6-dihydro-4H-pyrrolo[3,4-d][1,3]thiazepin-2-yl]-N-methylglycine (11, 310 mg, yield 100%), a white solid. LC_MS: (ES+): m / z 338.95 [M+H] + .

[0166] Example 12: Synthesis of Compound 12

[0167]

[0168] Synthetic Compound 12-1

[0169] At room temperature, sodium hydride (52 mg, 1.299 mmol) was weighed into a 50 mL three-necked flask, and nitrogen was displaced; dry tetrahydrofuran (5 mL) was added and the temperature was lowered to 0 °C. The raw material (7-1, 500 mg, 1.237 mmol) was dissolved in 1 mL of tetrahydrofuran, added to the reaction solution, and stirred at 0 °C for another half hour. tert-Butyl glycolate (163 mg, 1.237 mmol) was dissolved in 5 mL of tetrahydrofuran and slowly added dropwise to the above reaction solution at 0 °C. After the addition was complete, the temperature was naturally raised to room temperature and stirring was continued for 3 hours. The reaction was monitored by LCMS. The reaction solution was slowly poured into a cold saturated ammonium chloride solution, extracted with ethyl acetate (20 mL × 2), the organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained crude product was purified by column chromatography (DCM / MeOH = 120:1 - 60:1) to obtain 90 mg of a white solid with a yield of 16%. LC_MS: (ES+): m / z 456.35 [M+H] + .

[0170] Synthesis of Compound 12

[0171] At room temperature, the raw material (12-1, 101 mg, 0.221 mmol) was dissolved in acetonitrile (8.5 mL), and anhydrous p-toluenesulfonic acid (76 mg, 0.442 mmol) was added. The reaction system was heated to 90 °C and stirred overnight. The reaction was monitored by LCMS. The reaction solution was directly concentrated and prepared by high performance liquid chromatography to obtain 41 mg of a white solid with a yield of 57%. LC_MS: (ES+): m / z 325.65 [M+H] + .

[0172] Example 13: Synthesis of Compound 13

[0173]

[0174] Compound 13-1 and 13 were synthesized by referring to the preparation methods of Reference Compounds 12-1 and 12. LC_MS of Compound 13-1: (ES+): m / z 456.00 [M+H] + . LC_MS of Compound 13: (ES+): m / z 325.70 [M+H] + .

[0175] Example 14: Synthesis of Compound 14

[0176]

[0177] A mixture of (3S)-3-(2-bromo-4-oxo-5,6-dihydro-4H-pyrrolo[3,4-d][1,3]thiazepin-5-yl)hexahydropyridine-2,6-dione (300 mg, 0.91 mmol), mercaptoacetic acid (100 mg, 1.09 mmol) and potassium carbonate (276 mg, 2.0 mmol) in N,N-dimethylformamide (15 mL) was reacted at 70 °C for 16 h. LCMS showed that the reaction was complete. The reaction mixture was poured into water (20 mL), and the pH was adjusted to 2 - 3 with 1 M hydrochloric acid, then concentrated to dryness by rotary evaporation. The crude product was purified by a C18 reverse-phase column to obtain 244 mg of a white solid with a yield of 78%. LC_MS: (ES+): m / z 341.85 [M+H] + . 1HNMR (400 MHz, DMSO-d6): δ 13.13 (s, 1H), 10.98 (s, 1H), 5.05 - 5.01 (m, 1H), 4.52 - 4.31 (m, 2H), 4.23 (s, 2H), 2.92 - 2.84 (m, 1H), 2.61 - 2.56 (m, 1H), 2.40 - 2.29 (m, 1H), 2.04 - 1.99 (m, 1H).

[0178] Example 15: Synthesis of Compound 15

[0179]

[0180] At room temperature, Compound 3 (500 mg, 1.5 mmol) was dissolved in N,N-dimethylformamide (10 mL), mercaptoacetic acid (167 mg, 1.8 mmol) and potassium carbonate (460 mg, 3.3 mmol) were added, and the mixture was stirred at 70 °C overnight. LCMS showed that the reaction was complete. Water was added to the reaction mixture, and the pH was adjusted to 3 - 4 with hydrochloric acid, then extracted with ethyl acetate. The organic phase was concentrated under reduced pressure to obtain 530 mg of a white solid with a yield of 97%. LC_MS: (ES+): m / z 341.85 [M+H] + .

[0181] Biological Activity Assay

[0182] The activities of the above Compounds 1 - 3 and the control compound in binding to CRBN were tested by the following method: 10 μL of Cereblon protein (1.5-fold concentration of the compound or the control compound) was mixed with the compound / control compound and incubated at room temperature for 15 minutes, and then the fluorescence polarization signal was measured at 485 nm (excitation wavelength) / 520 nm (emission wavelength). The corresponding IC 50 value was calculated by the formula, and the specific results are shown in Table 1. Among them, the structural formula of the control compound is:

[0183]

[0184] Table 1: Results of CRBN Binding Activity

[0185]

[0186]

[0187] It can be seen that the compounds of the present invention have better binding activity to CRBN than the control compounds.

[0188] The description of the above embodiments is only used to help understand the method of the present invention and its core idea. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and modifications can be made to the present invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention.

Claims

1. A CRBN ligand having a structure represented by formula (I) or formula (II), and its derivatives, tautomers, mesomers, racemates, enantiomers, diastereomers, isotopic derivatives, or pharmaceutically acceptable salts or solvates thereof, in: X and Y are each independently selected from -CR2R3- or -C(=O)-, wherein R2 and R3 are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy or C1-C6 cycloalkyl; R1 is selected from hydrogen, halogen, cyano, hydroxyl, thiol, carboxyl, ester, amide, aldehyde; or, R1 is selected from the following groups which are unsubstituted or substituted by one or more first substituents: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 cycloalkyl, C3-C6 cycloalkoxy, amine, C1-C6 alkylthio, C1-C6 alkenyl, C1-C6 alkynyl, C4-C10 heterocyclyl, aryl, C5-C10 heteroaryl, -NH-R4-NR5R6, -NH-R4-OR6, -NR7-R4-COOH, -O-NR5R6, -Ar-(C=O)-NR5R6, -O-R5-R 12 、-CO-R 13 、-NH-CO-NH-R 14 ; Wherein, R4 is C1-C6 alkyl, R5, R6 and R7 are each independently H or C1-C6 alkyl, R 12 is a C3-C6 cycloalkyl group, R 13 is C1-C6 alkyl, R 14 is phenyl or phenyl C1-C6 alkyl; the first substituent is selected from deuterium, halogen, hydroxyl, amine, carboxyl, aldehyde, ester, amide, aryl alkyl, halogen-substituted aryl alkyl, carboxyl-substituted aryl alkyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 cycloalkyl, C1-C6 alkenyl, C1-C6 alkynyl, aryl, aryloxy or cyano.

2. The CRBN ligand and its derivatives, tautomers, mesomers, racemates, enantiomers, diastereomers, isotopic derivatives or pharmaceutically acceptable salts and solvates thereof according to claim 1, characterized in that: Said X is -C(=O)-, and Y is -CH2-; or said X is -CH2-, and Y is -C(=O)-.

3. The CRBN ligand and its derivatives, tautomers, mesomers, racemates, enantiomers, diastereomers, isotopic derivatives or pharmaceutically acceptable salts and solvates thereof according to claim 1, characterized in that: The R1 is selected from hydrogen, halogen, amine, cyano, hydroxyl, sulfhydryl, carboxyl, ester, aldehyde, and amide.

4. The CRBN ligand and its derivatives, tautomers, mesomers, racemates, enantiomers, diastereomers, isotopic derivatives or pharmaceutically acceptable salts and solvates thereof according to claim 1, characterized in that: R1 is selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, halogenated C1-C6 alkyl, halogenated C1-C6 cycloalkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkoxy, aryl-substituted C1-C6 alkoxy, C1-C6 cycloalkyl, C1-C6 cycloalkyloxy or Preferably, R1 is selected from methyl, methoxy, methylthio, trifluoromethyl, trifluoromethoxy, trideuteromethyl, difluoromethoxy, difluoromethyl, dideuteromethyl, cyclohexyl, cyclopentyloxy, C1-C6 alkoxy substituted with a benzene ring, and difluorocyclohexyl.

5. The CRBN ligand and its derivatives, tautomers, mesomers, racemates, enantiomers, diastereomers, isotopic derivatives or pharmaceutically acceptable salts and solvates thereof according to claim 1, characterized in that: The R1 is selected from an amine group substituted by one or two C1-C6 alkyl groups, an amine group substituted by one or two arylalkyl groups, an amine group substituted by an aryl group, an amine group substituted by a halogenated arylalkyl group, an amine group substituted by an aldehyde group, a C1-C6 alkyl group substituted by an amine group, -NH-R4-OR6, -NH-R4-NR5R6, -O-NR5R6, R8-O-NR5R6; Wherein, R4 is C1-C6 alkyl, R5 and R6 are each independently H or C1-C6 alkyl, and R8 is C1-C6 alkyl; preferably, R1 is selected from CH3NH-, (CH3)2N-, (CH2CH3)2N-, NH2-(CH2) n -, Ar-CH2-NH-, Ar-NH-, R9-(C=O)NH-, X-Ar-CH2-NH-, (CH3)2N-O-, NH2-O-, -NH-CH2CH2O-CH3, -NHCH2CH2N(CH3)2; wherein n is 1, 2, or 3; R9 is C1-C6 alkyl; X is halogen.

6. The CRBN ligand and its derivatives, tautomers, mesomers, racemates, enantiomers, diastereomers, isotopic derivatives or pharmaceutically acceptable salts and solvates thereof according to claim 1, characterized in that: The R1 is selected from the following groups which are unsubstituted or substituted by one or more first substituents: C4-C6 heterocyclic group, phenyl group or C5-C8 heteroaryl group; the C4-C6 heterocyclic group contains 1-2 heteroatoms, and the heteroatoms are selected from N or O; the C5-C8 heteroaryl group contains 1-2 N atoms; the first substituent is selected from Ar-CH2-, halogen, COOH-Ar-CH2-, amide group, N(CH3)2(C=O)- or cyano group.

7. The CRBN ligand and its derivatives, tautomers, mesomers, racemates, enantiomers, diastereomers, isotopic derivatives or pharmaceutically acceptable salts and solvates thereof according to claim 6, characterized in that: The C4-C6 heterocyclic group is selected from The C5-C8 heteroaryl group is selected from Preferably, the R1 is selected from or phenyl.

8. The CRBN ligand and its derivatives, tautomers, mesomers, racemates, enantiomers, diastereomers, isotopic derivatives or pharmaceutically acceptable salts and solvates thereof according to claim 1, characterized in that: The R1 is selected from -R 10 -COOH, -OR 10 -COOR 11 、-SR 10 -COOR 11 、-NR5-R 10 -COOH, -OR 10 -CONH2, -SR 10 -CONH2 or Where R 10 is selected from C1-C6 alkylene, C3-C6 cycloalkylene, C2-C6 alkynylene which are unsubstituted or substituted by one or more deuterium or halogen; R 11 R5 is selected from H or C1-C6 alkyl.

9. The CRBN ligand and its derivatives, tautomers, mesomers, racemates, enantiomers, diastereomers, isotopic derivatives or pharmaceutically acceptable salts and solvates thereof according to claim 1, characterized in that: The R1 is selected from C1-C6 alkenyl, halogenated C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 alkenyloxy, C1-C6 alkynyloxy, C1-C6 alkenylthio, C1-C6 alkynylthio, CN-R 13 -O-、CN-R 13 -S-, where R 13 is C1-C6 alkylene; preferably, R1 is selected from vinyl, ethynyl, CH2=CH-CH2-O-, CH2=CH-CH2-S-, CN-CH2-O-, CN-CH2-S-, CF2=CH-, 10. The CRBN ligand and its derivatives, tautomers, mesomers, racemates, enantiomers, diastereomers, isotopic derivatives or pharmaceutically acceptable salts and solvates thereof according to claim 1, characterized in that: The CRBN ligand is selected from the compounds shown in the following structures:

11. A pharmaceutical composition, characterized in that: The invention comprises one or more CRBN ligands as claimed in any one of claims 1 to 10 and their derivatives, tautomers, mesomorphs, racemates, enantiomers, diastereomers, isotopic derivatives or pharmaceutically acceptable salts and solvates thereof.

12. Use of the CRBN ligand and its derivatives, tautomers, mesomers, racemates, enantiomers, diastereomers, isotopic derivatives or pharmaceutically acceptable salts and solvates as described in any one of claims 1 to 10 in the preparation of PROTACs or molecular glue degraders.

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