1-oxoisoindoline derivative and application thereof

Abstract

The invention discloses a 1-oxo-isoindoline derivative with a structure as shown in a formula (I) and pharmaceutically acceptable salt, solvate, crystal form or stereoisomer thereof, the 1-oxo-isoindoline derivative can be used as a molecular glue degradation agent of GSPT1, has high degradation activity on GSPT1, and has good potential safety. The derivative can be used for degrading GSPTl, preparing drugs for treating diseases related to GSPTl activity and preparing antibody coupling degradation drugs. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technologies, and particularly to a 1-oxoisoindoline derivative and its application. Background Art

[0002] Protein degradation plays an important role in various cellular functions in organisms, that is, by protein degradation, the controlled proteins are converted into various small peptide molecules, so as to regulate the concentration of the controlled proteins, thereby maintaining the health and reproduction of cells. Specific targeted protein degradation provides an attractive prospect for targeting oncoproteins that are currently intractable to drug development (such as transcription factors and chimeric fusion oncoproteins).

[0003] The ubiquitin-proteasome system (UPS) can be manipulated with different small molecules to trigger the targeted degradation of specific target proteins.

[0004] In the past two decades, the targeted protein degradation technology (TPD) based on the ubiquitin-proteasome system has become one of the hottest technologies in the field of new drug research and development, mainly including PROTAC (Proteolysis-targeting chimera) and molecular glue degraders.

[0005] The concept of PROTAC was proposed in 2001. It is a heterobifunctional degrader composed of an E3 ligase ligand, a target protein ligand, and a linker (linker) that connects the two. PROTAC brings the target protein and the E3 ligase closer, resulting in the ubiquitination and degradation of the target protein. Most PROTACs are rationally designed according to the binding mode of the ligand to the target protein, so the target proteins and molecular mechanisms of PROTACs are predictable.

[0006] The concept of molecular glue was proposed in the early 1990s. It is a small molecule that induces the proximity and interaction of biomolecules (such as proteins), and can precisely control various biological processes in terms of time, such as signal transduction, translation, chromatin regulation, protein folding, localization, and degradation. As a chemical inducer that promotes molecular proximity, molecular glue promotes the dimerization or co-localization of two proteins by forming a ternary complex, thereby generating a variety of biological and pharmacological functions. This new mechanism of chemically induced protein interaction, especially molecular glue-induced protein degradation, is becoming an effective strategy for exploring biological processes and drug development.

[0007] For molecular glue degraders, although they are also bifunctional protein degraders like PROTACs, they have different mechanisms of action and structural characteristics. First, the target proteins and mechanisms of PROTACs are usually clear, so there are some established design and optimization strategies for the development of PROTACs; while the discovery of molecular glue degraders is mostly accidental, and their mechanisms of action were initially unknown. The discovery of molecular glue is often accompanied by the discovery of new mechanisms of action and new drug targets. Second, PROATCs usually have high molecular weights and poor cell permeability; while the physicochemical properties of molecular glue are similar to those of traditional small molecule drugs. Therefore, in terms of lower molecular weight, increased oral bioavailability, and improved pharmacology and pharmacokinetics, molecular glue is theoretically more drug-like than PROTAC.

[0008] Compared with traditional small molecule enzyme inhibitors or receptor antagonists, molecular glue degraders also have multiple advantages. First, in terms of mechanism of action, molecular glue degraders drive the ubiquitination and degradation of target proteins in a sub-stoichiometric and catalytic manner. Second, molecular glue can degrade target proteins that were previously inaccessible or undruggable. Classical small molecule inhibitors act by binding to the ligand pocket on the target protein. In contrast, molecular glue does not act by competing to occupy the protein spatial structure, but rather induces or strengthens the interaction between the receptor and the target protein in an indirect manner, changing the protein to form a new configuration, and then driving these proteins to have new functions to exert their physiological functions. Therefore, molecular glue can reach therapeutic targets that are difficult to handle with traditional drugs, expanding the range of druggable targets for small molecule drugs. In recent years, it has become one of the hottest research directions in the field of innovative drug research and development.

[0009] Although the discovery of most molecular glue degraders is accidental, important progress has recently been made in the rational discovery or design of molecular glue degraders, especially in the development of molecular glue based on the CRBN E3 ligase. These molecular glue compounds based on CRBN E3 ligase ligands are called cereblon (CRBN) E3 ligase modulators (CELMoD) or immunomodulatory drugs (IMiDs). They specifically bind to the cereblon (CRBN) E3 ligase. CRBN forms a Cullin Ring ligase 4 (CRL4) complex with DNA damage-binding protein 1 (DDB1). This complex induces the recruitment of IKAROS family zinc finger proteins 1 (IKZF1) and 3 (IKZF3) to form a ternary complex with the substrate protein, further ubiquitinating it through the ubiquitination system and transporting it to the 26S proteasome for degradation.

[0010] Studies have shown that although various IMiDs and CELMoDs are very similar in structure, small changes in the molecular glue structure may significantly alter the substrate recognition specificity of the E3 ligase CRBN, thereby enabling molecular glue degraders to exhibit different degradation functions and thus different therapeutic effects. For example, both pomalidomide and lenalidomide can degrade IKZF1 / 3, but only lenalidomide can degrade casein kinase la (CKla). The degradation of IKZF1 / 3 can be used to treat multiple myeloma, while CKla may be an effective target for 5q myelodysplastic syndrome.

[0011] GSPT1, also known as eukaryotic release factor 3a (eRF3), forms a complex with the translation termination factor eRF1, mediates translation termination, and regulates mammalian cell growth. GSPT1 is significantly overexpressed in various cancer tissues and cells. Therefore, the downregulation of GSPT1 can lead to abnormal expression of key proteins in various tumor cells, thereby inhibiting proliferation or inducing apoptosis. GSPT1 is currently widely studied as a target protein in myeloid leukemia.

[0012] GSPT1 is a regulatory factor required for almost all cell division and growth. On the one hand, GSPT1 molecular glue degraders can be developed independently as small molecule drugs, and on the other hand, they can be used as payloads in antibody-drug conjugates for degradation, further enriching the diversity of tumor treatment methods.

[0013] Patent WO2008027542 discloses the molecular glue degrader CC-885, which can degrade IKZF1 / 3 and can more efficiently induce the degradation of the translation termination factor G1 to S phase transition protein 1 (GSPT1). Although CC-885 has excellent anti-tumor activity in AML and other cancer cell lines by degrading GSPT1, its cytotoxicity to various cells is not discriminatory, resulting in its potential toxicity.

[0014] Patent WO2023078410 discloses a molecular glue degrader of GSPT1, but its activity is not high enough. Summary of the Invention

[0015] The technical problem to be solved by the present invention is to provide a novel class of 1-oxoisoindoline derivatives in view of the disadvantages and deficiencies of the prior art. These derivatives can be used as molecular glue degraders of GSPT1, have high degradation activity against GSPT1, and relatively good potential safety.

[0016] To solve the above technical problems, the present invention adopts the following technical solutions:

[0017] 1-oxoisoindoline derivatives having the structure shown in formula (I), and pharmaceutically acceptable salts, solvates, crystal forms or stereoisomers thereof,

[0018]

[0019] wherein:

[0020] A1 is selected from -(C=O)- or -CH2-;

[0021] R1 is selected from halogen, methyl, methoxy or cyano;

[0022] m is 0, 1, 2 or 3;

[0023] A2 is selected from a single bond, C1-6 alkylene, C1-3 alkylene substituted by a benzene ring, aromatic ring, heteroaromatic ring, C3-C8 saturated carbocyclic ring or heterocyclic ring, -OCH2-, -CH2O-, -CH2(-CH2-O-CH3)-;

[0024] Ring B is selected from an unsubstituted or substituted benzene ring, C5-8 heterocyclic ring, C8-C14 aromatic ring, C8-C14 heteroaromatic ring, C3-6 saturated carbocyclic ring or heterocyclic ring; the C5-8 heterocyclic ring contains 1-2 heteroatoms selected from O, N or S; the C8-C12 heteroaromatic ring contains 1-2 heteroatoms selected from O, N or S; the substituents are selected from halogen, cyano, nitro, amino, hydroxy, C1-6 alkyl, C3-8 alkyl interrupted by 1 or 2 heteroatoms selected from O and N, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, benzyl or substituted benzyl, C3-6 heterocyclic group, C3-6 heterocyclic C1-6 alkyl, wherein, A3 is selected from a single bond, C1-6 alkylene, C3-8 heteroalkylene;

[0025] n is 1, 2, 3 or 4; R3 is selected from H or C1-6 alkyl or C3-C8 cycloalkyl or cycloheteroalkyl.

[0026] In the present invention, the foregoing 1-7 refer to 1, 2, 3, 4, 5, 6 or 7.

[0027] In some embodiments, A1 is selected from -(C=O).

[0028] In some embodiments, m is 0.

[0029] In some embodiments, A2 is selected from a single bond, -CH2-, -CH(CH3)-, -CH2CH2-, -CH2CH2CH2-, -CH(Ph)-, -CH2O-, -CH2(-CH2-O-CH3)-.

[0030] In some embodiments, ring B is selected from a benzene ring which is unsubstituted or substituted with 1 - 5 (1, 2, 3, 4 or 5) substituents, and the substituents are selected from halogen, cyano, nitro, amino, hydroxy, C1 - 6 alkyl, C6 - 8 alkyl interrupted by 1 O atom and 1 N atom, C1 - 6 alkoxy, C1 - 6 haloalkyl, C1 - 6 haloalkoxy, benzyl,

[0031]

[0032] In some embodiments, ring B is selected from a benzene ring which is unsubstituted or substituted with 1 - 5 (1, 2, 3, 4 or 5) substituents, and the substituents are selected from halogen, nitro, amino, hydroxy, methyl, CH3NHCH2CH2OCH2CH2-, methoxy, trifluoromethyl, trifluoromethoxy, benzyl,

[0033]

[0034] In some embodiments, ring B is selected from a C5 - 8 heterocycle which is unsubstituted or substituted with a substituent selected from halogen, C1 - 6 alkyl or C1 - 6 alkoxy, and the C5 - 8 heterocycle is selected from

[0035] In some embodiments, ring B is selected from a C8 - C14 aromatic ring which is unsubstituted or substituted with a substituent selected from halogen, C1 - 6 alkyl or C1 - 6 alkoxy, and the C8 - C14 aromatic ring is selected from

[0036] In some embodiments, ring B is selected from a C8 - C14 heteroaromatic ring which is unsubstituted or substituted with a substituent selected from halogen, C1 - 6 alkyl or C1 - 6 alkoxy, and the C8 - C14 heteroaromatic ring is selected from

[0037]

[0038] In some embodiments, ring B is selected from cyclopropane, cyclobutane, cyclopentane or cyclohexane which is unsubstituted or substituted with a substituent selected from halogen, C1 - 6 alkyl or C1 - 6 alkoxy.

[0039] In some embodiments, ring B is selected from cyclopropane which is unsubstituted or substituted with 1 substituent selected from halogen or C1 - 6 alkyl.

[0040] In some embodiments, the 1 - oxoisoindoline derivative is selected from the compounds shown in the following structures:

[0041]

[0042]

[0043]

[0044]

[0045]

[0046] The present invention also provides a pharmaceutical composition comprising the above-mentioned 1-oxoisoindoline derivatives and their pharmaceutically acceptable salts, solvates, crystal forms or stereoisomers. The pharmaceutical composition may further comprise a pharmaceutically acceptable carrier.

[0047] The present invention also provides the use of the above-mentioned 1-oxoisoindoline derivatives and their pharmaceutically acceptable salts, solvates, crystal forms or stereoisomers in degrading GSPT1, preparing a drug for treating diseases related to GSPT1 activity, and preparing an antibody-drug conjugate for degradation.

[0048] In some embodiments, the diseases related to GSPT1 activity are selected from one or two of leukemia and myeloma.

[0049] In some embodiments, the leukemia is selected from acute myeloid leukemia (AML).

[0050] In some embodiments, the myeloma is selected from multiple myeloma (MM).

[0051] Due to the implementation of the above technical solutions, the present invention has the following advantages compared with the prior art:

[0052] The 1-oxoisoindoline derivative of the present invention can be used as a molecular glue degrader of GSPT1. Since its main chain structure contains a difluoroacetamide segment, it can improve the degradation activity against GSPT1. At the same time, the derivative of the present invention has differential killing effects on different types of cells and has relatively high potential safety. Detailed Embodiments

[0053] Definitions

[0054] For the compounds of the present invention, when any variable (e.g., R1, R2, etc.) appears more than once in any component, its definition for each occurrence is independent of its definition for each other occurrence. Similarly, combinations of substituents and variables are permitted, provided that the combination renders the compound stable. The line extending from a substituent into a ring system indicates that the bond so indicated can be attached to any ring atom capable of being substituted. 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 understood that one of ordinary skill in the art can select the substituents and substitution patterns of the compounds of the present invention to provide compounds that are chemically stable and can be readily synthesized from readily available starting materials by techniques known in the art and the methods set forth hereinafter. If a substituent itself is substituted by more than one group, it is understood that these groups can be on the same carbon atom or different carbon atoms, provided that the structure is stable.

[0055] 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" in "C1-6 alkyl" includes groups having 1, 2, 3, 4, 5, or 6 carbon atoms arranged in a straight-chain or branched-chain manner.

[0056] 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.

[0057] 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 can 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-(dimethylaminoethyl)-ethyl-amino]-methyl, 3-[2-(dimethylaminoethyl)-ethyl-amino]-propyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, methoxy, ethoxy, propoxy, methoxymethyl, 2-methoxyethyl).

[0058] As used herein, "haloalkyl" refers to a hydrocarbon group in which one or more hydrogen atoms are replaced by halogen atoms. Haloalkyl includes saturated alkyl and unsaturated alkenyl 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.

[0059] Alkenyl and alkynyl include straight-chain, branched-chain or cyclic olefins and alkynes.

[0060] As used herein, "cycloalkyl 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. "Cycloalkyl" as described herein refers to a mono- or polycyclic aliphatic alkyl group having a specific number of carbon atoms. Cycloalkylalkyl includes non-cyclic alkyl groups in which the hydrogen atoms bonded to the carbon atoms are replaced by cycloalkyl groups.

[0061] 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 a heteroatom selected from O, N, P and S in place of one or more carbon atoms. 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 attachment 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.

[0062] As used herein, "heteroaryl" refers to a single or multi-ring cycle 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, cinnolinyl, phthalazinyl, quinazolinyl and benzotriazinyl, indolizinyl, oxazopyridyl, imidazopyridyl, naphthyridinyl, dihydroindolyl, isochromanyl, chromanyl, tetrahydroisoquinolyl, isoindolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl, benzoxazolyl, pyridopyridyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, benzazinyl, phenothiazinyl, pteridinyl, benzothiazolyl, imidazopyridyl, imidazothiazolyl, 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, phthalazinyl-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 an acyclic alkyl in which a hydrogen atom bonded to a carbon atom is replaced by a heteroaryl.

[0063] As used herein, "halogen" is meant to include chlorine, fluorine, bromine and iodine.

[0064] 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, etc.

[0065] The term "substituted" refers to a moiety having a substituent replacing hydrogen on one or more carbons of the backbone. 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., does not spontaneously undergo transformations such as by rearrangement, cyclization, elimination, etc. As used herein, the term "substituted" is intended to include all allowable substituents of organic compounds. In a broad aspect, 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 group, C6-16 aryl group or aromatic or heteroaromatic moiety. Those skilled in the art will understand that, if appropriate, a substituted moiety on a hydrocarbon chain may itself be substituted. When referring to 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, and the C3-8 cycloalkyl is in turn substituted with a C1-3 alkoxy. For example, the structural formula of methoxycyclobutylmethyl is:

[0066] 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.

[0067] This text includes that the pharmaceutically acceptable salts of the compounds of the present invention can be synthesized by conventional chemical methods from the compounds of the present invention containing basic or acidic moieties. 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 reacting with a suitable inorganic or organic base.

[0068] The pharmaceutically acceptable salts of the compounds of the present invention include the 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 obtained from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc., and also include salts obtained 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.

[0069] If the compound of the present invention is acidic, then the appropriate "pharmaceutically acceptable salts" refer to salts prepared by pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts obtained 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 obtained from pharmaceutically acceptable organic non-toxic bases, said bases including 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.

[0070] 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 those of ordinary skill in the art can, by means of the prior art and the methods described in the present invention, select the substituents or substitution forms of the compounds of the present invention to provide compounds that are chemically stable and easily synthesized.

[0071] 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.

[0072] 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 process of using racemization or epimerization methods known to those of ordinary skill in the art, the products obtained may be mixtures of stereoisomers.

[0073] 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.

[0074] On the other hand, the compounds of the present invention include compounds of the present invention defined using various isotopes, for example, those in which there are radioactive isotopes, such as 3 H, 14 C and 18 F, or those in which there are non-radioactive isotopes, such as 2 H and 13 C.

[0075] 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. There is no particular limitation on the type of solvent forming the solvate, as long as the solvent is pharmaceutically acceptable. For example, solvents such as water, ethanol, propanol, acetone, and the like can be used.

[0076] Example 1: Synthesis of Compound 1

[0077] The synthesis steps are as follows:

[0078]

[0079] Synthesis of intermediate methyl 4-(2-ethoxy-1,1-difluoro-2-oxoethyl)-2-methylbenzoate (1-2)

[0080] At room temperature, copper powder (4.14 g, 65.2 mmol) and ethyl difluorobromoacetate (6.62 g, 32.6 mmol) were added to a solution of methyl 4-iodo-2-methylbenzoate (6 g, 21.7 mmol) in dimethyl sulfoxide (50 ml), and the reaction was stirred overnight at 50 °C. The reaction was monitored by TLC to completion. The reaction mixture was poured into semi-saturated brine (400 ml), filtered, extracted with ethyl acetate (100 ml), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give methyl 4-(2-ethoxy-1,1-difluoro-2-oxoethyl)-2-methylbenzoate (1-2, 5.6 g, yield 94%), and the product was a yellow liquid.

[0081] 1 HNMR (400 MHz, CDCl3): δ 7.97 (d, J = 8.8 Hz, 1H), 7.48 (d, J = 6.8 Hz, 2H), 4.33 (q, J = 7.2 Hz, 2H), 3.91 (s, 3H), 2.63 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H).

[0082] Synthesis of intermediate methyl 2-(bromomethyl)-4-(2-ethoxy-1,1-difluoro-2-oxoethyl)benzoate (1-3)

[0083] At room temperature, N-bromosuccinimide (1.44 g, 8.08 mmol) and benzoyl peroxide (88.97 mg, 0.367 mmol) were added to a solution of methyl 4-(2-ethoxy-1,1-difluoro-2-oxoethyl)-2-methylbenzoate (2 g, 7.35 mmol) in carbon tetrachloride (15 ml), and the mixture was stirred under reflux for 4 h. The reaction was monitored by LCMS to completion. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by column chromatography (petroleum ether:ethyl acetate = 40:1) to give methyl 2-(bromomethyl)-4-(2-ethoxy-1,1-difluoro-2-oxoethyl)benzoate (1-3, 0.753 g, yield 30%), and the product was a brown oil.

[0084] 1 HNMR (400 MHz, CDCl3): δ 8.03 (d, J = 8.4, 1H), 7.71 (s, 1H), 7.60 - 7.63 (m, 1H), 4.95 (s, 2H), 4.32 (q, J = 7.2, 2H), 3.97 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H).

[0085] Synthesis of intermediate 2-methylpropyl 4-formamido-4-[5-(2-ethoxy-1,1-difluoro-2-oxoethyl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]butyrate (1-4)

[0086] At room temperature, N,N-diisopropylethylamine (662.5 mg, 5.13 mmol) and 2-methylpropyl 4-formamidobutanoate (428.3 mg, 1.79 mmol) were added to a solution of methyl 2-(bromomethyl)-4-(2-ethoxy-1,1-difluoro-2-oxoethyl)benzoate (600 mg, 1.71 mmol) in acetonitrile (10 ml), and the mixture was stirred at 77 °C for 5 hours. LCMS showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure, dissolved in ethyl acetate (20 ml), washed with saturated ammonium chloride (10 ml), and the organic phase was concentrated under reduced pressure. The resulting crude product was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain 2-methylpropyl 4-formamido-4-[5-(2-ethoxy-1,1-difluoro-2-oxoethyl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]butanoate (1-4, 517 mg, yield 68%), and the product was a yellow solid.

[0087] LC_MS:(ES + ):m / z 441.25[M+H] + .

[0088] 1 1H NMR (400 MHz, CDCl3): δ 7.93 (d, J = 12.8 Hz, 1H), 7.72 - 7.74 (m, 2H), 6.31 (s, 1H), 5.39 (s, 1H), 4.91 - 4.95 (m, 1H), 4.48 - 4.66 (m, 2H), 4.31 (q, J = 7.2 Hz, 2H), 2.13 - 2.39 (m, 4H), 1.42 (s, 9H), 1.31 (t, J = 11.2 Hz, 3H).

[0089] Synthesis of intermediate 2-(2-{1-formamido-4-[(2-methylpropyl)oxy]-4-oxobutyl}-1-oxo-2,3-dihydro-1H-isoindol-5-yl)-2,2-difluoroacetic acid (1-5)

[0090] At room temperature, potassium carbonate (490 mg, 3.48 mmol) was added to a mixed solution of methyl 4-formamido-4-[5-(2-ethoxy-1,1-difluoro-2-oxoethyl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]butyrate (510 mg, 1.16 mmol) in methanol (5 ml) and water (5 ml), and the mixture was stirred at room temperature for 20 minutes. LCMS showed that the reaction was complete. The pH of the reaction solution was adjusted to 4-5, and the mixture was extracted with a mixed solvent of dichloromethane and isopropanol (3:1) (10 ml). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 2-(2-{1-formamido-4-[(2-methylpropan-2-yl)oxy]-4-oxobutyl}-1-oxo-2,3-dihydro-1H-isoindol-5-yl)-2,2-difluoroacetic acid (1-5, 440 mg, yield 92%). The product was a pale yellow solid.

[0091] LC_MS:(ES + ):m / z 413.10[M+H] + .

[0092] 1 HNMR(400MHz,CDCl3):δ7.71-7.80(m,3H),7.37(s,1H),7.25(s,1H),4.92-4.95(m,1H),4.43-4.57(m,2H),2.09-2.34(m,4H),1.42(s,9H).

[0093] Synthesis of intermediate methyl 4-formamido-4-(5-{2-[(4-chlorophenyl)amino]-1,1-difluoro-2-oxoethyl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)butyrate (1-6)

[0094] At room temperature, p-chloroaniline (68 mg, 0.53 mmol), triethylamine (162 mg, 1.59 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (304.6 mg, 0.795 mmol) were added to a solution of 2-(2-{1-formamido-4-[(2-methylpropan-2-yl)oxy]-4-oxobutyl}-1-oxo-2,3-dihydro-1H-isoindol-5-yl)-2,2-difluoroacetic acid (220 mg, 0.53 mmol) in N,N-dimethylformamide (3 ml), and the mixture was stirred at room temperature for 4 h. LCMS showed that the reaction was complete. Half-saturated brine (30 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 ml). The obtained crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to give 2-methylpropan-2-yl 4-formamido-4-(5-{2-[(4-chlorophenyl)amino]-1,1-difluoro-2-oxoethyl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)butanoate (1-6, 110 mg, yield 39%), and the product was a white solid.

[0095] LC_MS:(ES + ):m / z 522.20[M+H] + .

[0096] 1 HNMR(400MHz,DMSO-d6):δ8.21(s,1H),7.94(d,J=8.0Hz,1H),7.76-7.81(m,2H),7.32-7.55(m,4H),6.34(s,1H),5.39(s,1H),4.91-4.95(m,1H),4.49-4.67(m,2H),2.08-2.39(m,4H),1.41(s,9H).

[0097] Synthesis of N-(4-chlorophenyl)-2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoroacetamide (1)

[0098] A solution of 4-formamido-4-(5-{2-[(4-chlorophenyl)amino]-1,1-difluoro-2-oxoethyl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)butanoic acid 2-methylpropan-2-yl ester (130 mg, 0.25 mmol) and p-toluenesulfonic acid (85.8 mg, 0.5 mmol) in acetonitrile (3 ml) was stirred at 90 °C overnight. LCMS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and 2 ml of ethyl acetate was added to the obtained crude product. After stirring for 20 minutes, the solid was collected by filtration. Then 2 ml of water was added, stirred, and filtered. The obtained solid was dried to obtain N-(4-chlorophenyl)-2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoroacetamide (Compound 1, 32 mg, yield 28%). The product was a white solid.

[0099] LC_MS:(ES + ):m / z 447.90[M+H] + .

[0100] 1 HNMR(400MHz,d6-DMSO):δ11.01(d,J=8.0Hz,2H),7.82-7.96(m,3H),7.73(d,J=8.8Hz,2H),7.44(d,J=8.8Hz,2H),5.12-5.17(m,1H),4.42-4.59(m,2H),2.87-2.93(m,1H),2.59-2.64(m,1H),2.38-2.43(m,1H),2.00-2.04(m,1H).

[0101] Example 2: Synthesis of Compound 2

[0102] The synthesis steps are as follows:

[0103]

[0104] Synthesis of intermediate 4-formamido-4-[5-(2-{[(4-chlorophenyl)methyl]amino}-1,1-difluoro-2-oxoethyl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]butanoic acid 2-methylpropan-2-yl ester (2-1)

[0105] At room temperature, to a solution of 2-(2-{1-formamido-4-[(2-methylpropan-2-yl)oxy]-4-oxobutyl}-1-oxo-2,3-dihydro-1H-isoindol-5-yl)-2,2-difluoroacetic acid (700 mg, 1.70 mmol) in N,N-dimethylformamide (8 ml) was added 4-chlorobenzylamine (262.5 mg, 1.87 mmol), triethylamine (862.5 mg, 8.49 mmol) and 2-(7-azabenzotriazol)-tetramethyluronium hexafluorophosphate (HATU) (1.3 g, 3.39 mmol), and the mixture was stirred at room temperature overnight. LCMS showed that the reaction was complete. Water (20 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 ml). The obtained crude product was purified by column chromatography (petroleum ether and ethyl acetate = 1:1) to give 4-formamido-4-[5-(2-{[(4-chlorophenyl)methyl]amino}-1,1-difluoro-2-oxoethyl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]butanoic acid 2-methylpropan-2-yl ester (2-1, 440 mg, yield 48%), and the product was a white solid.

[0106] LC_MS:(ES + ):m / z 536.10[M+H] + .

[0107] 1 HNMR(400MHz,CDCl3):δ7.70-7.93(m,3H),7.32(d,J=8.4Hz,2H),7.21(d,J=8.4Hz,2H),6.87(s,1H),6.37(s,1H),5.40(s,1H),4.91-4.95(m,1H),4.47-4.65(m,4H),2.05-2.38(m,4H),1.42(s,9H).

[0108] Synthesis of N-[(4-chlorophenyl)methyl]-2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoroacetamide (2)

[0109] A solution of 4-formamido-4-[5-(2-{[(4-chlorophenyl)methyl]amino}-1,1-difluoro-2-oxoethyl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]butanoic acid 2-methylpropan-2-yl ester (400 mg, 0.746 mmol) and p-toluenesulfonic acid (257 mg, 1.49 mmol) in acetonitrile (8 ml) was stirred at 90 °C overnight. LCMS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and 2 ml of diethyl ether was added to the obtained crude product, followed by stirring for 20 minutes. The solid was collected by filtration. Then, 2 ml of water was added, followed by stirring and filtration. The obtained solid was dried to obtain N-[(4-chlorophenyl)methyl]-2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoroacetamide (Compound 2, 36 mg, yield 10%), and the product was a white solid.

[0110] LC_MS:(ES + ):m / z 461.90[M+H] + .

[0111] 1 HNMR(400MHz,d6-DMSO):δ11.02(s,1H),9.65(s,1H),7.71-7.90(m,3H),7.23-7.39(m,4H),5.12-5.17(m,1H),4.39-4.57(m,2H),4.33(d,J=6.0Hz,2H),2.87-2.94(m,1H),2.59-2.63(m,1H),2.36-2.46(m,1H),2.01-2.04(m,1H).

[0112] Example 3: Synthesis of Compound 3

[0113] The synthesis steps are as follows:

[0114]

[0115] Synthesis of intermediate ethyl 2,2-difluoro-2-[3-(methoxycarbonyl)-2-methylphenyl]acetate (3-2)

[0116] At room temperature, copper powder (2.9 g, 45.6 mmol) and ethyl difluorobromoacetate (3.7 g, 18.3 mmol) were added to a solution of methyl 3-iodo-2-methylbenzoate (4.2 g, 15.4 mmol) in dimethyl sulfoxide (30 ml), and the mixture was stirred overnight at 70 °C. The reaction was monitored by TLC until completion. The reaction mixture was poured into semi-saturated brine (200 ml), filtered, extracted with ethyl acetate (80 ml), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain ethyl 2,2-difluoro-2-[3-(methoxycarbonyl)-2-methylphenyl]acetate (3-2, 3.07 g, yield 74%), and the product was a pale yellow liquid. 1 HNMR (400 MHz, CDCl3): δ 7.76 - 7.88 (m, 2H), 7.35 (t, J = 8.0 Hz, 1H), 4.30 - 4.35 (m, 2H), 3.91 (s, 3H), 2.53 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H).

[0117] Synthesis of intermediate ethyl 2-[2-(bromomethyl)-3-(methoxycarbonyl)phenyl]-2,2-difluoroacetate (3-3)

[0118] At room temperature, N-bromosuccinimide (2.16 g, 12.12 mmol) and benzoyl peroxide (134 mg, 0.55 mmol) were added to a solution of ethyl 2,2-difluoro-2-[3-(methoxycarbonyl)-2-methylphenyl]acetate (3.0 g, 11.02 mmol) in carbon tetrachloride (25 ml), and the mixture was stirred at 82 °C for 2 h. The reaction was monitored by LCMS until completion. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by column chromatography (petroleum ether:ethyl acetate = 50:1) to obtain ethyl 2-[2-(bromomethyl)-3-(methoxycarbonyl)phenyl]-2,2-difluoroacetate (3-3, 3.1 g, yield 80%), and the product was a yellow liquid.

[0119] 1 HNMR (400 MHz, CDCl3): δ 7.97 (d, J = 7.8 Hz, 1H), 7.80 - 7.83 (m, 1H), 7.49 (t, J = 8.0 Hz, 1H), 5.13 (s, 2H), 4.32 - 4.36 (m, 2H), 3.97 (s, 3H), 1.32 (t, J = 7.8 Hz, 3H).

[0120] Synthesis of intermediate ethyl 2,2-difluoro-2-{2-[(1R)-1-formamido-4-[(2-methylpropan-2-yl)oxy]-4-oxobutyl]-1-oxo-2,3-dihydro-1H-isoindol-4-yl}acetate (3-4)

[0121] At room temperature, N,N-diisopropylethylamine (3.97 g, 30.76 mmol) and 2-methylpropyl 4-formamidobutanoate (2.69 g, 11.28 mmol) were added to a solution of ethyl 2-[2-(bromomethyl)-3-(methoxycarbonyl)phenyl]-2,2-difluoroacetate (3.6 g, 10.25 mmol) in acetonitrile (30 ml), and the mixture was stirred at 77 °C for 3 hours. LCMS showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure, dissolved in ethyl acetate (60 ml), washed three times with saturated ammonium chloride (20 ml), the organic phase was collected, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain ethyl 2,2-difluoro-2-{2-[(1R)-1-formamido-4-[(2-methylpropan-2-yl)oxy]-4-oxobutyl]-1-oxo-2,3-dihydro-1H-isoindol-4-yl}acetate (3-4, 1.12 g, yield 25%), and the product was a yellow oily product.

[0122] LC_MS:(ES + ):m / z 441.40[M+H] + .

[0123] 1 HNMR(400MHz,CDCl3):δ7.97(d,J=8.0Hz,1H),7.74(d,J=8.0Hz,1H),7.58(t,J=7.6Hz,1H),6.42(s,1H),5.42(s,1H),4.90-4.94(m,1H),4.64-4.81(m,2H),4.29-4.34(m,2H),2.14-2.43(m,4H),1.42(s,9H),1.32(t,J=7.2Hz,3H).

[0124] Synthesis of intermediate 2,2-difluoro-2-{2-[(1R)-1-formamido-4-[(2-methylpropan-2-yl)oxy]-4-oxobutyl]-1-oxo-2,3-dihydro-1H-isoindol-4-yl}acetic acid (3-5)

[0125] At room temperature, potassium carbonate (970 mg, 7.02 mmol) was added to a mixed solution of ethyl 2,2-difluoro-2-{2-[(1R)-1-formamido-4-[(2-methylpropan-2-yl)oxy]-4-oxobutyl]-1-oxo-2,3-dihydro-1H-isoindol-4-yl}acetate (1.03 g, 2.34 mmol) in methanol (10 ml) and water (10 ml), and the mixture was stirred at room temperature for 20 minutes. LCMS showed that the reaction was complete. The pH of the reaction solution was adjusted to 4 - 5, and the mixture was extracted 3 times with a mixed solvent of dichloromethane and isopropanol (3:1) (15 ml). The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 2,2-difluoro-2-{2-[(1R)-1-formamido-4-[(2-methylpropan-2-yl)oxy]-4-oxobutyl]-1-oxo-2,3-dihydro-1H-isoindol-4-yl}acetic acid (3 - 5, 680 mg, yield 71%). The product was a pale yellow solid.

[0126] LC_MS:(ES + ):m / z 413.15[M+H] + .

[0127] 1 HNMR(400MHz,CDCl3):δ7.90 - 7.92(m,1H),7.76 - 7.78(m,1H),7.64 - 7.70(m,2H),7.22(s,1H),4.58 - 4.79(m,3H),2.04 - 2.21(m,4H),1.41(s,9H).

[0128] Synthesis of intermediate (4R)-4-formamido-4-(4-{2-[(4-chlorophenyl)amino]-1,1-difluoro-2-oxoethyl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)butanoic acid 2-methylpropan-2-yl ester (3 - 6)

[0129] At room temperature, p-chloroaniline (93 mg, 0.727 mmol), triethylamine (147 mg, 1.46 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (277 mg, 0.727 mmol) were added to a solution of 2,2-difluoro-2-{2-[(1R)-1-formamido-4-[(2-methylpropan-2-yl)oxy]-4-oxobutyl]-1-oxo-2,3-dihydro-1H-isoindol-4-yl}acetic acid (200 mg, 0.485 mmol) in N,N-dimethylformamide (3 ml). The mixture was stirred at room temperature overnight. LCMS showed that the reaction was complete. Half-saturated brine (20 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 ml) three times. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain (4R)-4-formamido-4-(4-{2-[(4-chlorophenyl)amino]-1,1-difluoro-2-oxoethyl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)butanoic acid 2-methylpropan-2-yl ester (3-6, 168 mg, yield 60%), and the product was a white solid.

[0130] LC_MS:(ES + ):m / z 522.35[M+H] + .

[0131] 1 HNMR(400MHz,DMSO-d6):δ11.04(s,1H),7.87-7.93(m,2H),7.71-7.73(m,3H),7.64(s,1H),7.43(d,J=8.0,2H),7.23(s,1H),4.66-4.89(m,3H),1.99-2.19(m,4H),1.29(s,9H). 1 HNMR(400MHz,DMSO-d6):δ11.04(s,1H),7.87-7.93(m,2H),7.71-7.73(m,3H),7.64(s,1H),7.43(d,J=8.0Hz,2H),7.23(s,1H),4.66-4.89(m,3H),1.99-2.19(m,4H),1.29(s,9H).

[0132] Synthesis of N-(4-chlorophenyl)-2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-2,2-difluoroacetamide (3)

[0133] A solution of (4R)-4-carbamoyl-4-(4-{2-[(4-chlorophenyl)amino]-1,1-difluoro-2-oxoethyl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)butanoic acid 2-methylpropan-2-yl ester (125 mg, 0.24 mmol) and p-toluenesulfonic acid (82.5 mg, 0.48 mmol) in acetonitrile (4 ml) was stirred at 90 °C overnight. LCMS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and 2 ml of water was added to the obtained crude product, followed by stirring. The solid was collected by filtration. Then, 2 ml of diethyl ether was added, and the mixture was stirred for 20 minutes. After filtration, the obtained solid was dried to give N-(4-chlorophenyl)-2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-2,2-difluoroacetamide (Compound 3, 25 mg, yield 23%), and the product was a white solid.

[0134] LC_MS:(ES + ):m / z 448.10[M+H] + .

[0135] 1 HNMR(400MHz,d6-DMSO):δ11.02(s,2H),7.89-7.98(m,2H),7.70-7.76(m,3H),7.44(d,J=9.2Hz,2H),5.14-5.19(m,1H),4.59-4.72(m,2H),2.87-2.96(m,1H),2.59-2.68(m,1H),2.04-2.45(m,1H).

[0136] Example 4: Synthesis of Compound 4

[0137]

[0138] Synthesis of intermediate (4R)-4-carbamoyl-4-[4-(2-{[(4-chlorophenyl)methyl]amino}-1,1-difluoro-2-oxoethyl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]butanoic acid 2-methylpropan-2-yl ester (4-1)

[0139] At room temperature, to a solution of 2,2-difluoro-2-{2-[(1R)-1-carbamoyl-4-[(2-methylpropan-2-yl)oxy]-4-oxobutyl]-1-oxo-2,3-dihydro-1H-isoindol-4-yl}acetic acid (300 mg, 0.727 mmol) in N,N-dimethylformamide (4 ml) was added 4-chlorobenzylamine (154.5 mg, 1.09 mmol), triethylamine (221.3 mg, 2.18 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (415.5 mg, 1.09 mmol), and the mixture was stirred at room temperature overnight. LCMS showed that the reaction was complete. To the reaction mixture was added semi-saturated brine (30 ml), and the mixture was extracted with ethyl acetate (10 ml) three times and washed with saturated ammonium chloride (20 ml) three times. The obtained crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to give (4R)-4-carbamoyl-4-[4-(2-{[(4-chlorophenyl)methyl]amino}-1,1-difluoro-2-oxoethyl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]butanoic acid 2-methylpropan-2-yl ester (4-1, 140 mg, yield 36%), and the product was a light yellow solid.

[0140] LC_MS:(ES + ):m / z 537.05[M+H] + .

[0141] 1 HNMR(400MHz,DMSO-d6):δ9.72(t,J=10.0Hz,1H),7.90(d,J=7.2Hz,1H),7.63-7.77(m,3H),7.23-7.39(m,5H),4.59-4.83(m,3H),4.33(d,J=8.0Hz,2H),1.99-2.19(m,4H),1.32(s,9H).

[0142] Synthesis of N-[(4-chlorophenyl)methyl]-2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-2,2-difluoroacetamide (4)

[0143] A solution of (4R)-4-carbamoyl-4-[4-(2-{[(4-chlorophenyl)methyl]amino}-1,1-difluoro-2-oxoethyl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]butanoic acid 2-methylpropan-2-yl ester (100 mg, 0.186 mmol) and p-toluenesulfonic acid (65 mg, 0.377 mmol) in acetonitrile (4 ml) was stirred at 90 °C overnight. LCMS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure. The obtained crude product was added with 2 ml of water and stirred. The solid was collected by filtration, then 2 ml of ether was added, stirred for 20 minutes, and filtered. The obtained solid was dried to obtain N-[(4-chlorophenyl)methyl]-2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-2,2-difluoroacetamide (Compound 4, 13 mg, yield 15%). The product was a white solid.

[0144] LC_MS:(ES + ):m / z 462.75[M+H] + .

[0145] 1 HNMR(400MHz,d6-DMSO):δ11.03(s,1H),9.70(t,J=12.0Hz,1H),7.94(d,J=8.0Hz,1H),7.70-7.80(m,2H),7.24-7.40(m,4H),5.12-5.14(m,1H),4.51-4.63(m,2H),4.34(d,J=6.0Hz,2H),2.33-2.44(m,1H),2.00-2.04(m,1H).

[0146] Example 5: Synthesis of Compound 5

[0147]

[0148] Synthesis of intermediate ethyl 2,2-difluoro-2-[3-(methoxycarbonyl)-4-methylphenyl]acetate (5-2)

[0149] At room temperature, copper powder (1.31 g, 20.6 mmol) and ethyl difluorobromoacetate (1.68 g, 8.3 mmol) were added to a solution of methyl 5-iodo-2-methylbenzoate (1.9 g, 6.9 mmol) in dimethyl sulfoxide (15 ml), and the reaction was stirred overnight at 50 °C. The reaction was monitored by TLC until completion. The reaction mixture was poured into semi-saturated brine (120 ml), filtered, extracted with ethyl acetate (50 ml) three times, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (petroleum ether:ethyl acetate = 50:1) to obtain ethyl 2,2-difluoro-2-[3-(methoxycarbonyl)-4-methylphenyl]acetate (5-2, 1 g, yield 53%). The product was a yellow liquid.

[0150] 1 HNMR (400 MHz, CDCl3): δ 8.15 (s, 1H), 7.62 - 7.64 (m, 1H), 7.35 (d, J = 8.0 Hz, 1H), 4.30 (q, J = 7.2 Hz, 2H), 3.91 (s, 3H), 2.64 (s, 3H), 1.31 (t, J = 12.0, 3H).

[0151] Synthesis of intermediate ethyl 2-[4-(bromomethyl)-3-(methoxycarbonyl)phenyl]-2,2-difluoroacetate (5-3)

[0152] At room temperature, N-bromosuccinimide (1.14 g, 6.40 mmol) and benzoyl peroxide (75 mg, 0.31 mmol) were added to a solution of ethyl 2,2-difluoro-2-[3-(methoxycarbonyl)-4-methylphenyl]acetate (1.67 g, 6.14 mmol) in carbon tetrachloride (15 ml), and the reaction was stirred at 82 °C for 5 h. The reaction was monitored by LCMS until completion. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain crude ethyl 2-[4-(bromomethyl)-3-(methoxycarbonyl)phenyl]-2,2-difluoroacetate (5-3, 2.02 g).

[0153] Synthesis of intermediate (4S)-4-formamido-4-[6-(2-ethoxy-1,1-difluoro-2-oxoethyl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]butanoic acid 2-methylpropan-2-yl ester (5-4)

[0154] At room temperature, N,N-diisopropylethylamine (2.23 g, 17.29 mmol) and 2-methylpropyl 4-formamidobutanoate (1.51 g, 6.34 mmol) were added to a solution of ethyl 2-[4-(bromomethyl)-3-(methoxycarbonyl)phenyl]-2,2-difluoroacetate (2.02 g, 5.75 mmol) in acetonitrile (10 ml). The mixture was stirred at 77 °C for 5 hours. LCMS showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure, dissolved in ethyl acetate (20 ml), washed three times with saturated ammonium chloride (10 ml), the organic phase was collected, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain (4S)-4-formamido-4-[6-(2-ethoxy-1,1-difluoro-2-oxoethyl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]butanoic acid 2-methylpropyl ester (5-4, 960 mg, two-step yield 35%). The product was a yellow solid.

[0155] LC_MS:(ES + ):m / z441.30[M+H] + .

[0156] 1 1H NMR (400 MHz, CDCl3): δ 8.10 (s, 1H), 7.81 - 7.83 (m, 1H), 7.58 (d, J = 7.6 Hz, 1H), 6.37 (s, 1H), 5.36 (s, 1H), 4.91 - 4.95 (m, 1H), 4.57 - 4.66 (m, 2H), 4.27 - 4.33 (m, 2H), 2.12 - 2.39 (m, 4H), 1.41 (s, 9H), 1.31 (t, J = 6.8 Hz, 3H).

[0157] Synthesis of intermediate 2,2-difluoro-2-{2-[(1S)-1-formamido-4-[(2-methylpropan-2-yl)oxy]-4-oxobutyl]-3-oxo-2,3-dihydro-1H-isoindol-5-yl}acetic acid (5-5)

[0158] To a mixed solution of (4S)-4-formamido-4-[6-(2-ethoxy-1,1-difluoro-2-oxoethyl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]butanoic acid 2-methylpropan-2-yl ester (940 mg, 2.13 mmol) in methanol (7 ml) and water (7 ml) was added potassium carbonate (880 mg, 6.4 mmol), and the mixture was stirred at room temperature for 30 minutes. LCMS showed that the reaction was complete. The pH of the reaction solution was adjusted to 4 - 5, and the mixture was extracted with a mixed solvent of dichloromethane and isopropanol (3:1) (10 ml). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 2,2-difluoro-2-{2-[(1S)-1-formamido-4-[(2-methylpropan-2-yl)oxy]-4-oxobutyl]-3-oxo-2,3-dihydro-1H-isoindol-5-yl}acetic acid (5-5, 640 mg, yield 72%). The product was a white solid.

[0159] LC_MS:(ES + ):m / z 413.00[M+H] + .

[0160] 1 HNMR(400MHz,CDCl3):δ7.77-7.83(m,3H),7.58(s,1H),7.21(s,1H),4.73-4.77(m,1H),4.52-4.68(m,2H),1.98-2.18(m,4H),1.31(s,9H).

[0161] Synthesis of intermediate (4S)-4-formamido-4-(6-{2-[(4-chlorophenyl)amino]-1,1-difluoro-2-oxoethyl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)butanoic acid 2-methylpropan-2-yl ester (5-6)

[0162] At room temperature, p-chloroaniline (75 mg, 0.58 mmol), triethylamine (177 mg, 1.75 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (332 mg, 0.873 mmol) were added to a solution of 2,2-difluoro-2-{2-[(1S)-1-formamido-4-[(2-methylpropan-2-yl)oxy]-4-oxobutyl]-3-oxo-2,3-dihydro-1H-isoindol-5-yl}acetic acid (240 mg, 0.58 mmol) in N,N-dimethylformamide (3 ml), and the mixture was stirred at room temperature overnight. LCMS showed that the reaction was complete. Half-saturated brine (20 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 ml) three times. The obtained crude product was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to give (4S)-4-formamido-4-(6-{2-[(4-chlorophenyl)amino]-1,1-difluoro-2-oxoethyl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)butanoic acid 2-methylpropan-2-yl ester (5-6, 240 mg, yield 78%), and the product was a white solid.

[0163] LC_MS:(ES + ):m / z522.05[M+H] + .

[0164] 1 HNMR(400MHz,DMSO-d6):δ10.95(s,1H),7.99(s,1H),7.80-7.92(m,2H),7.70-7.72(m,2H),7.58(s,1H),7.42-7.44(m,2H),7.21(s,1H),4.74-4.77(m,1H),4.52-4.69(m,2H),1.99-2.21(m,4H),1.29(s,9H). Synthesis of N-(4-chlorophenyl)-2-[2-(2,6-dioxohexahydropyridin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoroacetamide (5)

[0165] A solution of (4S)-4-carbamoyl-4-(6-{2-[(4-chlorophenyl)amino]-1,1-difluoro-2-oxoethyl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)butanoic acid 2-methylpropan-2-yl ester (100 mg, 0.19 mmol) and p-toluenesulfonic acid (66 mg, 0.38 mmol) in acetonitrile (3 ml) was stirred at 90 °C overnight. LCMS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and 2 ml of acetonitrile was added to the obtained crude product. After stirring for 30 minutes, filtration was carried out, and the obtained solid was dried to obtain N-(4-chlorophenyl)-2-[2-(2,6-dioxohexahydropyridin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoroacetamide (Compound 5, 66 mg, yield 61%). The product was a white solid.

[0166] LC_MS:(ES + ):m / z 448.90[M+H] + .

[0167] 1 HNMR(400MHz,d6-DMSO):δ10.98(d,J=13.4Hz,2H),8.02(s,1H),7.82-7.95(m,2H),7.71(d,J=8.8Hz,2H),7.43(d,J=8.8Hz,2H),5.12-5.17(m,1H),4.41-4.59(m,2H),2.87-2.96(m,1H),2.59-2.64(m,1H),2.38-2.44(m,1H),2.01-2.04(m,1H).

[0168] Example 6: Synthesis of Compound 6

[0169]

[0170] Synthesis of Intermediate (4S)-4-carbamoyl-4-[6-(2-{[(4-chlorophenyl)methyl]amino}-1,1-difluoro-2-oxoethyl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]butanoic acid 2-methylpropan-2-yl ester (6-1)

[0171] At room temperature, to a solution of 2,2-difluoro-2-{2-[(1S)-1-carbamoyl-4-[(2-methylpropan-2-yl)oxy]-4-oxobutyl]-3-oxo-2,3-dihydro-1H-isoindol-5-yl}acetic acid (300 mg, 0.727 mmol) in N,N-dimethylformamide (4 ml) was added 4-chlorobenzylamine (157.5 mg, 1.09 mmol), triethylamine (445 mg, 4.36 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (554.6 mg, 1.45 mmol), and the mixture was stirred overnight at room temperature. LCMS showed that the reaction was complete. To the reaction mixture was added semi-saturated brine (30 ml), and the mixture was extracted with ethyl acetate (10 ml) three times. The obtained crude product was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to give (4S)-4-carbamoyl-4-[6-(2-{[(4-chlorophenyl)methyl]amino}-1,1-difluoro-2-oxoethyl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]butanoic acid 2-methylpropan-2-yl ester (6-1, 110 mg, yield 28%), and the product was a white solid.

[0172] LC_MS:(ES + ):m / z 536.05[M+H] + .

[0173] 1 HNMR(400MHz,DMSO-d6):δ9.64(t,J=10.0Hz,1H),7.90(d,J=7.2Hz,1H),7.77-7.83(m,2H),7.59(s,1H),7.37(d,J=8.8Hz,2H),7.21-7.26(m,3H),4.74-4.77(m,1H),4.52-4.69(m,2H),4.33(d,J=8.0Hz,2H),1.99-2.19(m,4H),1.31(s,9H).

[0174] Synthesis of N-[(4-chlorophenyl)methyl]-2-[2-(2,6-dioxohexahydropyridin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoroacetamide (6)

[0175] A solution of (4S)-4-carbamoyl-4-[6-(2-{[(4-chlorophenyl)methyl]amino}-1,1-difluoro-2-oxoethyl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]butanoic acid 2-methylpropan-2-yl ester (100 mg, 0.186 mmol) and p-toluenesulfonic acid (65 mg, 0.37 mmol) in acetonitrile (3 ml) was stirred at 90 °C overnight. LCMS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and 2 ml of acetonitrile was added to the obtained crude product, which was stirred for 30 minutes and then filtered. The obtained solid was dried to obtain N-[(4-chlorophenyl)methyl]-2-[2-(2,6-dioxohexahydropyridin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoroacetamide (Compound 6, 28 mg, yield 32%), and the product was a white solid.

[0176] LC_MS:(ES + ):m / z 461.95[M+H] + .

[0177] 1 HNMR(400MHz,d6-DMSO):δ11.02(s,1H),9.65(t,J=12.0Hz,1H),7.92(s,1H),7.79-7.85(m,2H),7.24-7.39(m,4H),5.13-5.17(m,1H),4.40-4.58(m,2H),4.34(d,J=6.0Hz,2H),2.88-2.93(m,1H),2.59-2.64(m,1H),2.38-2.430(m,1H),2.00-2.03(m,1H).

[0178] Example 7: Synthesis of Compound 7

[0179]

[0180] Synthesis of intermediate methyl 2-iodo-6-methylbenzoate (7-2)

[0181] Methyl iodide (3.98 g, 28.0 mmol) and potassium carbonate (4.37 g, 31.6 mmol) were added to a solution of 2-iodo-6-methylbenzoic acid (4.88 g, 18.6 mmol) in N,N-dimethylformamide (30 ml) at room temperature, and the mixture was stirred at room temperature for 2.5 h. TLC monitored that the reaction was complete. The reaction solution was poured into semi-saturated brine (240 ml), extracted with ethyl acetate (80 ml), the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain methyl 2-iodo-6-methylbenzoate (7-2, 3.65 g, yield 71%), and the product was a yellow liquid.

[0182] 1 HNMR (400 MHz, CDCl3): δ 7.65 (d, J = 8.0, 1H), 7.17 (d, J = 8.0, 1H), 6.99 (t, J = 16.0, 1H), 3.95 (s, 3H), 2.33 (s, 3H).

[0183] Synthesis of intermediate methyl 2-(2-ethoxy-1,1-difluoro-2-oxoethyl)-6-methylbenzoate (7-3)

[0184] At room temperature, copper powder (2.5 g, 39.3 mmol) and ethyl difluorobromoacetate (3.2 g, 15.8 mmol) were added to a solution of methyl 2-iodo-6-methylbenzoate (3.6 g, 13.1 mmol) in dimethyl sulfoxide (30 ml). Nitrogen was displaced, and the reaction was stirred overnight at 56 °C. The reaction was monitored by TLC until completion. The reaction mixture was poured into semi-saturated brine (240 ml), filtered, extracted with ethyl acetate (90 ml), the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain methyl 2-(2-ethoxy-1,1-difluoro-2-oxoethyl)-6-methylbenzoate (7-3, 2.65 g, yield 74%), and the product was a white solid.

[0185] 1 HNMR (400 MHz, CDCl3): δ 7.53 (d, J = 7.6 Hz, 2H), 7.42 (t, J = 7.6 Hz, 1H), 7.36 (d, J = 7.6 Hz, 1H), 7.28 - 4.33 (m, 2H), 3.86 (s, 3H), 2.39 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H).

[0186] Synthesis of intermediate methyl 6-(bromomethyl)-2-(2-ethoxy-1,1-difluoro-2-oxoethyl)benzoate (7-4)

[0187] At room temperature, N-bromosuccinimide (1.51 g, 8.48 mmol) and benzoyl peroxide (100 mg, 0.40 mmol) were added to a solution of methyl 2-(2-ethoxy-1,1-difluoro-2-oxoethyl)-6-methylbenzoate (2.2 g, 8.08 mmol) in carbon tetrachloride (18 ml). Nitrogen was displaced, and the reaction was stirred at 82 °C for 4 h. The reaction was monitored by LCMS until completion. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain crude methyl 6-(bromomethyl)-2-(2-ethoxy-1,1-difluoro-2-oxoethyl)benzoate (7-4, 3.25 g).

[0188] Synthetic intermediate (4R)-4-carbamoyl-4-[7-(2-ethoxy-1,1-difluoro-2-oxoethyl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]butanoic acid 2-methylpropan-2-yl ester (7-5)

[0189] At room temperature, N,N-diisopropylethylamine (3.59 g, 27.77 mmol) and 4-carbamoylbutanoic acid 2-methylpropan-2-yl ester (2.43 g, 10.18 mmol) were added to a solution of methyl 6-(bromomethyl)-2-(2-ethoxy-1,1-difluoro-2-oxoethyl)benzoate (3.25 g, 9.26 mmol) in acetonitrile (30 ml), and the mixture was stirred at 77 °C for 4.5 h. LCMS showed that the reaction was complete. The mixture was concentrated under reduced pressure, dissolved in ethyl acetate (60 ml), washed three times with saturated ammonium chloride (50 ml), and the organic phase was concentrated under reduced pressure. The resulting crude product was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain (4R)-4-carbamoyl-4-[7-(2-ethoxy-1,1-difluoro-2-oxoethyl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]butanoic acid 2-methylpropan-2-yl ester (7-5, 1.0 g, overall yield in two steps 26%), and the product was a yellow oily product.

[0190] LC_MS:(ES + ):m / z 441.40[M+H] + .

[0191] 1 HNMR(400MHz,CDCl3):δ7.82(d,J=12.8Hz,1H),7.60-7.69(m,2H),6.31(s,1H),5.41(s,1H),4.82-4.86(m,1H),4.47-4.65(m,2H),4.31(q,J=7.2Hz,2H),2.21-2.39(m,4H),1.42(s,9H),1.31(t,J=11.2Hz,3H). Synthesis of synthetic intermediate 2,2-difluoro-2-{2-[(1R)-1-carbamoyl-4-[(2-methylpropan-2-yl)oxy]-4-oxobutyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}acetic acid

[0192] At room temperature, potassium carbonate (860 mg, 6.22 mmol) was added to a mixed solution of methanol (5 ml) and water (5 ml) of (4R)-4-formamido-4-[7-(2-ethoxy-1,1-difluoro-2-oxoethyl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]butanoic acid 2-methylpropan-2-yl ester (950 mg, 2.16 mmol), and the mixture was stirred at room temperature for 1 h. LCMS showed that the reaction was complete. The pH of the reaction solution was adjusted to 4 - 5, and the mixture was extracted with a mixed solvent of dichloromethane and isopropanol (3:1) (10 ml). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 2,2-difluoro-2-{2-[(1R)-1-formamido-4-[(2-methylpropan-2-yl)oxy]-4-oxobutyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}acetic acid (7-6, 599 mg, yield 67%), and the product was a pale yellow solid.

[0193] LC_MS:(ES + ):m / z 413.20[M+H] + .

[0194] 1 HNMR(400MHz,CDCl3):δ7.71-7.80(m,3H),7.37(s,1H),7.25(s,1H),4.92-4.95(m,1H),4.43-4.57(m,2H),2.09-2.34(m,4H),1.42(s,9H).

[0195] Synthesis of intermediate (4R)-4-formamido-4-(7-{2-[(4-chlorophenyl)amino]-1,1-difluoro-2-oxoethyl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)butanoic acid 2-methylpropan-2-yl ester (7-7)

[0196] At room temperature, p-chloroaniline (85 mg, 0.666 mmol), triethylamine (133 mg, 1.31 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (253 mg, 0.666 mmol) were added to a solution of (4R)-4-formamido-4-(7-{2-[(4-chlorophenyl)amino]-1,1-difluoro-2-oxoethyl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)butanoic acid 2-methylpropan-2-yl ester (180 mg, 0.436 mmol) in N,N-dimethylformamide (2.5 ml). The mixture was stirred at room temperature overnight. LCMS showed that the reaction was complete. Half-saturated brine (20 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 ml). The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain ((4R)-4-formamido-4-(7-{2-[(4-chlorophenyl)amino]-1,1-difluoro-2-oxoethyl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)butanoic acid 2-methylpropan-2-yl ester, 126 mg, yield 54%), and the product was a white solid.

[0197] LC_MS:(ES + ):m / z 522.30[M+H] + .

[0198] 1 HNMR(400MHz,DMSO-d6):δ11.01(d,J=8.0Hz,2H),7.70-7.84(m,5H),7.61(s,2H),7.39-7.44(m,2H),7.21(s,1H),4.55-4.76(m,3H),1.98-2.19(m,4H),1.28(s,9H).

[0199] Synthesis of N-(4-chlorophenyl)-2-[2-(2,6-dioxohexahydropyridin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-4-yl]-2,2-difluoroacetamide (7)

[0200] A solution of (4R)-4-carbamoyl-4-(4-{2-[(4-chlorophenyl)amino]-1,1-difluoro-2-oxoethyl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)butanoic acid 2-methylpropan-2-yl ester (125 mg, 0.24 mmol) and p-toluenesulfonic acid (85 mg, 0.483 mmol) in acetonitrile (4 ml) was stirred at 90 °C overnight. LCMS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure. 2 ml of water was added to the obtained crude product and stirred. The solid was collected by filtration. Then 2 ml of ether was added and stirred for 30 minutes. After filtration, the obtained solid was dried to give N-(4-chlorophenyl)-2-[2-(2,6-dioxohexahydropyridin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-4-yl]-2,2-difluoroacetamide (Compound 7, 36 mg, yield 33%), and the product was a white solid.

[0201] LC_MS:(ES + ):m / z 448.85[M+H] + .

[0202] 1 HNMR(400MHz,d6-DMSO):δ11.96(d,J=8.0Hz,2H),7.80-7.86(m,3H),7.73(d,J=8.8Hz,2H),7.44(d,J=8.8Hz,2H),5.12-5.17(m,1H),4.42-4.59(m,2H),2.87-2.93(m,1H),2.59-2.64(m,1H),2.38-2.43(m,1H),1.97-2.04(m,1H).

[0203] Example 8: Synthesis of Compound 8

[0204]

[0205] Synthesis of intermediate 4-carbamoyl-4-[7-(2-{[(4-chlorophenyl)methyl]amino}-1,1-difluoro-2-oxoethyl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]butanoic acid 2-methylpropan-2-yl ester (8-1)

[0206] At room temperature, p-chlorobenzylamine (103 mg, 0.728 mmol), triethylamine (147 mg, 1.46 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (277 mg, 0.728 mmol) were added to a solution of (4R)-4-formamido-4-(7-{2-[(4-chlorophenyl)amino]-1,1-difluoro-2-oxoethyl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)butanoic acid 2-methylpropan-2-yl ester (200 mg, 0.48 mmol) in N,N-dimethylformamide (3 ml). The mixture was stirred at room temperature overnight. LCMS showed that the reaction was complete. Half-saturated brine (20 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 ml). The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain 4-formamido-4-[7-(2-{[(4-chlorophenyl)methyl]amino}-1,1-difluoro-2-oxoethyl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]butanoic acid 2-methylpropan-2-yl ester (8-1, 106 mg, yield 40%), and the product was a white solid.

[0207] LC_MS:(ES + ):m / z 536.75[M+H] + .

[0208] 1 HNMR(400MHz,DMSO-d6):δ9.34-9.37(m,1H),7.72-7.82(m,3H),7.62(s,1H),7.34-7.39(m,4H),7.25(s,1H),4.53-4.76(m,3H),4.33-4.36(m,2H),1.99-2.22(m,4H),1.33(s,9H).

[0209] Synthesis of N-[(4-chlorophenyl)methyl]-2-[2-(2,6-dioxohexahydropyridin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-4-yl]-2,2-difluoroacetamide (8)

[0210] A solution of 4-formamido-4-[7-(2-{[(4-chlorophenyl)methyl]amino}-1,1-difluoro-2-oxoethyl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]butanoic acid 2-methylpropan-2-yl ester (106 mg, 0.197 mmol) and p-toluenesulfonic acid (68 mg, 0.395 mmol) in acetonitrile (3.5 ml) was stirred at 90 °C overnight. LCMS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure. 3 ml of water was added to the obtained crude product and stirred. The solid was collected by filtration, 2 ml of ether was added, and stirred for 30 minutes. After filtration, the obtained solid was dried to obtain N-[(4-chlorophenyl)methyl]-2-[2-(2,6-dioxohexahydropyridin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-4-yl]-2,2-difluoroacetamide (Compound 8, 51 mg, yield 56%), and the product was a white solid.

[0211] LC_MS:(ES + ):m / z 462.0[M+H] + .

[0212] 1 HNMR(400MHz,d6-DMSO):δ11.04(s,1H),9.36(t,J=6.0Hz,1H),7.76-7.82(m,3H),7.33-7.38(m,4H),5.05-5.10(m,1H),4.04-4.56(m,2H),4.34(t,J=5.2Hz,2H),2.87-2.95(m,1H),2.60-2.68(m,1H),2.33-2.50(m,1H),1.98-2.01(m,1H).

[0213] Example 9: Synthesis of Compound 9

[0214]

[0215] Synthesis of intermediate 2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoroacetic acid (1-5-1)

[0216] A solution of 2-(2-{1-carbamoyl-4-[(2-methylpropan-2-yl)oxy]-4-oxobutyl}-1-oxo-2,3-dihydro-1H-isoindol-5-yl)-2,2-difluoroacetic acid (1.6 g, 3.89 mmol) and p-toluenesulfonic acid (1.34 g, 7.78 mmol) in acetonitrile (50 ml) was stirred at 90 °C overnight. LCMS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure. 10 ml of ethyl acetate was added to the obtained crude product, and it was stirred for 20 minutes. The solid was collected by filtration, and the obtained solid was dried to obtain 2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoroacetic acid (1-5-1, 800 mg).

[0217] LC_MS:(ES+):m / z 338.75[M+H]+.

[0218] Synthesis of N-(4-chlorophenyl)-2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoroacetamide (9)

[0219] At room temperature, benzylamine (23.79 mg, 0.222 mmol), triethylamine (44.82 mg, 0.443 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (84.52 mg, 0.222 mmol) were added to a solution of 2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoroacetic acid (50 mg, 0.148 mmol) in N,N-dimethylformamide (1.5 ml), and it was stirred at room temperature overnight. LCMS showed that the reaction was complete. Water (5 ml) was added to the reaction solution, and it was extracted with ethyl acetate. The organic phase was collected and washed with water three times. The obtained crude product was purified by column chromatography (dichloromethane:methanol = 20:1) to obtain N-(4-chlorophenyl)-2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoroacetamide (Compound 9, 2.4 mg, yield 3.8%), and the product was a white solid.

[0220] LC_MS:(ES+):m / z 427.90[M+H]+.

[0221] 1H NMR (400 MHz, d6-DMSO): δ 7.78 - 7.94 (m, 3H), 7.24 - 7.33 (m, 5H), 5.18 - 5.22 (m, 1H), 4.52 - 4.63 (m, 2H), 4.45 - 4.46 (m, 2H), 2.78 - 2.97 (m, 2H), 2.51 - 2.55 (m, 1H), 2.19 - 2.24 (m, 1H).

[0222] The following compounds were prepared by the similar method described above. Unless otherwise specified, the amines used were commercially available products.

[0223] Example 10: Synthesis of compound 2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoro-N-(1-phenylethyl)acetamide (10)

[0224]

[0225] Chemical formula: C 23 H 21 F2N3O4; Chemical molecular weight: 441.43.

[0226] LC_MS: (ES+): m / z 441.90 [M + H]+.

[0227] 1H NMR (400 MHz, d6-DMSO): δ 7.77 - 7.93 (m, 3H), 7.23 - 7.33 (m, 5H), 5.17 - 5.22 (m, 1H), 5.05 - 5.10 (m, 1H), 4.50 - 4.63 (m, 2H), 2.78 - 2.98 (m, 2H), 2.47 - 2.58 (m, 1H), 2.17 - 2.24 (m, 1H), 1.52 - 1.54 (m, 3H).

[0228] Example 11: Synthesis of compound N-benzyl-2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-N-ethyl-2,2-difluoroacetamide (11)

[0229]

[0230] Chemical formula: C 24 H 23 F2N3O4; Chemical molecular weight: 455.46.

[0231] LC_MS: (ES+): m / z 456.00 [M + H]+.

[0232] 1H NMR (400 MHz, d6-DMSO): δ 7.74 - 7.97 (m, 3H), 7.03 - 7.36 (m, 5H), 5.17 - 5.22 (m, 1H), 4.51 - 4.70 (m, 4H), 3.36 - 3.42 (m, 2H), 2.78 - 2.97 (m, 2H), 2.51 - 2.55 (m, 1H), 2.19 - 2.23 (m, 1H), 1.07 - 1.13 (m, 3H).

[0233] Example 12: Synthesis of compound 2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoro-N-{[4-(pyridin-4-yl)phenyl]methyl}acetamide (12)

[0234]

[0235] Chemical formula: C 27 H 22 F2N4O4; Chemical molecular weight: 504.49.

[0236] LC_MS: (ES+): m / z 505.35 [M + H]+.

[0237] 1H NMR (400 MHz, d6-DMSO): δ 8.82 (d, J = 6.8 Hz, 2H), 8.31 (d, J = 6.8 Hz, 2H), 7.91 - 7.95 (m, 4H), 7.81 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 8.4 Hz, 2H), 5.18 - 5.23 (m, 1H), 4.53 - 4.64 (m, 4H), 2.78 - 2.99 (m, 2H), 2.47 - 2.58 (m, 1H), 2.18 - 2.24 (m, 1H).

[0238] Example 13: Synthesis of compound 2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoro-N-[(2-nitrophenyl)methyl]acetamide (13)

[0239]

[0240] Chemical formula: C 22 H 18 F2N4O6; Chemical molecular weight: 472.40.

[0241] LC_MS: (ES+): m / z 472.90 [M + H]+.

[0242] 1H NMR (400 MHz, d6-DMSO): δ 11.03 (s, 1H), 9.71 (t, J = 5.6 Hz, 1H), 8.04 - 8.06 (m, 1H), 7.88 - 7.92 (m, 2H), 7.70 - 7.76 (m, 2H), 7.70 - 7.76 (m, 2H), 7.54 - 7.58 (m, 1H), 7.42 (d, J = 7.6 Hz, 1H), 5.13 - 5.18 (m, 1H), 4.66 (d, J = 6.0 Hz, 2H), 4.41 - 4.58 (m, 2H), 2.88 - 2.97 (m, 1H), 2.59 - 2.64 (m, 1H), 2.40 - 2.44 (m, 1H), 2.04 - 2.08 (m, 1H).

[0243] Example 14: Synthesis of compound N-(benzo[d][1,3]dioxol-5-ylmethyl)-2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoroacetamide (14)

[0244]

[0245] Chemical formula: C 23 H 19 F2N3O6; Chemical molecular weight: 471.42.

[0246] LC_MS: (ES+): m / z 471.90 [M + H]+.

[0247] 1H NMR (400 MHz, d6-DMSO): δ 7.77 - 7.94 (m, 3H), 6.73 (d, J = 8.8 Hz, 3H), 5.93 (s, 2H), 5.18 - 5.22 (m, 1H), 4.52 - 4.63 (m, 2H), 4.35 (d, J = 6.0 Hz, 2H), 2.78 - 2.98 (m, 2H), 2.48 - 2.57 (m, 1H), 2.18 - 2.24 (m, 1H).

[0248] Example 15: Synthesis of compound 2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoro-N-[(4-fluorophenyl)methyl]acetamide (15)

[0249]

[0250] Chemical formula: C 22 H 18 F3N3O4; Chemical molecular weight: 445.40.

[0251] LC_MS:(ES+):m / z 445.95[M+H]+.

[0252] 1HNMR(400MHz, d6-DMSO): δ7.78 - 7.94(m, 3H), 7.26 - 7.296(m, 2H), 7.02 - 7.07(m, 2H), 5.17 - 5.22(m, 1H), 4.52 - 4.63(m, 2H), 4.43(s, 2H), 2.780 - 2.98(m, 2H), 2.49 - 2.57(m, 1H), 2.19 - 2.25(m, 1H).

[0253] Example 16: Synthesis of compound 2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoro-N-[(3-fluorophenyl)methyl]acetamide (16)

[0254]

[0255] Chemical formula: C 22 H 18 F3N3O4; Chemical molecular weight: 445.40.

[0256] LC_MS:(ES+):m / z 446.05[M+H]+.

[0257] 1HNMR(400MHz, d6-DMSO): δ7.79 - 7.95(m, 3H), 7.30 - 7.35(m, 1H), 6.96 - 7.07(m, 3H), 5.18 - 5.22(m, 1H), 4.53 - 4.63(m, 2H), 4.46(s, 2H), 2.78 - 2.98(m, 2H), 2.47 - 2.58(m, 1H), 2.18 - 2.24(m, 1H).

[0258] Example 17: Synthesis of compound 2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoro-N-[(3-nitrophenyl)methyl]acetamide (17)

[0259]

[0260] Chemical formula: C 22 H 18 F2N4O6; Chemical molecular weight: 472.40.

[0261] LC_MS:(ES+):m / z 472.90[M+H]+.

[0262] 1H NMR (400 MHz, d6-DMSO): δ 8.13 - 8.15 (m, 1H), 8.07 (s, 1H), 7.90 - 7.95 (m, 2H), 7.82 (d, J = 8.0 Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.57 (t, J = 8.0 Hz, 1H), 5.18 - 5.23 (m, 1H), 4.53 - 4.64 (m, 4H), 2.78 - 2.97 (m, 2H), 2.48 - 2.59 (m, 1H), 2.19 - 2.25 (m, 1H).

[0263] Example 18: Synthesis of compound 2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoro-N-{[4-(trifluoromethyl)phenyl]methyl}acetamide (18)

[0264]

[0265] Chemical formula: C 23 H 18 F5N3O4; Chemical molecular weight: 495.41.

[0266] LC_MS: (ES+): m / z 495.95 [M + H]+.

[0267] 1H NMR (400 MHz, d6-DMSO): δ 7.80 - 7.96 (m, 3H), 7.63 (d, J = 8.0 Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H), 5.18 - 5.23 (m, 1H), 4.53 - 4.59 (m, 4H), 2.89 - 2.99 (m, 1H), 2.78 - 2.84 (m, 1H), 2.47 - 2.58 (m, 1H), 2.19 - 2.24 (m, 1H).

[0268] Example 19: Synthesis of compound N-[(3-bromophenyl)methyl]-2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoroacetamide (19)

[0269]

[0270] Chemical formula: C 22 H 18 BrF2N3O4; Chemical molecular weight: 506.30.

[0271] LC_MS:(ES+):m / z 507.70[M+H]+.

[0272] 1HNMR(400MHz, d6-DMSO): δ7.80 - 7.96(m, 3H), 7.217 - 7.420(m, 4H), 5.179 - 5.226(m, 1H), 4.540 - 4.642(m, 2H), 4.439(d, J=6.0, 2H), 2.778 - 2.950(m, 2H), 2.508 - 2.553(m, 1H), 2.189 - 2.230(m, 1H).

[0273] Example 20: Synthesis of compound 2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoro-N-[(3-methylphenyl)methyl]acetamide (20)

[0274]

[0275] Chemical formula: C 23 H 21 F2N3O4; Chemical molecular weight: 441.43.

[0276] LC_MS:(ES+):m / z 441.90[M+H]+.

[0277] 1HNMR(400MHz, d6-DMSO): δ7.79 - 7.95(m, 3H), 7.02 - 7.20(m, 4H), 5.18 - 5.22(m, 1H), 4.52 - 4.63(m, 2H), 4.41(s, 2H), 2.78 - 2.98(m, 2H), 2.51 - 2.55(m, 1H), 2.28(s, 3H), 2.19 - 2.24(m, 1H).

[0278] Example 21: Synthesis of compound N-[(3-chlorophenyl)methyl]-2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoroacetamide (21)

[0279]

[0280] Chemical formula: C 22 H 18 ClF2N3O4; Chemical molecular weight: 461.85.

[0281] LC_MS:(ES+):m / z 461.85[M+H]+.

[0282] 1H NMR (400 MHz, d6-DMSO): δ 7.798 - 7.96 (m, 3H), 7.17 - 7.32 (m, 4H), 5.18 - 5.23 (m, 1H), 4.53 - 4.64 (m, 2H), 4.45 (d, J = 4.4 Hz, 2H), 2.78 - 2.99 (m, 2H), 2.47 - 2.59 (m, 1H), 2.18 - 2.24 (m, 1H).

[0283] Example 22: Synthesis of compound N-[(4-bromophenyl)methyl]-2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoroacetamide (22)

[0284]

[0285] Chemical formula: C 22 H 18 BrF2N3O4; Chemical molecular weight: 506.30.

[0286] LC_MS: (ES+): m / z 507.70 [M + H]+.

[0287] 1H NMR (400 MHz, d6-DMSO): δ 7.78 - 7.95 (m, 3H), 7.45 - 7.49 (m, 2H), 7.18 (d, J = 8.4 Hz, 2H), 5.18 - 5.23 (m, 1H), 4.52 - 4.63 (m, 2H), 4.41 (s, 2H), 2.78 - 2.99 (m, 2H), 2.47 - 2.59 (m, 1H), 2.18 - 2.25 (m, 1H).

[0288] Example 23: Synthesis of compound N-[(3,4-difluorophenyl)methyl]-2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoroacetamide (23)

[0289]

[0290] Chemical formula: C 22 H 17 F4N3O4; Chemical molecular weight: 463.39.

[0291] LC_MS: (ES+): m / z 463.90 [M + H]+.

[0292] 1H NMR (400 MHz, d6-DMSO): δ 7.77 - 7.95 (m, 3H), 7.05 - 7.25 (m, 3H), 5.18 - 5.23 (m, 1H), 4.53 - 4.64 (m, 2H), 4.42 (s, 2H), 2.78 - 2.99 (m, 2H), 2.47 - 2.59 (m, 1H), 2.18 - 2.24 (m, 1H).

[0293] Example 24: Synthesis of compound N-[(4-chloro-3-fluorophenyl)methyl]-2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoroacetamide (24)

[0294]

[0295] Chemical formula: C 22 H 17 ClF3N3O4; Chemical molecular weight: 479.84.

[0296] LC_MS: (ES+): m / z 479.90 [M + H]+.

[0297] 1H NMR (400 MHz, d6-DMSO): δ 7.76 - 7.93 (m, 3H), 7.40 (t, J = 8.0 Hz, 1H), 7.03 - 7.11 (m, 2H), 5.16 - 5.20 (m, 1H), 4.50 - 4.61 (m, 2H), 4.42 (d, J = 6.0 Hz, 2H), 2.75 - 2.96 (m, 2H), 2.45 - 2.56 (m, 1H), 2.16 - 2.22 (m, 1H).

[0298] Example 25: Synthesis of compound N-[(3-cyanophenyl)methyl]-2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoroacetamide (25)

[0299]

[0300] Chemical formula: C 23 H 18 F2N4O4; Chemical molecular weight: 452.42.

[0301] LC_MS: (ES+): m / z 452.90 [M + H]+.

[0302] 1H NMR (400 MHz, d6-DMSO): δ 7.77 - 7.93 (m, 3H), 7.46 - 7.62 (m, 4H), 5.16 - 5.20 (m, 1H), 4.51 - 4.62 (m, 2H), 4.47 (s, 2H), 2.75 - 2.96 (m, 2H), 2.44 - 2.56 (m, 1H), 2.16 - 2.23 (m, 1H).

[0303] Example 26: Synthesis of compound N-[(4-bromophenyl)methyl]-2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoroacetamide (26)

[0304]

[0305] Chemical formula: C 23 H 21 F2N3O5; Chemical molecular weight: 457.43.

[0306] LC_MS: (ES+): m / z 458.00 [M + H]+.

[0307] 1H NMR (400 MHz, d6-DMSO): δ 7.79 - 7.95 (m, 3H), 7.24 - 7.29 (m, 1H), 7.12 - 7.14 (m, 1H), 6.86 - 6.97 (m, 2H), 5.18 - 5.23 (m, 1H), 4.45 - 4.65 (m, 4H), 3.79 (s, 3H), 2.79 - 2.99 (m, 2H), 2.49 - 2.58 (m, 1H), 2.19 - 2.24 (m, 1H).

[0308] Example 27: Synthesis of compound 2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoro-N-[(3-methoxyphenyl)methyl]acetamide (27)

[0309]

[0310] Chemical formula: C 23 H 21 F2N3O5; Chemical molecular weight: 457.43.

[0311] LC_MS: (ES+): m / z 457.95 [M + H]+.

[0312] 1H NMR (400 MHz, d6-DMSO): δ 7.80 - 7.95 (m, 3H), 7.21 (t, J = 8.0 Hz, 1H), 6.74 - 6.82 (m, 3H), 5.18 - 5.23 (m, 1H), 4.52 - 4.65 (m, 2H), 4.43 (s, 2H), 3.71 (s, 3H), 2.78 - 2.99 (m, 2H), 2.48 - 2.59 (m, 1H), 2.19 - 2.24 (m, 1H).

[0313] Example 28: Synthesis of compound 2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoro-N-[(4-methoxyphenyl)methyl]acetamide (28)

[0314]

[0315] Chemical formula: C 23 H 21 F2N3O5; Chemical molecular weight: 457.43.

[0316] LC_MS: (ES+): m / z 457.90 [M + H]+.

[0317] 1H NMR (400 MHz, d6-DMSO): δ 7.79 - 7.91 (m, 3H), 7.14 - 7.16 (m, 2H), 6.83 - 6.86 (m, 2H), 5.15 - 5.20 (m, 1H), 4.49 - 4.61 (m, 2H), 4.36 (s, 2H), 3.75 (s, 3H), 2.75 - 2.96 (m, 2H), 2.45 - 2.56 (m, 1H), 2.15 - 2.22 (m, 1H).

[0318] Example 29: Synthesis of compound N-[(2-aminophenyl)methyl]-2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoroacetamide (29)

[0319]

[0320] Chemical formula: C 22 H 20 F2N4O4; Chemical molecular weight: 442.42.

[0321] LC_MS: (ES+): m / z 443.20 [M + H]+.

[0322] 1H NMR (400 MHz, d6-DMSO): δ 7.78 - 7.93 (m, 3H), 7.03 - 7.09 (m, 2H), 6.63 - 6.74 (m, 2H), 5.18 - 5.22 (m, 1H), 4.51 - 4.65 (m, 2H), 4.38 (s, 2H), 2.78 - 2.98 (m, 2H), 2.47 - 2.58 (m, 1H), 2.19 - 2.23 (m, 1H).

[0323] Example 30: Synthesis of compound 2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoro-N-(1,3-thiazol-5-ylmethyl)acetamide (30)

[0324]

[0325] Chemical formula: C 19 H 16 F2N4O4S; Chemical molecular weight: 434.42.

[0326] LC_MS: (ES+): m / z 435.10 [M + H]+.

[0327] 1H NMR (400 MHz, d6-DMSO): δ 8.92 (s, 1H), 7.76 - 7.94 (m, 4H), 7.03 - 7.08 (m, 2H), 5.18 - 5.23 (m, 1H), 4.52 - 4.69 (m, 4H), 2.78 - 2.98 (m, 2H), 2.47 - 2.58 (m, 1H), 2.18 - 2.24 (m, 1H).

[0328] Example 31: Synthesis of compound N-[(2,4-dimethoxyphenyl)methyl]-2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoroacetamide (31)

[0329]

[0330] Chemical formula: C 24 H 23 F2N3O6; Chemical molecular weight: 487.46.

[0331] LC_MS: (ES+): m / z 488.80 [M + H]+.

[0332] 1H NMR (400 MHz, d6-DMSO): δ 7.75 - 7.91 (m, 3H), 7.04 (d, J = 8.4 Hz, 1H), 6.41 - 6.50 (m, 2H), 5.15 - 5.20 (m, 1H), 4.49 - 4.60 (m, 2H), 4.36 (d, J = 5.6 Hz, 2H), 3.76 (s, 3H), 3.72 (s, 3H), 2.75 - 2.96 (m, 2H), 2.50 - 2.56 (m, 1H), 2.17 - 2.21 (m, 1H).

[0333] Example 32: Synthesis of compound N-(2,3-dihydro-1H-indenyl)-2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoroacetamide (32)

[0334]

[0335] Chemical formula: C 24 H 21 F2N3O4; Chemical molecular weight: 453.45.

[0336] LC_MS: (ES+): m / z 453.95 [M + H]+.

[0337] 1H NMR (400 MHz, d6-DMSO): δ 7.83 - 7.97 (m, 3H), 7.06 - 7.27 (m, 4H), 5.44 - 5.50 (m, 1H), 5.19 - 5.24 (m, 1H), 4.54 - 4.66 (m, 2H), 2.79 - 2.96 (m, 4H), 2.48 - 2.56 (m, 2H), 2.20 - 2.25 (m, 1H), 1.94 - 2.03 (m, 1H).

[0338] Example 33: Synthesis of compound 2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoro-N-{[3-(trifluoromethyl)phenyl]methyl}acetamide (33)

[0339]

[0340] Chemical formula: C 23 H 18 F5N3O4; Chemical molecular weight: 495.41.

[0341] LC_MS: (ES+): m / z 496.90 [M + H]+.

[0342] 1H NMR (400 MHz, d6-DMSO): δ 7.79 - 7.95 (m, 3H), 7.51 - 7.58 (m, 4H), 5.19 - 5.23 (m, 1H), 4.53 - 4.58 (m, 4H), 2.90 - 2.94 (m, 1H), 2.82 - 2.84 (m, 1H), 2.51 - 2.55 (m, 1H), 2.19 - 2.23 (m, 1H).

[0343] Example 34: Synthesis of compound 2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoro-N-[(4-methylphenyl)methyl]acetamide (34)

[0344]

[0345] Chemical formula: C 23 H 21 F2N3O4; Chemical molecular weight: 441.43.

[0346] LC_MS: (ES+): m / z 441.90 [M + H]+.

[0347] 1H NMR (400 MHz, d6-DMSO): δ 7.75 - 7.91 (m, 3H), 7.10 (s, 4H), 5.15 - 5.20 (m, 1H), 4.49 - 4.60 (m, 2H), 4.38 (d, J = 6.0 Hz, 2H), 2.75 - 2.96 (m, 2H), 2.45 - 2.56 (m, 1H), 2.29 (s, 3H), 2.16 - 2.22 (m, 1H).

[0348] Example 35: Synthesis of compound 2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoro-N-(thiophen-2-ylmethyl)acetamide (35)

[0349]

[0350] Chemical formula: C 20 H 17 F2N3O4S; Chemical molecular weight: 433.43.

[0351] LC_MS: (ES+): m / z 433.85 [M + H]+.

[0352] 1H NMR (400 MHz, d6-DMSO): δ 7.74 - 7.91 (m, 3H), 7.26 - 7.28 (m, 1H), 6.91 - 6.97 (m, 2H), 5.15 - 5.20 (m, 1H), 4.49 - 4.60 (m, 4H), 2.75 - 2.96 (m, 2H), 2.45 - 2.56 (m, 1H), 2.15 - 2.28 (m, 1H).

[0353] Example 36: Synthesis of compound 2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoro-N-(2-phenylethyl)acetamide (36)

[0354]

[0355] Chemical formula: C 23 H 21 F2N3O4; Chemical molecular weight: 441.43.

[0356] LC_MS: (ES+): m / z 441.90 [M + H]+.

[0357] 1H NMR (400 MHz, d6-DMSO): δ 7.65 - 7.90 (m, 3H), 7.09 - 7.19 (m, 5H), 5.19 - 5.24 (m, 1H), 4.51 - 4.65 (m, 2H), 3.54 (t, J = 7.2 Hz, 2H), 2.79 - 2.85 (m, 4H), 2.49 - 2.60 (m, 1H), 2.19 - 2.25 (m, 1H).

[0358] Example 37: Synthesis of compound 2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoro-N-(furan-2-ylmethyl)acetamide (37)

[0359]

[0360] Chemical formula: C 20 H 17 F2N3O5; Chemical molecular weight: 417.37.

[0361] LC_MS: (ES+): m / z 417.80 [M + H]+.

[0362] 1H NMR (400 MHz, d6-DMSO): δ 7.78 - 7.94 (m, 3H), 7.43 - 7.44 (m, 1H), 6.35 - 6.36 (m, 1H), 6.23 - 6.24 (m, 1H), 5.18 - 5.22 (m, 1H), 4.52 - 4.65 (m, 2H), 4.45 (s, 2H), 2.78 - 2.98 (m, 2H), 2.47 - 2.58 (m, 1H), 2.18 - 2.24 (m, 1H).

[0363] Example 38: Synthesis of compound 2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-N-(diphenylmethyl)-2,2-difluoroacetamide (38)

[0364]

[0365] Chemical formula: C 28 H 23 F2N3O4; Chemical molecular weight: 503.51.

[0366] LC_MS: (ES+): m / z 504.00 [M + H]+.

[0367] 1H NMR (400 MHz, d6-DMSO): δ 7.81 - 7.94 (m, 3H), 7.21 - 7.36 (m, 10H), 6.28 (d, J = 8.4 Hz, 1H), 5.18 - 5.23 (m, 1H), 4.51 - 4.62 (m, 2H), 2.78 - 2.98 (m, 2H), 2.48 - 2.58 (m, 1H), 2.18 - 2.24 (m, 1H).

[0368] Example 39: Synthesis of compound 2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoro-N-(1,3-oxazolidin-2-ylmethyl)acetamide (39)

[0369]

[0370] Chemical formula: C 19 H 16 F2N4O5; Chemical molecular weight: 418.36.

[0371] LC_MS: (ES+): m / z 418.80 [M + H]+.

[0372] 1HNMR(400MHz, d6-DMSO): δ 9.80 (t, J = 5.6 Hz, 1H), 8.07 (s, 1H), 7.75 - 7.91 (m, 3H), 7.18 (s, 1H), 5.13 - 5.18 (m, 1H), 4.40 - 4.58 (m, 4H), 2.88 - 2.97 (m, 1H), 2.59 - 2.68 (m, 1H), 2.33 - 2.46 (m, 1H), 1.98 - 2.05 (m, 1H).

[0373] Example 40: Synthesis of compound 2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoro-N-(1H-indol-2-ylmethyl)acetamide (40)

[0374]

[0375] Chemical formula: C 24 H 20 F2N4O4; Molecular weight: 466.44.

[0376] LC_MS: (ES+): m / z 466.90 [M + H]+.

[0377] 1HNMR(400MHz, d6-DMSO): δ 7.78 - 7.91 (m, 3H), 7.44 (d, J = 8.0 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.05 (t, J = 7.2 Hz, 1H), 6.96 (t, J = 7.6 Hz, 1H), 6.26 (s, 1H), 5.14 - 5.18 (m, 1H), 4.58 (d, J = 5.6 Hz, 2H), 4.39 - 4.50 (m, 2H), 2.75 - 2.95 (m, 2H), 2.41 - 2.52 (m, 1H), 2.14 - 2.20 (m, 1H).

[0378] Example 41: Synthesis of compound N-(4-benzylphenyl)-2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoroacetamide (41)

[0379]

[0380] Chemical formula: C 28 H 23 F2N3O4; Molecular weight: 503.51.

[0381] LC_MS: (ES+): m / z 504.05 [M + H]+.

[0382] 1H NMR (400 MHz, d6-DMSO): δ 7.87 - 7.97 (m, 3H), 7.53 - 7.55 (m, 2H), 7.18 - 7.29 (m, 7H), 5.18 - 5.23 (m, 1H), 4.54 - 4.65 (m, 2H), 3.96 (s, 2H), 2.17 - 2.98 (m, 4H).

[0383] Example 42: Synthesis of compound N-[(3-chloro-4-methylphenyl)methyl]-2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoroacetamide (42)

[0384]

[0385] Chemical formula: C 23 H 20 ClF2N3O4; Chemical molecular weight: 475.88.

[0386] LC_MS: (ES+): m / z 475.85 [M + H]+.

[0387] 1H NMR (400 MHz, d6-DMSO): δ 7.79 - 7.95 (m, 3H), 7.06 - 7.23 (m, 3H), 5.18 - 5.23 (m, 1H), 4.53 - 4.63 (m, 2H), 4.40 (d, J = 6.0 Hz, 2H), 2.78 - 2.98 (m, 2H), 2.47 - 2.58 (m, 1H), 2.33 (s, 3H), 2.19 - 2.23 (m, 1H).

[0388] Example 43: Synthesis of compound 2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoro-N-[(2-methylphenyl)methyl]acetamide (43)

[0389]

[0390] Chemical formula: C 23 H 21 F2N3O4; Chemical molecular weight: 441.43.

[0391] LC_MS: (ES+): m / z 441.90 [M + H]+.

[0392] 1H NMR (400 MHz, d6-DMSO): δ 7.80 - 7.95 (m, 3H), 7.14 - 7.17 (m, 4H), 5.18 - 5.23 (m, 1H), 4.53 - 4.63 (m, 2H), 4.47 (d, J = 5.6 Hz, 2H), 2.78 - 2.98 (m, 2H), 2.49 - 2.59 (m, 1H), 2.27 (s, 3H), 2.18 - 2.25 (m, 1H).

[0393] Example 44: Synthesis of compound 2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoro-N-[(4-hydroxyphenyl)methyl]acetamide (44)

[0394]

[0395] Chemical formula: C 22 H 19 F2N3O5; Chemical molecular weight: 443.41.

[0396] LC_MS: (ES+): m / z 443.85 [M + H]+.

[0397] 1H NMR (400 MHz, d6-DMSO): δ 7.77 - 7.93 (m, 3H), 7.08 - 7.10 (m, 2H), 6.71 - 6.73 (m, 2H), 5.18 - 5.22 (m, 1H), 4.51 - 4.62 (m, 2H), 4.35 (s, 2H), 2.78 - 2.98 (m, 2H), 2.47 - 2.58 (m, 1H), 2.18 - 2.24 (m, 1H).

[0398] Example 45: Synthesis of compound N-[3-(3,4-dimethoxyphenyl)propyl]-2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoroacetamide (45)

[0399]

[0400] Chemical formula: C 26 H 27 F2N3O6; Chemical molecular weight: 515.51.

[0401] LC_MS: (ES+): m / z 516.00 [M + H]+.

[0402] 1H NMR (400 MHz, d6-DMSO): δ 7.80 - 7.95 (m, 3H), 6.66 - 6.86 (m, 3H), 5.17 - 5.22 (m, 1H), 4.52 - 4.63 (m, 2H), 3.79 (d, J = 4.4, 6H), 3.27 - 3.30 (m, 2H), 2.77 - 2.98 (m, 2H), 2.46 - 2.57 (m, 3H), 2.17 - 2.24 (m, 1H), 1.81 - 1.88 (m, 2H).

[0403] Example 46: Synthesis of compound N-(benzo[d][1,3]thiazepin-2-ylmethyl)-2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoroacetamide (46)

[0404]

[0405] Chemical formula: C 23 H 18 F2N4O4S; Chemical molecular weight: 484.48.

[0406] LC_MS: (ES+): m / z 484.90 [M + H]+.

[0407] 1H NMR (400 MHz, d6-DMSO): δ 7.84 - 7.96 (m, 5H), 7.39 - 7.52 (m, 2H), 5.16 - 5.21 (m, 1H), 4.86 (s, 2H), 4.51 - 4.62 (m, 2H), 2.76 - 2.93 (m, 2H), 2.49 - 2.53 (m, 1H), 2.17 - 2.22 (m, 1H).

[0408] Example 47: Synthesis of compound N-(cyclopropylmethyl)-2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoroacetamide (47)

[0409]

[0410] Chemical formula: C 19 H 19 F2N3O4; Chemical molecular weight: 391.37.

[0411] LC_MS: (ES+): m / z 391.95 [M + H]+.

[0412] 1H NMR (400 MHz, d6-DMSO): δ 7.77 - 7.92 (m, 3H), 5.15 - 5.20 (m, 1H), 4.51 - 4.62 (m, 2H), 3.19 (d, J = 7.2 Hz, 2H), 2.75 - 2.96 (m, 2H), 2.45 - 2.56 (m, 1H), 2.16 - 2.22 (m, 1H).

[0413] Example 48: Synthesis of compound N-[(3-chloro-2-fluorophenyl)methyl]-2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoroacetamide (48)

[0414]

[0415] Chemical formula: C 22 H 17 ClF3N3O4; Chemical molecular weight: 479.84.

[0416] LC_MS: (ES+): m / z 479.95 [M+H]+.

[0417] 1H NMR (400 MHz, Methonal-D4): δ 9.618 - 9.608 (m, 1H), 7.944 - 7.779 (m, 3H), 7.413 - 7.377 (m, 1H), 7.219 - 7.181 (m, 1H), 7.131 - 7.087 (m, 1H), 5.217 - 5.172 (m, 1H), 4.582 - 4.523 (m, 4H), 2.984 - 2.886 (m, 1H), 2.826 - 2.782 (m, 1H), 2.584 - 2.466 (m, 1H), 2.231 - 2.192 (m, 1H).

[0418] Example 49: Synthesis of compound N-[(2-chlorophenyl)methyl]-2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoroacetamide (49)

[0419]

[0420] Chemical formula: C 22 H 18 ClF2N3O4; Chemical molecular weight: 461.85.

[0421] LC_MS: (ES+): m / z 462.25 [M+H]+.

[0422] 1H NMR (400 MHz, Methonal - D4): δ 9.536 - 9.523 (m, 1H), 7.957 - 7.817 (m, 3H), 7.418 - 7.253 (m, 4H), 5.229 - 5.183 (m, 1H), 4.640 - 4.531 (m, 4H), 2.987 - 2.895 (m, 1H), 2.842 - 2.781 (m, 1H), 2.589 - 2.478 (m, 1H), 2.249 - 2.185 (m, 1H).

[0423] Example 50: Synthesis of compound N-(1H-indol-4-ylmethyl)-2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoroacetamide (50)

[0424]

[0425] Chemical formula: C 24 H 20 F2N4O4; Chemical molecular weight: 466.44.

[0426] LC_MS: (ES+): m / z 466.95 [M + H]+.

[0427] 1H NMR (400 MHz, Methonal - D4): δ 9.425 - 9.398 (m, 1H), 7.898 - 7.878 (d, J = 8.0, 1H), 7.809 - 7.771 (m, 2H), 7.341 - 7.320 (d, J = 8.4, 1H), 7.178 - 7.170 (d, J = 3.2, 1H), 7.067 - 7.029 (t, J = 7.2, 1H), 6.923 - 6.905 (d, J = 7.2, 1H), 6.343 - 6.335 (d, J = 3.2, 1H), 5.220 - 5.174 (m, 1H), 4.747 - 4.732 (d, J = 6.0, 2H), 4.554 - 4.449 (m, 2H), 2.983 - 2.892 (m, 1H), 2.839 - 2.778 (m, 1H), 2.574 - 2.464 (m, 1H), 2.239 - 2.175 (m, 1H).

[0428] Example 51: Synthesis of compound N-(1H-indol-5-ylmethyl)-2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoroacetamide (51)

[0429]

[0430] Chemical formula: C 24 H 20 F2N4O4; Chemical molecular weight: 466.44.

[0431] LC_MS: (ES+): m / z 466.90 [M+H]+.

[0432] 1HNMR(400MHz, Methonal-D4): δ9.534 - 9.506(m, 1H), 7.924 - 7.903(m, 1H), 7.803 - 7.793(d, J = 4.0, 2H), 7.502 - 7.482(d, J = 8.0, 1H), 7.294(s, 1H), 7.224 - 7.216(d, J = 3.2, 1H), 6.947 - 6.924(m, 1H), 6.421 - 6.413(d, J = 3.2, 1H), 5.209 - 5.163(m, 1H), 4.555 - 4.433(m, 4H), 2.977 - 2.885(m, 1H), 2.836 - 2.775(m, 1H), 2.556 - 2.446(m, 1H), 2.227 - 2.169(m, 1H).

[0433] Example 52: Synthesis of compound N-(1H-indol-6-ylmethyl)-2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoroacetamide (52)

[0434]

[0435] Chemical formula: C 24 H 20 F2N4O4; Chemical molecular weight: 466.44.

[0436] LC_MS: (ES+): m / z 466.90 [M+H]+.

[0437] 1H NMR (400 MHz, Methonal-D4): δ 9.492 - 9.467 (m, 1H), 7.922 - 7.901 (d, J = 8.4, 1H), 7.799 - 7.784 (d, J = 6.0, 2H), 7.431 (s, 1H), 7.333 - 7.313 (d, J = 8.0, 1H), 7.234 - 7.226 (d, J = 3.2, 1H), 7.028 - 7.004 (m, 1H), 6.388 - 6.380 (d, J = 3.2, 1H), 5.210 - 5.164 (m, 1H), 4.536 - 4.436 (m, 4H), 2.977 - 2.885 (m, 1H), 2.836 - 2.774 (m, 1H), 2.554 - 2.443 (m, 1H), 2.227 - 2.163 (m, 1H).

[0438] Example 53: Synthesis of compound 2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoro-N-(pyridin-4-ylmethyl)acetamide (53)

[0439]

[0440] Chemical formula: C 21 H 18 F2N4O4; Chemical molecular weight: 428.40.

[0441] LC_MS: (ES+): m / z 429.50 [M + H]+.

[0442] 1H NMR (400 MHz, Methonal-D4): δ 8.71 (s, 1H), 7.95 - 7.89 (m, 2H), 7.82 - 7.77 (m, 3H), 5.21 - 5.16 (m, 1H), 4.69 - 4.56 (m, 4H), 2.92 - 2.76 (m, 2H), 2.53 - 2.45 (m, 1H), 2.21 - 2.18 (m, 1H).

[0443] Example 54: Synthesis of compound 2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoro-N-(pyrazin-2-ylmethyl)acetamide (54)

[0444]

[0445] Chemical formula: C 20 H 17 F2N5O4; Chemical molecular weight: 429.38.

[0446] LC_MS:(ES+): m / z 430.05 [M+H]+.

[0447] 1H NMR(400 MHz, Methonal-D4): δ 8.56 - 8.48 (m, 3H), 7.93 - 7.81 (m, 3H), 5.20 - 5.16 (m, 1H), 4.62 - 4.51 (m, 4H), 3.31 - 2.82 (m, 1H), 2.81 - 2.76 (m, 1H), 2.53 - 2.49 (m, 1H), 2.22 - 2.17 (m, 1H).

[0448] Example 55: Synthesis of compound 2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoro-N-(pyridin-2-ylmethyl)acetamide (55)

[0449]

[0450] Chemical formula: C 21 H 18 F2N4O4; Chemical molecular weight: 428.39.

[0451] LC_MS:(ES+): m / z 429.20 [M+H]+.

[0452] 1H NMR(400 MHz, Methonal-D4): δ 8.64 - 8.62 (m, 1H), 8.20 - 8.16 (m, 1H), 7.94 - 7.79 (m, 3H), 7.66 - 7.57 (m, 2H), 5.21 - 5.16 (m, 1H), 4.67 (s, 2H), 4.62 - 4.51 (m, 2H), 2.96 - 2.87 (m, 1H), 2.82 - 2.76 (m, 1H), 2.56 - 2.46 (m, 1H), 2.22 - 2.16 (m, 1H).

[0453] Example 56: Synthesis of compound 2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoro-N-(pyridin-3-ylmethyl)acetamide (56)

[0454]

[0455] Chemical formula: C 21 H 18 F2N4O4; Chemical molecular weight: 428.39.

[0456] LC_MS:(ES+):m / z 429.05[M+H]+.

[0457] 1HNMR(400MHz,Methonal-D4):δ8.66(s,2H),8.27-8.25(d,J=8.0,1H),7.93-7.76(m,4H),5.21-5.16(m,1H),4.61-4.50(m,4H),2.96-2.87(m,1H),2.82-2.76(m,1H),2.56-2.45(m,1H),2.21-2.17(m,1H).

[0458] Example 57: Synthesis of compound N-(1H-indazol-3-ylmethyl)-2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoroacetamide (57)

[0459]

[0460] Chemical formula: C 23 H 19 F2N5O4; Chemical molecular weight: 467.43.

[0461] LC_MS:(ES+):m / z 468.05[M+H]+.

[0462] 1HNMR(400MHz,Methonal-D4):δ9.59(s,1H),7.86-7.75(m,3H),7.46-7.44(d,J=8.0,2H),7.35-7.31(m,1H),6.97-6.93(m,1H),5.20-5.15(m,1H),4.82-4.81(m,2H),4.51-4.41(m,2H),2.96-2.87(m,1H),2.82-2.75(m,1H),2.51-2.47(m,1H),2.21-2.15(m,1H).

[0463] Example 58: Synthesis of compound 2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoro-N-(pyrimidin-4-ylmethyl)acetamide (58)

[0464]

[0465] Chemical formula: C 20 H 17 F2N5O4; Chemical molecular weight: 429.38.

[0466] LC_MS: (ES+): m / z 430.00 [M+H]+.

[0467] 1H NMR (400 MHz, Methonal-D4): δ 9.68 (s, 1H), 9.09 (s, 1H), 8.72 (s, 1H), 7.95 - 7.84 (m, 3H), 7.35 - 7.34 (d, J = 4.0, 1H), 5.21 - 5.16 (m, 1H), 4.63 - 4.52 (m, 4H), 2.96 - 2.87 (m, 1H), 2.82 - 2.76 (m, 1H), 2.54 - 2.49 (m, 1H), 2.21 - 2.17 (m, 1H).

[0468] Example 59: Synthesis of compound N-(1H-indazol-3-ylmethyl)-2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoroacetamide (59)

[0469]

[0470] Chemical formula: C 23 H 19 F2N5O4; Chemical molecular weight: 467.43.

[0471] LC_MS: (ES+): m / z 468.15 [M+H]+.

[0472] 1H NMR (400 MHz, Acetonitrile-D6): δ 9.33 (s, 1H), 8.86 (s, 1H), 7.82 - 7.72 (m, 5H), 7.51 - 7.49 (d, J = 8.0, 2H), 5.11 - 5.06 (m, 1H), 4.89 - 4.88 (d, J = 4.0, 2H), 4.47 - 4.36 (m, 2H), 2.83 - 2.73 (m, 2H), 2.46 - 2.37 (m, 1H), 2.14 - 2.10 (m, 1H).

[0473] Example 60: Synthesis of compound 60

[0474]

[0475] Synthesis of intermediate {1-[2-chloro-4-({2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoroacetyl}amino)phenyl]-6-aza-3-oxahept-6-yl} 2-methylprop-2-yl carbonate (60-1)

[0476] At room temperature, to a solution of 2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoroacetic acid (50 mg, 0.148 mmol) in N,N-dimethylformamide (1.5 ml) was added [1-(4-amino-2-chlorophenyl)-6-aza-3-oxahept-6-yl] 2-methylprop-2-yl carbonate (73 mg, 0.222 mmol), triethylamine (44.82 mg, 0.443 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (84.52 mg, 0.222 mmol), and the mixture was stirred at room temperature overnight. LCMS showed that the reaction was complete. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was washed with water, and the obtained crude product was purified by column chromatography (dichloromethane:methanol = 20:1) to give {1-[2-chloro-4-({2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoroacetyl}amino)phenyl]-6-aza-3-oxahept-6-yl} 2-methylprop-2-yl carbonate (60-1, 18 mg, yield 18.7%), and the product was a white solid.

[0477] LC_MS:(ES+):m / z 427.90[M+H]+.

[0478] 1HNMR(400MHz,d6-DMSO):δ7.79-7.98(m,4H),7.50-7.52(m,1H),7.32(d,J=8.4Hz,1H),5.18-5.23(m,1H),4.54-4.65(m,2H),3.68(t,J=6.8Hz,2H),3.55(t,J=5.6Hz,2H),3.37(t,J=5.6Hz,2H),2.77-3.01(m,7H),2.50-2.55(m,1H),2.19-2.23(m,1H),1.43(s,9H).

[0479] Synthesis of compound N-[3-chloro-4-(6-aza-3-oxahept-1-yl)phenyl]-2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoroacetamide (60)

[0480] At room temperature, a solution of methyl 2-methylprop-2-yl {1-[2-chloro-4-({2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoroacetyl}amino)phenyl]-6-aza-3-oxohept-6-yl}methanecarboxylate (18 mg, 0.0277 mmol) in dichloromethane (0.7 ml) was added to a 1,4-dioxane solution of hydrochloric acid (0.7 ml), and the mixture was stirred at room temperature for 0.5 h. LCMS showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was purified by column chromatography to obtain N-[3-chloro-4-(6-aza-3-oxohept-1-yl)phenyl]-2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoroacetamide (Compound 60, 10.1 mg, yield 66.4%). The product was a white solid.

[0481] Example 61: Synthesis of compound N-({3-chloro-4-[4-(piperidin-4-yloxy)piperidin-1-yl]phenyl}methyl)-2-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoroacetamide (61)

[0482]

[0483] Synthesis of intermediate 2-methylpropyl 4-{[1-(2-chloro-4-cyanophenyl)piperidin-4-yl]oxy}piperidine-1-carboxylate (61-1)

[0484]

[0485] Under nitrogen protection, to a solution of 3-chloro-4-fluorobenzene-1-carbonitrile (500 mg, 3.214 mmol) in NMP (3 ml) were added 2-methylpropyl 4-(piperidin-4-yloxy)piperidine-1-carboxylate (609 mg, 2.143 mmol) and DIPEA (1.39 g, 10.714 mmol), and the mixture was stirred at 90 °C for 6 h. LCMS showed that the reaction was complete. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, and concentrated. The resulting crude product was purified by column chromatography to obtain 2-methylpropyl 4-{[1-(2-chloro-4-cyanophenyl)piperidin-4-yl]oxy}piperidine-1-carboxylate (61-1, 300 mg, yield 33%). The product was a white solid.

[0486] Chemical formula: C 22 H 30 ClN3O3; Chemical molecular weight: 419.95.

[0487] LC_MS:(ES+):m / z 419.95[M+H]+.

[0488] 1HNMR(400MHz,d6-DMSO):δ7.934 - 7.929(d,J=2.0,4H),7.737 - 7.711(m,1H),7.250 - 7.229(d,J=8.4,1H),3.662 - 3.632(m,4H),3.295 - 3.280(m,2H),3.039 - 2.864(m,4H),1.950 - 1.550(m,6H),1.390(s,9H),

[0489] 1.350 - 1.280(m,2H).

[0490] Synthetic intermediate 4 - ({1 - [4 - (aminomethyl)-2 - chlorophenyl]piperidin - 4 - yl}oxy)piperidine - 1 - carboxylic acid 2 - methylpropan - 2 - yl ester (61 - 2)

[0491]

[0492] Under a hydrogen atmosphere, at room temperature, Raney nickel (200 mg) was added to a solution of 4 - {[1 - (2 - chloro - 4 - cyanophenyl)piperidin - 4 - yl]oxy}piperidine - 1 - carboxylic acid 2 - methylpropan - 2 - yl ester (250 mg, 0.595 mmol) in tetrahydrofuran (5 ml). The mixture was stirred at room temperature overnight. LCMS showed that the reaction was complete. The reaction mixture was filtered and concentrated under reduced pressure. The resulting crude product was purified by column chromatography to obtain 4 - ({1 - [4 - (aminomethyl)-2 - chlorophenyl]piperidin - 4 - yl}oxy)piperidine - 1 - carboxylic acid 2 - methylpropan - 2 - yl ester (61 - 2, 100 mg, yield 39%). The product was a white solid.

[0493] Chemical formula: C 31 H 35 ClF2N4O7; Chemical molecular weight: 423.98.

[0494] LC_MS:(ES+):m / z 424.30[M+H]+.

[0495] 1H NMR (400 MHz, d6-DMSO): δ 7.413 - 7.408 (d, J = 2.0, 4H), 7.24 - 7.22 (m, 1H), 7.10 - 7.08 (d, J = 8.0, 1H), 3.69 - 3.60 (m, 6H), 3.14 - 3.02 (m, 4H), 2.76 - 2.71 (m, 2H), 1.94 - 1.90 (m, 2H), 1.79 - 1.75 (m, 2H), 1.61 - 1.57 (m, 2H), 1.40 (s, 9H), 1.37 - 1.29 (m, 2H).

[0496] Synthetic intermediate 4 - [(1 - {2 - chloro - 4 - [({2 - [2 - (2,6 - dioxohexahydropyridin - 3 - yl)-1 - oxo - 2,3 - dihydro - 1H - isoindol - 5 - yl]-2,2 - difluoroacetyl}amino)methyl]phenyl}hexahydropyridin - 4 - yl)oxy]hexahydropyridine - 1 - carboxylic acid 2 - methylpropan - 2 - yl ester (61 - 3)

[0497]

[0498] At room temperature, to a solution of 2 - [2 - (2,6 - dioxohexahydropyridin - 3 - yl)-1 - oxo - 2,3 - dihydro - 1H - isoindol - 5 - yl]-2,2 - difluoroacetic acid (50 mg, 0.118 mmol) in N,N - dimethylformamide (1.5 ml) were added 4 - ({1 - [4 - (aminomethyl)-2 - chlorophenyl]hexahydropyridin - 4 - yl}oxy)hexahydropyridine - 1 - carboxylic acid 2 - methylpropan - 2 - yl ester (40 mg, 0.118 mmol), triethylamine (35.82 mg, 0.354 mmol) and 2 - (7 - azabenzotriazol)-tetramethyluronium hexafluorophosphate (HATU) (67.4 mg, 0.177 mmol), and the mixture was stirred at room temperature overnight. LCMS showed that the reaction was complete. Water (6 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was washed with water, and the resulting crude product was purified by preparative plate to obtain 4 - [(1 - {2 - chloro - 4 - [({2 - [2 - (2,6 - dioxohexahydropyridin - 3 - yl)-1 - oxo - 2,3 - dihydro - 1H - isoindol - 5 - yl]-2,2 - difluoroacetyl}amino)methyl]phenyl}hexahydropyridin - 4 - yl)oxy]hexahydropyridine - 1 - carboxylic acid 2 - methylpropan - 2 - yl ester (61.3, 18 mg, yield 20%), and the product was a white solid.

[0499] Chemical formula: C 37 H 44 ClF2N5O7; Chemical molecular weight: 744.23.

[0500] LC_MS:(ES+):m / z 744.15[M+H]+.

[0501] 1HNMR(400MHz,d6-DMSO):δ8.02-7.96(m,2H),7.80(s,1H),7.74-7.72(d,J=8.0,1H),7.25-7.24(d,J=4.0,1H),7.11-7.09(m,1H),7.01-6.99(m,1H),6.99(s,1H),5.26-5.21(m,1H),4.58-4.39(m,4H),3.78-3.59(m,4H),3.27-3.24(m,2H),3.13-3.07(m,2H),2.97-2.77(m,4H),2.44-2.33(m,1H),2.26-2.20(m,1H),1.97-1.76(m,6H),1.57-1.51(m,2H),1.46(s,9H).

[0502] Synthesis of N-({3-chloro-4-[4-(piperidin-4-yloxy)piperidin-1-yl]phenyl}methyl)-2-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoroacetamide (61)

[0503]

[0504] To a solution of tert-butyl 4-[(1-{2-chloro-4-[({2-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoroacetyl}amino)methyl]phenyl}piperidin-4-yl)oxy]piperidine-1-carboxylate (18 mg, 0.0242 mmol) in dichloromethane (0.3 ml) was added trifluoroacetic acid (0.3 ml) at room temperature, and the mixture was stirred at room temperature for 0.5 h. LCMS showed that the reaction was complete. The mixture was concentrated under reduced pressure, and the resulting crude product was purified by preparative purification to give N-({3-chloro-4-[4-(piperidin-4-yloxy)piperidin-1-yl]phenyl}methyl)-2-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2,2-difluoroacetamide (61, 12.2 mg, yield 81%), and the product was a white solid.

[0505] Chemical formula: C 32 H 36 ClF2N5O5; Chemical molecular weight: 644.12.

[0506] LC_MS:(ES+):m / z 644.45[M+H]+.

[0507] 1HNMR(400MHz, Methonal-D4): δ9.588 - 9.549(m, 1H), 7.941 - 7.921(d, J=8.0, 1H), 7.856(s, 1H), 7.794 - 7.774(d, J=8.0, 1H), 7.200 - 7.060(m, 3H), 5.229 - 5.183(m, 1H), 4.626 - 4.521(m, 2H), 4.378 - 4.368(d, J=4.0, 1H), 3.901 - 3.869(m, 1H), 3.678 - 3.660(m, 1H), 3.251 - 3.118(m, 5H), 2.988 - 2.786(m, 5H),

[0508] 2.242 - 2.179(m, 1H), 2.048 - 2.000(m, 4H), 1.910 - 1.720(m, 4H).

[0509] Biological activity assay

[0510] The activities of the above-mentioned compounds and the control compound CC-885 (whose structural formula is ), CC-90009 (whose structural formula is ) in degrading GSPT1 were tested by the following method: Inoculate 2x10 6 MV-4-11 cells into a six-well plate, and at the same time add each compound or the control compound (the final concentration is 10 nM, dissolved in DMSO), and continue to culture in suspension (the final concentration of DMSO is 0.2%) for 6 h, then centrifuge at 1200 rpm for 5 minutes to collect the cells. Add RIPA lysis buffer (containing protease inhibitor) to lyse the cells by ultrasound, let it stand on ice for 30 min, quantify by BCA method, dilute the protein with 5x protein loading buffer and heat it at 100 °C for 10 min for denaturation. Separate the protein samples by SDS-PAGE, transfer them to a PVDF membrane, block with 5% skim milk for 1 h, incubate with the primary antibody at 1:2000 at 4 °C overnight. Wash the membrane with TBST, incubate with the secondary antibody at 1:30000 at room temperature for 30 min, wash the membrane and then expose and image it in a chemiluminescence imager (Tianneng, Shanghai). Analyze the gray value of the band with Image J software, and calculate the degradation rate of the compound on GSPT1 protein at a concentration of 10 nM.

[0511] The cell proliferation inhibitory activity was tested by the following method: Inoculate 2x10 4After inoculating MV-4-11 cells into 96-well plates, different concentrations of the compound or the control compound were added respectively, and the cells were further cultured in an incubator at 37 °C and 5% CO2 for 72 h. The CCK8 assay was used to measure cell viability, and the specific steps were as follows: CCK8 (1 / 10 of the original culture medium volume) was added to the original culture medium, and the cells were incubated in an incubator for 1 h. The absorbance (OD value) at a wavelength of 450 nm was measured using a full-wavelength reader, and the compound concentration (IC50) with a growth inhibition rate of 50% was calculated. The specific results are shown in Table 1. The following levels were used for the protein degradation rate of GSPT1 at a concentration of 10 nM: I ≤ 20%; 20% < II ≤ 40%; 40% < III ≤ 60%; 60% < IV ≤ 80%; 80% < V ≤ 100%. The following levels were used for the cell proliferation inhibition activity with respect to IC50: I ≤ 3 nM; 3 nM < II ≤ 5 nM; 5 nM < III ≤ 10 nM; 10 nM < IV ≤ 20 nM; 20 nM < V ≤ 30 nM, where "-" in the cell proliferation inhibition activity means not tested.

[0512] Table 1: Activity results of degrading GSPT1

[0513] Compound GSPT1 Cell proliferation inhibitory activity 1 III - 2 V II 3 II - 9 III - 10 II - 11 II - 12 II - 13 III - 14 IV V 15 IV II 16 III - 18 II - 19 IV - 20 IV - 21 IV II 22 IV II 23 III - 24 V I 26 III II 27 III - 29 III - 31 II - 32 III - 33 IV - 34 III - 39 II - 40 V I 41 IV - 42 V - 43 V - 46 III - 48 IV - 49 IV - 50 III - 51 II - 52 II - CC-885 IV I CC-90009 II -

[0514] It can be seen that the compound of the present invention has comparable or better degradation activity against GSPT1 than the control compound, and also has better cell proliferation inhibition activity. The description of the above examples 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. 1-oxoisoindoline derivatives having the structure shown in formula (I), and pharmaceutically acceptable salts, solvates, crystal forms or stereoisomers thereof, wherein: A1 is selected from -(C=O)- or -CH2-; R1 is selected from halogen, methyl, methoxy or cyano; m is 0, 1, 2 or 3; A2 is selected from a single bond, C1-6 alkylene, C1-3 alkylene substituted by a benzene ring, aromatic ring, heteroaromatic ring, C3-C8 saturated carbocyclic ring or heterocyclic ring, -OCH2-, -CH2O-, -CH2(-CH2-O-CH3)-; ring B is selected from an unsubstituted or substituted benzene ring, C5-8 heterocyclic ring, C8-C14 aromatic ring, C8-C14 heteroaromatic ring, C3-6 saturated carbocyclic ring or heterocyclic ring; the C5-8 heterocyclic ring contains 1-2 heteroatoms selected from O, N or S; the C8-C12 heteroaromatic ring contains 1-2 heteroatoms selected from O, N or S; the substituents are selected from halogen, cyano, nitro, amino, hydroxy, C1-6 alkyl, C3-8 alkyl interrupted by 1 or 2 heteroatoms selected from O and N, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, benzyl or substituted benzyl, C3-6 heterocyclic group, C3-6 heterocyclic C1-6 alkyl, Among them, A3 is selected from a single bond, a C1-6 alkylene group, and a C3-8 heteroalkylene group; n is 1, 2, 3 or 4; R3 is selected from H or C1-6 alkyl or C3-C8 cycloalkyl or cycloheteroalkyl.

2. The 1-oxoisoindoline derivative and its pharmaceutically acceptable salt, solvate, crystal form or stereoisomer according to claim 1, characterized in that: A1 is selected from -(C=O); and / or, m is 0.

3. The 1-oxoisoindoline derivative and its pharmaceutically acceptable salt, solvate, crystal form or stereoisomer according to claim 1, characterized in that: A2 is selected from a single bond, -CH2-, -CH(CH3)-, -CH2CH2-, -CH2CH2CH2-, -CH(Ph)-, -CH2O-, -CH2(-CH2-O-CH3)-.

4. The 1-oxoisoindoline derivative and its pharmaceutically acceptable salt, solvate, crystal form or stereoisomer according to claim 1, characterized in that: Ring B is selected from benzene rings which are unsubstituted or substituted with 1 to 5 substituents, and the substituents are selected from halogen, cyano, nitro, amino, hydroxyl, C1-6 alkyl, C6-8 alkyl interrupted by 1 O atom and 1 N atom, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, benzyl, 5. The 1-oxoisoindoline derivative and its pharmaceutically acceptable salt, solvate, crystal form or stereoisomer according to claim 1, characterized in that: Ring B is selected from benzene rings which are unsubstituted or substituted with 1 to 5 substituents, and the substituents are selected from halogen, nitro, amino, hydroxyl, methyl, CH3NHCH2CH2OCH2CH2-, methoxy, trifluoromethyl, trifluoromethoxy, benzyl, 6. The 1-oxoisoindoline derivative, pharmaceutically acceptable salt, solvate, crystal form or stereoisomer thereof according to claim 1, characterized in that: Ring B is selected from a C5-8 heterocycle which is unsubstituted or substituted with a substituent selected from halogen, C1-6 alkyl or C1-6 alkoxy, and the C5-8 heterocycle is selected from 7. The 1-oxoisoindoline derivative, pharmaceutically acceptable salt, solvate, crystal form or stereoisomer according to claim 1, characterized in that: Ring B is selected from C8-C14 aromatic rings which are unsubstituted or substituted by substituents selected from halogen, C1-6 alkyl or C1-6 alkoxy, and the C8-C14 aromatic rings are selected from 8. The 1-oxoisoindoline derivative and its pharmaceutically acceptable salt, solvate, crystal form or stereoisomer according to claim 1, characterized in that: Ring B is selected from C8-C14 heteroaryl rings which are unsubstituted or substituted by substituents selected from halogen, C1-6 alkyl or C1-6 alkoxy, and the C8-C14 heteroaryl rings are selected from 9. The 1-oxoisoindoline derivative and its pharmaceutically acceptable salt, solvate, crystal form or stereoisomer according to claim 1, characterized in that: ring B is selected from cyclopropane, cyclobutane, cyclopentane or cyclohexane which is unsubstituted or substituted by a substituent selected from halogen, C1-6 alkyl or C1-6 alkoxy.

10. The 1-oxoisoindoline derivative and its pharmaceutically acceptable salt, solvate, crystal form or stereoisomer according to claim 1, characterized in that: The 1-oxoisoindoline derivative is a compound selected from those shown in the following structures:

11. A pharmaceutical composition, characterized in that: Comprising one or more of the 1-oxoisoindoline derivatives and pharmaceutically acceptable salts, solvates, crystal forms or stereoisomers thereof as described in any one of claims 1 to 10, and a pharmaceutically acceptable carrier.

12. Use of the 1-oxoisoindoline derivatives and pharmaceutically acceptable salts, solvates, crystal forms or stereoisomers thereof as described in any one of claims 1 to 10 in degrading GSPTl, preparing a drug for treating diseases related to GSPTl activity, and preparing an antibody-conjugated degradable drug.

13. The use according to claim 12, wherein: The diseases related to GSPTl activity are selected from one or two of leukemia and myeloma.

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