CN112745298B

CN112745298B - Polysubstituted isoindoline compound, preparation method, pharmaceutical composition and application thereof

Info

Publication number: CN112745298B
Application number: CN202011192647.0A
Authority: CN
Inventors: 陈小华; 李佳; 李少铜; 周宇波; 聂辉军; 魏丹; 徐高亚; 周宾山; 阚伟娟
Original assignee: Shanghai Institute of Materia Medica of CAS
Current assignee: Shanghai Institute of Materia Medica of CAS
Priority date: 2019-10-30
Filing date: 2020-10-30
Publication date: 2024-04-09
Anticipated expiration: 2040-10-30
Also published as: CN112745298A; WO2021083328A1

Abstract

The invention relates to a polysubstituted isoindoline compound represented by a general formula (1), a preparation method, a pharmaceutical composition and application thereof. Specifically, the polysubstituted isoindoline compound provided by the invention is used as CRL4 with novel structure ^CRBN The E3 ubiquitin ligase regulator has stronger anti-tumor activity and anti-tumor spectrum, and can be used for preparing treatment and CRL4 ^CRBN Medicine for E3 ubiquitin ligase complex related diseasesAnd (3) an object.

Description

Polysubstituted isoindoline compound, preparation method, pharmaceutical composition and application thereof

Technical Field

The invention relates to a polysubstituted isoindoline compound with a novel structure, pharmaceutically acceptable salts, solvates and pharmaceutical compositions thereof and application of the polysubstituted isoindoline compound in preparing medicaments for treating or preventing various diseases.

Background

Tight regulation of intracellular protein expression plays an important role in cell function, cell survival and division, and many primary or acquired diseases are often related to protein dysfunction. Traditional approaches to modulating protein dysfunction have been through the design of targeted inhibitors or agonists that play an important role in the treatment of disease. Nevertheless, to achieve satisfactory efficacy, these inhibitors or agonists often need to be maintained at higher drug concentrations to achieve effective therapeutic effects, which also results in adverse drug reactions to some extent. Another approach to regulate protein dysfunction is to alter the dynamic balance of pathology-related proteins, including protein synthesis and degradation, e.g., small interfering RNAs (sirnas), antisense oligonucleotides or gene editing techniques can be used to knock-out or silence target protein genes, which alter protein synthesis by acting on the transcription and translation processes of the target protein, which is limited to a degree by the lower in vivo stability and bioavailability of the nucleic acid, which in turn limits its use. Another strategy for regulating the dynamic balance of proteins is to regulate the degradation process of the protein, and the amount of target protein expressed in the cell can be directly changed by promoting or inhibiting the degradation of the protein. Ubiquitin-proteasome systems (UPS) play an important role in the degradation of proteins, and under the action of a range of ubiquitinating enzymes, target proteins can be ubiquitinated, and proteins with specific ubiquitin tags can be transported to and degraded by the proteasome.

The ubiquitination process of proteins is a serial multi-step reaction process, and three types of enzymes are mainly involved: an E1 ubiquitin activating enzyme, an E2 ubiquitin binding enzyme, an E3 ubiquitin ligase. First, the C-terminus of ubiquitin is activated by ATP and forms an active thioester structure with the cysteine thiol of the E1 ubiquitin activating enzyme active center. This active intermediate then covalently links ubiquitin to the E2 ubiquitin conjugating enzyme through a novel thioester structure by transesterification. Finally, the E3 ubiquitin ligase recruits the substrate protein and simultaneously binds to the E2 ubiquitin binding enzyme-ubiquitin activity intermediate, transferring ubiquitin to the substrate protein to complete the ubiquitination process of the substrate protein. In the whole ubiquitination process, the E3 ubiquitin ligase plays an important role, plays a bridge role, enables two reaction components (the E2 ubiquitin-conjugated enzyme-ubiquitin conjugate and the substrate protein) to be spatially close to each other, plays an enzyme catalysis role, and accelerates the ubiquitination rate of the substrate protein. Since E3 ubiquitin ligases require specific recognition of substrates, the mammalian genome encodes over 600E 3 ubiquitin ligases. In contrast, only two E1 ubiquitin activating enzymes and E2 ubiquitin binding enzyme in about 40 are currently found.

CRL4 ^CRBN The E3 ubiquitin ligase belongs to RING family E3 ubiquitin ligase, which is a protein complex assembled by a plurality of subunits, and the whole complex comprises a substrate protein recognition module (CRBN), an E2 ubiquitin binding enzyme recognition module (RING domain) and a connecting part (Cullin protein) between the two. CRBN binds directly to the substrate in the whole protein complex, controlling the substrate specificity of the whole ubiquitination process.

Small molecule modulators that act directly on CRBN can control CRL4 ^CRBN Substrate selectivity of E3 ubiquitin ligase. New studies have found that Cereblon (Gene name: CRBN) is a direct target for the immunomodulator thalidomide and its analogues (Science, 2010,327,1345; science,2014,343,301; science,2014,343,305; nature,2015,523, 183.). Research proves that in a multiple myeloma cell line, the brightness amine immunomodulator selectively induces transcription factors IKZF1 and IKZF3 to be ubiquitinated and degraded by regulating and controlling the activity of a CRBN-ubiquitin ligase complex, and the process changes the functions of T cells and B cells and simultaneously generates toxic effects on the multiple myeloma cells, thereby achieving the effect of treating malignant marrow system tumors including multiple myeloma. Recent studies have shown that lenalidomide, an analogue of thalidomide, can pass through CRL4 ^CRBN E3 ubiquitin ligase selectively induces ubiquitination and degradation of CK1 alpha to treat 5 q-deleted myelodysplastic syndrome (MDS), while another structural analogue of thalidomide (CC-885) is capable of acting on CRL4 ^CRBN The E3 ubiquitin ligase selectively induces and degrades GSPT1, and shows strong cytotoxicity to various tumor cells.

The existing research results show that: after interaction between amine medicine molecules with different degrees and target CRBN, the target CRBN has different substrate protein degradation specificities. For example, lenalidomide has the curative effect mainly realized by selectively degrading IKZF1 and IKZF3 when treating multiple myeloma; and in the treatment of myelodysplastic syndrome (del (5 q) MDS) with 5q loss, therapeutic effects are achieved mainly by degradation of CK1 alpha. Because the lenalidomide has stronger degradation activity on CK1 alpha in the currently developed domide analogues, the lenalidomide is the most important clinically effective domide drug for treating myelodysplastic syndrome del (5 q) MDS. With the development of new domide drugs and the development of clinical experiments, the indications of the domide drug molecules are also in continuous expansion, such as the application of the FDA approved thalidomide in the treatment of leprosy nodular erythema, the application of the lenalidomide in the clinical experiments in the treatment of prostate cancer, and the application of the pomalidomide in the clinical experiments in the treatment of myelofibrosis.

The structures of the lenalidomide, pomalidomide, CC-122, CC-220 and CC-885 reported compounds are similar to the sandy degree, and the compounds are characterized in that after structural change and adjustment, the compounds have different pharmacological activities and completely different therapeutic effects, so that the compounds can be clinically used for treating different indications.

WO2008115516A2, US8153659B2, US9181216B2, US9920027B2 disclose compounds represented by the general formula S1:

the main representative R1 in the general formula S1 is aryl, arylalkyl, heterocyclylalkyl and the like.

WO2011100380A1, CN102822165B discloses a class of compounds represented by the general formula S2:

r1 in the general formula S2 is a plurality of substituted aryl groups substituted, and a representative compound is CC-220:

WO2016065980A1、CN105566290A、US10017492B2

representative compounds in formula S3 are:

WO2007027527A2, CN101291924A, US8481568B2 disclose a class of compounds represented by the general formula S3:

representative compounds in the general formulae S4, S5 are:

WO2008027542A2, US8877780B2, US9447070B2 disclose a class of compounds represented by the general formula S3:

representative compounds in the general formulae S6, S7 are:

the mechanism of action of lenalidomide and the partial molecules is as follows: compounds of different structures are able to bind to CRBN, causing a change in the conformation of the CRBN binding moiety, thereby recruiting the binding of different endogenous biological macromolecules to CRBN; furthermore, the potential different endogenous substrate proteins are ubiquitinated and degraded, so that different pharmacological activities can be generated, and the protein can be used for treating different indications in clinical experiments.

In conclusion, lenalidomide is mainly used for treating multiple myeloma and myelodysplastic syndrome, and has an unsatisfactory effect on other indications; other compounds mentioned above, such as CC-122, CC-885 and CC-220, are still in preclinical or clinical studies. Thus, novel compounds were developed as CRL4 ^CRBN The E3 ubiquitin ligase regulator can realize the clinical demands of new indications of the amine medicines for further improving the treatment effect treatment and the expansion degree of tumors; neither the pharmacological activity nor the pharmacological properties of structurally diverse amine molecules are known, and the properties and effects of each have uncertainty. Based on the action mechanism of the amine molecule, the amine molecule with a new structure is developed, so that the recruitment of a new protein substrate can be realized, and further, the improvement of the treatment effect and the expansion of new indications are realized. Therefore, development of novel structure of CRL4 is continued ^CRBN The E3 ubiquitin ligase regulator has very important research value and practical significance for expanding new indications.

Disclosure of Invention

The inventors of the present invention obtained the following important information by analyzing the complex crystal structure of CRBN with small molecules (PDB ID:4CI2, 5 HXB): the CRBN and the small molecule have a plurality of binding pockets, so that the small molecule with a plurality of binding sites with complex structures can be developed, and the effective binding of the CRBN and the small molecule can be realized. Meanwhile, according to the characteristics of the crystal structure, the different structures of the connecting chain of the hydrophobic segment determine the binding mode and the binding capacity of the small molecule and CRBN. Therefore, the invention utilizes a molecular dynamics simulation method to analyze the structure dynamics and the binding site of the model molecule and the E3 ubiquitin ligase interface, the binding molecule is in butt joint and the pharmacophore is matched based on the compound, and the binding mode and the interaction of the compound at the E3 ubiquitin ligase active site are evaluated through a scoring function, so that the novel CRBN small molecule regulator with specific connecting chain is obtained. Based on this information, the inventors designed and synthesized a series of small molecule modulators of CRBN as described herein and tested the activity of the compounds. The test results show that the novel small molecule regulator has very high cell growth inhibition activity, and after the small molecule regulator acts on organisms, Degradation of substrate proteins can be regulated and controlled by regulating a ubiquitin-proteasome mediated protein degradation pathway in organisms, so that effective disease treatment based on CRBN targets is realized. The compound designed and synthesized by the invention is used for preparing the therapeutic and CRL4 ^CRBN Use in medicine of E3 ubiquitin ligase related diseases or disorders, mainly including cancer, inflammation, pain, nervous system diseases and immune system diseases.

It is an object of the present invention to provide a compound represented by the following general formula (I) or a tautomer, enantiomer, diastereomer, racemate, isotopic compound, metabolic precursor, metabolite, pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or crystal form thereof.

It is another object of the present invention to provide important intermediates of such compounds and processes for preparing the same. Enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates or crystal forms

It is another object of the present invention to provide a pharmaceutical composition comprising a therapeutically effective amount of one or more selected from the group consisting of a compound of formula (I), a tautomer, enantiomer, diastereomer, racemate, isotopic compound, metabolic precursor, metabolite, pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate and crystalline form thereof, and at least one pharmaceutically acceptable carrier.

The pharmaceutical composition may further comprise one or more additional pharmaceutically active ingredients. The compounds of the general formula (I), tautomers, enantiomers, diastereomers, racemates, isotopic compounds, metabolic precursors, metabolites, pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates or crystalline forms thereof, of the invention may act synergistically with one or more additional pharmaceutically active ingredients in the prevention or treatment of a particular disease or disorder. The compounds of formula (I), tautomers, enantiomers, diastereomers, racemates, isotopic compounds, metabolic precursors, metabolites, pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates or crystalline forms thereof, according to the invention, may also reduce or eliminate the toxic or side effects of one or more other pharmaceutically active ingredients in the prevention or treatment of specific diseases or disorders, and vice versa.

Additional one or more pharmaceutically therapeutically active ingredients as described above, including macromolecular compounds such as proteins, polysaccharides, nucleic acids, and the like; and small molecule compounds such as inorganic compounds, organometallic compounds, organic small molecule compounds of synthetic or natural origin, and the like.

It is another object of the present invention to provide a pharmaceutical composition comprising one or more selected from the group consisting of a compound represented by the general formula (I), a tautomer, enantiomer, diastereomer, racemate, isotopic compound, metabolic precursor, metabolite, pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate and crystalline form thereof, for use in preparing a pharmaceutical composition for treating and/or preventing CRL4 ^CRBN The use of a medicament for E3 ubiquitin ligase related diseases or disorders, preferably including, but not limited to, cancer, pain, neurological diseases and immune system diseases.

In order to achieve the above object, the present invention provides a compound represented by the following general formula (I) or a tautomer, enantiomer, diastereomer, racemate, metabolic precursor, metabolite, isotopic compound, pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or crystal form thereof:

wherein n is 1, 2, 3, 4 or 5;

X ₁ is-CH ₂ -, -NH-; -S-or-O-;

X ₂ is-CH ₂ -or-CO-;

R ₁ 、R ₂ 、R ₃ each independently hydrogen, deuterium, or halogen;

l is absent or is a substituted or unsubstituted linear alkylene group containing 1 to 5 carbon atoms, one or more hydrogen atoms of said alkylene group optionally being substituted with: deuterium, halogen, carbonyl, hydroxy, amino, cyano;

A is:

i)A ₁ -NH-,

A ₁ is a 6-10 membered aryl, a 5-10 membered heteroaryl, (6-10 membered aryl) - (CH) ₂ ) _b1 -, (5-10 membered heteroaryl) - (CH) ₂ ) _b1 -the aforementioned aryl or heteroaryl group is optionally substituted with one or more of the following groups: deuterium, halogen, cyano, nitro, amino, hydroxy, C ₁ -C ₆ Alkyl, halogen substituted C ₁ -C ₆ Alkyl, hydroxy substituted C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₁ -C ₆ Alkoxycarbonyl, halogen substituted C ₁ -C ₆ Alkoxy, hydroxy-substituted C ₁ -C ₆ Alkoxy, cyano-substituted C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl, C ₃ -C ₆ Cycloalkyloxy, phenyl, 5-6 membered heteroaryl, 3-6 membered heterocyclyl, -NHC (O) Ra ₅ 、-NHC(O)ORa ₆ and-NRa ₇ Ra ₈ Wherein Ra is ₅ 、Ra ₆ 、Ra ₇ And Ra (Ra) ₈ Each independently is a hydrogen atom, a halogen, a hydroxy group, C ₁ -C ₆ Alkoxy, cyano, nitro substituted or unsubstituted C _1-6 Alkyl, or from halogen, hydroxy, C ₁ -C ₆ Alkoxy, cyano, nitro substituted or unsubstituted C _3-6 Cycloalkyl;

b ₁ 1 or 2;

or A ₁ Is selected from the following groups:

n ₁ 0, 1, 2, 3 or 4;

R ₅ each independently selected from deuterium, halogen, hydroxy, amino, cyano, nitro, straight or branched C ₁ -C ₆ Alkyl, straight or branched C ₁ -C ₆ Alkoxy, C ₁ -C ₃ Acylamino, aminocarbonyl, phenyl, 5-6 membered heteroaryl, 3-6 membered heterocyclyl, C ₃ -C ₆ Cycloalkyl, C ₃ -C ₆ Cycloalkyl oxy, C ₁ -C ₃ Alkylaminocarbonyl, C ₁ -C ₃ Alkylsulfonyl, phenyloxy or 5-6 membered heteroaryloxy, when n ₁ >1, each R ₅ May be the same or different;

ii) a heterocyclic group selected from:

X ₃ c, N or O;

n ₄ 0, 1, 2 or 3;

n ₅ is 0, 1, 2 or 3,

Y ₁ 、Y ₂ each independently is hydrogen, deuterium, halogen, cyano, carboxyl, nitro, hydroxyl, amino, aminocarbonyl, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₁ -C ₆ Alkylcarbonyl, C ₁ -C ₆ Alkoxycarbonyl group, C ₁ -C ₆ Alkylsulfonyl, C ₁ -C ₆ Alkylaminocarbonyl, C ₃ -C ₆ Cycloalkyl or heterocyclyl, C ₁ -C ₆ Acylamino, halogen substituted C ₁ -C ₆ Alkyl, halogen substituted C ₁ -C ₆ Alkoxy, C ₁ -C ₃ Alkenyl, C ₁ -C ₃ Alkynyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, 6-10 membered aryl or 5-10 membered heteroaryl substituted C ₁ -C ₃ Wherein said substituted or unsubstituted 6-10 membered aryl or 5-10 membered heteroaryl means substituted with one or more of the following substituents: deuterium, halogen, cyano, nitro, hydroxy, amino, aminocarbonyl, C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Alkylcarbonyl, C ₁ -C ₃ Alkoxycarbonyl group, C ₁ -C ₃ Alkylsulfonyl, C ₁ -C ₃ Alkylaminocarbonyl, C ₃ -C ₆ Cycloalkyl or heterocyclyl, C ₁ -C ₃ Acylamino, halogen substituted C ₁ -C ₃ Alkyl, halogen substituted C ₁ -C ₃ An alkoxy group;

Y ₃ absent, or hydrogen, C ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkylaminocarbonyl, C ₁ -C ₆ Alkoxycarbonyl, halogen substituted C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkylsulfonyl, C ₁ -C ₆ Alkylcarbonyl, aminocarbonyl, C ₃ -C ₆ Heterocyclyl, C ₁ -C ₆ Acylamino, halogen substituted C ₁ -C ₆ Alkoxy, C ₁ -C ₃ Alkenyl, C ₁ -C ₃ Alkynyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, C ₅ -C ₁₀ Aryl or heteroaryl substituted C ₁ -C ₃ Wherein said substituted or unsubstituted 6-10 membered aryl or 5-10 membered heteroaryl means substituted with one or more of the following substituents: deuterium, halogen, cyano, nitro, hydroxy, amino, aminocarbonyl, C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Alkylcarbonyl, C ₁ -C ₃ Alkoxycarbonyl group, C ₁ -C ₃ Alkylsulfonyl, C ₁ -C ₃ Alkylaminocarbonyl, C ₃ -C ₆ Cycloalkyl or heterocyclyl, C ₁ -C ₃ Acylamino, halogen substituted C ₁ -C ₃ Alkyl, halogen substituted C ₁ -C ₃ An alkoxy group;

Y ₄ 、Y ₅ y being one or more substituents on the heterocycle in which it is located ₄ 、Y ₅ Each independently is deuterium, halogen, oxygen, C ₁ -C ₃ Alkyl, C ₁ -C ₃ Cycloalkyl, halogen substituted C ₁ -C ₃ Alkyl groupOr phenyl;

iii) A fused heterocyclic group selected from the group consisting of:

X ₄ c, N or O;

n ₆ 0, 1, 2 or 3;

n ₇ 0, 1, 2 or 3;

n ₈ 0, 1, 2, 3 or 4;

is a 6-10 membered aryl ring or a 5-10 membered heteroaryl ring, preferably, -/->The ring is selected from benzene ring, pyridine ring, thiophene ring, indole ring, benzothiophene ring, benzimidazole ring, naphthalene ring, quinoline ring or isoquinoline ring;

R ₈ each independently selected from hydrogen, deuterium, C ₁ -C ₃ Alkoxy, halogen, C ₁ -C ₃ Alkyl, C ₃ -C ₆ Cycloalkyl, carboxyl, C ₁ -C ₃ Alkylaminocarbonyl, C ₁ -C ₃ Alkoxycarbonyl, nitro, amino, cyano, halogen substituted C ₁ -C ₃ Alkyl, hydroxy, C ₁ -C ₃ Alkylsulfonyl, C ₁ -C ₃ Alkylamino, C ₁ -C ₃ Acylamino, aminocarbonyl, C ₃ -C ₆ Is substituted by C with heterocyclic groups, halogen ₁ -C ₃ Alkoxy, phenyl or 5-6 membered heteroaryl;

Y ₆ 、Y ₇ one or more substituents on the heterocycle in which they are located and are each independently selected from deuterium, halogen, C ₁ -C ₃ Alkyl, C ₁ -C ₃ Cycloalkyl, halogen substituted C ₁ -C ₃ An alkyl group;

iv) a spiroheterocyclyl selected from the group consisting of:

n _c1 0, 1, 2 or 3;

n _c2 0, 1, 2 or 3;

n _c3 1, 2 or 3;

n ₉ 0, 1, 2, 3 or 4;

is a 6-10 membered aryl ring or a 5-10 heteroaryl ring;

R ₉ independently selected from the following substituents: deuterium, halogen, cyano, nitro, hydroxy, amino, C ₁ -C ₃ Alkylamino, C ₁ -C ₃ Acylamino, aminocarbonyl, straight-chain or branched C ₁ -C ₆ Alkyl, straight or branched C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl oxy, C ₃ -C ₆ Cycloalkyl or heterocycloalkyl, C ₁ -C ₃ Alkylaminocarbonyl, C ₁ -C ₃ Alkoxycarbonyl group, C ₁ -C ₃ Alkylsulfonyl, halogen substituted C ₁ -C ₃ Alkyl, halogen substituted C ₁ -C ₃ Alkoxy, phenyl, 5-6 membered heteroaryl;

R ₁₀ 、R ₁₁ independently selected from the group consisting of hydrogen, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, said substitution pattern being as defined aboveR is a substituent on the ring ₉ The same;

Y ₈ is a substituent in the non-aromatic structural part of the spiro structure, wherein the substituent is optionally substituted by hydrogen atom, and Y8 is optionally substituted by deuterium, halogen or C ₁ -C ₃ Alkyl, C ₁ -C ₃ Cycloalkyl, halogen substituted C ₁ -C ₃ Alkyl substituents are substituted.

Preferably, in the compound represented by the general formula (I), n is 1, 2, 3, 4 or 5;

X ₁ is-CH ₂ -, -NH-; -S-or-O-;

X ₂ is-CH ₂ -or-CO-;

R ₁ 、R ₂ 、R ₃ each independently hydrogen, deuterium, or halogen;

a is:

i)A ₁ -NH-：

b ₁ 1 or 2;

or A ₁ Is selected from the following groups:

n ₁ 0, 1, 2, 3 or 4;

ii) a heterocyclic group selected from:

wherein Y is ₁ 、Y ₂ Each independently is hydrogen, deuterium, halogen, cyano, carboxyl, nitro, hydroxyl, amino, aminocarbonyl, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₁ -C ₆ Alkylcarbonyl, C ₁ -C ₆ Alkoxycarbonyl group, C ₁ -C ₆ Alkylsulfonyl, C ₁ -C ₆ Alkylaminocarbonyl, C ₃ -C ₆ Cycloalkyl or heterocyclyl, C ₁ -C ₆ Acylamino, halogen substituted C ₁ -C ₆ Alkyl, halogen substituted C ₁ -C ₆ Alkoxy, C ₁ -C ₃ Alkenyl, C ₁ -C ₃ Alkynyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, 6-10 membered aryl or 5-10 membered heteroaryl substituted C ₁ -C ₃ Wherein said substituted or unsubstituted 6-10 membered aryl or 5-10 membered heteroaryl means substituted with one or more of the following substituents: deuterium, halogen, cyano, nitro, hydroxy, amino, aminocarbonyl, C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Alkylcarbonyl, C ₁ -C ₃ Alkoxycarbonyl group, C ₁ -C ₃ Alkylsulfonyl, C ₁ -C ₃ Alkylaminocarbonyl, C ₃ -C ₆ Cycloalkyl or heterocyclyl, C ₁ -C ₃ Acylamino, halogen substituted C ₁ -C ₃ Alkyl, halogen substituted C ₁ -C ₃ An alkoxy group;

Y ₃ absent, or C ₁ -C ₆ Alkylcarbonyl, aminocarbonyl, C ₃ -C ₆ Heterocyclyl, C ₁ -C ₆ Acylamino, halogen substituted C ₁ -C ₆ Alkoxy, C ₁ -C ₃ Alkenyl, C ₁ -C ₃ Alkynyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, C ₅ -C ₁₀ Aryl or heteroaryl substituted C ₁ -C ₃ Wherein said substituted or unsubstituted 6-10 membered aryl or 5-10 membered heteroaryl means substituted with one or more of the following substituents: deuterium, halogen, cyano, nitro, hydroxy, amino, aminocarbonyl, C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Alkylcarbonyl, C ₁ -C ₃ Alkoxycarbonyl group, C ₁ -C ₃ Alkylsulfonyl, C ₁ -C ₃ Alkylaminocarbonyl, C ₃ -C ₆ Cycloalkyl or heterocyclyl, C ₁ -C ₃ Acylamino, halogen substituted C ₁ -C ₃ Alkyl, halogen substituted C ₁ -C ₃ An alkoxy group; the aforementioned 6-10 membered aryl group is preferably selected from phenyl, naphthyl, and the aforementioned 5-10 membered heteroaryl group is preferably selected from thienyl, pyridyl, benzothienyl, benzimidazolyl, indolyl, quinolinyl, isoquinolinyl;

Y ₄ 、Y ₅ y being one or more substituents on the heterocycle in which it is located ₄ Y5 is each independently deuterium, halogen, oxygen, C ₁ -C ₃ Alkyl, C ₁ -C ₃ Cycloalkyl or phenyl;

iii) A fused heterocyclic group selected from the group consisting of:

n ₈ 0, 1, 2, 3 or 4;

X ₄ c, N or O;

is a 6-10 membered aryl ring or a 5-10 membered heteroaryl ring, wherein +.>The ring is preferably selected from a benzene ring, a pyridine ring, a thiophene ring, an indole ring, a naphthalene ring, a benzothiophene ring, a benzimidazole ring, a quinoline ring or an isoquinoline ring;

R ₈ each independently selected from hydrogen, deuterium, C ₁ -C ₃ Alkoxy, halogen, C ₁ -C ₃ Alkyl, C ₃ -C ₆ Cycloalkyl, carboxyl, C ₁ -C ₃ Alkylaminocarbonyl, C ₁ -C ₃ Alkoxycarbonyl, nitro, amino, cyano, halogen substituted C ₁ -C ₃ Alkyl, hydroxy, C ₁ -C ₃ Alkylsulfonyl, C ₁ -C ₃ Alkylamino, C ₁ -C ₃ Acylamino, aminocarbonyl, C ₃ -C ₆ Is substituted by C with heterocyclic groups, halogen ₁ -C ₃ Alkoxy, phenyl or 5-6 membered heteroaryl, wherein when n ₈ >1, each R ₈ May be the same or different;

or iv) a spiroheterocyclyl selected from the group consisting of:

wherein n is ₉ 0, 1, 2, 3 or 4;

is a 6-to 10-membered aryl ring or a 5-to 10-heteroaryl ring, preferably a thiophene ring, a pyrrole ring, a benzene ring, a pyridine ring, a benzothiophene ring, a benzimidazole ring, an indole ring, a quinoline ring, and an isoquinoline ring;

R ₉ independently selected from the following substituents: deuterium, halogen, cyano, nitro, hydroxy, amino, C ₁ -C ₃ Alkylamino, C ₁ -C ₃ Acylamino, aminocarbonyl, straight-chain or branched C ₁ -C ₆ Alkyl, straight or branched C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl oxy, C ₃ -C ₆ Cycloalkyl or heterocycloalkyl, C ₁ -C ₃ Alkylaminocarbonyl, C ₁ -C ₃ Alkoxycarbonyl group, C ₁ -C ₃ Alkylsulfonyl, halogen substituted C ₁ -C ₃ Alkyl, halogen substituted C ₁ -C ₃ Alkoxy, phenyl, 5-6 membered heteroaryl, wherein when n ₉ >1, each R ₉ May be the same or different;

Further preferably, in the compound represented by the general formula (I), n is 1, 2, 3, 4 or 5;

X ₁ is-CH ₂ -, -NH-; -S-or-O-;

X ₂ is-CH ₂ -or-CO-;

R ₁ 、R ₂ 、R ₃ each independently hydrogen, deuterium or fluorine;

l is (CH) ₂ ) _b3 Or is absent;

b ₃ 1, 2, 3, 4 or 5;

a is:

i)A ₁ -NH-：

A ₁ is a 6-10 membered aryl, a 5-10 membered heteroaryl, (6-10 membered aryl) - (CH) ₂ ) _b1 -, (5-10 membered heteroaryl) - (CH) ₂ ) _b1 -, the aforementioned 6-10 membered aryl or 5-10 membered heteroaryl may be unsubstituted or substituted;

the substituted or unsubstituted 6-10 membered aryl or 5-10 membered heteroaryl is selected from the following groups:

b ₁ 1 or 2;

n ₂ 0, 1, 2 or 3;

n ₃ 0, 1, 2 or 3;

R ₆ 、R ₇ each independently selected from the following groups: deuterium, halogen, cyano, nitro, amino, hydroxy, C ₁ -C ₆ Alkyl, halogen substituted C ₁ -C ₆ Alkyl, hydroxy substituted C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₁ -C ₆ Alkoxycarbonyl, halogen substituted C ₁ -C ₆ Alkoxy, hydroxy-substituted C ₁ -C ₆ Alkoxy, cyano-substituted C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl, C ₃ -C ₆ Cycloalkyloxy, phenyl, C ₅ -C ₆ Heteroaryl, C ₃ -C ₆ Heterocyclyl, -NHC (O) Ra ₅ 、-NHC(O)ORa ₆ 、-NRa ₇ Ra ₈ The method comprises the steps of carrying out a first treatment on the surface of the Wherein Ra is ₅ 、Ra ₆ 、Ra ₇ And Ra (Ra) ₈ Each independently is a hydrogen atom, C substituted by halogen, hydroxy, cyano _1-6 Alkyl, or C substituted by halogen, hydroxy, cyano _3-6 Cycloalkyl, wherein when n ₂ >1 or n ₃ >1, R ₆ And R is ₇ Each of which may be the same or different;

or A ₁ Is selected from the following groups:

n ₁ 0, 1, 2, 3 or 4;

ii) a heterocyclic group selected from:

n ₁₀ 0, 1, 2, 3, 4 or 5;

Y ₁ selected from hydrogen, deuterium, halogen, cyano, carboxyl, nitro, hydroxyl, amino, aminocarbonyl, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₁ -C ₆ Alkylcarbonyl, C ₁ -C ₆ Alkoxycarbonyl group, C ₁ -C ₆ Alkylsulfonyl, C ₁ -C ₆ Alkylaminocarbonyl, C ₃ -C ₆ Cycloalkyl or heterocyclyl, C ₁ -C ₆ Acylamino, halogen substituted C ₁ -C ₆ Alkyl, halogen substituted C ₁ -C ₆ Alkoxy, C ₁ -C ₃ Alkenyl, C ₁ -C ₃ Alkynyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, 6-10 membered aryl or 5-10 membered heteroaryl substituted C ₁ -C ₃ Wherein said substituted or unsubstituted 6-10 membered aryl or 5-10 membered heteroaryl means substituted with one or more of the following substituents: deuterium, halogen, cyano, nitro, hydroxy, amino, aminocarbonyl, C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Alkylcarbonyl, C ₁ -C ₃ Alkoxycarbonyl group, C ₁ -C ₃ Alkylsulfonyl, C ₁ -C ₃ Alkylaminocarbonyl, C ₃ -C ₆ Cycloalkyl or heterocyclyl, C ₁ -C ₃ Acylamino, halogen substituted C ₁ -C ₃ Alkyl, halogen substituted C ₁ -C ₃ An alkoxy group;

selected from substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, preferably 6-10 membered aryl or 5-10 membered heteroaryl is preferably selected from thienyl, pyridyl, phenyl, benzothienyl, benzimidazolyl, indolyl, naphthyl, quinolinyl, isoquinolinyl;

R ₁₀ each independently is deuterium, halogen, cyano, nitro, hydroxy, amino, aminocarbonyl, C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Alkylcarbonyl, C ₁ -C ₃ Alkoxycarbonyl group, C ₁ -C ₃ Alkylsulfonyl, C ₁ -C ₃ Alkylaminocarbonyl, C ₃ -C ₆ Cycloalkyl or heterocyclyl, C ₁ -C ₃ Acylamino, halogen substituted C ₁ -C ₃ Alkyl, halogen substituted C ₁ -C ₃ Alkoxy, when n ₁₀ >1, each ofR ₁₀ May be the same or different;

Y ₄ 、Y ₅ y being one or more substituents on the heterocycle in which it is located ₄ Y5 is each independently deuterium, halogen, methyl, ethyl, cyclopropyl or phenyl;

iii) A fused heterocyclic group selected from the group consisting of:

n ₈ 0, 1, 2, 3 or 4;

X ₄ c, N or O;

Y ₆ 、Y ₇ one or more substituents on the heterocycle on which they are located, and are each independently selected from deuterium, halogen, methyl, ethyl, cyclopropyl, trifluoromethyl;

or iv) a spiroheterocyclyl selected from the group consisting of:

wherein n is ₉ 0, 1, 2, 3 or 4;

R ₉ each independently selected from the following substituents: deuterium, halogen, cyano, nitro, hydroxyAmino, C ₁ -C ₃ Alkylamino, C ₁ -C ₃ Acylamino, aminocarbonyl, straight-chain or branched C ₁ -C ₆ Alkyl, straight or branched C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl oxy, C ₃ -C ₆ Cycloalkyl or heterocycloalkyl, C ₁ -C ₃ Alkylaminocarbonyl, C ₁ -C ₃ Alkoxycarbonyl group, C ₁ -C ₃ Alkylsulfonyl, halogen substituted C ₁ -C ₃ Alkyl, halogen substituted C ₁ -C ₃ Alkoxy, phenyl, 5-6 membered heteroaryl, wherein when n ₉ >1, each R ₉ May be the same or different;

Y ₈ y8 is optionally substituted with deuterium, halogen, methyl, ethyl, cyclopropyl, trifluoromethyl substituents, which are substituents in the non-aromatic moiety of the spiro structure.

In a preferred embodiment, wherein the compound represented by the general formula (I) is a compound represented by any one of the general formulae (I-1) to (I-8):

wherein n is 1, 2, 3, 4 or 5;

X ₁ is-CH ₂ -, -NH-; -S-or-O-;

X ₂ is-CH ₂ -or-CO-;

R ₁ 、R ₂ 、R ₃ each independently hydrogen, deuterium or fluorine;

l is (CH) ₂ ) _b3 Or is absent;

b ₃ 1, 2, 3, 4 or 5;

n ₉ 0, 1, 2, 3 or 4;

is a 6-10 membered aryl ring or a 5-10 heteroaryl ring, and +.>Condensed with the spiro nucleus to form a spiroheterocyclyl group, preferably, -/->Thiophene ring, pyrrole ring, benzene ring, pyridine ring, benzothiophene ring, benzimidazole ring, indole ring, quinoline ring and isoquinoline ring;

Y ₈ a substituent optionally substituted for a hydrogen atom in the non-aromatic moiety of the spiro structure, Y8 being optionally substituted with deuterium, halogen, methyl, ethyl, cyclopropyl, trifluoromethyl substituents;

R ₉ each independently selected from the following substituents: deuterium, halogen, cyano, nitro, hydroxy, amino, C ₁ -C ₃ Alkylamino, C ₁ -C ₃ Acylamino, aminocarbonyl, straight-chain or branched C ₁ -C ₆ Alkyl, straight or branched C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl oxy, C ₃ -C ₆ Cycloalkyl or heterocycloalkyl, C ₁ -C ₃ Alkylaminocarbonyl, C ₁ -C ₃ Alkoxycarbonyl group, C ₁ -C ₃ Alkylsulfonyl, halogen substituted C ₁ -C ₃ Alkyl, halogen substituted C ₁ -C ₃ Alkoxy, phenyl, 5-6 membered heteroaryl, wherein when n ₉ >1, each R ₉ May be the same or different.

In a preferred embodiment, wherein the compound represented by the general formula (I) is a compound represented by any one of the general formulae (I-9) to (I-16):

wherein n is 1, 2, 3, 4 or 5;

X ₁ is-CH ₂ -, -NH-; -S-or-O-;

X ₂ is-CH ₂ -or-CO-;

R ₁ 、R ₂ 、R ₃ each independently hydrogen, deuterium or fluorine;

l is (CH) ₂ ) _b3 Or is absent;

b ₃ 1, 2, 3, 4 or 5;

n ₉ 0, 1, 2, 3 or 4;

R ₉ each independently selected from the following substituents: deuterium, halogen, cyano, nitro, hydroxy, amino, C ₁ -C ₃ Alkylamino, C ₁ -C ₃ Acylamino, aminocarbonyl, straight-chain or branched C ₁ -C ₆ Alkyl, straight or branched C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl oxy, C ₃ -C ₆ Cycloalkyl or heterocycloalkyl, C ₁ -C ₃ Alkylaminocarbonyl, C ₁ -C ₃ Alkoxycarbonyl group, C ₁ -C ₃ Alkylsulfonyl, halogen substituted C ₁ -C ₃ Alkyl, halogen substituted C ₁ -C ₃ Alkoxy, phenyl, 5-6 membered heteroaryl, wherein when n ₉ >1, each R ₉ May be the same or different;

In a preferred embodiment, wherein the compound represented by the general formula (I) is a compound represented by any one of the general formulae (I-17) or (I-18):

wherein n is 1, 2, 3, 4 or 5;

X ₁ is-CH ₂ -, -NH-; -S-or-O-;

X ₂ is-CH ₂ -or-CO-;

R ₁ 、R ₂ 、R ₃ each independently hydrogen, deuterium or fluorine;

l is (CH) ₂ ) _b3 Or is absent;

b ₃ 1, 2, 3, 4 or 5;

n ₉ 0, 1, 2, 3 or 4;

n ₁₀ 0, 1, 2, 3, 4 or 5;

Y ₁ each independently selected from hydrogen, deuterium, halogen, cyano, carboxyl, nitro, hydroxyl, amino, aminocarbonyl, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₁ -C ₆ Alkylcarbonyl, C ₁ -C ₆ Alkoxycarbonyl group, C ₁ -C ₆ Alkylsulfonyl, C ₁ -C ₆ Alkylaminocarbonyl, C ₃ -C ₆ Cycloalkyl or heterocyclyl, C ₁ -C ₆ Acylamino, halogen substituted C ₁ -C ₆ Alkyl, halogen substituted C ₁ -C ₆ Alkoxy, C ₁ -C ₃ Alkenyl, C ₁ -C ₃ Alkynyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, 6-10 membered aryl or 5-10 membered heteroaryl substituted C ₁ -C ₃ Wherein said substituted or unsubstituted 6-10 membered aryl or 5-10 membered heteroaryl means substituted with one or more of the following substituents: deuterium, halogen, cyano, nitro, hydroxy, amino, aminocarbonyl, C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Alkylcarbonyl, C ₁ -C ₃ Alkoxycarbonyl group, C ₁ -C ₃ Alkylsulfonyl, C ₁ -C ₃ Alkylaminocarbonyl, C ₃ -C ₆ Cycloalkyl or heterocyclyl, C ₁ -C ₃ Acylamino, halogen substituted C ₁ -C ₃ Alkyl, halogen substituted C ₁ -C ₃ An alkoxy group;

selected from substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, preferably 6-10 membered aryl orThe 5-10 membered heteroaryl is selected from thienyl, pyridyl, phenyl, benzothienyl, benzimidazolyl, indolyl, naphthyl, quinolinyl, isoquinolinyl;

R ₁₀ each independently selected from deuterium, halogen, cyano, nitro, hydroxy, amino, aminocarbonyl, C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Alkylcarbonyl, C ₁ -C ₃ Alkoxycarbonyl group, C ₁ -C ₃ Alkylsulfonyl, C ₁ -C ₃ Alkylaminocarbonyl, C ₃ -C ₆ Cycloalkyl or heterocyclyl, C ₁ -C ₃ Acylamino, halogen substituted C ₁ -C ₃ Alkyl, halogen substituted C ₁ -C ₃ Alkoxy, when n ₁₀ >1, each R ₁₀ May be the same or different.

In a preferred embodiment, wherein the compound represented by the general formula (I) is a compound represented by any one of the general formulae (I-19) to (I-22):

wherein n is 1, 2, 3, 4 or 5;

X ₁ is-CH ₂ -, -NH-; -S-or-O-;

X ₂ is-CH ₂ -or-CO-;

R ₁ 、R ₂ 、R ₃ each independently hydrogen, deuterium or fluorine;

l is (CH) ₂ ) _b3 Or is absent;

b ₃ 1, 2, 3, 4 or 5;

n ₈ 0, 1, 2, 3 or 4;

X ₄ c, N or O;

R ₈ each independently is hydrogen, deuterium, C ₁ -C ₃ Alkoxy, halogen, C ₁ -C ₃ Alkyl, C ₃ -C ₆ Cycloalkyl, carboxyl, C ₁ -C ₃ AlkylaminocarbonylRadical, C ₁ -C ₃ Alkoxycarbonyl, nitro, amino, cyano, halogen substituted C ₁ -C ₃ Alkyl, hydroxy, C ₁ -C ₃ Alkylsulfonyl, C ₁ -C ₃ Alkylamino, C ₁ -C ₃ Acylamino, aminocarbonyl, C ₃ -C ₆ Is substituted by C with heterocyclic groups, halogen ₁ -C ₃ Alkoxy, phenyl or 5-6 membered heteroaryl, wherein when n ₈ >1, each R ₈ May be the same or different;

Y ₆ 、Y ₇ is one or more substituents on the heterocycle in which it is located, and each is independently selected from deuterium, halogen, methyl, ethyl, cyclopropyl, trifluoromethyl.

In a preferred embodiment, wherein the compound represented by the general formula (I) is a compound represented by any one of the general formulae (I-23) to (I-32):

wherein n is 1, 2 or 3;

X ₂ is-CH ₂ -or-CO-;

R ₁ 、R ₂ 、R ₃ each independently hydrogen, deuterium or fluorine;

l is (CH) ₂ ) _b3 Or is absent;

b ₃ 1, 2, 3, 4 or 5;

n ₈ 、n ₉ 、n ₁₀ each independently selected from 0, 1, 2, 3 or 4;

X ₄ c, N or O;

R ₉ selected from the following substituents: deuterium, halogen, cyano, nitro, hydroxy, amino, C ₁ -C ₃ Alkylamino, C ₁ -C ₃ Acylamino, aminocarbonyl, straight-chain or branched C ₁ -C ₆ Alkyl, straight or branched C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl oxy, C ₃ -C ₆ Cycloalkyl or heterocycloalkyl,C ₁ -C ₃ Alkylaminocarbonyl, C ₁ -C ₃ Alkoxycarbonyl group, C ₁ -C ₃ Alkylsulfonyl, halogen substituted C ₁ -C ₃ Alkyl, halogen substituted C ₁ -C ₃ Alkoxy, phenyl, 5-6 membered heteroaryl, wherein when n ₉ >1, each R ₉ May be the same or different;

selected from substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, preferably 6-10 membered aryl or 5-10 membered heteroaryl selected from thienyl, pyridyl, phenyl, benzothienyl, benzimidazolyl, indolyl, naphthyl, quinolinyl, isoquinolinyl;

R ₁₀ each independently selected from deuterium, halogen, cyano, nitro, hydroxy, amino, aminocarbonyl, C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Alkylcarbonyl, C ₁ -C ₃ Alkoxycarbonyl group, C ₁ -C ₃ Alkylsulfonyl, C ₁ -C ₃ Alkylaminocarbonyl, C ₃ -C ₆ Cycloalkyl or heterocyclyl, C ₁ -C ₃ Acylamino, halogen substituted C ₁ -C ₃ Alkyl, halogen substituted C ₁ -C ₃ Alkoxy, when n ₁₀ >1, each R ₁₀ May be the same or different;

R ₈ each independently selected from hydrogen, deuterium, C ₁ -C ₃ Alkoxy, halogen, C ₁ -C ₃ Alkyl, C ₃ -C ₆ Cycloalkyl, carboxyl, C ₁ -C ₃ Alkylaminocarbonyl, C ₁ -C ₃ Alkoxycarbonyl, nitro, amino, cyano, halogen substituted C ₁ -C ₃ Alkyl, hydroxy, C ₁ -C ₃ Alkylsulfonyl, C ₁ -C ₃ Alkylamino, C ₁ -C ₃ Acylamino, aminocarbonyl, C ₃ -C ₆ Is substituted by C with heterocyclic groups, halogen ₁ -C ₃ Alkoxy radicalRadicals, phenyl radicals or 5-to 6-membered heteroaryl radicals, when n ₈ >1, each R ₈ May be the same or different.

In a preferred embodiment, wherein the compound represented by the general formula (I) is a compound represented by any one of the general formulae (I-33) to (I-42):

wherein n is 1, 2 or 3;

X ₂ is-CH ₂ -or-CO-;

R ₁ 、R ₂ 、R ₃ each independently hydrogen, deuterium or fluorine;

l is (CH) ₂ ) _b3 Or is absent;

b ₃ 1, 2, 3, 4 or 5;

n ₈ 、n ₉ 、n ₁₀ each independently 0, 1, 2, 3, or 4;

X ₄ selected from C, N or O;

R ₉ each independently selected from the following substituents: deuterium, halogen, cyano, nitro, hydroxy, amino, C ₁ -C ₃ Alkylamino, C ₁ -C ₃ Acylamino, aminocarbonyl, straight-chain or branched C ₁ -C ₆ Alkyl, straight or branched C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl oxy, C ₃ -C ₆ Cycloalkyl or heterocycloalkyl, C ₁ -C ₃ Alkylaminocarbonyl, C ₁ -C ₃ Alkoxycarbonyl group, C ₁ -C ₃ Alkylsulfonyl, halogen substituted C ₁ -C ₃ Alkyl, halogen substituted C ₁ -C ₃ Alkoxy, phenyl, 5-6 membered heteroaryl, when n ₉ >1, each R ₉ May be the same or different;

selected from substituted or unsubstituted 6-10 membered aryl, substitutedOr unsubstituted 5-10 membered heteroaryl, preferably 6-10 membered aryl or 5-10 membered heteroaryl is selected from thienyl, pyridyl, phenyl, benzothienyl, benzimidazolyl, indolyl, naphthyl, quinolinyl, isoquinolinyl;

R ₈ each independently selected from hydrogen, deuterium, C ₁ -C ₃ Alkoxy, halogen, C ₁ -C ₃ Alkyl, C ₃ -C ₆ Cycloalkyl, carboxyl, C ₁ -C ₃ Alkylaminocarbonyl, C ₁ -C ₃ Alkoxycarbonyl, nitro, amino, cyano, halogen substituted C ₁ -C ₃ Alkyl, hydroxy, C ₁ -C ₃ Alkylsulfonyl, C ₁ -C ₃ Alkylamino, C ₁ -C ₃ Acylamino, aminocarbonyl, C ₃ -C ₆ Is substituted by C with heterocyclic groups, halogen ₁ -C ₃ Alkoxy, phenyl or 5-6 membered heteroaryl, wherein when n ₈ >1, each R ₈ May be the same or different.

In a preferred embodiment, wherein the compound represented by the general formula (I) is a compound represented by any one of the general formulae (I-43) to (I-50):

wherein n is 1, 2 or 3;

X ₁ is-CH ₂ -or-O-;

X ₂ is-CH ₂ -or-CO-;

R ₁ 、R ₂ 、R ₃ each independently hydrogen, deuterium or fluorine;

l is (CH) ₂ ) _b3 Or is absent;

b ₃ 1, 2, 3, 4 or 5;

n ₂ 0, 1, 2 or 3;

n ₃ 0, 1, 2 or 3;

n ₁₁ 0, 1 or 2;

R ₆ and R is ₇ Each independently selected from the following groups: deuterium, halogen, cyano, nitro, amino, hydroxy, C ₁ -C ₆ Alkyl, halogen substituted C ₁ -C ₆ Alkyl, hydroxy substituted C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₁ -C ₆ Alkoxycarbonyl, halogen substituted C ₁ -C ₆ Alkoxy, hydroxy-substituted C ₁ -C ₆ Alkoxy, cyano-substituted C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl, C ₃ -C ₆ Cycloalkyloxy, phenyl, C ₅ -C ₆ Heteroaryl, C ₃ -C ₆ Heterocyclyl, -NHC (O) Ra ₅ 、-NHC(O)ORa ₆ 、-NRa ₇ Ra ₈ Wherein Ra is ₅ 、Ra ₆ 、Ra ₇ And Ra (Ra) ₈ Each independently selected from hydrogen atom, C substituted or unsubstituted by one or more substituents selected from halogen, hydroxy, cyano _1-6 Alkyl, C substituted or unsubstituted by one or more substituents selected from halogen, hydroxy, cyano _3-6 Cycloalkyl, when n ₂ >1 or n ₃ >1, R ₆ And R is ₇ Each may be the same or different.

In a preferred embodiment, wherein the compound represented by the general formula (I) is a compound represented by any one of the general formulae (I-51) to (I-58):

wherein n is 1, 2 or 3;

X ₁ is-CH ₂ -or-O-;

X ₂ is-CH ₂ -or-CO-;

R ₁ 、R ₂ 、R ₃ each independently hydrogen, deuterium or fluorine;

l is (CH) ₂ ) _b3 Or is absent;

b ₃ 1, 2, 3, 4 or 5;

n ₁ 0, 1, 2, 3 or 4;

R ₅ each independently selected from deuterium, halogen, hydroxy, amino, cyano, nitro, straight or branched C ₁ -C ₆ Alkyl, straight or branched C ₁ -C ₆ Alkoxy, C ₁ -C ₃ Acylamino, aminocarbonyl, phenyl, 5-6 membered heteroaryl, 3-6 membered heterocyclyl, C ₃ -C ₆ Cycloalkyl, C ₃ -C ₆ Cycloalkyl oxy, C ₁ -C ₃ Alkylaminocarbonyl, C ₁ -C ₃ Alkylsulfonyl, phenyloxy or 5-6 membered heteroaryloxy, when n ₁ >1, each R ₅ May be the same or different.

Most preferably, the compound represented by the general formula (I) is one of the following compounds:

/>

the compounds of formula (I) may contain one or more asymmetric or chiral centers and may therefore exist in different stereoisomeric forms. The compounds of the present invention include all stereoisomeric forms, including but not limited to diastereomers, enantiomers and atropisomers, and mixtures thereof (e.g., racemates), and are included within the scope of the present invention.

The term "substituted" means that one or more hydrogen atoms on a particular group is replaced with a particular substituent. Specific substituents are those described above with respect to the corresponding substituents, or those found in each of the examples. Unless otherwise specified, an optionally substituted group may have a substituent selected from a specific group at any substitutable site of the group, which may be the same or different at each position. A cyclic substituent, such as a heterocycloalkyl group, may be attached to another ring, such as a cycloalkyl group, to form a spirobicyclic ring system, e.g., two rings share one carbon atom.

Those skilled in the art will appreciate that combinations of substituents contemplated by the present invention are those that are stable or chemically achievable. Structural substitutions of interest in this invention, including both substituted and unsubstituted, e.g. "optionally" substituted with a substituent, are meant to include the meaning of substituted or unsubstituted with a substituent.

The R substituents mentioned in the present invention may be the same or different substituents when the number of substituents is >1, meaning that when the number of substituents is plural in a certain structure, the combination of substituents for R may be a substituent selected from plural different types.

The term "substitution" applies only to sites that can be substituted with substituents, excluding substitutions that are not available on existing chemical knowledge.

The compounds of formula (I) may also exist in different tautomeric forms, all of which are included within the scope of the invention.

The term "tautomer" refers to structural isomers of different energies that are interconverted via a low energy barrier, the reaction generally resulting in a shift in the form of hydrogen atoms or protons with a transition between a single bond and an adjacent double bond.

The term "enantiomer" refers to stereoisomers that are mirror images of each other and that are non-overlapping.

"diastereomers" refers to stereoisomers that have two or more chiral neutrals and that are not mirror images.

"racemate" refers to two stereoisomers that are mirror images of each other, having opposite optical rotations that cancel each other.

By "pharmaceutically acceptable salts" is meant those salts of the drug molecule with the corresponding organic acid, inorganic acid or organic base, inorganic base, such as hydrochloric acid, formic acid, trifluoroacetic acid, succinic acid, methanesulfonic acid, and the like.

"prodrugs" refers to compounds that are inactive or less active in vitro and which release active agents in vivo by enzymatic or non-enzymatic conversion to exert their potency.

"hydrate" refers to a compound that contains water.

The term "halogen" includes fluorine, chlorine, bromine or iodine.

The term "hydrocarbyl" refers to substituents containing only carbon and hydrogen atoms and includes, without limitation, methyl, ethyl, isopropyl, propyl, cyclohexyl, phenyl, and the like.

The term "C1-C6 alkyl" refers to straight or branched chain alkyl groups having 1 to 6 carbon atoms and includes, without limitation, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like.

The term "C1-C6 alkoxy" refers to straight or branched chain alkoxy groups having 1 to 6 carbon atoms, including without limitation methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like.

The term "C1-C6 alkoxycarbonyl" includes, without limitation, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentoxycarbonyl, and hexyloxycarbonyl, and the like.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent. Monocyclic cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentenyl, cyclohexyl. Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.

The term "heterocyclyl" refers to a heteroatom containing one or more saturated and/or partially saturated monocyclic or polycyclic cyclic substituents wherein one or more ring atoms are selected from nitrogen, oxygen, sulfur or S (O) m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon; for example, propylene oxide, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl; the heterocyclic group may be fused to an aryl, heteroaryl, or cycloalkyl ring, with the ring attached to the parent structure being a heterocyclic group.

The term "aryl" refers to a 6-14 membered all-carbon monocyclic or fused multicyclic group having a conjugated p-electron system, preferably a 6 to 10 membered ring, more preferably phenyl and naphthyl, most preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring.

The term "heteroaryl" refers to a 5-14 membered aryl group having 1 to 4 heteroatoms as ring atoms, the remaining ring atoms being carbon, wherein the heteroatoms include oxygen, sulfur and nitrogen. Preferably 5-10 membered. Heteroaryl is preferably 5-or 6-membered, such as thienyl, pyridyl, pyrrolyl, and the like. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring,

the term "spiroheterocyclyl" refers to a polycyclic heterocyclic group having one atom in common between the monocyclic rings, known as a spiro atom, wherein one or more of the ring atoms is selected from nitrogen, oxygen, sulfur or a heteroatom of S (O) m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon. The spiroheterocycle may be fused to a 6-10 membered aryl or 5-10 membered heteroaryl ring, wherein the ring attached to the parent structure is a spiroheterocycle.

The term "halo-substituted alkyl" refers to a straight, branched or cyclic alkyl substituted with single or multiple halo groups, including without limitation 2-bromoethyl, 2-bromopropyl, and the like.

The term "alkenyl" refers to alkenyl groups which may be 2 to 10 carbons, such as ethenyl, propenyl, butenyl, styryl, phenylpropenyl.

The term "alkynyl" refers to alkynyl groups which may be 2 to 10 carbons such as ethynyl, propynyl, butynyl, phenylethynyl, phenylpropynyl.

The term "C3-C8 cycloalkyl" refers to a cyclic alkyl group having 3 to 8 carbon atoms in the ring, including, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

The term "5-10 membered heterocyclyl" refers to a ring containing one or more saturated and/or partially saturated rings comprising 5 to 10 ring atoms, wherein one or more ring atoms are selected from nitrogen, oxygen, sulfur or S (O) heteroatoms m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon; for example, propylene oxide, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl.

The term "C3-C6 heterocyclyl" refers to a heteroatom containing one or more saturated and/or partially saturated rings comprising 3 to 6 ring atoms, wherein one or more ring atoms are selected from nitrogen, oxygen, sulfur or S (O) m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon; for example, propylene oxide, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl.

The term "hydroxy-substituted alkyl" refers to a straight, branched or cyclic alkyl group substituted with a single or multiple hydroxy groups, including without limitation (S) -1-hydroxyisobutyr-2-yl, (R) -1-hydroxyisobutyr-2-yl, and the like.

In the present invention, unless otherwise indicated, terms used have the ordinary meanings known to those skilled in the art.

The present invention also encompasses any of the novel intermediates disclosed herein.

In another aspect, the present invention provides a process for preparing a compound of formula (I), said process being selected from one of the following:

synthesis references WO2008115516A2, WO 2011100380A 1, WO2016065980A1, WO2007027527A2, WO2008027542A2 for the starting compounds, 1A, 2A.

The synthesis method comprises the following steps:

wherein R is ₁ 、R ₂ 、R ₃ 、X ₂ And n is as defined above;

m ₁ is an integer of 1 to 4;

compound H ₂ Definition of A in N-A and definition of i) A in A above ₁ -NH-, ii) heterocyclyl, iii) fused heterocyclyl, iv) spiroheterocyclyl are as defined;

step 1-1: the compound 1A and the 1B dibromo fatty alkane are subjected to nucleophilic reaction in the presence of potassium carbonate to obtain a compound 1C;

step 1-2: reacting the compound 1C with carboxyl-protected amino acid 1D in the presence of potassium carbonate to obtain a compound 1E;

step 1-3: closing the ring of the compound 1E in the presence of potassium tert-butoxide to obtain a piperidone derivative 1F;

step 1-4: removing the protecting group of the compound 1F under the acidic condition of dioxane hydrochloride to obtain 1G;

Step 1-5: compounds 1G and 1H gave 1I under condensing agent conditions;

the synthesis method II comprises the following steps:

wherein R is ₁ 、R ₂ 、R ₃ 、X ₂ And n is as defined above;

m ₂ is an integer of 1 to 3;

step 2-1 Compounds 2A and 2B in dipolar organic solvent such as DMF, DMA, etc. as solvent, pd catalyst (such as Pd (PPh) ₃ ) ₄ 、Pd(PPh ₃ ) ₂ Cl ₂ Etc.), a monovalent copper catalyst (iodinated ketone) and a base (such as triethylamine or diisopropylethylamine, etc.), and carrying out a Sonogashira coupling reaction at room temperature or under heating conditions to obtain a compound 2C;

step 2-2 Compound 2C is reduced to Compound 2D by hydrogen under the catalysis of Pd/C, raney Nickel or other metal catalysts (e.g., wilkinson catalyst),

step 2-3, reacting the compound 2D in the presence of triphenylphosphine and carbon tetrabromide to obtain a compound 2E;

step 2-4, reacting the compound 2E with carboxyl-protected amino acid 1D in the presence of potassium carbonate to obtain a compound 2F;

step 2-5: removing the protecting group of the compound 2F under the acidic condition of dioxane hydrochloride to obtain 2G;

step 2-6: compounds 2G and 1H gave 2I under condensing agent conditions.

The compound of the invention can be prepared into pharmaceutically acceptable salts including inorganic acid salts and organic acid salts when the compound contains basic groups. Suitable salts forming acids include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid, and organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, and the like; acidic amino acids such as aspartic acid and glutamic acid.

The compound shown in the general formula (I) of the invention, tautomer, diastereomer, racemate, metabolic precursor, metabolite, isotopic compound, pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or crystal form of the compound can regulate CRL4 ^CRBN E3 ubiquitin ligase activity.

In another aspect, the invention provides a pharmaceutical composition comprising a therapeutically effective amount of one or more selected from the group consisting of a compound of formula (I), a tautomer, diastereomer, racemate, metabolic precursor, metabolite, isotopic compound, pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, and crystal form thereof, and at least one pharmaceutically acceptable carrier.

The pharmaceutical compositions of the present invention may also comprise one or more additional pharmaceutically active ingredients. The compound shown in the general formula (I), or a tautomer, enantiomer, diastereomer, racemate, metabolic precursor, metabolite, isotopic compound, pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or crystal form thereof can generate synergistic effect with one or more other pharmaceutically active ingredients in the process of preventing or treating specific diseases or functional disorders, or can also reduce or eliminate toxic and side effects generated by one or more other pharmaceutically active ingredients in the process of preventing or treating specific diseases or functional disorders, and vice versa.

The additional one or more pharmaceutically therapeutically active ingredients include macromolecular compounds such as proteins, polysaccharides, nucleic acids, and the like; and small molecule compounds such as inorganic compounds, organometallic compounds, organic small molecule compounds of synthetic or natural origin, and the like.

Typical formulations of the pharmaceutical compositions of the present invention are prepared by mixing one or more selected from the group consisting of the compounds represented by the general formula (I) of the present invention, tautomers, diastereomers, racemates, metabolic precursors, metabolites, isotopic compounds, pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates and crystal forms thereof, and a carrier (e.g., diluent, excipient, etc.). Suitable carriers are well known to those skilled in the art and include materials such as carbohydrates, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like. The particular carrier, diluent or excipient used will depend upon the manner and purpose of use of the compounds of the present invention. The solvent is generally selected based on the solvent that one of ordinary skill in the art would consider to be safe and effective for administration to mammals. Generally, safe solvents are non-toxic aqueous solvents such as pharmaceutical water, and other non-toxic solvents that are soluble in or miscible with water. Suitable aqueous solvents include one or more of water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG400, PEG 300), and the like. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, flavorants, flavoring agents or other known additives to make or use the compound represented by formula (I) in an acceptable form.

When the compound of formula (I) of the present invention is used in combination with at least one other drug, the two or more drugs may be used separately or in combination, preferably in the form of a pharmaceutical composition. The compounds or pharmaceutical compositions of the invention of formula (I) may be administered to a subject separately or together in any known form of oral, intravenous, rectal, vaginal, transdermal, other topical or systemic administration.

These pharmaceutical compositions may also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, flavorants, flavoring agents or other known additives to make the pharmaceutical composition acceptable for manufacture or use.

The medicament of the invention is preferably administered orally. Solid dosage forms for oral administration may include capsules, tablets, powders or granular formulations. In solid dosage forms, the compounds or pharmaceutical compositions of the invention are admixed with at least one inert excipient, diluent or carrier. Suitable excipients, diluents or carriers include substances such as sodium citrate or dicalcium phosphate, or starches, lactose, sucrose, mannitol, silicic acid and the like; binders such as carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, acacia, and the like; humectants such as glycerin and the like; disintegrants such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, specific complex silicates, sodium carbonate, and the like; solution retarders such as paraffin and the like; absorption promoters such as quaternary ammonium compounds and the like; adsorbents such as kaolin, bentonite, and the like; lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and the like. In the case of capsules and tablets, the dosage form may also include buffering agents. Solid compositions of a similar type may also be used as fillers in soft and hard filled gelatin capsules using lactose as well as high molecular weight polyethylene glycols and the like as excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the compounds of the present invention or compositions thereof, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents; solubilizing agents and emulsifiers such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide; oils (e.g., cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, sesame oil, etc.); glycerol; tetrahydrofurfuryl alcohol; fatty acid esters of polyethylene glycol and sorbitan; or a mixture of several of these, etc.

In addition to these inert diluents, the compositions can also include excipients such as one or more of wetting agents, emulsifying agents, suspending agents, sweetening, flavoring and perfuming agents.

For the suspension, in addition to the compound or combination of the present invention, a carrier such as suspending agent, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, sorbitan ester, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth, or a mixture of several of these substances, and the like may be further contained.

Compositions for rectal or vaginal administration, preferably suppositories, may be prepared by mixing the compounds or combinations of the present invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycols or suppository waxes which are solid at ordinary room temperature but liquid at body temperature and melt in the rectum or vagina to release the active compound.

The compounds or pharmaceutical compositions of the present invention may be administered in other topical dosage forms, including ointments, powders, sprays and inhalants. The medicament may be mixed under sterile conditions with a pharmaceutically acceptable excipient, diluent or carrier, and with any preservative, buffer or propellant required. Ophthalmic formulations, ophthalmic ointments, powders and solutions are also intended to be included within the scope of the present invention.

It is a further object of the present invention to provide a monotherapy or a combination therapy comprising administering at least one selected from the group consisting of a compound of general formula (I), a tautomer, a diastereomer, a racemate, a metabolic precursor, a metabolite, an isotopic compound, a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate) and a crystal form thereof to a subject in need of such treatment. When used in combination therapy, comprises a therapeutically effective dose of at least one member selected from the group consisting of compounds of formula (I), tautomers, diastereomers, racemates, metabolic precursors, metabolites, isotopic compounds, pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates, and crystalline forms thereof, and additionally one or more pharmaceutically active ingredients. The other one or more components with pharmaceutical therapeutic activity comprise macromolecular compounds such as proteins (antibodies or polypeptides), polysaccharides and nucleic acids (DNA or RNA) and the like; and small molecule compounds such as inorganic compounds, organometallic compounds, organic small molecule compounds of synthetic or natural origin, and the like; in addition, radiation, surgery, cell therapy, hormone therapy, cytokine therapy, or the like. The compound shown in the general formula (I), tautomer, diastereomer, racemate, metabolic precursor, metabolite, isotopic compound, pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or crystal form can generate synergistic effect with one or more other components with pharmaceutical therapeutic activity in the process of preventing or treating specific diseases or functional disorders, or can also reduce or eliminate toxic and side effects generated by one or more other components with pharmaceutical therapeutic activity in the process of preventing or treating specific diseases or functional disorders, and vice versa.

Another aspect of the present invention provides a pharmaceutical composition comprising one or more compounds selected from the group consisting of a compound represented by general formula (I), a tautomer, a diastereomer, a racemate, a metabolic precursor, a metabolite, an isotopic compound, a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, and crystalline form thereof, for use in preparing a therapeutic agent or CRL4 ^CRBN Use of a medicament for E3 ubiquitin ligase related diseases or disorders. The invention is described by CRL4 ^CRBN The related diseases or disorders in which the E3 ubiquitin ligase is involved include, but are not limited to, cancer, inflammation, pain, neurological diseases and immune system diseases.

In a preferred embodiment, the disease or disorder includes, but is not limited to: cancer, angiogenesis-related diseases or disorders, pain (including but not limited to complex regional pain syndrome), macular degeneration and related disorders, skin diseases, pulmonary disorders, immunodeficiency disorders, damage to the central nervous system, tnfα -related diseases or disorders.

In another preferred embodiment, the cancer includes (but is not limited to): skin cancer (such as melanoma), lymphatic system cancer, breast cancer, cervical cancer, uterine cancer, digestive tract cancer, lung cancer, ovarian cancer, prostate cancer, colon cancer, rectal cancer, oral cancer, brain tumor, head and neck cancer, throat cancer, testicular cancer, kidney cancer, pancreatic cancer, spleen cancer, liver cancer, bladder cancer, throat cancer, and cancer associated with aids. The compounds provided by the invention are also useful for treating hematological and myeloma, such as multiple myeloma, lymphoma and acute and chronic leukemia. The compounds provided by the invention can also be used for preventing or treating primary tumors and metastatic tumors.

The term "deuterium (D)" as used in the present invention is a non-radioactive isotope of hydrogen in a stable form having an atomic weight of 2.0144. The hydrogen in nature is in the form of a mixture of H (hydrogen or protium), D (2H or deuterium) and T (3H or tritium) isotopes, with deuterium abundance of 0.0156%. In all the structural formulae of the compounds containing natural hydrogen atoms, the hydrogen atoms are actually represented as a mixture of H, D and T, according to the knowledge of the person skilled in the art. Thus, compounds should be considered unnatural or deuterium-enriched when deuterium abundance at any site in the compound is greater than 0.0156% of their natural abundance.

The term "isotopic compound" as used herein means a compound of formula (I) of the present invention, a tautomer, diastereomer, racemate, metabolic precursor, metabolite, pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or crystal form thereof, comprising one or more isotopes of atoms in natural or unnatural abundance. Isotopically-labeled compounds of the present invention are also encompassed by the present invention except for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine, such as: ² Hydrogen, hydrogen, ³ Hydrogen, hydrogen, ¹¹ Carbon (C), ¹³ Carbon (C), ¹⁴ Carbon (C), ¹³ Nitrogen (N), ¹⁵ Nitrogen (N), ¹⁵ Oxygen (O), ¹⁷ Oxygen (O), ¹⁸ Oxygen (O), ³¹ Phosphorus (P), ³² Phosphorus (P), ³⁵ Sulfur, sulfur, ¹⁸ Fluorine (F), ¹²³ Iodine (I), ¹²⁵ Iodine and its preparation method ³⁶ Chlorine.

Certain isotopically-labeled compounds of the present invention (e.g., those labeled with 3H and 14C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3H) and carbon-14 (i.e., 14C) isotopes are particularly preferred because of their ease of preparation and detection. Moreover, substitution of heavier isotopes such as deuterium (i.e., 2H) can afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and therefore can be preferred in certain circumstances. Positron emitting isotopes, such as 15O, 13N, 11C and 18F, are used in Positron Emission Tomography (PET) studies to examine substrate receptor occupancy. Isotopically-labeled compounds of the present invention can generally be prepared following procedures analogous to those disclosed in the schemes and/or in the examples hereinbelow by substituting an isotopically-labeled reagent for a non-isotopically-labeled reagent. All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

Drawings

FIG. 1 shows the effect of compounds 82 and 150 on Ikaros and Aiolos protein levels.

Figure 2 shows the rate and pathway of degradation of Ikaros and Aiolos proteins by compound 82.

Detailed Description

The invention is further illustrated below in connection with specific examples which are not intended to limit the scope of the invention.

1. Preparation example

In all of the embodiments described herein, the present invention, ¹ h NMR was recorded by a nuclear magnetic resonance apparatus of Bruker Avance III-300 or Avance III-400 type, chemical shifts being expressed in delta (ppm); mass spectra were determined by MS mass spectrometry UPLC-MS (ESI); wherein UPLC model is Waters HPLC H-CLASS, MS (ESI) model is Waters SQ Detector; the anhydrous tetrahydrofuran is prepared by reflux drying and deoxidizing benzophenone/metallic sodium, and the anhydrous toluene and the anhydrous methylene dichloride are prepared by reflux drying of calcium chloride; solvents for column chromatography mobile phases such as petroleum ether, ethyl acetate and methylene dichloride are purchased from national pharmaceutical chemicals company; the thin layer chromatography silica gel plate (HSGF 254) used in the reaction detection is from the limited chemical reagent of the national medicine groupA company; the compound is separated from 200-300 mesh silica gel of chemical reagent company of national medicine group. The starting materials for the present invention may be obtained commercially, such as the main reagents purchased from national pharmaceutical community chemical reagent limited, or prepared by methods of inhibition in the art, or prepared according to the methods described in the present invention.

Reference is made to the synthesis method in synthesis method 1-synthesis method 2 described above.

1. Synthesis of intermediate compounds

Reference is made to the synthesis method of the above-mentioned synthesis method one and synthesis method two.

3-bromo-2-bromomethylbenzoic acid methyl ester:

after the reaction, the solvent was removed under reduced pressure, and the obtained residue was subjected to silica gel column chromatography to obtain 5.3g of methyl 3-bromo-2-bromomethylbenzoate as a colorless oil, with a yield of 98%; ¹ H NMR(400MHz,CDCl ₃ )δ7.88(dd,J＝7.8,1.3Hz,1H),7.76(dd,J＝8.0,1.3Hz,1H),7.22(t,J＝7.9Hz,1H),5.12(s,2H),3.95(s,3H).

3- (4-bromo-1-oxoisoindoline-2-) piperidine-2, 6 dione:

mmol), the reaction mixture was reacted at 80℃for 18 hours. After the reaction, the solvent was removed under reduced pressure, and the resultant precipitate was filtered and dried under reduced pressure to give 3- (4-bromo-1-oxoisoindoline-2-) piperidine-2, 6-dione (3.35 g, 60%) which was dispersed in a mixed solution of water-ethyl acetate-petroleum ether (v/v/v, 2:1:1). ¹ H NMR(400MHz,DMSO)δ11.03(s,1H),7.87(dd,J＝7.9,0.7Hz,1H),7.79-7.75(m,1H),7.51(t,J＝7.7Hz,1H),5.15(dd,J＝13.3,5.1Hz,1H),4.42(d,J＝17.6Hz,1H),4.26(d,J＝17.6Hz,1H),2.92(ddd,J＝17.5,13.7,5.4Hz,1H),2.64-2.55(m,1H),2.55-2.39(m,1H),2.02(dtd,J＝12.5,5.2,2.0Hz,1H).

3- (4- (5-hydroxypentyl-1-yn-1-) -1-oxoisoindoline-2-) piperidine-2, 6-dione:

mg,0.62 mmol) of the mixture is dissolved in 10mL of dry DMF, the reaction solution is replaced by high-purity nitrogen for 3 times, 10mL of triethylamine is added, the reaction solution is replaced by high-purity nitrogen for one time, the reaction solution is heated to 60 ℃ for overnight reaction, the solvent is removed under reduced pressure after the reaction is finished, and the crude product is subjected to silica gel column chromatography to obtain 1.03g of 3- (4- (5-hydroxypentyl-1-alkyne-1-) -1-oxo-isoindoline-2-) piperidine-2, 6-dione as a white solid with the yield of 100%; ¹ H NMR(400MHz,DMSO)δ11.02(s,1H),7.71(d,J＝7.6Hz,0.8Hz,1H),7.64(dd,J＝7.6,0.8Hz,1H),7.53(t,J＝7.6Hz,1H),5.15(dd,J＝13.3,5.1Hz,1H),4.57(t,J＝5.1Hz,1H),4.46(d,J＝17.8Hz,1H),4.31(d,J＝17.8Hz,1H),3.54(dd,J＝11.4,6.1Hz,2H),2.99-2.86(m,1H),2.65-2.57(m,1H),2.56-2.39(m,3H),2.06-1.97(m,1H),1.77-1.67(m,2H).

3- (4- (5-hydroxypentyl) -1-oxoisoindoline-2-) piperidine-2, 6-dione:

after completion of the reaction, the catalyst was removed by filtration by heating to 40℃for 7 hours in the presence of hydrogen (260 psi) and concentrating the filtrate under reduced pressure and subjecting it to silica gel column chromatography to give 1.02g of 3- (4- (5-hydroxypentyl) -1-oxoisoindoline-2-) piperidine-2, 6-dione as a white solid in 100% yield; ¹ H NMR(400MHz,DMSO)δ10.99(s,1H),7.58-7.53(m,1H),7.48-7.43(m,2H),5.13(dd,J＝13.2,5.2Hz,1H),4.46(d,J＝17.1Hz,1H),4.35(t,J＝5.1Hz,1H),4.30(d,J＝17.1Hz,1H),3.38(dd,J＝11.6,6.4Hz,2H),2.92(ddd,J＝17.4,13.8,5.6Hz,1H),2.68-2.56(m,3H),2.48-2.37(m,1H),2.06-1.96(m,1H),1.66-1.54(m,2H),1.45(td,J＝13.4,6.5Hz,2H),1.33(dt,J＝9.4,7.5Hz,2H).

3- (4- (5-bromopentyl) -1-oxoisoindoline-2-) piperidine-2, 6-dione:

mg,3.036 mmol) was dissolved in 40mL dry tetrahydrofuran, and carbon tetrabromide (1.506 g,4.5 g was added to the reaction mixture4 mmol) and the resulting reaction mixture was reacted at room temperature for 1 hour. After the reaction of T is finished, the solvent is removed under reduced pressure, and the obtained residue is subjected to silica gel column chromatography to obtain 588mg of 3- (4- (5-bromopentyl) -1-oxo-isoindoline-2-) piperidine-2, 6-dione as white solid with the yield of 99%;1H NMR (500 MHz, DMSO). Delta.11.01 (s, 1H), 7.62 (dd, J=11.8, 7.3Hz, 1H), 7.56 (dd, J=6.5, 4.0Hz, 1H), 7.48-7.43 (m, 1H), 5.14 (dd, J=13.4, 5.2Hz, 1H), 4.47 (d, J=17.1 Hz, 1H), 4.31 (d, J=17.1 Hz, 1H), 3.54 (t, J=6.6 Hz, 2H), 2.98-2.87 (m, 1H), 2.63 (dd, J=22.8, 14.8Hz, 3H), 2.43 (ddd, J=26.4, 13.4.3 Hz, 1H), 2.06-1.97 (m, 1H), 1.94-1.76 (m, 2H), 1.54 (t, J=6.6 Hz, 2H), 2.98-2.87 (m, 1H), 2.63 (dd, J=22.8, 14.8Hz, 3H), 1.94-1.76 (m, 1H).

5-amino-4- (4- (2-bromoethoxy) -1-oxoisoindol-2-yl) -5-oxopentanoic acid methyl ester:

compound a (497 mg,1.70mmol,1.0 equiv) was dissolved in 10ml acetonitrile, 1, 2-dibromoethane (1.6 g,8.5mmol,5.0 equiv) was added, potassium carbonate (352 mg,2.55mmol,1.5 equiv) was added and reacted overnight at 60℃as monitored by TLC. After the reaction is completed, the solid is obtained by vacuum concentration, is redissolved in ethyl acetate solution, is washed by saturated ammonium chloride solution and saturated sodium chloride solution in sequence, is dried by anhydrous sodium sulfate, and is subjected to column chromatography after vacuum concentration. 462mg of white solid, 68% yield; ¹ H NMR(400MHz,CDCl ₃ )δ7.45-7.38(m,2H),6.98(dd,J＝7.4,1.3Hz,1H),6.58(s,1H),5.63(s,1H),4.93(dd,J＝8.9,6.0Hz,1H),4.51(d,J＝17.7Hz,1H),4.39(dd,J＝14.5,8.3Hz,3H),3.66(t,J＝6.1Hz,2H),3.63(s,3H),2.47-2.30(m,3H),2.20(ddd,J＝10.5,8.1,4.7Hz,1H).ESI-MS[M+H] ⁺ m/z＝401.21,[M-H] ^- ＝399.22.

d-proline (2- (((2- (1- (5-amino-5-methoxy-1, 5-dioxolan-2-yl) -1-oxoisoindol-4-yl) oxy) ethyl) tert-butyl):

compound b (518 mg,1.30mmol,1.0 equiv) was dissolved in 10ml acetonitrile, D-proline hydrochloride (323.4 mg,1.557mmol,1.2 equiv) was added, potassium carbonate (449.2 mg,3.25mmol,2.5 equiv) was added and reacted overnight at 130℃as monitored by TLC. After the reaction is completed, the solid is obtained by vacuum concentration, is redissolved in ethyl acetate solution, is washed by saturated ammonium chloride solution and saturated sodium chloride solution in sequence, is dried by anhydrous sodium sulfate, and is subjected to column chromatography after vacuum concentration. 242mg of colorless oily liquid was obtained in 38% yield; ¹ H NMR(400MHz,DMSO)δ7.59(s,1H),7.44(t,J＝7.8Hz,1H),7.27(d,J＝7.5Hz,1H),7.20(d,J＝7.9Hz,2H),4.73(dd,J＝10.3,4.7Hz,1H),4.50(d,J＝17.6Hz,1H),4.35(d,J＝17.6Hz,1H),4.19(t,J＝5.0Hz,2H),3.51(s,3H),3.23(dd,J＝8.8,4.5Hz,1H),3.06(dt,J＝11.5,6.1Hz,2H),2.94-2.86(m,2H),2.72(dt,J＝10.0,6.5Hz,1H),2.58-2.52(m,1H),2.30-2.23(m,2H),2.22-2.16(m,1H),2.05-1.97(m,2H),1.32(s,9H).ESI-MS[M+H] ⁺ m/z＝490.42.

D-proline tert-butyl (2- ((2- (2-, 2, 6-dioxopiperidin-3-yl) -1-oxoisoindol-4-yl) oxy) ethyl:

compound c (242 mg, 0.944 mmol,1.0 equiv.) is dissolved in 10ml anhydrous tetrahydrofuran and potassium tert-butoxide (61 mg,0.5434mmol,1.1 equiv.) is added at-78℃and the reaction is allowed to proceed for half an hour, as monitored by LC-MS. After completion of the reaction, the reaction mixture was quenched with 1N hydrochloric acid solution, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated in vacuo, followed by column chromatography. 163mg of white solid, yield 70%; ¹ H NMR(400MHz,DMSO)δ7.59(s,1H),7.45(t,J＝7.8Hz,1H),7.26(d,J＝7.4Hz,1H),7.19(d,J＝7.9Hz,2H),4.72(dd,J＝10.4,4.5Hz,1H),4.49(d,J＝17.5Hz,1H),4.32(d,J＝17.6Hz,1H),4.15(ddd,J＝9.4,6.3,3.3Hz,2H),3.50(s,3H),3.04(dd,J＝8.4,4.7Hz,2H),2.92-2.86(m,1H),2.84-2.79(m,1H),2.72(dt,J＝10.0,6.5Hz,1H),2.59-2.54(m,1H),2.26(dd,J＝11.1,4.3Hz,2H),2.21-2.15(m,1H),1.92-1.87(m,2H),1.75(dd,J＝6.4,4.3Hz,2H),1.61(dd,J＝12.3,5.9Hz,2H),1.40(s,9H).ESI-MS[M+H] ⁺ m/z＝472.87.

(3- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindol-4-yl) oxy) propyl) -D-proline:

compound d (163 mg,0.3458mmol,1.0 equiv) was dissolved in dichloromethane and 5ml dioxane hydrochloride solution was added and monitored by LC-MS at room temperature overnight. After the reaction is finished, the reaction system is concentrated in vacuum to obtain 163mg of white solid, and the yield is more than 99%; ¹ H NMR(400MHz,CDCl ₃ )δ7.59(s,1H),7.45(t,J＝7.8Hz,1H),7.26(d,J＝7.4Hz,1H),7.19(d,J＝7.9Hz,2H),4.72(dd,J＝10.4,4.5Hz,1H),4.49(d,J＝17.5Hz,1H),4.32(d,J＝17.6Hz,1H),4.15(ddd,J＝9.4,6.3,3.3Hz,2H),3.50(s,3H),3.04(dd,J＝8.4,4.7Hz,2H),2.92-2.86(m,1H),2.84-2.79(m,1H),2.72(dt,J＝10.0,6.5Hz,1H),2.59-2.54(m,1H),2.26(dd,J＝11.1,4.3Hz,2H),2.21-2.15(m,1H),1.92-1.87(m,2H),1.75(dd,J＝6.4,4.3Hz,2H),1.61(dd,J＝12.3,5.9Hz,2H).ESI-MS[M+H] ⁺ m/z＝402.31,[M-H] ^- ＝400.28.

2. synthesis of Compounds of examples

The compound of the example was synthesized by referring to the synthesis method in the above synthesis method one and synthesis method two

Example 1:3- (2, 5-dichlorophenyl) -1- ((2- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindol-4-yl) oxy) ethyl) -D-prolyl) piperidine-4-carbonitrile (1)

Compound e (40 mg,0.0996mmol,1.0 equiv) was dissolved in 5ml DMF, HATU (44 mg,0.1195mmol,1.1 equiv) was added, DIPEA (37.2 mg,0.2988mmol,3 equiv) was added and reacted for 10min, and after further addition of compound f (30 mg,0.1096mmol,1.2 equiv) was reacted at room temperature for 30min, LC-MS monitoring. After the reaction was completed, diluted with ethyl acetate, dissolved in water and saturated sodium chlorideThe solution was washed, dried over anhydrous sodium sulfate and concentrated in vacuo, and the resulting crude product was isolated by HPLC to give pure 3- (2, 5-dichlorophenyl) -1- ((2- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindol-4-yl) oxy) ethyl) -D-prolyl) piperidine-4-carbonitrile (1) as a white solid. ¹ H NMR(400MHz,DMSO)δ10.97(s,1H),7.60(d,J＝8.5Hz,1H),7.57-7.51(m,1H),7.48(d,J＝2.3Hz,1H),7.44(d,J＝7.7Hz,1H),7.28(d,J＝7.5Hz,1H),7.23(d,J＝6.2Hz,1H),5.08(dd,J＝7.1,4.6Hz,1H),4.53(dd,J＝9.2,10.7Hz,2H),4.37(d,J＝7.3Hz,2H),4.20(ddd,J＝5.7,10.4,5.1Hz,4H),3.16(s,1H),3.05-2.96(m,2H),2.93-2.83(m,2H),2.79(d,J＝6.2Hz,2H),2.66(s,1H),2.59(s,1H),2.44(s,1H),2.13-2.08(m,1H),1.98(dd,J＝12.9,6.9Hz,2H),1.84-1.71(m,4H).ESI-MS[M+H] ⁺ m/z= 638.55, found 638.38.

Example 2:4- (3, 4-Dimethoxyphenyl) -1- ((3- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindol-4-yl) oxy) propyl) -D-prolyl) piperidine-4-carbonitrile (2)

7.21(d,J＝12.7Hz,1H),7.07-6.92(m,3H),5.10(d,J＝8.6Hz,1H),4.52(s,2H),4.33(d,J＝17.7Hz,1H),4.18(s,2H),3.75(d,J＝6.7Hz,6H),3.63-3.48(m,1H),3.18(d,J＝5.3Hz,2H),2.99-2.86(m,2H),2.86-2.70(m,2H),2.59(s,1H),2.40(s,2H),2.16(d,J＝2.5Hz,2H),1.97(d,J＝8.9Hz,2H),1.90(s,2H),1.80(s,2H),1.37(d,J＝5.5Hz,2H),1.23(s,2H).ESI-MS[M+H] ⁺ m/z= 644.64, found 644.38.

Example 3:1- ((3- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindol-4-yl) oxy) propyl) -D-prolyl) -4- (4- (trifluoromethyl) phenyl) piperidine-4-carbonitrile (3)The procedure is as in scheme one and example 1 to give pure 1- ((3- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindol-4-yl) oxy) propyl) -D-prolyl) -4- (4- (trifluoromethyl) phenyl) piperidine-4-carbonitrile (3). ¹ H NMR(600MHz,DMSO)δ10.98(s,1H),7.89-7.84(m,2H),7.79(d,J＝8.2Hz,2H),7.75(s,2H),7.48-7.36(m,1H),5.11(s,1H),4.57(s,2H),4.34(dd,J＝7.3,3.9Hz,1H),4.26-4.14(m,3H),3.11(s,1H),3.00(s,2H),2.95(s,2H),2.91(d,J＝7.5Hz,4H),2.83-2.78(m,1H),2.58(t,J＝7.2Hz,1H),2.45-2.38(m,2H),2.32(d,J＝5.1Hz,1H),2.27-2.22(m,2H),2.17(d,J＝4.1Hz,2H),2.00-1.97(m,1H),1.89(d,J＝5.6Hz,2H),1.77(d,J＝4.7Hz,2H).ESI-MS[M+H]+m/z= 652.69, found 562.65.

Example 4:4- (3, 4-Dimethoxyphenyl) -1- ((2- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindol-4-yl) oxy) ethyl) -D-prolyl) piperidine-4-carbonitrile (4)

(400MHz,DMSO)δ10.98(s,1H),7.50-7.41(m,1H),7.30(d,J＝7.5Hz,1H),7.26-7.19(m,1H),7.03(s,1H),6.95(d,J＝7.6Hz,2H),5.10(dd,J＝3.1,4.5Hz,1H),4.55-4.48(m,1H),4.36(d,J＝17.5Hz,1H),4.21(s,2H),3.76(d,J＝7.3Hz,6H),3.66-3.47(m,2H),3.33(s,2H),3.23(dd,J＝5.8,2.7Hz,2H),3.01(d,J＝6.3Hz,1H),2.95-2.88(m,1H),2.78(dd,J＝m,2H),2.57(d,J＝17.5Hz,1H),2.42(d,J＝1.6Hz,1H),2.27-2.03(m,4H),1.97(s,1H),1.79(s,4H).ESI-MS[M+H]+m/z= 630.71, found 630.48.

Example 5:1- ((4- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindol-4-yl) butyl) -D-prolyl) -4- (2- (trifluoromethoxy) phenyl) piperidine-4-carbonitrile (5)

7.29-7.21(m,1H),5.18-5.10(m,1H),4.79(d,J＝51.8Hz,1H),4.56(s,1H),4.48-4.35(m,1H),4.24(dd,J＝20.3,4.7Hz,3H),4.03-3.86(m,1H),3.72(s,1H),3.16(s,1H),3.04(d,J＝10.3Hz,1H),2.99-2.87(m,2H),2.61(d,J＝12.4Hz,2H),2.43-2.32(m,3H),2.13(s,4H),2.01(d,J＝12.6Hz,2H),1.90(s,2H),1.38(s,2H).ESI-MS[M+H] ⁺ m/z= 666.41, found 666.44.

Example 6: (2R) -1- (2- (((2- (2, 6-dioxopiperidin-3-yl) 1-oxoisoindol-4-yl) oxy) ethyl) -N- (4- (trifluoromethyl) benzyl) pyrrolidine-2-carboxamide (6)

MHz,DMSO)δ10.98(s,1H),8.16(d,J＝25.5Hz,1H),7.45(t,J＝7.7Hz,1H),7.30(d,J＝7.4Hz,1H),7.16(d,J＝7.8Hz,2H),7.13(d,J＝7.2Hz,2H),7.10(d,J＝8.2Hz,1H),5.10(ddd,J＝13.3,4.8,2.3Hz,1H),4.32(dd,J＝17.3,3.9Hz,1H),4.21(d,J＝4.2Hz,1H),4.19-4.17(m,1H),4.13(dd,J＝15.4,6.1Hz,2H),4.07-4.02(m,1H),3.50(d,J＝4.2Hz,4H),3.36(s,2H),3.14(s,1H),2.91(ddd,J＝14.4,11.1,5.3Hz,1H),2.73(s,1H),2.58(d,J＝17.0Hz,2H),2.44-2.38(m,1H),2.27(s,6H),2.07(s,2H),1.96(dd,J＝11.1,6.4Hz,1H),1.90-1.84(m,2H),1.73(dd,J＝23.6,5.4Hz,4H).ESI-MS[M+H] ⁺ m/z= 604.72, found 604.09.

Example 7: (2R) -1- (3- ((2- (2, 6-Dioxopiperidin-3-yl) -1-oxoisoindol-4-yl) oxy) propyl) -N- (4- (trifluoromethyl) benzyl) pyrrolidine-2-carboxamide (7)

7.78(d,J＝8.1Hz,1H),7.65-7.58(m,4H),7.46-7.40(m,1H),7.28(dd,J＝19.3,7.5Hz,1H),5.14-5.07(m,1H),4.49-4.45(m,1H),4.35(dd,J＝9.2,6.0Hz,1H),4.32(t,J＝5.3Hz,1H),4.27(dd,J＝11.5,6.3Hz,1H),4.22-4.13(m,2H),3.03-2.99(m,1H),2.74(td,J＝6.6,7.3Hz,1H),2.59-2.56(m,1H),2.42(ddd,J＝6.0,4.9,3.9Hz,1H),2.33-2.29(m,1H),2.25(dd,J＝6.4,5.4Hz,1H),2.10-2.05(m,2H),1.98(dd,J＝7.8,8.0Hz,1H),1.90(dd,J＝4.3,5.9Hz,2H),1.79-1.68(m,4H).ESI-MS[M+H] ⁺ m/z= 573.39, found 573.51.

Example 8: (2R) -N- (3, 5-Dimethoxyphenyl) -1- (3- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindol-4-yl) oxy) propyl) pyrrolidine-2-carboxamide (8)

Group) pyrrolidine-2-carboxamide (28) as a white solid. ¹ H NMR(600MHz,DMSO)δ10.94(d,J＝7.3Hz,1H),9.55(d,J＝8.6Hz,1H),7.43(td,J＝7.8,4.6Hz,1H),7.28-7.20(m,2H),6.92(d,J＝2.2Hz,1H),6.77(d,J＝2.2Hz,1H),6.13(dt,J＝4.6,2.2Hz,1H),5.06-4.98(m,1H),4.29-4.22(m,2H),4.01(q,J＝7.2Hz,2H),3.66(s,3H),3.60(s,3H),3.26-3.21(m,1H),3.09-3.04(m,1H),2.94-2.87(m,1H),2.86-2.73(m,1H),2.58(ddd,J＝6.6,5.6,4.5Hz,2H),2.36(ddd,J＝2.5,2.5,4.9Hz,1H),2.27-2.20(m,1H),2.16-2.09(m,1H),1.97-1.88(m,3H),1.81-1.75(m,3H).ESI-MS[M+H] ⁺ m/z= 551.61, found 551.48.

Example 9: (2R) -N-benzyl-1- (3- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindol-4-yl) oxy) propyl) pyrrolidine-2-carboxamide (9)

Pyrrolidine-2-carboxamide (30). ¹ H NMR(600MHz,DMSO)δ10.98(s,1H),7.60(s,1H),7.47-7.43(m,1H),7.30(d,J＝7.5Hz,1H),7.27-7.23(m,6H),5.10(dd,J＝13.3,5.2Hz,1H),4.46(dd,J＝9.9,4.3Hz,2H),4.33-4.29(m,2H),3.50(s,2H),2.99(d,J＝6.5Hz,1H),2.94-2.87(m,1H),2.74-2.71(m,1H),2.58-2.54(m,2H),2.40(dd,J＝12.0,6.8Hz,1H),2.29(s,1H),2.25(s,1H),1.98(dd,J＝4.2,6.2Hz,1H),1.90(d,J＝6.1Hz,2H),1.71(dd,J＝6.5,4.0Hz,4H).ESI-MS[M+H] ⁺ m/z= 505.51, found 505.29.

Example 10: n- (3, 5-Dimethoxybenzyl) -1- (3- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindol-4-yl) oxy) propyl) pyrrolidine-2-carboxamide (10)

DMSO)δ10.97(s,1H),8.18(dt,J＝7.2,6.3Hz,1H),7.44(t,J＝7.8Hz,1H),7.29(dd,J＝7.5,1.2Hz,1H),7.16-7.12(m,1H),6.34(d,J＝2.2Hz,1H),6.32(d,J＝2.2Hz,1H),6.31(dd,J＝4.3,2.1Hz,1H),5.09(dd,J＝3.4,5.1Hz,1H),4.31(dd,J＝7.3,5.1Hz,1H),4.21(dd,J＝5.0,6.4Hz,1H),4.16(ddd,J＝7.2,9.0,4.6Hz,2H),4.12-4.02(m,2H),3.67(d,J＝1.8Hz,6H),3.16-3.12(m,1H),3.01-2.97(m,1H),2.90(ddd,J＝7.4,6.7,5.4Hz,1H),2.76-2.70(m,1H),2.61-2.55(m,2H),2.44-2.35(m,1H),2.29(dd,J＝16.0,7.8Hz,1H),2.10-2.03(m,1H),1.97(ddt,J＝7.7,5.3,4.1Hz,1H),1.89(dq,J＝3.0,6.4Hz,2H),1.77-1.67(m,3H).ESI-MS[M+H] ⁺ m/z= 565.64, found 565.28.

Example 11:3- (4- (2- ((R) -2- (4- (3, 5-dichlorophenyl) piperazine-1-carbonyl) pyrrolidin-1-yl) ethoxy) -1-oxoisoindol-2-yl) piperidine-2, 6-dione (11)

/>

(600MHz,DMSO)δ10.97(s,1H),7.46(t,J＝7.8Hz,1H),7.29(d,J＝7.4Hz,1H),7.24(d,J＝4.0Hz,1H),6.92(s,2H),6.87(s,1H),5.09(dd,J＝13.3,5.1Hz,1H),4.36(d,J＝17.3Hz,1H),4.27-4.19(m,3H),3.73(d,J＝40.9Hz,2H),3.55(d,J＝7.3Hz,2H),3.17(d,J＝14.3Hz,4H),3.03-2.97(m,1H),2.93-2.86(m,1H),2.79(dd,J＝12.4,6.3Hz,1H),2.57(t,J＝21.9Hz,1H),2.42(ddd,J＝19.1,13.7,7.1Hz,2H),2.09(dd,J＝19.8,8.3Hz,1H),1.96(dd,J＝15.4,7.9Hz,1H),1.78(dt,J＝15.6,7.7Hz,2H),1.76-1.69(m,1H).ESI-MS[M+H] ⁺ m/z= 615.51, found 615.44.

Example 12:3- (4- (2- ((R) -2- (2H-spiro [ benzofuran-3, 4 '-piperidine ] -1' -carbonyl) pyrrolidin-1-yl) ethoxy) -1-oxoisoindol-2- (yl) piperidine-2, 6-dione (12)

MHz,DMSO)δ10.99(s,1H),8.24(s,1H),7.49(t,J＝7.6Hz,1H),7.33(dd,J＝6.6,3.4Hz,1H),7.25(d,J＝8.0Hz,1H),7.10(dd,J＝16.2,7.9Hz,2H),6.80(t,J＝7.3Hz,1H),6.75(d,J＝8.0Hz,1H),5.18-5.03(m,1H),4.38(dd,J＝14.4,7.5Hz,2H),4.23(s,4H),4.02(s,4H),3.14(d,J＝28.9Hz,2H),2.93-2.80(m,2H),2.71-2.60(m,1H),2.38(dd,J＝24.1,11.6Hz,1H),2.14-2.06(m,1H),1.97(s,1H),1.69(dd,J＝46.3,26.2Hz,8H).ESI-MS[M+H] ⁺ m/z= 591.55, found 591.37.

Example 13: (2R) -1- (3- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindol-4-yl) oxy) propyl) -N, N-diethylpyrrolidine-2-carboxamide (13)

Hz,1H),7.47(t,J＝7.8Hz,1H),7.30(d,J＝7.5Hz,1H),7.22(dd,J＝8.1,1.7Hz,1H),5.11(dt,J＝13.2,5.4Hz,1H),4.35(dd,J＝17.2,6.0Hz,1H),4.23-4.18(m,1H),4.16(t,J＝6.6Hz,2H),3.37(dd,J＝16.1,8.2Hz,2H),3.20(dd,J＝13.8,6.8Hz,2H),3.12(s,1H),2.96-2.88(m,1H),2.74(d,J＝21.8Hz,1H),2.59(d,J＝16.7Hz,1H),2.41(ddd,J＝26.2,13.1,4.1Hz,2H),2.05(d,J＝8.7Hz,1H),2.01-1.97(m,1H),1.85(dt,J＝13.0,6.4Hz,2H),1.77(dd,J＝13.3,6.7Hz,2H),1.63(dt,J＝9.5,8.4Hz,1H),1.26-1.22(m,2H),1.07(t,J＝6.5Hz,3H),0.95(td,J＝7.0,2.3Hz,3H).ESI-MS[M+H] ⁺ m/z= 471.55, found 471.92.

Example 14:1- ((2- ((2- (2-, 2, 6-dioxopiperidin-3-yl) -1-oxoisoindol-4-yl) oxy) ethyl) -D-prolyl) -4-phenylpiperidine-4-carbonitrile (14)

Preparation method same as in scheme one and example 1, ESI-MS [ M+H ]] ⁺ m/z= 560.86, found 560.23;

example 15:4- (3, 4-Dimethoxyphenyl) -1- ((3- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindol-4-yl) oxy) propyl) -D-prolyl) piperidine-4-carbonitrile (26)

6.92(m,3H),5.10(d,J＝13.5,5.1Hz,1H),4.52(s,2H),4.33(d,J＝17.7Hz,1H),4.18(s,2H),3.75(d,J＝6.7Hz,6H),3.63-3.48(m,1H),3.21-3.16(m,2H),2.99-2.86(m,2H),2.86-2.70(m,2H),2.59(s,1H),2.40(s,2H),2.12-2.01(m,2H),1.97(d,J＝8.9Hz,2H),1.90(s,2H),1.80(s,2H),1.76-1.62(m,4H).ESI-MS[M+H] ⁺ = 644.74, found 644.95.

Example 16: (2S) -N- (3-chloro-4-methylphenyl) -1- (3- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindol-4-yl) oxy) propyl) pyrrolidine-2-carboxamide (34)

1H),7.75(d,J＝8.4Hz,1H),7.49(t,J＝7.8Hz,1H),7.40-7.30(m,3H),7.24(dd,J＝8.1,2.7Hz,1H),5.11(dd,J＝13.0,4.6Hz,1H),4.42-4.31(m,1H),4.28-4.20(m,3H),3.74(d,J＝7.4Hz,1H),3.47(s,1H),3.34(s,3H),3.27(d,J＝7.6Hz,2H),2.92(dd,J＝8.2,3.4Hz,1H),2.62-2.52(m,2H),2.35-2.28(m,3H),2.13(s,2H),2.06-1.91(m,3H).ESI-MS[M+H] ⁺ = 539.20, found 539.33.

Example 17:3- (4- (3- ((R) -2- (4- (benzo [ b ] thiophen-7-yl ] piperazine-1-carbonyl ] pyrrolidin-1-yl) propoxy) -1-oxoisoindol-2- (yl) piperidine-2, 6-dione (82)

1.6Hz,1H),7.63(d,J＝7.8Hz,1H),7.45(d,J＝7.5Hz,1H),7.43-7.39(m,1H),7.31-7.27(m,1H),7.27-7.21(m,2H),6.83-6.76(m,1H),5.09(dt,J＝11.8,5.7Hz,1H),4.36(d,J＝17.3Hz,1H),4.29-4.15(m,3H),3.93-3.83(m,1H),3.79(s,1H),3.71-3.61(m,2H),3.19-3.10(m,1H),2.99(s,3H),2.96-2.81(m,4H),2.58-2.52(m,1H),2.43-2.28(m,2H),2.19-2.10(m,1H),2.04-1.87(m,4H),1.85-1.72(m,3H).ESI-MS[M+H] ⁺ = 616.75, found 616.89.

Example 18:3- (1-oxo-4- (3- ((R) -2- (4- (phenyl-d 5) piperazine-1-carbonyl) pyrrolidin-1-yl) propoxy) isoindol-2-yl) piperidine-2, 6-dione (84)

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5.10-5.05(m,1H),4.30(d,J＝17.2Hz,1H),4.21(d,J＝17.3Hz,1H),4.17(t,J＝5.6Hz,2H),3.92-3.81(m,1H),3.71-3.58(m,3H),3.51-3.44(m,2H),3.41-3.36(m,2H),2.99-2.92(m,2H),2.90-2.84(m,1H),2.79(dt,J＝13.7,7.4Hz,1H),2.59-2.53(m,1H),2.44-2.32(m,2H),2.30-2.20(m,1H),2.12-2.02(m,1H),1.92-1.86(m,2H),1.83-1.68(m,4H).ESI-MS[M+H] ⁺ = 565.70, found 565.45.

Example 19:3- (4- (2- ((R) -2- (4- (3, 4-dichlorophenyl) piperazine-1-carbonyl) pyrrolidin-1-yl) ethoxy) -1-oxoisoindol-2-yl) piperidine-2, 6-dione (131)

7.48(t,J＝7.8Hz,1H),7.27(d,J＝7.4Hz,1H),7.23(d,J＝4.0Hz,2H),6.92(d,J＝1.9Hz,1H),6.62(d,J＝2.4Hz,1H),5.07(dd,J＝13.5,5.1Hz,1H),4.36(d,J＝17.3Hz,1H),4.28-4.19(m,3H),3.72(d,J＝4.9Hz,2H),3.55(d,J＝7.3Hz,2H),3.17(d,J＝14.3Hz,4H),3.05-2.99(m,1H),2.93-2.86(m,1H),2.79(dd,J＝12.4,6.3Hz,1H),2.55(t,J＝7.6Hz,1H),2.45-2.41(m,2H),2.14-2.07(m,1H),1.99-1.95(m,1H),1.82-1.76(m,2H),1.74-1.68(m,3H).ESI-MS[M+H] ⁺ = 615.52, found 615.89.

Example 20: tert-butyl (2- ((2S) -1- (3- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) oxy) propyl) pyrrolidine-2-carboxamide) carbamic acid ethyl ester (132)

Urethane (132). ¹ H NMR(500MHz,DMSO)δ11.00(s,1H),8.68(s,1H),7.50(t,J＝7.7Hz,1H),7.34(d,J＝7.5Hz,1H),7.24(dd,J＝8.1,3.6Hz,1H),6.87(s,1H),5.13(dd,J＝13.3,5.1Hz,1H),4.39(d,J＝17.3Hz,1H),4.24(d,J＝19.2Hz,1H),4.20(dd,J＝11.1,7.2Hz,2H),4.04(s,1H),3.64(s,1H),3.38(s,1H),3.15(s,2H),3.04(s,2H),2.98-2.85(m,2H),2.73(s,1H),2.60(d,J＝16.9Hz,1H),2.46-2.33(m,2H),2.04(dt,J＝12.2,4.8Hz,4H),1.87(s,2H),1.35(s,9H).ESI-MS[M+H] ⁺ = 558.65, found 558.90.

Example 21:3- (4- (2- ((S) -2- (4- (2, 5-dichlorophenyl) piperazine-1-carbonyl) pyrrolidin-1-yl) ethoxy) -1-oxoisoindol-2-yl) piperidine-2, 6-dione (133)

7.48(t,J＝7.8Hz,1H),7.44(dd,J＝8.3,1.2Hz,1H),7.31(d,J＝7.5Hz,1H),7.25(d,J＝8.1Hz,1H),7.14-7.09(m,2H),5.10(dd,J＝13.3,5.0Hz,1H),4.37(d,J＝17.3Hz,1H),4.30-4.20(m,3H),3.73-3.65(m,2H),3.54-3.48(m,2H),3.27(s,2H),3.12-3.05(m,1H),2.98-2.84(m,6H),2.63-2.53(m,2H),2.40(qd,J＝12.9,3.9Hz,1H),2.20-2.10(m,1H),2.01-1.94(m,1H),1.87-1.71(m,3H).ESI-MS[M+H] ⁺ = 614.19, found 614.32.

Example 22:3- (4- (3- ((R) -2- (4- (4-fluorophenyl) piperazine-1-carbonyl ] pyrrolidin-1-yl) propoxy) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (134)

6.93(s,2H),5.12(dd,J＝13.4,4.8Hz,1H),4.35(d,J＝17.2Hz,1H),4.20(dd,J＝18.8,12.3Hz,3H),3.62(d,J＝3.7Hz,3H),3.32(s,6H),3.06(dd,J＝24.3,12.9Hz,4H),2.97-2.87(m,2H),2.62-2.53(m,2H),2.41-2.33(m,1H),2.03-1.95(m,3H),1.87-1.79(m,2H).ESI-MS[M+H] ⁺ = 578.66, found 578.44.

Example 23:3- (4- (3- ((R) -2- (4- (2-nitrophenyl) piperazin-1-carbonyl) pyrrolidin-1-yl) propoxy) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (135)

1H),7.59-7.55(m,1H),7.46(t,J＝7.8Hz,1H),7.28(d,J＝7.5Hz,1H),7.23(d,J＝8.0Hz,1H),7.21(d,J＝8.0Hz,1H),7.16(t,J＝7.7Hz,1H),5.10(dd,J＝13.3,5.1Hz,1H),4.35(d,J＝17.3Hz,1H),4.22(d,J＝17.3Hz,1H),4.18(dt,J＝6.3,4.5Hz,2H),3.86-3.77(m,1H),3.65(dd,J＝10.9,6.9Hz,1H),3.61-3.56(m,1H),3.50-3.45(m,1H),3.24-3.17(m,1H),2.99-2.93(m,3H),2.89(dt,J＝13.6,5.2Hz,4H),2.62-2.52(m,2H),2.44-2.36(m,2H),2.11(s,1H),2.00-1.90(m,3H),1.84-1.72(m,3H).ESI-MS[M+H] ⁺ = 605.66, found 605.44.

Example 24:3- (4- (3- ((R) -2- (4- (2, 4-difluorophenyl) piperazine-1-carbonyl) pyrrolidin-1-yl) propoxy) -1-oxoisoindol-2-yl) piperidine-2, 6-dione (136)

J＝7.4Hz,1H),7.22(d,J＝8.3Hz,1H),7.20-7.16(m,1H),6.97-6.90(m,2H),5.10(dd,J＝13.3,5.2Hz,1H),4.33(d,J＝17.3Hz,1H),4.22(s,1H),4.18(t,J＝5.6Hz,2H),3.93-3.87(m,1H),3.71-3.59(m,2H),3.50-3.43(m,1H),3.39-3.34(m,2H),3.15-3.10(m,1H),2.89-2.86(m,2H),2.85-2.72(m,3H),2.59-2.53(m,1H),2.39(tt,J＝13.3,7.8Hz,2H),2.25-2.21(m,1H),2.11-2.03(m,1H),1.97-1.93(m,1H),1.93-1.85(m,2H),1.81-1.71(m,3H).ESI-MS[M+H] ⁺ = 596.65, found 596.86.

Example 25:1- ((2- ((2- (2-, 2, 6-dioxopiperidin-3-yl) -1-oxoisoindol-4-yl) oxy) ethyl) -L-prolyl) -4- (2-fluorophenyl) piperidine-4-carbonitrile (137)

7.42(m,3H),7.36-7.32(m,1H),7.32-7.27(m,2H),7.27-7.22(m,1H),5.11(dd,J＝13.3,5.0Hz,1H),4.94-4.84(m,1H),4.59-4.48(m,3H),4.44-4.25(m,2H),4.16(s,1H),3.94-3.79(m,2H),3.39-3.26(m,4H),3.00-2.88(m,3H),2.88-2.79(m,1H),2.64-2.56(m,1H),2.26-2.11(m,3H),2.03-1.94(m,2H),1.88-1.80(m,2H).ESI-MS[M+H] ⁺ = 588.65, found 588.86.

Example 26:1- ((2- ((2- (2-, 2, 6-dioxopiperidin-3-yl) -1-oxoisoindol-4-yl) oxy) ethyl) -L-prolyl) -4-phenylpiperidine-4-carbonitrile (138)

1H),7.51-7.42(m,3H),7.40(d,J＝6.7Hz,2H),7.37-7.32(m,1H),7.27(td,J＝8.2,3.6Hz,1H),5.11(dd,J＝13.3,5.0Hz,1H),4.94-4.74(m,1H),4.55-4.44(m,3H),4.41(d,J＝17.6Hz,1H),4.38(s,1H),4.32(dd,J＝11.0,6.3Hz,1H),3.94-3.79(m,2H),3.69-3.57(m,2H),3.06-2.77(m,3H),2.66-2.58(m,1H),2.45-2.31(m,1H),2.45-2.31(m,3H),,2.02(dd,J＝14.8,7.7Hz,2H),1.98-1.78(m,3H),1.63-1.54(m,1H).ESI-MS[M+H] ⁺ = 570.66, found 570.40.

Example 27:1- ((3- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindol-4-yl) oxy) propyl) -D-prolyl) -4-phenylpiperidine-4-carbonitrile (139)

7.42(m,3H),7.40(d,J＝6.7Hz,2H),7.37-7.32(m,1H),7.27(td,J＝8.2,3.6Hz,1H),5.11(dd,J＝13.3,5.0Hz,1H),4.84-4.74(m,1H),4.55-4.44(m,3H),4.41(d,J＝17.6Hz,1H),4.38(s,1H),4.32(dd,J＝11.0,6.3Hz,1H),3.94-3.79(m,2H),3.69-3.57(m,2H),3.06-2.77(m,3H),2.66-2.58(m,1H),2.45-2.31(m,1H),2.45-2.31(m,3H),2.26-2.11(m,2H),2.05-1.99(m,2H),1.98-1.78(m,4H).ESI-MS[M+H] ⁺ = 584.69, found 584.45.

Example 28:1- ((3- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindol-4-yl) oxy) propyl) -D-prolyl) -4- (2-fluorophenyl) piperidine-4-carbonitrile (140)

7.36-7.32(m,1H),7.32-7.27(m,2H),7.27-7.22(m,1H),5.11(dd,J＝13.3,5.0Hz,1H),4.82-4.71(m,1H),4.59-4.48(m,2H),4.44-4.25(m,4H),4.16(s,1H),3.92-3.77(m,2H),3.69-3.57(m,2H),3.39-3.26(m,2H),3.00-2.88(m,3H),2.88-2.79(m,2H),2.64-2.56(m,1H),2.26-2.11(m,1H),2.03-1.94(m,2H),1.88-1.80(m,4H).ESI-MS[M+H] ⁺ = 602.68, found 602.49.

Example 29:1- ((3- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindol-4-yl) oxy) propyl) -L-prolyl) -4- (4-fluorophenyl) piperidine-4-carbonitrile (141)

(ddd,J＝8.9,5.1,2.3Hz,1H),7.50(m,1H),7.36-7.33(m,1H),7.33-7.31(m,1H),7.31-7.29(m,1H),7.26(t,J＝7.9Hz,1H),5.14(ddd,J＝13.3,8.1,5.5Hz,1H),4.70(ddd,J＝13.3,8.1,5.5Hz,1H),4.55(s,1H),4.43-4.35(m,1H),4.31-4.24(m,1H),4.22(d,J＝11.7Hz,2H),3.93-3.83(m,1H),3.74(s,1H),3.22(td,J＝12.4,6.1Hz,1H),3.17-3.10(m,1H),3.05-2.98(m,1H),2.92(ddd,J＝13.8,9.4,5.4Hz,1H),2.61(d,J＝7.2Hz,1H),2.58-2.52(m,1H),2.41-2.34(m,1H),2.30-2.22(m,2H),2.17-2.07(m,4H),2.06-1.83(m,6H).ESI-MS[M+H] ⁺ = 602.68, found 602.49.

Example 30:1- ((3- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindol-4-yl) oxy) propyl) -L-prolyl) -4- (3-fluorophenyl) piperidine-4-carbonitrile (142)

7.44(m,1H),7.43-7.38(m,1H),7.34(dd,J＝8.5,7.5Hz,1H),7.26(t,J＝7.9Hz,2H),5.18-5.11(m,1H),4.70(d,J＝17.3Hz,1H),4.55(d,J＝17.5Hz,1H),4.42-4.35(m,1H),4.32-4.25(m,1H),4.22(t,J＝5.8Hz,2H),3.93-3.83(m,1H),3.72(s,1H),3.43-3.37(m,2H),3.24(m,1H),3.18-3.11(m,2H),3.05-2.98(m,1H),2.97-2.88(m,1H),2.64-2.54(m,1H),2.42-2.34(m,1H),2.29(m,2H),2.18-2.09(m,3H),2.08-1.83(m,5H).ESI-MS[M+H] ⁺ = 602.68, found 602.87.

Example 31:1- (2, 5-Dimethoxyphenyl) -4- ((3- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindol-4-yl) oxy) propyl) -L-prolyl) cyclohexane-1-carbonitrile (143)

The procedure is as in scheme one and example 1 to give pure 1- (2, 5-dimethoxyphenyl) -4- ((3- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindol-4-yl) oxy) propyl) -L-prolyl) cyclohexane-1-carbonitrile (143). ¹ H NMR(400MHz,DMSO)δ10.99(s,1H),7.50-7.38(m,1H),7.29(s,1H),7.21(d,J＝8.7Hz,1H),7.07(d,J＝2.3Hz,1H),6.95(d,J＝8.1Hz,1H),6.87(d,J＝8.1,2.3Hz,1H),5.10(d,J＝13.5,5.1Hz,1H),4.52(s,2H),4.33(d,J＝17.7Hz,1H),4.18(s,2H),3.75(d,J＝6.7Hz,6H),3.63-3.48(m,1H),3.21-3.16(m,2H),2.99-2.86(m,2H),2.86-2.70(m,2H),2.59(s,1H),2.40(s,2H),2.12-2.01(m,1H),1.97(d,J＝8.9Hz,2H),1.80(s,2H),1.76-1.62(m,2H).ESI-MS[M+H] ⁺ = 643.75, found 643.55.

Example 32:3- (1-oxo-4- (2- ((S) -2- (3-oxo-2, 3-dihydrospiro [ indene-1, 4 '-piperidine ] -1' -carbonyl) ] pyrrolidin-1-yl) ethoxy) isoindolin-2-yl) piperidine-2, 6-dione (144)

DMSO-d ₆ )δ10.98(s,1H),7.65(t,J＝8.0Hz,1H),7.61(d,J＝8.1Hz,1H),7.56-7.49(m,1H),7.46-7.43(m,1H),7.40-7.33(m,1H),7.30(d,J＝8.1Hz,1H),7.25(d,J＝8.0Hz,1H),5.12(dd,J＝13.3,5.1Hz,1H),4.43-4.39(m,1H),4.36(d,J＝13.3Hz,1H),4.30(d,J＝5.8Hz,2H),4.23(d,J＝17.0Hz,1H),4.19-4.06(m,1H),3.34(s,4H),3.15-3.07(m,1H),2.95-2.86(m,1H),2.72-2.65(m,2H),2.64-2.50(m,2H),2.44-2.32(m,1H),2.25(s,2H),2.04-1.97(m,1H),1.95-1.83(m,3H),1.82-1.72(m,2H),1.57-1.43(m,2H).ESI-MS[M+H] ⁺ = 585.67, found 585.45.

Example 33:3- (4- (2- ((S) -2- (2, 3-Dihydropiro [ indene-1, 4 '-piperidine ] ] -1' -carbonyl) pyrrolidin-1-yl) ethoxy) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (145)

1H),7.54-7.48(m,1H),7.35(t,J＝6.0Hz,1H),7.30-7.23(m,1H),7.18(d,J＝6.1Hz,1H),7.15-7.06(m,3H),5.12(dd,J＝13.2,5.0Hz,1H),4.39(d,J＝17.0Hz,1H),4.35-4.22(m,4H),4.04(s,1H),3.20-3.07(m,2H),2.95-2.90(m,1H),2.86(dt,J＝13.9,5.4Hz,3H),2.74-2.66(m,1H),2.65-2.52(m,2H),2.44-2.32(m,1H),2.19(s,1H),2.05-1.94(m,3H),1.94-1.72(m,4H),1.70-1.53(m,2H),1.52-1.38(m,3H).ESI-MS[M+H] ⁺ = 571.69, found 571.88.

Example 34:3- (1-oxo-4- (3- ((R) -2- (3-oxo-2, 3-dihydrospiro [ indene-1, 4 '-piperidine ] -1' -carbonyl) ] pyrrolidin-1-yl) propoxy) isoindolin-2-yl) piperidine-2, 6-dione (146)

-7.56(m,3H),7.52-7.40(m,2H),7.31(t,J＝6.9Hz,1H),7.24(dd,J＝6.9,8.3Hz,1H),5.10(dd,J＝13.6,5.1Hz,1H),4.43(d,J＝17.3Hz,1H),4.33(d,J＝17.3Hz,1H),4.21(t,J＝6.1Hz,2H),3.44(s,1H),3.19-3.06(m,2H),2.96-2.88(m,2H),2.87-2.73(m,2H),2.68(s,1H),2.62-2.53(m,2H),2.47-2.32(m,2H),2.31-2.24(m,1H),2.09(s,1H),2.00-1.88(m,3H),1.87-1.68(m,6H),1.51-1.43(m,2H).ESI-MS[M+H] ⁺ = 599.70, found 599.43.

Example 35:3- (4- (3- ((S) -2- (6-methyl-3H-spiro [ isobenzofuran-1, 4 '-piperidine ] -1' -carbonyl) pyrrolidin-1-yl) propoxy) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (147)

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7.51(dd,J＝8.5,7.6Hz,1H),7.35(dd,J＝7.4,3.3Hz,1H),7.27(dd,J＝8.5,8.2Hz,1H),7.17(d,J＝7.6Hz,1H),7.09(m,2H),5.19-5.10(m,1H),4.98(s,2H),4.39(m,2H),4.27(d,J＝3.5Hz,1H),4.23(d,J＝6.8Hz,1H),3.72(s,2H),3.42(m,2H),3.30(s,1H),3.17(d,J＝5.1Hz,1H),3.07-3.01(m,1H),2.97-2.86(m,2H),2.63-2.54(m,2H),2.29(m,4H),2.21-1.75(m,9H),1.71-1.65(m,2H).ESI-MS[M+H] ⁺ = 601.72, found 601.91.

Example 36:3- (4- (3- ((S) -2- (6-chloro-3H-spiro [ isobenzofuran-1, 4 '-piperidine ] -1' -carbonyl) pyrrolidin-1-yl) propoxy) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (148)

1H),7.54-7.49(m,1H),7.41-7.32(m,4H),7.31-7.24(m,1H),5.19-5.11(m,1H),5.02(s,2H),4.40(m,2H),4.29-4.26(m,1H),4.22(dd,J＝9.9,4.2Hz,1H),3.78-3.67(m,2H),3.49-3.38(m,2H),3.32-3.22(m,2H),3.21-3.12(m,1H),3.10-2.92(m,2H),2.91-2.87(m,1H),2.67-2.53(m,1H),2.43-2.29(m,1H),2.22-1.82(m,9H),1.81-1.72(m,2H)..MW:621.13,ESI-MS[M+H] ⁺ = 621.24, found 621.87.

Example 37:3- (4- (3- ((S) -2- (2, 3-dihydrospiro [ indene-1, 4 '-piperidine ] ] -1' -carbonyl) pyrrolidin-1-yl) propoxy) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (149)

7.8,2.4Hz,1H),7.35(d,J＝7.4Hz,1H),7.28-7.23(m,3H),7.17-7.11(m,2H),5.17-5.10(m,1H),4.43-4.33(m,2H),4.26(d,J＝17.3Hz,1H),4.24-4.21(m,1H),3.77-3.66(m,2H),3.46-3.35(m,2H),3.32-3.23(m,2H),3.15(m,1H),2.99-2.91(m,4H),2.66-2.52(m,2H),2.41-2.27(m,1H),2.20-1.83(m,9H),1.80-1.63(m,2H),1.56(t,J＝6.5Hz,2H).ESI-MS[M+H] ⁺ = 585.72, found 585.90.

Example 38:3- (4- (3- ((R) -2- (4- (3, 5-dichlorophenyl) piperazine-1-carbonyl) pyrrolidin-1-yl) propoxy) -1-oxoisoindol-2-yl) piperidine-2, 6-dione (150)

Hz,1H),7.61(dd,J＝8.3,2.0Hz,1H),7.55(d,J＝1.6Hz,1H),7.50(t,J＝7.8Hz,1H),7.35(d,J＝7.4Hz,1H),7.27(d,J＝6.9Hz,1H),7.23(d,J＝8.1Hz,1H),5.13(dd,J＝13.3,5.1Hz,1H),4.41-4.34(m,3H),4.28-4.22(m,1H),4.19(s,2H),3.67(dd,J＝8.9,4.9Hz,1H),3.49-3.36(m,3H),3.25-3.17(m,1H),2.97-2.88(m,2H),2.63-2.55(m,1H),2.42-2.29(m,1H),2.14-2.06(m,3H),2.04-1.98(m,1H),1.96-1.85(m,2H).ESI-MS[M+H] ⁺ = 573.16, found 573.30.

Example 39: (2R) -1- (3- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindol-4-yl) oxy) propyl) -N- (4-morpholinophenyl) pyrrolidine-2-carboxamide (151)

(s,1H),7.45(dd,J＝7.8,8.0Hz,1H),7.40(d,J＝8.0Hz,1H),7.29-7.26(m,2H),7.22(t,J＝8.0Hz,1H),6.78(d,J＝8.0Hz,1H),6.67(d,J＝8.0Hz,1H),5.01(dd,J＝13.5,5.0Hz,1H),4.28-4.16(m,2H),4.06(d,J＝17.4Hz,1H),3.93(d,J＝17.3Hz,1H),3.71(s,4H),3.26-3.19(m,1H),3.01-2.94(m,4H),2.92-2.78(m,2H),2.65-2.53(m,2H),2.40-2.26(m,2H),2.25-2.16(m,1H),2.14-2.07(m,1H),1.97-1.90(m,3H),1.81-1.75(m,3H).ESI-MS[M+H] ⁺ = 576.67, found 576.42.

Example 40: (2S) -1- (3- ((2- (2, 6-Dioxopiperidin-3-yl) -1-oxoisoindol-4-yl) oxy) propyl) -N- (4- (trifluoromethyl) benzyl) pyrrolidine-2-carboxamide (152)

1H),7.71(d,J＝6.5Hz,2H),7.50(t,J＝7.9Hz,3H),7.34(d,J＝7.5Hz,1H),7.23(d,J＝8.1Hz,1H),5.13(dd,J＝13.3,5.1Hz,1H),4.50-4.44(m,2H),4.38(d,J＝17.3Hz,1H),4.28-4.23(m,1H),4.22-4.19(m,2H),3.67(d,J＝6.4Hz,1H),3.45-3.40(m,1H),3.31(dd,J＝6.9,2.4Hz,1H),3.22(dt,J＝14.5,7.6Hz,1H),2.97-2.85(m,3H),2.64-2.55(m,1H),2.38-2.30(m,1H),2.09(m,3H),2.04-1.97(m,1H),1.94-1.86(m,2H).ESI-MS[M+H] ⁺ = 573.59, found 573.39.

Example 41: (2S) -1- (3- ((2- (2-, 2, 6-dioxopiperidin-3-yl) -1-oxoisoindol-4-yl) oxy) propyl) -N- (4- (morpholinomethyl) benzyl) pyrrolidine-2-carboxamide (153)

J＝7.4,4.8Hz,3H),7.24(dd,J＝8.1,3.6Hz,1H),5.13(dd,J＝13.2,4.9Hz,1H),4.50-4.39(m,2H),4.37(d,J＝9.9Hz,1H),4.32(s,2H),4.26(d,J＝12.5Hz,1H),4.22-4.18(m,2H),3.95(d,J＝3.1Hz,2H),3.68(d,J＝8.2Hz,1H),3.62(d,J＝4.5Hz,2H),3.40(d,J＝5.8Hz,1H),3.32(d,J＝3.8Hz,1H),3.21(s,2H),3.09(s,2H),2.96-2.87(m,1H),2.69(s,2H),2.61-2.52(m,2H),2.34(m,1H),2.10(s,3H),2.05-1.97(m,1H),1.95-1.86(m,2H).ESI-MS[M+H] ⁺ = 604.72, found 604.44.

Example 42: (2S) -N- (((1 r,3R,5S, 7S) -3, 5-Dimethyladamantan-1-yl) -1- (3- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) oxy) propyl) pyrrolidine-2-carboxamide (154)

11.01(s,1H),8.19(s,1H),7.51(t,J＝7.8Hz,1H),7.35(d,J＝7.5Hz,1H),7.23(d,J＝8.1Hz,1H),5.14(dd,J＝13.3,5.0Hz,1H),4.37(dd,J＝17.2,4.2Hz,1H),4.25(dd,J＝17.2,2.2Hz,1H),4.20(t,J＝6.1Hz,2H),4.01-3.93(m,1H),3.66(d,J＝4.3Hz,1H),3.32-3.27(m,2H),3.23-3.14(m,1H),2.99-2.89(m,1H),2.60(d,J＝2.0Hz,1H),2.44-2.31(m,2H),2.12-1.98(m,5H),1.90-1.72(m,4H),1.61-1.52(m,4H),1.27(m,6H),0.80(s,6H).ESI-MS[M+H] ⁺ = 577.74, found 577.96.

Example 43: l-proline tert-butyl (3- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) oxy) propyl (155)

MHz,DMSO)δ10.97(s,1H),7.47(t,J＝7.8Hz,1H),7.30(d,J＝7.5Hz,1H),7.22(d,J＝8.2Hz,1H),5.11(dd,J＝13.3,5.0Hz,1H),4.35(d,J＝17.3Hz,1H),4.24-4.14(m,3H),3.07-2.99(m,2H),2.96-2.87(m,1H),2.84-2.77(m,1H),2.62-2.52(m,2H),2.47-2.40(m,1H),2.36(m,1H),2.02-1.95(m,2H),1.88(d,J＝6.5Hz,2H),1.78-1.71(m,3H),1.35(s,9H).ESI-MS[M+H] ⁺ = 472.55, found 472.42.

Example 44: (2S) -N- (3, 5-difluorobenzyl) -1- (3- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindol-4-yl) oxy) propyl) pyrrolidine-2-carboxamide (156)

J＝7.6,5.4Hz,1H),7.50(t,J＝7.8Hz,1H),7.34(d,J＝7.4Hz,1H),7.23(d,J＝8.1Hz,1H),7.14(t,J＝8.3Hz,1H),7.01(d,J＝6.7Hz,2H),5.13(dd,J＝13.3,5.1Hz,1H),4.40(d,J＝5.4Hz,2H),4.39-4.34(m,1H),4.28-4.23(m,1H),4.22-4.18(m,2H),3.69(s,1H),3.45-3.27(m,4H),3.24-3.19(m,1H),2.97-2.88(m,1H),2.59-2.52(m,2H),2.40-2.29(m,1H),2.10(s,2H),2.04-1.97(m,1H),1.96-1.85(m,2H).ESI-MS[M+H] ⁺ = 541.57, found 541.83.

Example 45: tert-butyl (6- ((2S) -1- (3- ((2- (2, 6-dioxopiperidin-3-yl) -1-dioxopiperidin-4-yl) oxy-propyl) pyrrolidine-2-carboxamide) carbamic acid hexyl ester (157)

Pyrrolidine-2-carboxamide) hexyl carbamate (157). ¹ H NMR(500MHz,DMSO)δ11.00(s,1H),8.60(s,1H),7.50(t,J＝7.8Hz,1H),7.34(d,J＝7.4Hz,1H),7.24(d,J＝8.1Hz,1H),6.76(s,1H),5.14(dd,J＝13.1,4.5Hz,1H),4.39(dd,J＝17.3,7.9Hz,1H),4.23(dt,J＝11.4,7.7Hz,3H),4.12-4.03(m,1H),3.66(s,1H),3.21-3.06(m,3H),3.01-2.82(m,4H),2.64-2.57(m,2H),2.41(m,2H),2.16-1.97(m,4H),1.87(m,2H),1.47-1.39(m,2H),1.36(s,9H),1.23(s,6H).ESI-MS[M+H] ⁺ = 614.76, found 614.51.

Example 46: (2S) -1- (3- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindol-4-yl) oxy) propyl) -N, N-diethylpyrrolidine-2-carboxamide (158)

¹ H NMR(500MHz,DMSO)δ10.99(s,1H),7.49(t,J＝7.8Hz,1H),7.32(d,J＝7.5Hz,1H),7.24(dd,J＝8.2,1.6Hz,1H),5.17-5.09(m,1H),4.36(d,J＝17.2Hz,1H),4.24(d,J＝17.2Hz,1H),4.19(dd,J＝13.1,7.6Hz,2H),3.63-3.58(m,1H),3.34(d,J＝7.1Hz,1H),3.31-3.26(m,2H),3.12(s,1H),2.99-2.88(m,2H),2.67-2.56(m,2H),2.46-2.35(m,2H),2.05-1.92(m,5H),1.86(s,2H),1.73(s,1H),1.11(t,J＝6.6Hz,3H),1.01(t,J＝6.8Hz,3H).ESI-MS[M+H] ⁺ = 471.57, found 471.84.

Example 47: (2S) -N- (3, 5-Dimethoxybenzyl) -1- (3- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindol-4-yl) oxy) propyl) pyrrolidine-2-carboxamide (159)

(s,1H),7.50(t,J＝7.8Hz,1H),7.34(d,J＝7.5Hz,1H),7.23(dd,J＝8.1,2.2Hz,1H),6.42(s,2H),6.39(d,J＝1.8Hz,1H),5.12(dd,J＝13.4,4.8Hz,1H),4.42-4.36(m,1H),4.34-4.31(m,1H),4.25(m,2H),4.20(d,J＝9.8Hz,2H),3.70(d,J＝2.8Hz,6H),3.39(s,2H),3.22(m,1H),2.97-2.84(m,5H),2.57(m,1H),2.40-2.26(m,1H),2.09(s,2H),2.02-1.96(m,1H),1.94-1.86(m,2H).ESI-MS[M+H] ⁺ = 565.64, found 565.42.

Example 48:3- ((2S) -1- (3- ((2- (2, 6-Dioxopiperidin-3-yl) -1-Dioxopiperidin-4-yl) oxy) propyl) pyrrolidine-2-carboxamide) benzoic acid ethyl ester (160)

10.86(s,1H),8.25(s,1H),7.86(t,J＝8.2Hz,1H),7.73(d,J＝7.8Hz,1H),7.53(td,J＝8.0,1.9Hz,1H),7.49(td,J＝8.0,2.2Hz,1H),7.33(d,J＝7.5Hz,1H),7.25(dd,J＝8.1,4.1Hz,1H),5.13-5.09(m,1H),4.40-4.35(m,1H),4.32-4.26(m,3H),4.22(dd,J＝11.7,5.0Hz,2H),3.74(s,1H),3.53-3.45(m,1H),3.36(s,1H),3.29(s,1H),2.95-2.86(m,1H),2.63-2.55(m,2H),2.35-2.27(m,1H),2.19-2.07(m,3H),2.10-2.04(m,2H),2.00-1.92(m,2H),1.41-1.32(m,3H).ESI-MS[M+H] ⁺ = 563.62, found 563.43.

Example 49:2- (3- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindol-4-yloxy) propyl) -N- (4-fluoro-3- (trifluoromethyl) phenyl) pyrrolidine-1-carboxamide (161)

1H),8.07-8.02(m,1H),7.87-7.83(m,1H),7.59-7.53(m,1H),7.49(t,J＝7.8Hz,1H),7.34(d,J＝7.5Hz,1H),7.26-7.23(m,1H),5.12(dd,J＝13.3,5.0Hz,1H),4.41-4.34(m,1H),4.33-4.28(m,1H),4.23-4.19(m,2H),3.74(td,J＝10.8,5.2Hz,1H),3.51-3.45(m,1H),3.28(dt,J＝17.2,8.3Hz,2H),2.97-2.88(m,1H),2.62-2.53(m,2H),2.34(td,J＝13.2,4.5Hz,1H),2.17-2.11(m,3H),2.10-2.06(m,1H),2.03-1.91(m,3H).ESI-MS[M+H] ⁺ = 577.55, found 577.35.

Referring to synthesis method one and synthesis method two and the above examples, the following compounds can be synthesized:

/>

2. Experimental examples:

tumor cell proliferation inhibition experimental method: the present inventors tested all of the example compounds against hematological tumor cells, multiple myeloma MM1s cell lines and some of the example compounds against acute leukemia cell MV-4-11 cell lines, with the following methods and results of activity testing.

1. Inhibition of mm.1s cell proliferation by compounds MTS cell viability assay:

1) The experimental method comprises the following steps:

mm.1s cells were cultured with 1640 plus 10% fetal bovine serum and collected, the cell concentration was diluted for 7 days, and 180ul of cell suspension was added to each well of a 96-well cell plate to make the number of cells 20000. Control wells were added with 20ul of DMSO at a final concentration of 0.2%, and the compound was diluted 5-fold in a 10mM stock solution, as well as 20ul to compound wells (DMSO at a final concentration of 0.2%). Placing the cells at 37deg.C and 5% CO ₂ Incubators were incubated for 7 days. After preparing the reaction solution according to MTS kit (Promega, G5430), 20. Mu.L of 5% CO was added to each well at 37℃ ₂ Incubators were incubated for 3-4 hours. The absorbance at 490nm was read with an ELISA plate and the absorbance at 690nm was used as background and the OD490-OD690 as final raw data. The inhibition rate of the compound is calculated as follows: inhibition ratio= (OD _DMSO -OD _{Compounds of formula (I)} )/(OD _DMSO -O _{Blank space} ) X 100%. Proliferation inhibition IC50 of the compounds was fitted by Graph Pad Prism 5.0. Experiments were repeated three times, and the mean and standard deviation were calculated with three parallel experiments each time.

Cell activity test results: * Cell activity IC ₅₀ >20. Mu.M, 1. Mu.M for cell activity<IC ₅₀ <20. Mu.M, which represents the cellular activity of 100nM<IC ₅₀ <1 μM, representing cell activity IC ₅₀ <100nM。

2) Experimental results:

2. compound assay for substrate degradation in mm.1s cells:

and selecting compounds 82 and 150 with better activity for relevant biological experiments, and verifying whether the designed degradation agent has the function of down-regulating endogenous proteins.

The effect of designed degradants on the known degradation substrates Ikaros and Aiolos protein levels of immunomodulators was initially verified by Western Blot experiments.

Samples were prepared by treating MM.1S cells with different concentrations (0.01,0.1,1.0, 10. Mu.M) of the compound for 12h, and Western Blot experiments were performed, the results of which are shown in FIG. 1. FIG. 1 shows the effect of compounds 82 and 150 on Ikaros and Aiolos protein levels.

As can be seen from fig. 1, compounds 82 and 150 significantly reduced the protein levels of Ikaros and Aiolos in a dose-dependent manner in mm.1s cells. Compound 82 significantly degraded Ikaros and Aiolos at 10nM compared to lenalidomide; compound 150 begins to degrade transcription factors at 100 nM. The above experimental results show that the synthesized novel compounds 82 and 150 have more remarkable effect on degradation of the corresponding substrates than lenalidomide which is a marketed drug.

Samples were prepared by treatment with the indicated concentrations of compound (0.1,1.0. Mu.M) at different times and Western Blot experiments were performed, the results of which are shown in the left panel of FIG. 2. As can be seen from the left panel of fig. 2, compound 82 is time dependent on the degradation of transcription factors Ikaros and Aiolos and can significantly down-regulate Ikaros and Aiolos protein levels from 3 h. This indicates that compound 82 can rapidly degrade after entering the cell. When the cells were pretreated with the E1 inhibitor MLN4924 and then the compound was added, western Blot experiments were performed, and the results are shown in the right panel of FIG. 2. As can be seen from the right panel of FIG. 2, compound 82 does not substantially degrade Ikaros and Aiolos when MLN4924 is added, initially indicating that such molecules function as degradation is dependent on the E1 activating enzyme.

Based on the cell growth inhibition activity test results of the compounds and the substrate degradation experiments, the compounds in some embodiments of the invention have good inhibition activity on the growth of the MMs 1s cells of the multiple myeloma, and the activity of part of the compounds is equivalent to or better than that of positive compounds; and experiments show that the preparation method has a better and remarkable effect on degradation of the substrate in the MM1s cell of the multiple myeloma. On the other hand, the development of the compound with various structures can obtain more active drug molecules and molecules with better pharmaceutical properties, and provides alternative molecular structures and sources of molecular entities for new drug development. Thus, the engineered compounds of the invention can be used for the prevention, treatment and modulation of CRBN (CRL 4 ^CRBN E3 ubiquitin ligase) activity-related disorders such as multiple myeloma or non-limiting including other underlying neoplastic disorders, pain, neurological disorders and immune system disorders.

In summary, the invention provides a polysubstituted isoindoline compound with a novel structure, wherein the representative compound shows very strong proliferation inhibition activity on tested hematological tumor cells. In addition, the representative compound provided by the invention can effectively overcome the application limitation of the traditional domide drug, and has more remarkable effect in the aspect of degrading the substrate. The characteristics not only can effectively make up the defects of the traditional amine medicines, but also can expand the indications to the new field, so that the traditional amine medicine has very strong research potential and application prospect.

Claims

1. A compound represented by the following general formula (I) or a tautomer, enantiomer, diastereomer, racemate, isotopic compound or pharmaceutically acceptable salt thereof:

wherein n is 1, 2, 3, 4 or 5;

X ₁ is-CH ₂ -or-O-;

X ₂ is-CH ₂ -；

R ₁ 、R ₂ 、R ₃ Each independently hydrogen, deuterium, or halogen;

l is a substituted or unsubstituted linear alkylene group containing 1 to 5 carbon atoms;

a is:

i)A ₁ -NH-,

A ₁ is a 6-10 membered aryl, a 5-10 membered heteroaryl, (6-10 membered aryl) - (CH) ₂ ) _b1 -, (5-10 membered heteroaryl) - (CH) ₂ ) _b1 -the aforementioned aryl or heteroaryl group is optionally substituted with one or more of the following groups: deuterium, halogen, cyano, nitro, amino, hydroxy, C ₁ -C ₆ Alkyl, halogen substituted C ₁ -C ₆ Alkyl, hydroxy substituted C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₁ -C ₆ Alkoxycarbonyl, halogen substituted C ₁ -C ₆ Alkoxy, hydroxy-substituted C ₁ -C ₆ Alkoxy, cyano-substituted C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl, C ₃ -C ₆ Cycloalkyloxy, phenyl, 5-6 membered heteroaryl, 3-6 membered heterocyclyl;

b ₁ 1 or 2;

or A ₁ Selected from the following groups:

ii) a heterocyclic group selected from:

X ₃ is N or O;

n ₄ 0, 1, 2 or 3;

n ₅ is 0, 1, 2 or 3,

Y ₁ 、Y ₂ each independently is hydrogen, deuterium, halogen, cyano, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, 6-10 membered aryl or 5-10 membered heteroaryl substituted C ₁ -C ₃ Wherein said substituted 6-10 membered aryl or 5-10 membered heteroaryl refers to being substituted with one or more of the following substituents: deuterium, halogen, cyano, nitro, hydroxy, amino, aminocarbonyl, C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Alkylcarbonyl, C ₁ -C ₃ Alkoxycarbonyl group, C ₁ -C ₃ Alkylsulfonyl, C ₁ -C ₃ Alkylaminocarbonyl, C ₁ -C ₃ Acylamino, halogen substituted C ₁ -C ₃ Alkyl, halogen substituted C ₁ -C ₃ An alkoxy group;

Y ₃ absent, or hydrogen, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, C ₅ -C ₁₀ Aryl or heteroaryl substituted C ₁ -C ₃ Wherein said substituted 6-10 membered aryl or 5-10 membered heteroaryl means substituted with one or more of the following substituents: deuterium, halogen, cyano, nitro, hydroxy, amino, aminocarbonyl, C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Alkylcarbonyl, C ₁ -C ₃ Alkoxycarbonyl group, C ₁ -C ₃ Alkylsulfonyl, C ₁ -C ₃ Alkylaminocarbonyl, C ₁ -C ₃ Acylamino, halogen substituted C ₁ -C ₃ Alkyl, halogen substituted C ₁ -C ₃ An alkoxy group;

Y ₄ 、Y ₅ y being one or more substituents on the heterocycle in which it is located ₄ 、Y ₅ Each independently deuterium, halogen;

iv) a spiroheterocyclyl selected from the group consisting of:

n _c1 0, 1, 2 or 3;

n _c2 0, 1, 2 or 3;

n _c3 1, 2 or 3;

n ₉ 0, 1, 2, 3 or 4;

is a 6-10 membered aryl ring or a 5-10 heteroaryl ring;

R ₉ independently selected from the following substituents: deuterium, halogen, cyano, nitro, hydroxy, straight or branched C ₁ -C ₆ Alkyl, straight or branched C ₁ -C ₆ Alkoxy, halogen substituted C ₁ -C ₃ Alkyl, halogen substituted C ₁ -C ₃ An alkoxy group;

Y ₈ is a substituent in the non-aromatic structural part of the spiro structure, wherein the substituent is optionally substituted by hydrogen atom, and Y8 is optionally deuterium, halogen or C ₁ -C ₃ Alkyl, halogen substituted C ₁ -C ₃ An alkyl group.

2. A compound according to claim 1, or a tautomer, enantiomer, diastereomer, racemate, isotopic compound or pharmaceutically acceptable salt thereof,

wherein n is 1, 2, 3, 4 or 5;

X ₁ is-CH ₂ -or-O-;

X ₂ is-CH ₂ -；

R ₁ 、R ₂ 、R ₃ Each independently hydrogen, deuterium, or halogen;

a is:

i)A ₁ -NH-：

b ₁ 1 or 2;

or A ₁ Selected from the following groups:

ii) a heterocyclic group selected from:

wherein Y is ₁ 、Y ₂ Each independently is hydrogen, deuterium, halogen, cyano, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, 6-10 membered aryl or 5-10 membered heteroaryl substituted C ₁ -C ₃ Wherein said substituted 6-10 membered aryl or 5-10 membered heteroaryl refers to being substituted with one or more of the following substituents: deuterium, halogen, cyano, nitro,Hydroxy, amino, aminocarbonyl, C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Alkylcarbonyl, C ₁ -C ₃ Alkoxycarbonyl group, C ₁ -C ₃ Alkylsulfonyl, C ₁ -C ₃ Alkylaminocarbonyl, C ₁ -C ₃ Acylamino, halogen substituted C ₁ -C ₃ Alkyl, halogen substituted C ₁ -C ₃ An alkoxy group;

Y ₃ absent, or substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, C ₅ -C ₁₀ Aryl or heteroaryl substituted C ₁ -C ₃ Wherein said substituted 6-10 membered aryl or 5-10 membered heteroaryl refers to being substituted with one or more of the following substituents: deuterium, halogen, cyano, nitro, hydroxy, amino, aminocarbonyl, C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Alkylcarbonyl, C ₁ -C ₃ Alkoxycarbonyl group, C ₁ -C ₃ Alkylsulfonyl, C ₁ -C ₃ Alkylaminocarbonyl, C ₁ -C ₃ Acylamino, halogen substituted C ₁ -C ₃ Alkyl, halogen substituted C ₁ -C ₃ An alkoxy group;

Y ₄ 、Y ₅ y being one or more substituents on the heterocycle in which it is located ₄ Y5 is independently deuterium, halogen;

or iv) a spiroheterocyclyl selected from the group consisting of:

wherein n is ₉ 0, 1, 2, 3 or 4;

Is a 6-10 membered aryl ring or a 5-10 heteroaryl ring;

R ₉ independently selected from the following substituents: deuterium, halogen, cyano, nitro, hydroxy, straight or branched C ₁ -C ₆ Alkyl, straight or branched C ₁ -C ₆ Alkoxy, halogen substituted C ₁ -C ₃ Alkyl, halogen substituted C ₁ -C ₃ Alkoxy, wherein when n ₉ >1, each R ₉ The same or different;

3. The compound of claim 2, or a tautomer, enantiomer, diastereomer, racemate, isotopic compound, or pharmaceutically acceptable salt thereof, wherein,

in the definition of A as heterocyclic group, the 6-10 membered aryl is selected from phenyl and naphthyl, and the 5-10 membered heteroaryl is selected from thienyl, pyridyl, benzothienyl, benzimidazolyl, indolyl, quinolinyl and isoquinolinyl;

selected from the group consisting of thiophene ring, pyrrole ring, benzene ring, pyridine ring, benzothiophene ring, benzimidazole ring, indole ring, quinoline ring, and isoquinoline ring.

4. A compound according to claim 1, or a tautomer, enantiomer, diastereomer, racemate, isotopic compound or pharmaceutically acceptable salt thereof,

Wherein n is 1, 2, 3, 4 or 5;

X ₁ is-CH ₂ -or-O-;

X ₂ is-CH ₂ -；

R ₁ 、R ₂ 、R ₃ Each independently hydrogen, deuterium or fluorine;

l is (CH) ₂ ) _b3 ；

b ₃ 1, 2, 3, 4 or 5;

a is:

i)A ₁ -NH-：

A ₁ is a 6-10 membered aryl, a 5-10 membered heteroaryl, (6-10 membered aryl) - (CH) ₂ ) _b1 -, (5-10 membered heteroaryl) - (CH) ₂ ) _b1 -the aforementioned 6-10 membered aryl or 5-10 membered heteroaryl is unsubstituted or substituted;

n ₁ 1 or 2;

n ₂ 0, 1, 2 or 3;

n ₃ 0, 1, 2 or 3;

R ₆ 、R ₇ each independently selected from the following groups: deuterium, halogen, cyano, nitro, amino, hydroxy, C ₁ -C ₆ Alkyl, halogen substituted C ₁ -C ₆ Alkyl, hydroxy substituted C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₁ -C ₆ Alkoxycarbonyl, halogen substituted C ₁ -C ₆ Alkoxy, hydroxy-substituted C ₁ -C ₆ Alkoxy, cyano-substituted C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl, C ₃ -C ₆ Cycloalkyloxy, phenyl, 5-6 membered heteroaryl, 3-6 membered heterocyclyl;

or A ₁ Selected from the following groups:

ii) a heterocyclic group selected from:

n ₁₀ 0, 1, 2, 3, 4 or 5;

Y ₁ selected from hydrogen, deuterium, halogen, cyano;

selected from substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl;

R ₁₀ each independently is deuterium, halogen, cyano, nitro, hydroxy, amino, aminocarbonyl, C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Alkylcarbonyl, C ₁ -C ₃ Alkoxycarbonyl group, C ₁ -C ₃ Alkylsulfonyl, C ₁ -C ₃ Alkylaminocarbonyl, C ₁ -C ₃ Acylamino, halogen substituted C ₁ -C ₃ Alkyl, halogen substituted C ₁ -C ₃ Alkoxy, when n ₁₀ >1, each R ₁₀ The same or different;

or iv) a spiroheterocyclyl selected from the group consisting of:

wherein n is ₉ 0, 1, 2, 3 or 4;

R ₉ each independently selected from the following substituents: deuterium, halogen, cyano, nitro, hydroxy, straight or branched C ₁ -C ₆ Alkyl, straight or branched C ₁ -C ₆ Alkoxy, halogen substituted C ₁ -C ₃ Alkyl, halogen substituted C ₁ -C ₃ Alkoxy, wherein when n ₉ >1, each R ₉ The same or different;

Y ₈ is a substituent in the non-aromatic structural part of the spiro structure, wherein the substituent is optionally substituted by hydrogen atoms, and Y8 is optionally deuterium, halogen, methyl, ethyl and trifluoromethyl.

5. The compound of claim 4, or a tautomer, enantiomer, diastereomer, racemate, isotopic compound, or pharmaceutically acceptable salt thereof, wherein,the 6-10 membered aryl or 5-10 membered heteroaryl is selected from thienyl, pyridyl, phenyl, benzothienyl, benzimidazolyl, indolyl, naphthyl, quinolinyl, isoquinolinyl.

6. The compound according to claim 1, or a tautomer, enantiomer, diastereomer, racemate, isotopic compound, or pharmaceutically acceptable salt thereof, wherein the compound represented by general formula (I) is a compound represented by any one of general formulae (I-1) to (I-8):

wherein n is 1, 2, 3, 4 or 5;

X ₁ is-CH ₂ -or-O-;

X ₂ is-CH ₂ -；

R ₁ 、R ₂ 、R ₃ Each independently hydrogen, deuterium or fluorine;

l is (CH) ₂ ) _b3

b ₃ 1, 2, 3, 4 or 5;

n ₉ 0, 1, 2, 3 or 4;

is a 6-10 membered aryl ring or a 5-10 heteroaryl ring, ->Condensed with the spiro nucleus to form spiro heterocyclyl;

Y ₈ is a substituent in the non-aromatic moiety of the spiro structure, which hydrogen atom is optionally substituted, Y8 is optionally deuterium, halogen, methyl, ethyl, trifluoromethyl;

R ₉ each independently selected from the following substituents: deuterium, halogen, cyano, nitro, hydroxy, straight or branched C ₁ -C ₆ Alkyl, straight or branched C ₁ -C ₆ Alkoxy, halogen substituted C ₁ -C ₃ Alkyl, halogen substituted C ₁ -C ₃ Alkoxy, wherein when n ₉ >1, each R ₉ The same or different.

7. The compound of claim 6, or a tautomer, enantiomer, diastereomer, racemate, isotopic compound, or pharmaceutically acceptable salt thereof, wherein,selected from the group consisting of thiophene ring, pyrrole ring, benzene ring, pyridine ring, benzothiophene ring, benzimidazole ring, indole ring, quinoline ring, and isoquinoline ring.

8. The compound according to claim 1, or a tautomer, enantiomer, diastereomer, racemate, isotopic compound, or pharmaceutically acceptable salt thereof, wherein the compound represented by general formula (I) is a compound represented by any one of general formulae (I-9) to (I-16):

wherein n is 1, 2, 3, 4 or 5;

X ₁ is-CH ₂ -or-O-;

X ₂ is-CH ₂ -；

R ₁ 、R ₂ 、R ₃ Each independently hydrogen, deuterium or fluorine;

l is (CH) ₂ ) _b3 ；

b ₃ 1, 2, 3, 4 or 5;

n ₉ 0, 1, 2, 3 or 4;

9. A compound represented by the general formula (I-17) or (I-18) or a tautomer, enantiomer, diastereomer, racemate, isotopic compound or pharmaceutically acceptable salt thereof,

wherein n is 1, 2, 3, 4 or 5;

X ₁ is-CH ₂ -or-O-;

X ₂ is-CH ₂ -；

R ₁ 、R ₂ 、R ₃ Each independently hydrogen, deuterium or fluorine;

l is (CH) ₂ ) _b3 ；

b ₃ 1, 2, 3, 4 or 5;

n ₉ 0, 1, 2, 3 or 4;

n ₁₀ 0, 1, 2, 3, 4 or 5;

Y ₁ each independently selected from hydrogen, deuterium, halogen, and cyano;

R ₁₀ each independently selected from deuterium, halogen, cyano, nitro, hydroxy, amino, aminocarbonyl, C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Alkylcarbonyl, C ₁ -C ₃ Alkoxycarbonyl group, C ₁ -C ₃ Alkylsulfonyl, C ₁ -C ₃ Alkylaminocarbonyl, C ₁ -C ₃ Acylamino, halogen substituted C ₁ -C ₃ Alkyl, halogen substituted C ₁ -C ₃ Alkoxy, when n ₁₀ >1, each R ₁₀ The same or different.

10. The compound of claim 9, or a tautomer, enantiomer, diastereomer, racemate, isotopic compound, or pharmaceutically acceptable salt thereof, wherein,the 6-10 membered aryl or 5-10 membered heteroaryl is selected from thienyl, pyridyl, phenyl, benzothienyl, benzimidazolyl, indolyl, naphthyl, quinolinyl, isoquinolinyl.

11. A compound represented by any one of the general formulae (I-23) to (I-32) or a tautomer, enantiomer, diastereomer, racemate, isotopic compound or pharmaceutically acceptable salt thereof:

wherein n is 1, 2 or 3;

X ₂ is-CH ₂ -；

R ₁ 、R ₂ 、R ₃ Each independently hydrogen, deuterium or fluorine;

L is (CH) ₂ ) _b3 ；

b ₃ 1, 2, 3, 4 or 5;

n ₈ 、n ₉ 、n ₁₀ each independently selected from 0, 1, 2, 3 or 4;

R ₉ selected from the following substituents: deuterium, halogen, cyano, nitro, hydroxy, straight or branched C ₁ -C ₆ Alkyl, straight or branched C ₁ -C ₆ Alkoxy, halogen substituted C ₁ -C ₃ Alkyl, halogen substituted C ₁ -C ₃ Alkoxy, wherein when n ₉ >1, each R ₉ The same or different;

12. The compound of claim 11, or a tautomer, enantiomer, diastereomer, racemate, isotopic compound, or pharmaceutically acceptable salt thereof, wherein,the 6-10 membered aryl or 5-10 membered heteroaryl is selected from thienyl, pyridyl, phenyl, benzothienyl, benzimidazolyl, indolyl, naphthyl, quinolinyl, iso-thienylQuinolinyl.

13. A compound represented by any one of the general formulae (I-33) to (I-42) or a tautomer, enantiomer, diastereomer, racemate, isotopic compound or pharmaceutically acceptable salt thereof:

Wherein n is 1, 2 or 3;

X ₂ is-CH ₂ -；

R ₁ 、R ₂ 、R ₃ Each independently hydrogen, deuterium or fluorine;

l is (CH) ₂ ) _b3 ；

b ₃ 1, 2, 3, 4 or 5;

n ₈ 、n ₉ 、n ₁₀ each independently 0, 1, 2, 3, or 4;

R ₉ each independently selected from the following substituents: deuterium, halogen, cyano, nitro, hydroxy, straight or branched C ₁ -C ₆ Alkyl, straight or branched C ₁ -C ₆ Alkoxy, halogen substituted C ₁ -C ₃ Alkyl, halogen substituted C ₁ -C ₃ Alkoxy, phenyl, 5-6 membered heteroaryl, when n ₉ >1, each R ₉ The same or different;

14. The compound of claim 13, or a tautomer, enantiomer, diastereomer, racemate, isotopic compound, or pharmaceutically acceptable salt thereof, wherein,the 6-10 membered aryl or 5-10 membered heteroaryl is selected from thienyl, pyridyl, phenyl, benzothienyl, benzimidazolyl, indolyl, naphthyl, quinolinyl, isoquinolinyl.

15. A compound represented by any one of the general formulae (I-51) to (I-58) or a tautomer, enantiomer, diastereomer, racemate, isotopic compound or pharmaceutically acceptable salt thereof:

wherein n is 1, 2 or 3;

X ₁ is-CH ₂ -or-O-;

X ₂ is-CH ₂ -；

R ₁ 、R ₂ 、R ₃ Each independently hydrogen, deuterium or fluorine;

l is (CH) ₂ ) _b3 ；

b ₃ 1, 2, 3, 4 or 5;

n ₁ 0, 1, 2, 3 or 4;

R ₅ each independently selected from deuterium, halogen, hydroxy, amino, cyano, nitro, straight or branched C ₁ -C ₆ Alkyl, straight or branched C ₁ -C ₆ Alkoxy, C ₁ -C ₃ Acylamino, aminocarbonyl, phenyl, 5-6 membered heteroaryl, 3-6 membered heterocycleRadical, C ₃ -C ₆ Cycloalkyl, C ₃ -C ₆ Cycloalkyl oxy, C ₁ -C ₃ Alkylaminocarbonyl, C ₁ -C ₃ Alkylsulfonyl, phenyloxy or 5-6 membered heteroaryloxy, when n ₁ >1, each R ₅ The same or different.

16. A compound selected from the group consisting of the following compounds, or a tautomer, enantiomer, diastereomer, racemate, isotopic compound, or pharmaceutically acceptable salt thereof:

/>

17. a compound or tautomer, enantiomer, diastereomer, racemate, isotopic compound or pharmaceutically acceptable salt thereof:

18. a process for preparing a compound represented by the general formula (I) according to claim 1, which is selected from one of the following processes:

The synthesis method comprises the following steps:

wherein R is ₁ 、R ₂ 、R ₃ 、X ₂ And n is as defined in claim 1;

m ₁ is an integer of 1 to 5;

compound H ₂ N-A ₁ In A of ₁ Is defined in claim 1 and A in the definition of A ₁ The definition is the same;

step 1-5: compounds 1G and 1H gave 1I under condensing agent conditions;

the synthesis method II comprises the following steps:

/>

wherein R is ₁ 、R ₂ 、R ₃ 、X ₂ And n is as defined in claim 1;

m ₂ is an integer of 1 to 3;

step 2-1, performing a Sonogashira coupling reaction on the compounds 2A and 2B in a dipolar organic solvent in the presence of a Pd catalyst, a monovalent copper catalyst and alkali at room temperature or under heating conditions to obtain a compound 2C;

step 2-2, reducing the compound 2C into a compound 2D by hydrogen under the catalysis of Pd/C, raney nickel or Wilkinson catalyst,

step 2-6: compounds 2G and 1H gave 2H under condensing agent conditions.

19. A pharmaceutical composition comprising a therapeutically effective amount of one or more of the compounds selected from the group consisting of tautomers, enantiomers, diastereomers, racemates, isotopic compounds and pharmaceutically acceptable salts thereof, and at least one other pharmaceutically acceptable carrier.

20. The pharmaceutical composition of claim 19, further comprising one or more additional pharmaceutically active ingredients.

21. The pharmaceutical composition according to claim 20, wherein the further one or more pharmaceutically active ingredients comprise macromolecular compounds selected from the group consisting of proteins, polysaccharides and nucleic acids and small molecular compounds selected from the group consisting of inorganic compounds, organometallic compounds, small organic molecular compounds of synthetic or natural origin.

22. One or more selected from the group consisting of a compound according to any one of claims 1 to 17, a tautomer, enantiomer, diastereomer, racemate, isotopic compound, and pharmaceutically acceptable salt thereof, for use in preparing a pharmaceutical composition for treating and/or preventing CRL4 ^CRBN Use of E3 ubiquitin ligase related diseases or disorders in medicine.

23. The use of claim 22, wherein the disease or disorder comprises cancer, inflammation, pain, a neurological disease, and an immune system disease.