Sulfur-containing isoindoline derivatives, methods for preparing the same, and their pharmaceutical applications.

Abstract

The present disclosure relates to sulfur-containing isoindoline derivatives, their preparation methods, and their pharmaceutical applications. Specifically, the present disclosure relates to sulfur-containing isoindoline derivatives represented by general formula (I), their preparation methods, pharmaceutical compositions containing the derivatives, and their use as therapeutic agents, particularly in the field of treating multiple myeloma as cereblon modulators. TIFF2023534528000157.tif3984

Description

[Technical Field]

[0001] This disclosure pertains to the pharmaceutical field and relates to sulfur-containing isoindoline derivatives, methods for preparing the same, and their pharmaceutical applications. In particular, this disclosure relates to a sulfur-containing isoindoline derivative represented by general formula (I), a method for preparing the same, a pharmaceutical composition containing the derivative, and its use as a cereblon modulator in the field of treatment for multiple myeloma. [Background technology]

[0002] Multiple myeloma (MM) is a malignant tumor whose main symptoms include hypercalcemia, kidney damage, anemia, and skeletal disorders. MM is the second most common hematological malignancy after non-Hodgkin lymphoma, affecting 4 to 6 people per 100,000 worldwide annually, and approximately 1.6 people per 100,000 in China annually. Current treatments mainly consist of drug therapy and autologous stem cell transplantation.

[0003] Currently, there are four main types of drugs widely used clinically: immunomodulatory agents (domides), proteasome inhibitors, hormones, and monoclonal antibodies. Drugs in the clinical research stage include biantibodies, ADCs, and CAR-T receptor receptors. These drugs have different mechanisms of action, and better therapeutic effects are often obtained when administered in combination. Clinically, two-drug, three-drug, and even four-drug combinations are commonly used, but the combination of immunomodulatory agents, proteasome inhibitors, and hormones is the most common, and antibodies may also be added. Of these, lenalidomide is the most commonly used immunomodulatory agent, and it is used in first-line treatment, maintenance therapy after stem cell transplantation, and second and third-line treatment after relapse. Sales of this drug reached $9.7 billion in 2018 / 2019. Furthermore, the overall market for MM is quite substantial and growing very rapidly. This is because continuous improvements and completeness in the diagnosis and treatment of MM are leading to longer patient survival times and consequently longer treatment durations. The MM market is expected to reach $33 billion in 2022, with immunomodulatory agents, represented by lenalidomide, still holding the largest share.

[0004] The mechanism by which immunomodulators (IMiDs) treat myeloma (MM) is primarily through the binding of IMiD drugs to the cereblon (CRBN) protein, followed by activation of the CRBN E3 ligase. This selective binding then leads to the rapid ubiquitination and degradation of the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3). Downregulation of Ikaros / Aiolos results in the downregulation of c-Myc, followed by IRF4, ultimately inhibiting myeloma cell growth and leading to apoptosis. Furthermore, IKZF3 can inhibit the transcription of IL2 and TNF cytokines in T / NK cells. Degradation of IKZF3 releases this inhibition, promoting the release of these cytokines and thus contributing to immunomodulation. Clinical trials have also shown a correlation between the clinical benefits of IMiD drugs and high CRBN expression levels. In lenalidomide-sensitive cell lines (OPM2 and KMS18), knockdown of CRBN eliminated the inhibitory activity of lenalidomide on cell growth, leading to drug resistance. It was discovered that the level of CRBN knockdown was linked to the degree of drug resistance. Cell proliferation experiments showed that reducing the expression level of CRBN in cells (U266-CRBN60 and U266-CRBN75) reduced the inhibitory activity of both lenalidomide and pomalidomide on cell growth.

[0005] Currently, the IMiD drugs that have already been approved for market include thalidomide, lenalidomide, and pomalidomide, all manufactured by Celgene (now merged into BMS). The three compounds have progressively stronger binding affinity to CRBN, resulting in progressively lower clinical doses. The main indication for all three compounds is myelodysplastic syndrome (MM), while thalidomide and lenalidomide have additional indications, with lenalidomide in particular being applicable to the treatment of myelodysplastic syndrome (MDS). Regarding side effects, lenalidomide and pomalidomide have similar performance and exhibit significant myelosuppressive effects, which are target-related toxicities. Thalidomide also has other side effects such as sedation, constipation, and neurological side effects.

[0006] The adipimide moiety of all IMiDs binds to a hydrophobic pocket defined by three tryptophan residues in CRBN (known as the "thalidomide binding pocket"). Conversely, the phthalimide / isoindrone ring modulates substrate recognition by altering the molecular surface of CRBN upon exposure to solvents. Different IMiDs result in distinct modifications to the CRBN molecular surface and differing substrate recognition preferences. Therefore, modifications to IMiDs can lead to the degradation of other transcription factors, potentially causing unwanted toxicity and side effects. This mode of action, like that of IMiDs, is also known as molecular glue, vividly demonstrating the adhesion of such small molecules to two different protein substrates.

[0007] Currently, the median survival time for multiple myeloma is over 5 years. This extension of survival time has led to a high rate of drug resistance in many patients to currently available drugs such as lenalidomide and pomalidomide, severely reducing the effectiveness of these medications. Therefore, the goal is to develop drug molecules with improved activity to resolve the drug resistance problem and minimize the toxicity and side effects of such compounds.

[0008] The disclosed patent applications for the Cereblon modulator include WO2008115516A2, WO2011100380A1, WO2019226770A1, WO2019014100A1, and WO2020064002A1, among others. [Overview of the project]

[0009] This disclosure aims to provide compounds represented by general formula (I) or their tautomers, meso compounds, racemic compounds, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof: [ka] Eventually, Ring A is an aryl group or a heteroaryl group, Ring B is a cycloalkyl group or a heterocyclyl group. Y is either CH2 or C(O), R 1 These are homologous or homologous, and each is independently selected from a hydrogen atom, halogen, alkyl group, alkenyl group, alkynyl group, alkoxy group, haloalkyl group, haloalkoxy group, hydroxyalkyl group, cyano group, amino group, nitro group and hydroxyl group. R 2 The group is selected from hydrogen atoms, halogens, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, hydroxyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, and each of the alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups is independently and optionally substituted with one or more substituents selected from halogens, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cyano groups, amino groups, nitro groups, hydroxyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups. R 3 These are homologous or homologous, and each is independently selected from a hydrogen atom, halogen, alkyl group, alkenyl group, alkynyl group, alkoxy group, haloalkyl group, haloalkoxy group, hydroxyalkyl group, cyano group, amino group, nitro group and hydroxyl group. R 4The group is selected from hydrogen atoms, halogens, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cyano groups, amino groups, nitro groups, hydroxy groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, and each of the alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups is independently and optionally substituted with one or more substituents selected from halogens, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cyano groups, amino groups, nitro groups, hydroxy groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups. R 5 and R 6 These are homologous or homologous, and each is independently selected from hydrogen atoms, halogens, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, hydroxyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups. n is 0, 1, 2, or 3. p is 0, 1, 2, 3, or 4. q is 0, 1, or 2, and t is 0, 1, 2, or 3.

[0010] In some preferred embodiments of the present disclosure, the compound represented by the above general formula (I) or its tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, is the compound represented by the general formula (I-1) or its tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof: [ka] Eventually, Ring A, Ring B, Y, R 1 ~R 6, n, p, q, and t are as defined in general formula (I).

[0011] In some preferred embodiments of the present disclosure, the compound represented by the above general formula (I) or its tautomer, meso form, racemic form, enantiomer, diastereomer, or a mixture thereof, or its pharmaceutically acceptable salt is the compound represented by general formula (I-2) or its tautomer, meso form, racemic form, enantiomer, diastereomer, or a mixture thereof, or its pharmaceutically acceptable salt:

Chemical formula

[0012] In some preferred embodiments of the present disclosure, the compound represented by the above general formula (I) or its tautomer, meso form, racemic form, enantiomer, diastereomer, or a mixture thereof, or its pharmaceutically acceptable salt is the compound represented by general formula (II) or its tautomer, meso form, racemic form, enantiomer, diastereomer, or a mixture thereof, or its pharmaceutically acceptable salt:

Chemical formula

[0013] In some preferred embodiments of the present disclosure, the compound represented by general formula (I) or general formula (II) above, or its tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, is the compound represented by general formula (II-1) or general formula (II-2) above, or its tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof: [ka] Eventually, Ring A, Ring B, Y, R 1 ~R 4 n, p, and t are as defined in general formula (II).

[0014] In some embodiments of the present disclosure, in the form of a compound represented by general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1), or general formula (II-2) above, or a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, ring A is a phenyl group or a 5-6 membered heteroaryl group, preferably selected from a phenyl group, a pyridyl group, and a pyrimidinyl group.

[0015] In some embodiments of the present disclosure, a compound represented by the above general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1), or general formula (II-2) or its tautomers, meso compounds, racemic compounds, enantiomers, diastereomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, [ka] teeth [ka] Selected from, R 3 p and are defined as shown in general formula (I).

[0016] In some embodiments of the present disclosure, in the form of a compound represented by general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1), or general formula (II-2) above, or a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, ring B is a 3- to 8-membered heterocyclyl group, preferably selected from a piperidinyl group, a pyrrolidinyl group, and an azetidinyl group, more preferably ring B is a 6-membered heterocyclyl group, and most preferably ring B is a piperidinyl group.

[0017] In some embodiments of the present disclosure, a compound represented by the above general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1), or general formula (II-2) or its tautomers, meso compounds, racemic compounds, enantiomers, diastereomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, [ka] teeth [ka] And J is 0 or 1, k is 0 or 1, preferably, [ka] teeth [ka] And R 4a and R 4bThe atoms are homologous or homologous, and each is independently selected from a hydrogen atom, halogen, alkyl group, alkenyl group, alkynyl group, alkoxy group, haloalkyl group, haloalkoxy group, cyano group, amino group, nitro group, hydroxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group, of which the alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group are independently and optionally substituted with one or more substituents selected from halogen, alkyl group, alkenyl group, alkynyl group, alkoxy group, haloalkyl group, haloalkoxy group, cyano group, amino group, nitro group, hydroxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group, and r is 0, 1, or 2.

[0018] In some preferred embodiments of the present disclosure, the compound represented by general formula (I) or general formula (II) above, or its tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, is the compound represented by general formula (IIG) or its tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof: [ka] Eventually, G 1 , G 2 and G 3 These are homologous or different, and each is independently a carbon atom or a nitrogen atom. R 4a and R 4bThese groups are homologous or homologous, and each is independently selected from hydrogen atoms, halogens, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cyano groups, amino groups, nitro groups, hydroxy groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, of which the alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups are independently and optionally substituted with one or more substituents selected from halogens, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cyano groups, amino groups, nitro groups, hydroxy groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups. r is 0, 1, or 2. J is either 0 or 1. k is either 0 or 1. Y, R 1 ~R 3 n and p are as defined in general formula (I).

[0019] In some preferred embodiments of this disclosure, the compound represented by general formula (I), general formula (I-1), general formula (II), general formula (II-1), or general formula (IIG) above, or in the form of its tautomers, meso compounds, racemic compounds, enantiomers, diastereomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, is the compound represented by general formula (IIG-1) or its tautomers, meso compounds, racemic compounds, enantiomers, diastereomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof: [ka] Eventually, G 1 , G 2 and G 3 These are homologous or different, and each is independently a carbon atom or a nitrogen atom. R 4a and R 4bThese groups are homologous or homologous, and each is independently selected from hydrogen atoms, halogens, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cyano groups, amino groups, nitro groups, hydroxy groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, of which the alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups are independently and optionally substituted with one or more substituents selected from halogens, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cyano groups, amino groups, nitro groups, hydroxy groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups. r is 0, 1, or 2. J is either 0 or 1. k is either 0 or 1. Y, R 1 ~R 3 n and p are as defined in general formula (I).

[0020] In some preferred embodiments of this disclosure, the compound represented by general formula (I), general formula (I-2), general formula (II), general formula (II-2), or general formula (IIG) above, or in the form of its tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, is the compound represented by general formula (IIG-2) or its tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof: [ka] Eventually, G 1 , G 2 and G 3 These are homologous or different, and each is independently a carbon atom or a nitrogen atom. R 4a and R 4bThese groups are homologous or homologous, and each is independently selected from hydrogen atoms, halogens, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cyano groups, amino groups, nitro groups, hydroxy groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, of which the alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups are independently and optionally substituted with one or more substituents selected from halogens, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cyano groups, amino groups, nitro groups, hydroxy groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups. r is 0, 1, or 2. J is either 0 or 1. k is either 0 or 1. Y, R 1 ~R 3 n and p are as defined in general formula (I).

[0021] In some preferred embodiments of the present disclosure, the compound represented by the above general formula (IIG), general formula (IIG-1), or general formula (IIG-2), or its tautomers, meso compounds, racemic compounds, enantiomers, diastereomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, G 2 is a nitrogen atom, G 1 and G 3 is a carbon atom, or G 1 is a nitrogen atom, G 2 and G 3 is a carbon atom, or G 1 , G 2 and G 3 Both are carbon atoms, or G 2 and G 3 Both are nitrogen atoms, G 1 It is a carbon atom.

[0022] In some preferred embodiments of the present disclosure, the compound represented by general formula (I), general formula (II), or general formula (IIG) above, or its tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is the compound represented by general formula (III), or its tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] Eventually, R 4a and R 4b These groups are homologous or homologous, and each is independently selected from hydrogen atoms, halogens, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cyano groups, amino groups, nitro groups, hydroxy groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, of which the alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups are independently and optionally substituted with one or more substituents selected from halogens, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cyano groups, amino groups, nitro groups, hydroxy groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups. r is 0, 1, or 2. Y, R 1 ~R 3 n and p are as defined in general formula (I).

[0023] In some preferred embodiments of this disclosure, the compound represented by general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (IIG), general formula (IIG-1), or general formula (III) above, or in the form of its tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, is the compound represented by general formula (III-1) or its tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof: [ka] Eventually, Y, R 1 ~R 3 , R 4a , R 4b , r, n, and p are as defined in general formula (III).

[0024] In some preferred embodiments of this disclosure, the compound represented by general formula (I), general formula (I-2), general formula (II), general formula (II-2), general formula (IIG), general formula (IIG-2), or general formula (III) above, or in the form of its tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, is the compound represented by general formula (III-2) or its tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof: [ka] Eventually, Y, R 1 ~R 3 , R 4a , R 4b , r, n, and p are as defined in general formula (III).

[0025] In some preferred embodiments of the present disclosure, in the form of a compound represented by general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1), general formula (II-2), general formula (IIG), general formula (IIG-1), general formula (IIG-2), general formula (III), general formula (III-1), or general formula (III-2), or a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, Y is CH2.

[0026] In some preferred embodiments of the present disclosure, in the form of a compound represented by the above general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1), or general formula (II-2), or a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, R 4 They are homologous or different, and each is independently a hydrogen atom, a halogen, and C. 1-6 Selected from alkyl groups, 3-8 membered cycloalkyl groups, 3-8 membered heterocyclyl groups, 6-10 membered aryl groups, and 5-10 membered heteroaryl groups, of which the above 3-8 membered cycloalkyl groups, 3-8 membered heterocyclyl groups, 6-10 membered aryl groups, and 5-10 membered heteroaryl groups can be independently and optionally selected from halogens, C 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, Halo C 1-6 Alkyl, halo C 1-6 Alkoxy groups, cyano groups, amino groups, nitro groups, hydroxyl groups and C 1-6 It is substituted with one or more substituents selected from hydroxyalkyl groups.

[0027] In some preferred embodiments of the present disclosure, in the form of a compound represented by the above general formula (IIG), general formula (IIG-1), general formula (IIG-2), general formula (III), general formula (III-1), or general formula (III-2), or a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, R 4a The group is selected from a 3-8 member cycloalkyl group, a 3-8 member heterocyclyl group, a 6-10 member aryl group, and a 5-10 member heteroaryl group, of which the above 3-8 member cycloalkyl group, 3-8 member heterocyclyl group, 6-10 member aryl group, and 5-10 member heteroaryl group can be independently and optionally selected from a halogen, C 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, Halo C 1-6 Alkyl, halo C 1-6 Alkoxy groups, cyano groups, amino groups, nitro groups, hydroxyl groups and C 1-6 Substituted with one or more substituents selected from hydroxyalkyl groups, R 4b They are homologous or different, and each is independently a hydrogen atom, a halogen, and C. 1-6 Selected from alkyl groups and 3- to 8-membered cycloalkyl groups, preferably R 4a teeth [ka] And R 4b It is a hydrogen atom.

[0028] In some preferred embodiments of the present disclosure, a compound represented by the above general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1), general formula (II-2), general formula (IIG), general formula (IIG-1), general formula (IIG-2), general formula (III), general formula (III-1), or general formula (III-2), or in the form of a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, R 1are the same or different and each independently is a hydrogen atom, a halogen and C 1-6 selected from an alkyl group, preferably, R 1 is a hydrogen atom.

[0029] In some embodiments of the present disclosure, in the compound represented by the above general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1), general formula (II-2), general formula (IIG), general formula (IIG-1), general formula (IIG-2), general formula (III), general formula (III-1) or general formula (III-2), or a tautomer, meso form, racemic form, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, R 2 is a hydrogen atom, C 1-6 selected from an alkyl group and a 3- to 8-membered cycloalkyl group, preferably, R 2 is a hydrogen atom.

[0030] In some embodiments of the present disclosure, in the compound represented by the above general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1), general formula (II-2), general formula (IIG), general formula (IIG-1), general formula (IIG-2), general formula (III), general formula (III-1) or general formula (III-2), or a tautomer, meso form, racemic form, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, R 3 are the same or different and each independently is a hydrogen atom, a halogen and C 1-6 selected from an alkyl group.

[0031] In some embodiments of the present disclosure, in the compound represented by the above general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1), general formula (II-2), general formula (IIG), general formula (IIG-1), general formula (IIG-2), general formula (III), general formula (III-1) or general formula (III-2), or a tautomer, meso form, racemic form, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, R 3These elements are homologous or different, and each is independently a hydrogen atom or a halogen, preferably a hydrogen atom.

[0032] In some embodiments of the present disclosure, in the form of a compound represented by general formula (I), general formula (I-1), or general formula (I-2) above, or a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, q is 0 or 1, preferably q is 0.

[0033] In some embodiments of the present disclosure, in the form of a compound represented by general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1), general formula (II-2), general formula (IIG), general formula (IIG-1), general formula (IIG-2), general formula (III), general formula (III-1), or general formula (III-2), or a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, n is 0 or 1.

[0034] In some embodiments of the present disclosure, in the form of a compound represented by the above general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1), general formula (II-2), general formula (IIG), general formula (IIG-1), general formula (IIG-2), general formula (III), general formula (III-1), or general formula (III-2), or a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, p is 0, 1, or 2.

[0035] In some embodiments of the present disclosure, in the form of a compound represented by the above general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1), or general formula (II-2), or a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, t is 0, 1, or 2.

[0036] In some embodiments of the present disclosure, in the form of a compound represented by the above general formula (IIG), general formula (IIG-1), general formula (IIG-2), general formula (III), general formula (III-1) or general formula (III-2), or a tautomer, meso form, racemic form, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, r is 0 or 1.

[0037] In some embodiments of the present disclosure, in the form of a compound represented by the above general formula (III), general formula (III-1) or general formula (III-2), or a tautomer, meso form, racemic form, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, Y is CH2, and R 1 are the same or different and are each independently selected from a hydrogen atom, a halogen, and a C 1-6 alkyl group, R 2 is a hydrogen atom, R 3 are the same or different and are each independently a hydrogen atom or a halogen, R 4a is

Chemical formula

[0038] Typical compounds of the present disclosure include, but are not limited to, the following. Table A

Table 1-1

Table 1-2

Table 1-3

【Table​​​​​​​ [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] [Table 1-16] [Table 1-17] [Table 1-18]

[0039] Another aspect of this disclosure relates to a compound represented by general formula (IA) or its tautomers, meso compounds, racemic compounds, enantiomers, diastereomers, or mixtures thereof, or salts thereof. [ka] Eventually, Ring A is selected from a phenyl group, a pyridyl group, and a pyrimidinyl group, and is preferably a phenyl group. Ring B is a heterocyclyl group, preferably a 3- to 8-membered heterocyclyl group, more preferably a piperidinyl group, a pyrrolidinyl group, or an azetidinyl group. R 2 ~R 6 p, q, and t are as defined in general formula (I).

[0040] Another aspect of this disclosure relates to a compound represented by general formula (IIA) or its tautomers, meso compounds, racemic compounds, enantiomers, diastereomers, or mixtures thereof, or salts thereof. [ka] Eventually, Ring A is selected from a phenyl group, a pyridyl group, and a pyrimidinyl group, and is preferably a phenyl group. Ring B is a heterocyclyl group, preferably a 3- to 8-membered heterocyclyl group, more preferably a piperidinyl group, a pyrrolidinyl group, or an azetidinyl group. R 2 ~R 4 p and t are as defined in general formula (II).

[0041] Another aspect of this disclosure relates to a compound represented by general formula (IIGA) or its tautomers, meso compounds, racemic compounds, enantiomers, diastereomers, or mixtures thereof, or salts thereof. [ka] Eventually, G 1 , G 2 , G 3 , R 2 , R 3 , R 4a , R 4b , J, k, p, and r are as defined in general formula (IIG).

[0042] Another aspect of this disclosure relates to a compound represented by general formula (IIIA) or its tautomers, meso compounds, racemic compounds, enantiomers, diastereomers, or mixtures thereof, or salts thereof. [ka] Eventually, R 2 , R 3 , R 4a , R 4b p and r are as defined in general formula (III).

[0043] Typical intermediate compounds of this disclosure include, but are not limited to, the following: [Table 2-1] [Table 2-2] [Table 2-3]

[0044] Another aspect of this disclosure relates to a compound represented by general formula (IC) or in the form of its tautomers, meso compounds, racemic compounds, enantiomers, diastereomers, or mixtures thereof, or salts thereof. [ka] Eventually, R m C 1-6 It is an alkyl group, preferably a tert-butyl group, Ring A, Ring B, Y, R 1 ~R 6 n, p, q, and t are as defined in general formula (I).

[0045] Another aspect of this disclosure relates to a compound represented by general formula (I-1C) or its tautomers, meso compounds, racemic compounds, enantiomers, diastereomers, or mixtures thereof, or salts thereof. [ka] Eventually, R m C 1-6 It is an alkyl group, preferably a tert-butyl group, Ring A, Ring B, Y, R 1 ~R 6 n, p, q, and t are as defined in general formula (I-1).

[0046] Another aspect of this disclosure relates to a compound represented by general formula (IIC) or its tautomers, meso compounds, racemic compounds, enantiomers, diastereomers, or mixtures thereof, or salts thereof. [ka] Eventually, R m C 1-6 It is an alkyl group, preferably a tert-butyl group, Ring A, Ring B, Y, R 1 ~R 4 n, p, and t are as defined in general formula (II).

[0047] Another aspect of this disclosure relates to a compound represented by general formula (II-1C) or its tautomers, meso compounds, racemic compounds, enantiomers, diastereomers, or mixtures thereof, or salts thereof. [ka] Eventually, R m C 1-6 It is an alkyl group, preferably a tert-butyl group, Ring A, Ring B, Y, R 1 ~R 4 n, p, and t are as defined in general formula (II-1).

[0048] Another aspect of this disclosure relates to a compound represented by general formula (IIGC) or its tautomers, meso compounds, racemic compounds, enantiomers, diastereomers, or mixtures thereof, or salts thereof. [ka] Eventually, R m C 1-6 It is an alkyl group, preferably a tert-butyl group, G 1 , G 2 , G 3 , Y, R 1 ~R 3 , R 4a , R 4b , J, k, r, n, and p are as defined in general formula (IIG).

[0049] Another aspect of this disclosure relates to a compound represented by general formula (IIGC-1) or its tautomers, meso compounds, racemic compounds, enantiomers, diastereomers, or mixtures thereof, or salts thereof. [ka] Eventually, R m C 1-6 It is an alkyl group, preferably a tert-butyl group, G 1 , G 2 , G 3 , Y, R 1 ~R 3 , R 4a , R 4b J, k, r, n, and p are as defined in general formula (IIG-1).

[0050] Another aspect of this disclosure relates to a compound represented by general formula (IIIC) or in the form of its tautomers, meso compounds, racemic compounds, enantiomers, diastereomers, mixtures thereof, or salts thereof. [ka] Eventually, R m C 1-6 It is an alkyl group, preferably a tert-butyl group, Y, R 1 ~R 3 , R 4a , R 4b , r, n, and p are as defined in general formula (III).

[0051] Another aspect of this disclosure relates to a compound represented by general formula (III-1C) or its tautomers, meso compounds, racemic compounds, enantiomers, diastereomers, or mixtures thereof, or salts thereof. [ka] Eventually, R m C 1-6 It is an alkyl group, preferably a tert-butyl group, Y, R 1 ~R 3 , R 4a , R 4b , r, n, and p are as defined in general formula (III-1).

[0052] Typical intermediate compounds of this disclosure include, but are not limited to, the following: [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6]

[0053] Another aspect of this disclosure relates to a method for preparing a compound represented by general formula (I) or a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method being: [ka] This includes reacting a compound of general formula (IA) with a compound of general formula (IB) to obtain a compound of general formula (I), Eventually, Ring A, Ring B, Y, R 1 ~R 6 n, p, q, and t are as defined in general formula (I).

[0054] Another aspect of this disclosure relates to a method for preparing a compound represented by general formula (I) or a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method being: [ka] This includes an intramolecular cyclization reaction of a compound of general formula (IC) to obtain a compound of general formula (I), Eventually, R m C 1-6 It is an alkyl group, preferably a tert-butyl group, Ring A, Ring B, Y, R 1 ~R 6 n, p, q, and t are as defined in general formula (I).

[0055] Another aspect of this disclosure relates to a method for preparing a compound represented by general formula (I-1) or a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method being: [ka] It includes subjecting a compound of general formula (I-1C) to an intramolecular cyclization reaction to obtain a compound of general formula (I-1). Among them, R m is a C 1-6 alkyl group, preferably a tert-butyl group, Ring A, Ring B, Y, R 1 ~R 6 , n, p, q and t are as defined in general formula (I-1).

[0056] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I-2) or a tautomer, meso form, racemic form, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof. The method

Chemical formula

[0057] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or a tautomer, meso form, racemic form, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof. The method

Chemical formula

[0058] Another aspect of this disclosure relates to a method for preparing a compound represented by general formula (II) or a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method being: [ka] This includes an intramolecular cyclization reaction of a compound of general formula (IIC) to obtain a compound of general formula (II), Eventually, R m C 1-6 It is an alkyl group, preferably a tert-butyl group, Ring A, Ring B, Y, R 1 ~R 4 n, p, and t are as defined in general formula (II).

[0059] Another aspect of this disclosure relates to a method for preparing a compound represented by general formula (II-1) or a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method being: [ka] This includes an intramolecular cyclization reaction of a compound of general formula (II-1C) to obtain a compound of general formula (II-1), Eventually, R m C 1-6 It is an alkyl group, preferably a tert-butyl group, Ring A, Ring B, Y, R 1 ~R 4 n, p, and t are as defined in general formula (II).

[0060] Another aspect of this disclosure relates to a method for preparing a compound represented by general formula (II-2) or a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method being: [ka] The method involves preparing a compound of general formula (II) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, by chiral resolution, thereby obtaining a single-configuration compound represented by general formula (II-2), or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof. Eventually, R m C 1-6 It is an alkyl group, preferably a tert-butyl group, Ring A, Ring B, Y, R 1 ~R 4 n, p, and t are as defined in general formula (II).

[0061] Another aspect of this disclosure relates to a method for preparing a compound represented by general formula (IIG) or a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method being: [ka] This includes reacting a compound of general formula (IIGA) with a compound of general formula (IB) to obtain a compound of general formula (IIG), Eventually, G 1 , G 2 , G 3 , Y, R 1 ~R 3 , R 4a , R 4b , J, k, n, p, and r are as defined in general formula (IIG).

[0062] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IIG) or a tautomer, meso form, racemic form, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising

Chemical formula

[0063] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IIG-1) or a tautomer, meso form, racemic form, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising

Chemical formula

[0064] Another aspect of this disclosure relates to a method for preparing a compound represented by general formula (IIG-2) or a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method being: [ka] The method involves preparing a compound of general formula (IIG) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, by chiral resolution, thereby obtaining a single-configuration compound represented by general formula (IIG-2), or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof. Eventually, R m C 1-6 It is an alkyl group, preferably a tert-butyl group, G 1 , G 2 , G 3 , Y, R 1 ~R 3 , R 4a , R 4b , J, k, n, p, and r are as defined in general formula (IIG).

[0065] Another aspect of this disclosure relates to a method for preparing a compound represented by general formula (III) or a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method being: [ka] This includes reacting a compound of general formula (IIIA) with a compound of general formula (IB) to obtain a compound of general formula (III), Eventually, Y, R 1 ~R 3 , R 4a , R 4b n, p, and r are as defined in general formula (III).

[0066] Another aspect of this disclosure relates to a method for preparing a compound represented by general formula (III) or a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method being: [ka] This involves an intramolecular cyclization reaction of a compound of general formula (IIIC) to obtain a compound of general formula (III), Eventually, R m C 1-6 It is an alkyl group, preferably a tert-butyl group, Y, R 1 ~R 3 , R 4a , R 4b n, p, and r are as defined in general formula (III).

[0067] Another aspect of this disclosure relates to a method for preparing a compound represented by general formula (III-1) or a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method being: [ka] This includes an intramolecular cyclization reaction of a compound of general formula (III-1C) to obtain a compound of general formula (III-1), Eventually, R m C 1-6 It is an alkyl group, preferably a tert-butyl group, Y, R 1 ~R 3 , R 4a , R 4b n, p, and r are as defined in general formula (III-1).

[0068] Another aspect of this disclosure relates to a method for preparing a compound represented by general formula (III-2) or a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method being: [ka] The method involves preparing a compound of general formula (III) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, by chiral resolution, thereby obtaining a single-configuration compound represented by general formula (III-2), or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof. Eventually, R m C 1-6 It is an alkyl group, preferably a tert-butyl group, Y, R 1 ~R 3 , R 4a , R 4b n, p, and r are as defined in general formula (III).

[0069] Another aspect of the present disclosure relates to pharmaceutical compositions comprising compounds represented by general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1), general formula (II-2), general formula (IIG), general formula (IIG-1), general formula (IIG-2), general formula (III), general formula (III-1), general formula (III-2) or the compounds shown in Table A, or their tautomers, meso compounds, racemic compounds, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable vectors, diluents, or excipients.

[0070] This disclosure further relates to the use of compounds represented by general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1), general formula (II-2), general formula (IIG), general formula (IIG-1), general formula (IIG-2), general formula (III), general formula (III-1), general formula (III-2), or the compounds shown in Table A, or their tautomers, meso compounds, racemic compounds, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them, in the preparation of agents for the treatment and / or prevention of diseases associated with the CRBN protein.

[0071] This disclosure further relates to compounds represented by general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1), general formula (II-2), general formula (IIG), general formula (IIG-1), general formula (IIG-2), general formula (III), general formula (III-1), general formula (III-2), or the compounds shown in Table A, or their tautomers, meso compounds, racemic compounds, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceuticals containing thereof. The present invention relates to the use of the composition in the preparation of agents for the treatment and / or prevention of cancer, angiogenesis-related conditions, pain, macular degeneration or related syndromes, skin diseases, lung diseases, asbestos-related diseases, parasitic diseases, immunodeficiency disorders, CNS diseases, CNS disorders, atherosclerosis or related conditions, sleep disorders or related conditions, infectious diseases, abnormal hemoglobin disorders or related conditions, or TNFα-related conditions, preferably in the preparation of agents for the treatment and / or prevention of cancer or CNS disorders.

[0072] The disclosure further relates to a method for treating and / or preventing diseases associated with the CRBN protein, comprising administering to a patient in need a therapeutically effective dose of a compound represented by formula (I), formula (I-1), formula (I-2), formula (II), formula (II-1), formula (II-2), formula (IIG), formula (IIG-1), formula (IIG-2), formula (III), formula (III-1), formula (III-2) or a compound shown in Table A, or a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing thereof.

[0073] This disclosure further relates to methods for treating and / or preventing cancer, angiogenesis-related conditions, pain, macular degeneration or related syndromes, skin diseases, lung diseases, asbestos-related diseases, parasitic diseases, immunodeficiency disorders, CNS diseases, CNS disorders, atherosclerosis or related conditions, sleep disorders or related conditions, infectious diseases, abnormal hemoglobin disorders or related conditions, or TNFα-related conditions, preferably methods for treating and / or preventing cancer or CNS disorders, wherein a therapeutically effective amount of general formula (I) is administered to patients in need. The present invention relates to a method of administering a compound represented by general formula (I-1), general formula (I-2), general formula (II), general formula (II-1), general formula (II-2), general formula (IIG), general formula (IIG-1), general formula (IIG-2), general formula (III), general formula (III-1), general formula (III-2), or a compound shown in Table A, or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same.

[0074] This disclosure further relates to compounds represented by general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1), general formula (II-2), general formula (IIG), general formula (IIG-1), general formula (IIG-2), general formula (III), general formula (III-1), general formula (III-2), or the compounds shown in Table A, or their tautomers, meso compounds, racemic compounds, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof or pharmaceutical compositions containing the same.

[0075] This disclosure further relates to compounds represented by general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1), general formula (II-2), general formula (IIG), general formula (IIG-1), general formula (IIG-2), general formula (III), general formula (III-1), general formula (III-2) or Table A, or in the form of tautomers, meso compounds, racemic compounds, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof or pharmaceutical compositions containing the same, for the treatment and / or prevention of diseases associated with the CRBN protein.

[0076] In this disclosure, the diseases associated with the CRBN protein are selected from cancer, angiogenesis-related conditions, pain, macular degeneration or related syndromes, skin diseases, lung diseases, asbestos-related diseases, parasitic diseases, immunodeficiency disorders, CNS diseases, CNS disorders, atherosclerosis or related conditions, sleep disorders or related conditions, infectious diseases, abnormal hemoglobin disorders or related conditions, or TNFα-related conditions, preferably cancer or CNS disorders.

[0077] This disclosure further relates to compounds represented by general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1), general formula (II-2), general formula (IIG), general formula (IIG-1), general formula (IIG-2), general formula (III), general formula (III-1), general formula (III-2) or in the form of tautomers, mesomorphs, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof or pharmaceutical compositions for treating and / or preventing cancer, angiogenesis-related conditions, pain, macular degeneration or related syndromes, skin diseases, lung diseases, asbestos-related diseases, parasitic diseases, immunodeficiency, CNS diseases, CNS disorders, atherosclerosis or related conditions, sleep disorders or related conditions, infectious diseases, abnormal hemoglobin disorders or related conditions, or TNFα-related conditions, preferably cancer or CNS disorders.

[0078] In this disclosure, the cancers are selected from leukemia, myeloma, lymphoma, melanoma, skin cancer, liver cancer, kidney cancer, lung cancer, nasopharyngeal cancer, stomach cancer, esophageal cancer, colorectal cancer, gallbladder cancer, bile duct cancer, choriocarcinoma, pancreatic cancer, polycythemia vera, pediatric tumors, cervical cancer, ovarian cancer, breast cancer, bladder cancer, urothelial carcinoma, ureteral tumors, prostate cancer, seminomas, testicular tumors, head and neck tumors, head and neck squamous cell carcinoma, endometrial cancer, thyroid cancer, sarcoma, osteoma, neuroblastoma, neuroendocrine cancer, brain tumors, CNS cancers, astrocytoma, and glioma, preferably, the liver cancer is hepatocellular carcinoma, the colorectal cancer is colon cancer or rectal cancer, the sarcoma is osteosarcoma or soft tissue sarcoma, and the glioma is glioblastoma. The leukemias described above are preferably chronic lymphocytic leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and hairy cell leukemia; the lymphomas described above are preferably small lymphocytic lymphoma, marginal zone lymphoma, follicular lymphoma, mantle cell lymphoma, non-Hodgkin lymphoma (NHL), lymphoplasmacytic lymphoma, extranodal marginal zone lymphoma, T-cell lymphoma, B-cell lymphoma, and diffuse large B-cell lymphoma; and the myelomas described above are preferably multiple myeloma (MM) and myelodysplastic syndrome (MDS). The cancers described in this disclosure include primary or metastatic cancers. The cancers described in this disclosure further include refractory cancers or cancers resistant to chemotherapy or radiotherapy. More preferably, the multiple myelomas described above are relapsed, refractory, or resistant. Most preferably, the multiple myeloma described above is refractory or resistant to lenalidomide or pomalidomide.

[0079] Examples of CNS disorders include, but are not limited to, the disorders described in U.S. Publication No. US2005 / 0143344A1, disclosed on June 30, 2005, and are incorporated herein by reference. Specific examples include, but are not limited to, amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, and other neuroimmunological disorders, such as Tourette syndrome, delusions, or transient disturbances of consciousness, or amnesia, or dispersed memory impairment occurring in the absence of other central nervous system disorders.

[0080] Examples of CNS disorders and related syndromes include, but are not limited to, the disorders described in U.S. Publication No. US2006 / 0122228A1, disclosed on June 8, 2006, and their contents are incorporated herein by reference. Specific examples include, but are not limited to, CNS disorders / injuries and associated syndromes, primary brain injury, secondary brain injury, traumatic brain injury, focal brain injury, diffuse axonal injury, cranial brain injury, concussion, postconcussion syndrome, cerebral contusion / laceration, subdural hematoma, epidermal hematoma, post-traumatic epilepsy, chronic vegetative state, complete SCI, incomplete SCI, acute SCI, subacute SCI, chronic SCI, central spinal syndrome, Brown-Séquard syndrome, anterior column syndrome, convex spinal cord syndrome, cauda equina syndrome, neurogenic shock, spinal shock, altered level of consciousness, headache, nausea, vomiting, memory impairment, dizziness, diplopia, blurred vision, emotional instability, sleep disorders, irritability, difficulty concentrating, nervousness, behavioral disorders, cognitive impairment, and epilepsy.

[0081] Diseases associated with angiogenesis include, but are not limited to, inflammatory diseases, autoimmune diseases, viral diseases, genetic diseases, allergic diseases, bacterial diseases, intraocular neovascular diseases, choroidal neovascular diseases, retinal neovascular diseases, and iris rubeosis (angle angiogenesis). Preferably, include, but are not limited to, arthritis, endometriosis, Crohn's disease, heart failure, severe heart failure, renal impairment, endotoxemia, toxic shock syndrome, osteoarthritis, retroviral replication, wasting diseases, meningitis, silica-induced fibrosis, asbestos-induced fibrosis, veterinary diseases, hypercalcemia associated with malignant tumors, stroke, circulatory shock, periodontitis, gingivitis, macrocytic anemia, refractory anemia, and 5q deletion syndrome.

[0082] The active compound can be prepared in a form suitable for administration by any suitable route, and the composition of this disclosure can be prepared by conventional methods using one or more pharmaceutically acceptable vectors. Accordingly, the active compound of this disclosure can be prepared in dosage forms for oral administration, injection (e.g., intravenous, intramuscular, or subcutaneous), inhalation, or inhalation. The compound of this disclosure may be prepared in dosage forms such as tablets, hard capsules or soft capsules, aqueous or oily suspensions, emulsions, injection solutions, dispersible powders or granules, suppositories, tablets, or syrups.

[0083] As a general guideline, the active compound is preferably in the form of a unit dose or in a form that the patient can self-administer as a monotherapy. The unit dose of the compound or composition relating to this disclosure may be expressed as a tablet, capsule, cachet, bottled solution, drug powder, granules, tablet, suppository, regenerated powder, or liquid formulation. A preferred unit dose may be 0.1 to 1000 mg.

[0084] The pharmaceutical composition relating to this disclosure may contain one or more additives in addition to the active compound, and these additives are selected from components such as fillers (diluents), binders, wetting agents, disintegrants, and excipients. Depending on the administration method, the composition may contain 0.1 to 99% by weight of the active compound.

[0085] The tablets comprise an active ingredient and non-toxic, pharmaceutically acceptable excipients suitable for mixing in the preparation of the tablets. These excipients may be inert excipients, granulators, disintegrants, binders, and lubricants. These tablets may be uncoated or coated by known techniques that mask the taste of the drug or slow its disintegration and absorption in the gastrointestinal tract, thereby providing a sustained-release effect over a long period.

[0086] An oral formulation may be provided in the form of a soft gelatin capsule containing the active ingredient and an inert solid diluent, or the active ingredient and a water-soluble vector or oily solvent.

[0087] The aqueous suspension comprises an active substance and an excipient suitable for mixing in the preparation of the aqueous suspension. Such an excipient is a suspending agent, a dispersing agent, or a wetting agent. The aqueous suspension may also contain one or more preservatives, one or more colorants, one or more flavoring agents, and one or more sweeteners.

[0088] Oil suspensions can be prepared by suspending the active ingredient in vegetable oil or mineral oil. The oil suspension may contain a thickening agent. Sweeteners and flavoring agents may be added to provide a palatable formulation. These compositions can be preserved by adding antioxidants.

[0089] The pharmaceutical compositions relating to this disclosure may be in the form of an oil-in-water emulsion. The oil phase may be vegetable oil, mineral oil, or a mixture thereof. A suitable emulsifier may be a naturally occurring phospholipid, and the emulsion may contain sweeteners, flavoring agents, preservatives, and antioxidants. Such formulations may also contain mitigating agents, preservatives, colorants, and antioxidants.

[0090] The pharmaceutical compositions relating to this disclosure may be in the form of sterile aqueous solutions for injection. Acceptable solvents or solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. The sterile injection formulation may also be a sterile oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase, and the injection solution or microemulsion can be injected into the patient's bloodstream by local injection in large quantities. Alternatively, it is preferable to administer the solution and microemulsion in a manner that can maintain a constant cycle concentration of the compound relating to this disclosure. A continuous intravenous infusion device can be used to maintain such a constant concentration. An example of such a device is the Deltec CADD-PLUS. TM. 5400 intravenous injection pump.

[0091] The pharmaceutical compositions relating to this disclosure may be in the form of sterile injection water or oil suspension for intramuscular and subcutaneous administration. Such suspensions can be prepared using the appropriate dispersants or wetting agents and suspending agents according to known techniques. The sterile injection formulation may also be a sterile injection solution or suspension prepared in a parenterally acceptable, non-toxic diluent or solvent. Furthermore, sterile fixative oils can be conveniently used as solvents or suspension media. For this purpose, any compounding fixative oil can be used. Fatty acids can also be used to prepare injection formulations.

[0092] The compounds relating to this disclosure may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid in the rectum, and therefore dissolves in the rectum to release the drug.

[0093] The compounds according to this disclosure can be administered by adding water to prepare aqueous, turbid, dispersible powders and granules. These pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersant, a wetting agent, a suspending agent, or one or more preservatives.

[0094] As is well known to those skilled in the art, the dosage of a drug depends on many factors, including, but not limited to, the activity of the specific compound used, the patient's age, weight, physical condition, behavior, diet, administration time, method of administration, excretion rate, drug composition, and disease severity. Furthermore, the optimal treatment method, such as the mode of treatment, the daily dose of the compound, or the type of pharmaceutically acceptable salt, can be determined according to conventional treatment plans.

[0095] Explanation of terms Unless otherwise specified, terms used in the specification and claims have the following meanings:

[0096] The term "alkyl group" refers to a saturated aliphatic hydrocarbon group that is a linear or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12), and more preferably an alkyl group containing 1 to 6 carbon atoms. The non-limiting examples include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, sec-butyl group, n-pentyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, 2-methylbutyl group, 3-methylbutyl group, n-hexyl group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2-ethylbutyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 2,3-dimethylbutyl group, n-heptyl group, 2-methylhexyl group, 3-methylhexyl group, 4-methylhexyl group, 5-methylhexyl Syl group, 2,3-dimethylpentyl group, 2,4-dimethylpentyl group, 2,2-dimethylpentyl group, 3,3-dimethylpentyl group, 2-ethylpentyl group, 3-ethylpentyl group, n-octyl group, 2,3-dimethylhexyl group, 2,4-dimethylhexyl group, 2,5-dimethylhexyl group, 2,2-dimethylhexyl group, 3,3-dimethylhexyl group, 4,4-dimethylhexyl group, 2 This includes -ethylhexyl group, 3-ethylhexyl group, 4-ethylhexyl group, 2-methyl-2-ethylpentyl group, 2-methyl-3-ethylpentyl group, n-nonyl group, 2-methyl-2-ethylhexyl group, 2-methyl-3-ethylhexyl group, 2,2-diethylpentyl group, n-decyl group, 3,3-diethylhexyl group, 2,2-diethylhexyl group, and various branched isomers thereof.More preferably, the lower alkyl group contains 1 to 6 carbon atoms, and non-limiting examples include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, sec-butyl group, n-pentyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, 2-methylbutyl group, 3-methylbutyl group, n-hexyl group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2-ethylbutyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 2,3-dimethylbutyl group, and the like. The alkyl group may be substituted or not, and if substituted, it may be substituted at any available linking point. Preferably, the substituent is one or more substituents independently and optionally selected from a D atom, halogen, alkoxy group, haloalkyl group, haloalkoxy group, cycloalkyloxy group, heterocyclyloxy group, hydroxy group, hydroxyalkyl group, cyano group, amino group, nitro group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group.

[0097] The term "alkylene group" refers to a saturated linear or branched aliphatic hydrocarbon group, which is a residue derived by removing two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkane, and is a linear or branched group containing 1 to 20 carbon atoms, preferably containing 1 to 12 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12), and more preferably containing 1 to 6 carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2)-, 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), 1,3-propylene (-CH2CH2CH2-), 1,4-butylene (-CH2CH2CH2CH2-), etc. The alkylene group may be substituted or not, and if substituted, it may be substituted at any available linking point. The substituent is preferably one or more substituents independently and optionally selected from alkenyl groups, alkynyl groups, alkoxy groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocyclyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, and oxo groups.

[0098] The term "alkenyl group" refers to an alkyl compound that contains at least one carbon-carbon double bond in its molecule, and the definition of an alkyl group is as described above. Alkenyl groups may or may not be substituted. If substituted, the substituent is preferably one or more groups independently selected from alkoxy groups, halogens, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups.

[0099] The term "alkynyl group" refers to an alkyl group compound that contains at least one carbon-carbon triple bond in its molecule, and the definition of an alkyl group is as described above. Alkynyl groups may or may not be substituted. If substituted, the substituent is preferably one or more groups independently selected from alkyl groups, alkoxy groups, halogens, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups.

[0100] The term "cycloalkyl group" refers to saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituents, where a cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms (which may be specific points or intervals consisting of any two points, e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 ring atoms, 4 to 11 ring atoms, 6 to 12 ring atoms, etc.), preferably 3 to 8 carbon atoms (e.g., 3, 4, 5, 6, 7 and 8), and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, and cyclooctyl groups, while polycyclic cycloalkyl groups include cycloalkyl groups of spiro rings, fused rings, and crosslinked rings.

[0101] The term "spirocycloalkyl group" refers to a polycyclic group with 5 to 20 members, in which monocyclic rings share one carbon atom (referred to as a spiro atom), and may contain one or more double bonds. Preferably, it has 6 to 14 members, and more preferably 7 to 10 members (e.g., 7, 8, 9, or 10 members). Spirocycloalkyl groups are classified into monospirocycloalkyl groups, bisspirocycloalkyl groups, or polyspirocycloalkyl groups depending on the number of spiro atoms shared between the rings, with monospirocycloalkyl groups and bisspirocycloalkyl groups being preferred. More preferably, they are 3-member / 5-member, 3-member / 6-member, 4-member / 4-member, 4-member / 5-member, 4-member / 6-member, 5-member / 5-member, or 5-member / 6-member monospirocycloalkyl groups. Non-limiting examples of spirocycloalkyl groups are: [ka] Includes.

[0102] The term "condensed cycloalkyl group" refers to a 5-20 membered, all-carbon polycyclic group in which each ring in the system shares one adjacent pair of carbon atoms with the other rings in the system, and one or more of these rings may contain one or more double bonds. Preferably, they are 6-14 membered, and more preferably 7-10 membered (e.g., 7, 8, 9, or 10 membered). Depending on the number of constituent rings, they can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic condensed cycloalkyl groups, preferably bicyclic or tricyclic, and more preferably 3-4 membered, 3-5 membered, 3-6 membered, 4-4 membered, 4-5 membered, 4-6 membered, 5-4 membered, 5-5 membered, 5-6 membered, 6-3 membered, 6-4 membered, 6-5 membered, and 6-6 membered bicycloalkyl groups. Non-limiting examples of condensed cycloalkyl groups are: [ka] Includes.

[0103] The term "crosslinked cycloalkyl group" refers to a 5-20 membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly linked, and may contain one or more double bonds. Preferably, it is 6-14 membered, and more preferably 7-10 membered (e.g., 7, 8, 9, or 10 membered). Depending on the number of rings, crosslinked cycloalkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of crosslinked cycloalkyl groups are: [ka] Includes.

[0104] The above cycloalkyl rings include those in which the above cycloalkyl group (including monocyclic, spirocyclic, fused, and crosslinked rings) is fused to an aryl group, a heteroaryl group, or a heterocycloalkyl ring, and among these, the ring linked to the parent structure is a cycloalkyl group, and non-limiting examples are: [ka] This includes, but [ka] It is preferable.

[0105] The cycloalkyl group may or may not be substituted, and if substituted, it may be substituted at any available linking point. Preferably, the substituent is one or more substituents independently and optionally selected from a hydrogen atom, halogen, alkyl group, alkoxy group, haloalkyl group, haloalkoxy group, cycloalkyloxy group, heterocyclyloxy group, hydroxy group, hydroxyalkyl group, cyano group, amino group, nitro group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group.

[0106] The term "alkoxy group" refers to an -O-(alkyl group), and the definition of an alkyl group is as described above. Non-exclusive examples of alkoxy groups include methoxy, ethoxy, propoxy, and butoxy groups. Alkoxy groups may be substituted or unsubstituted. If substituted, the substituent is preferably one or more groups independently selected from a D atom, halogen, alkoxy group, haloalkyl group, haloalkoxy group, cycloalkyloxy group, heterocyclyloxy group, hydroxy group, hydroxyalkyl group, cyano group, amino group, nitro group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group.

[0107] The term "heterocyclyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms, of which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, the sulfur being optionally substituted with an oxo group (i.e., forming a sulfoxide or sulfone), but not containing -OO-, -OS-, or -SS- ring portions, with the remaining ring atoms being carbon. Preferably comprising 3 to 12 ring atoms, of which 1 to 4 (e.g., 1, 2, 3, and 4) are heteroatoms; more preferably comprising 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) ring atoms, of which 1 to 3 (e.g., 1, 2, and 3) are heteroatoms; even more preferably comprising 3 to 6 ring atoms, of which 1 to 3 are heteroatoms; and most preferably comprising 5 or 6 ring atoms, of which 1 to 3 are heteroatoms. Non-restrictive examples of monocyclic heterocyclyl groups include oxetanyl, pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and homopiperazinyl groups. Polycyclic heterocyclyl groups include spiro-ring, fused, and bridging ring heterocyclyl groups.

[0108] The term "spiroheterocyclyl group" refers to a polycyclic heterocyclyl group having 5 to 20 members, in which monocyclic rings share one atom (referred to as a spiro atom), one or more of which ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, and the sulfur may optionally be substituted with an oxo group (i.e., to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds. Preferably, it has 6 to 14 members, and more preferably 7 to 10 members (e.g., 7, 8, 9, or 10 members). Depending on the number of spiro atoms shared between the rings, spiroheterocyclyl groups are classified into monospiroheterocyclyl groups, bisspiroheterocyclyl groups, or polyspiroheterocyclyl groups, with monospiroheterocyclyl groups and bisspiroheterocyclyl groups being preferred. More preferably, a 3-member / 5-member, 3-member / 6-member, 4-member / 4-member, 4-member / 5-member, 4-member / 6-member, 5-member / 5-member, or 5-member / 6-member monospiroheterocyclyl group. Non-limiting examples of spiroheterocyclyl groups are: [ka] Includes.

[0109] The term "condensed heterocyclyl group" refers to a polycyclic heterocyclyl group having 5 to 20 members, in which each ring in the system shares one pair of adjacent atoms with other rings in the system, and one or more rings may contain one or more double bonds, of which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, the sulfur may optionally be substituted with an oxo group (i.e., forming a sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it has 6 to 14 members, and more preferably 7 to 10 members (e.g., 7, 8, 9, or 10 members). Depending on the number of rings that make up the group, it can be classified into bicyclic, tricyclic, tetracyclic, or polycyclic condensed heterocyclyl groups, preferably bicyclic or tricyclic, and more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, and 6-membered / 6-membered bicyclic condensed heterocyclyl groups. Non-limiting examples of condensed heterocyclyl groups are: [ka] Includes.

[0110] The term "bridged heterocyclyl group" refers to a polycyclic heterocyclyl group having 5 to 14 members, in which any two rings share two atoms that are not directly linked, and which may contain one or more double bonds, of which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, the sulfur may optionally be substituted with an oxo group (i.e., forming a sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it has 6 to 14 members, and more preferably 7 to 10 members (e.g., 7, 8, 9, or 10 members). Depending on the number of rings, it can be classified into bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclyl groups, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups are: [ka] Includes.

[0111] The above heterocyclyl rings include those in which the above heterocyclyl group (including monocycles, spiroheterocycles, fused heterocycles, and crosslinked heterocycles) is fused to an aryl group, a heteroaryl group, or a cycloalkyl ring, and among these, the ring linked to the parent structure is a heterocyclyl group, and non-limiting examples thereof are: [ka] This includes, among others.

[0112] The heterocyclyl group may or may not be substituted, and if substituted, it may be substituted at any available linking point. Preferably, the substituent is one or more substituents independently and optionally selected from halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups.

[0113] The term "aryl group" refers to a 6-14 membered all-carbon monocyclic or fused polycyclic (a fused polycyclic is a ring that shares adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6-10 membered, such as a phenyl group and a naphthyl group. The above aryl ring includes those in which the aryl ring is fused to a heteroaryl group, a heterocyclyl group, or a cycloalkyl ring, where the ring linked to the parent structure is an aryl ring, and non-limiting examples include: [ka] Includes.

[0114] The aryl group may or may not be substituted, and if substituted, it may be substituted at any available linking point. Preferably, the substituent is independently and optionally selected from halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, one or more substituents.

[0115] The term "heteroaryl group" refers to a heteroaromatic system containing 1 to 4 heteroatoms (e.g., 1, 2, 3, and 4) and 5 to 14 ring atoms, of which the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl groups are preferably 5 to 10 membered (e.g., 5, 6, 7, 8, 9, or 10 membered), more preferably 5 or 6 membered, and examples include furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridadinyl, imidazolyl, pyrazolyl, triazolyl, and tetrazolyl groups. The above heteroaryl rings include those in which the above heteroaryl group is condensed with an aryl group, a heterocyclyl group, or a cycloalkyl ring, and of which the ring linked to the parent structure is a heteroaryl ring, and non-limiting examples are: [ka] Includes.

[0116] The heteroaryl group may or may not be substituted, and if substituted, it may be substituted at any available linking point. Preferably, the substituent is independently and optionally selected from halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups.

[0117] The above-mentioned cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups include residues derived by removing one hydrogen atom from the parent carbon atom, or residues derived by removing two hydrogen atoms from the same carbon atom or two different carbon atoms from the parent, i.e., "divalent cycloalkyl groups," "divalent heterocyclyl groups," "arylene groups," and "heteroarylene groups."

[0118] In the chemical structure of the compounds described in this disclosure, [ka] It is also possible to include both of these arrangements simultaneously.

[0119] Furthermore, the compounds and intermediates of this disclosure may exist in different tautomer forms, and all such forms are included within the scope of this disclosure. The terms “tautomer” or “tautomer form” refer to structural isomers of different energies that can be interconverted over a low energy barrier. For example, proton tautomers (also called proton transfer tautomers) include interconversion by protrisis, such as keto-enol and imine-enamine isomerization. An example of lactam-lactim equilibrium is between A and B as shown below. [ka]

[0120] All compounds in this disclosure can be depicted as either type A or type B. All tautomer forms are within the scope of this disclosure. The nomenclature of the compounds does not exclude any tautomer.

[0121] On the other hand, the compounds relating to this disclosure may exist in specific geometric or stereoisomeric forms. This disclosure includes all cis-trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures thereof and other mixtures, such as mixtures rich in enantiomers or diastereomers, and all such compounds are intended to be within the scope of this disclosure. Substituents such as alkyl groups may have other chiral carbon atoms. All such isomers and mixtures thereof are within the scope of this disclosure. Optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. To obtain one enantiomer of a compound of this disclosure, it may be prepared by asymmetric synthesis or by inductive action with chiral aids, from which the resulting diastereomer mixture can be separated and the group splitting assisted to provide the required pure enantiomer. Alternatively, if the molecule contains a basic functional group (e.g., an amino group) or an acidic functional group (e.g., a carboxyl group), a salt of the diastereomer is formed with a suitable optically active acid or base, and the diastereomer is divided by a conventional method known in the art, after which the pure enantiomer is recovered. Furthermore, the separation of the enantiomer and diastereomer is generally completed by chromatography, which employs a chiral stationary phase and is optionally combined with a chemical derivation method (e.g., generating a carbamate from an amine).

[0122] The term "amino protecting group" refers to a group that protects an amino group with an easily eliminated group so that the amino group is not altered when other parts of the molecule react. Non-limiting examples include (trimethylsilicone)ethoxymethyl, tetrahydropyranyl, tert-butoxycarbonyl, acetyl, benzyl, allyl, and p-methoxybenzyl groups. These groups can be optionally substituted with 1 to 3 substituents selected from halogens, alkoxy groups, or nitro groups. The above amino protecting groups are preferably (trimethylsilicone)ethoxymethyl and tert-butoxycarbonyl.

[0123] The term "hydroxy protecting group" refers to a group used to protect hydroxyl groups, as is known in this field, as described in the literature ("Protective Groups in Organic Synthesis", 5 Th The hydroxy protecting group in Ed. TW Greene & P. ​​GM Wuts is referenced. For example, preferably the hydroxy protecting group is a triethylsilyl group, triisopropylsilyl group, tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group, etc. (C 1-10 It may also be an alkyl or aryl)3-silane group, C 1-10 It may be an alkyl group or a substituted alkyl group, preferably an alkyl group substituted with an alkoxy group or an aryl group, more preferably C 1-6 C substituted with an alkoxy group 1-6 C substituted with alkyl or phenyl groups 1-6 Alkyl alkyl groups, most preferably C 1-4 C substituted with an alkoxy group 1-4 Alkyl groups include, for example, methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), and ethoxyethyl groups, as well as (C) groups such as formyl, acetyl, benzoyl, and p-nitrobenzoyl. 1-10 It may also be an alkyl or aryl acyl group, (C 1-6 It may also be an alkyl or 6-10 membered aryl)sulfonyl group, (C 1-6 The hydroxy protecting group may be an alkoxy or a 6-10 membered aryloxy)carbonyl group. The hydroxy protecting group is preferably p-nitrobenzoyl.

[0124] The term "heterocyclylalkyl group" refers to an alkyl group substituted with one or more heterocyclyl groups, where the heterocyclyl group and alkyl group are as defined above.

[0125] The term "heteroarylalkyl group" refers to an alkyl group substituted with one or more heteroaryl groups, where the heteroaryl group and alkyl group are as defined above.

[0126] The term "cycloalkyloxy group" refers to a cycloalkyl-O- group, where cycloalkyl is defined as described above.

[0127] The term "heterocyclyloxy group" refers to a heterocyclyl-O-, of which the heterocyclyl group is defined above.

[0128] The term "aryloxy group" refers to an aryl-O- group, of which the aryl group is defined as described above.

[0129] The term "heteroaryloxy group" refers to a heteroaryl-O- group, of which the heteroaryl group is defined as described above.

[0130] The term "alkylthio group" refers to an alkyl-S- group, where the alkyl group is defined as described above.

[0131] The term "haloalkyl group" refers to an alkyl group substituted with one or more halogens, where the alkyl group is as defined above.

[0132] The term "haloalkoxy group" refers to an alkoxy group substituted with one or more halogens, where the alkoxy group is as defined above.

[0133] The term "deuterated alkyl group" refers to an alkyl group substituted with one or more deuterium atoms, where the alkyl group is as defined above.

[0134] The term "hydroxyalkyl group" refers to an alkyl group substituted with one or more hydroxyl groups, where the alkyl group is as defined above.

[0135] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0136] The term "hydroxyl group" refers to the -OH group.

[0137] The term "mercapto group" refers to the -SH group.

[0138] The term "amino group" refers to -NH2.

[0139] The term "cyano group" refers to -CN.

[0140] The term "nitro group" refers to -NO2.

[0141] The term "oxo" or "oxo group" refers to "=O".

[0142] The term "carbonyl group" refers to C=O.

[0143] The term "carboxyl group" refers to -C(O)OH.

[0144] The term "carboxylic acid ester group" refers to -C(O)O(alkyl group), -C(O)O(cycloalkyl group), (alkyl group)C(O)O-, or (cycloalkyl group)C(O)O-, of which alkyl groups and cycloalkyl groups are as defined above.

[0145] The compounds relating to this disclosure include other isotopic derivatives. The term "isotopic derivative" refers to compounds that differ in structure only in the presence of one or more isotope-rich atoms. For example, a compound having the structure relating to this disclosure, but with hydrogen substituted with "deuterium" or "tritium," or 18 F-Fluorine label ( 18Fluorine is replaced with the fluorine isotope (F isotope), or 11 C-, 13 C-, or 14 C- rich carbon ( 11 C-, 13 C-, or 14 C-carbon label, 11 C-, 13 C-, or 14 Compounds in which carbon atoms are substituted with 1C isotopes are all within the scope of this disclosure. Such compounds may be used, for example, as analytical tools or probes in biometric measurements, or as imaging tracers for in vivo diagnosis of diseases, or as tracers in pharmacodynamic, pharmacokinetic, or receptor studies. Among these, the deuterated form of the compound is one in which each available hydrogen atom bonded to a carbon atom is independently substituted with a deuterium atom. Those skilled in the art can synthesize the deuterated form of the compound by referring to relevant literature. When preparing the deuterated form of the compound, commercially available deuterated starting materials may be used, or it may be synthesized using deuterating reagents by conventional techniques, including, but not limited to, deuterated borane, trihydrobolanetetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated iodoethane, and deuterated iodomethane. Deuterated compounds can generally maintain activity equivalent to that of non-deuterated compounds, and when deuteration is located at a specific site, they can obtain better metabolic stability and several therapeutic advantages.

[0146] "Optional" or "optionally" means that the event or situation described thereafter may or may not occur, and this description includes both cases in which the event or situation occurs and cases in which it does not occur. For example, "a heterocyclyl group optionally substituted with an alkyl group" means that an alkyl group may or may not be present, and this description includes both cases in which the heterocyclyl group is substituted with an alkyl group and cases in which the heterocyclyl group is not substituted with an alkyl group.

[0147] "Substituting" means that one or more hydrogen atoms in a group, preferably 1 to 5, more preferably 1 to 3, are substituted with a number of substituents that correspond to each other independently. Those skilled in the art can determine possible or impossible substitutions with little effort (by experiment or theory). For example, if an amino or hydroxyl group with free hydrogen is bonded to a carbon atom with an unsaturated (e.g., olefin) bond, it may become unstable.

[0148] "Pharmaceutical composition" means a mixture of one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs with other chemical components, and other components such as physiologically / pharmaceutically acceptable vectors and excipients. The pharmaceutical composition is intended to facilitate administration to a living organism and contribute to the absorption of the active ingredient, thereby further exerting biological activity.

[0149] A "pharmaceutically acceptable salt" is a salt of the compound relating to this disclosure that is safe and effective when used in the body of a mammal and possesses the desired biological activity. Salts may be prepared individually during the final separation and purification process of the compound, or by reacting a suitable group with a suitable base or acid. Generally, bases for producing pharmaceutically acceptable salts include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as ammonium. Generally, acids for producing pharmaceutically acceptable salts include inorganic acids and organic acids.

[0150] As used herein, unless otherwise specified, the term “prevention” means treating, or administering, a compound according to this specification, with or without other active compounds, before the onset of symptoms, to a patient who is at risk of cancer and / or has other medical conditions described herein. The term “prevention” includes suppression or reduction of symptoms of a particular disease. In some embodiments, patients with a family history of cancer may be candidates for a prevention program. Furthermore, patients with a history of symptom recurrence are also potential candidates for prevention. In this regard, the term “prevention” may be used interchangeably with the term “preventive treatment.”

[0151] With respect to drugs or pharmacological activators, the term "therapeutic effective dose" refers to a sufficient amount of the drug or agent that is non-toxic while producing the desired effect. The effective dose is determined on a human basis, depending on the subject's age and general condition, as well as the specific active substance. A suitable effective dose for an individual can be determined by a person skilled in the art through ordinary testing.

[0152] As used herein, the term “pharmaceutically acceptable” means that these compounds, materials, compositions and / or dosage forms are, within reasonable medical judgment, free from excessive toxicity, irritation, allergic reactions or other problems or complications, applicable to contact with patient tissue, have a reasonable profit-benefit ratio, and are effective for the desired use.

[0153] As used herein, the singular forms "one," "one type," and "the said" include multiple quotations, and vice versa, unless otherwise specified in the context.

[0154] The term "approximately," when used with parameters such as pH, concentration, and temperature, indicates that the parameter may vary within ±10%, and in some cases, more preferably within ±5%. As those skilled in the art will understand, when a parameter is not critical, it is generally presented as a number simply for illustrative purposes, not as a limitation.

[0155] Synthesis method of the compound related to this disclosure To achieve the objectives of this disclosure, this disclosure adopts the following technical proposals. Technical proposal 1 The compound represented by general formula (I) relating to this disclosure, or in the form of its tautomers, meso compounds, racemic compounds, enantiomers, diastereomers, or mixtures thereof, or a method for preparing a pharmaceutically acceptable salt thereof, [ka] The process includes the step of reacting a compound of general formula (IA) with a compound of general formula (IB) under basic conditions to obtain a compound of general formula (I), Eventually, Ring A, Ring B, Y, R 1 ~R 6 n, p, q, and t are as defined in general formula (I).

[0156] Technical proposal 2 The compound represented by general formula (I) relating to this disclosure, or in the form of its tautomers, meso compounds, racemic compounds, enantiomers, diastereomers, or mixtures thereof, or a method for preparing a pharmaceutically acceptable salt thereof, [ka] The process involves reacting a compound of general formula (IA) with a compound of general formula (ID) under basic conditions to obtain a compound of general formula (IC), and The method includes the step of undergoing an intramolecular cyclization reaction of a compound of general formula (IC) under acidic conditions to obtain a compound of general formula (I), Eventually, R m C 1-6 It is an alkyl group, preferably a tert-butyl group, Ring A, Ring B, Y, R 1 ~R 6 n, p, q, and t are as defined in general formula (I).

[0157] Technical proposal 3 The compound represented by general formula (I-1) relating to this disclosure, or its tautomers, meso compounds, racemic compounds, enantiomers, diastereomers, or mixtures thereof, or methods for preparing pharmaceutically acceptable salts thereof, are: [ka] The step of reacting a compound of general formula (IA) with a compound of general formula (I-1D) under basic conditions to obtain a compound of general formula (I-1C), The method includes the step of undergoing an intramolecular cyclization reaction of a compound of general formula (I-1C) under acidic conditions to obtain a compound of general formula (I-1), Eventually, R m C 1-6 It is an alkyl group, preferably a tert-butyl group, Ring A, Ring B, Y, R 1 ~R 6 n, p, q, and t are as defined in general formula (I-1).

[0158] Technical proposal 4 The compound represented by general formula (I-2) relating to this disclosure, or its tautomers, meso compounds, racemic compounds, enantiomers, diastereomers, or mixtures thereof, or methods for preparing pharmaceutically acceptable salts thereof, are: [ka] The process includes preparing a compound of general formula (I) or its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, by chiral resolution to obtain a single-configuration compound represented by general formula (I-2), or its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof. Eventually, R m C 1-6 It is an alkyl group, preferably a tert-butyl group, Ring A, Ring B, Y, R 1 ~R 6n, p, q, and t are as defined in general formula (I).

[0159] Technical proposal 5 The compound represented by general formula (II) relating to this disclosure, or its tautomers, meso compounds, racemic compounds, enantiomers, diastereomers, or mixtures thereof, or methods for preparing pharmaceutically acceptable salts thereof, are: [ka] The process includes the step of reacting a compound of general formula (IIA) with a compound of general formula (IB) under basic conditions to obtain a compound of general formula (II), Eventually, Ring A, Ring B, Y, R 1 ~R 4 n, p, and t are as defined in general formula (II).

[0160] Technical plan 6 The compound represented by general formula (II) relating to this disclosure, or its tautomers, meso compounds, racemic compounds, enantiomers, diastereomers, or mixtures thereof, or methods for preparing pharmaceutically acceptable salts thereof, are: [ka] The step involves reacting a compound of general formula (IIA) with a compound of general formula (ID) under basic conditions to obtain a compound of general formula (IIC), The method includes the step of undergoing an intramolecular cyclization reaction of a compound of general formula (IIC) under acidic conditions to obtain a compound of general formula (II), Eventually, R m C 1-6 It is an alkyl group, preferably a tert-butyl group, Ring A, Ring B, Y, R 1 ~R 4 n, p, and t are as defined in general formula (II).

[0161] Technical proposal 7 The compound represented by general formula (II-1) relating to this disclosure, or its tautomers, meso compounds, racemic compounds, enantiomers, diastereomers, or mixtures thereof, or methods for preparing pharmaceutically acceptable salts thereof, are: [ka] The step of reacting a compound of general formula (IIA) with a compound of general formula (I-1D) under basic conditions to obtain a compound of general formula (II-1C), The method includes the step of undergoing an intramolecular cyclization reaction of a compound of general formula (II-1C) under acidic conditions to obtain a compound of general formula (II-1), Eventually, R m C 1-6 It is an alkyl group, preferably a tert-butyl group, Ring A, Ring B, Y, R 1 ~R 4 n, p, and t are as defined in general formula (II-1).

[0162] Technical proposal 8 The compound represented by general formula (II-2) relating to this disclosure, or its tautomers, meso compounds, racemic compounds, enantiomers, diastereomers, or mixtures thereof, or methods for preparing pharmaceutically acceptable salts thereof, are: [ka] The method includes the step of preparing a compound of general formula (II) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, by chiral resolution to obtain a single-configuration compound represented by general formula (II-2), or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof. Eventually, R m C 1-6 It is an alkyl group, preferably a tert-butyl group, Ring A, Ring B, Y, R 1 ~R 4n, p, and t are as defined in general formula (II).

[0163] Technical proposal 9 The compound represented by the general formula (IIG) relating to this disclosure, or its tautomers, meso compounds, racemic compounds, enantiomers, diastereomers, or mixtures thereof, or methods for preparing pharmaceutically acceptable salts thereof, are: [ka] The process includes the step of reacting a compound of general formula (IIGA) with a compound of general formula (IB) under basic conditions to obtain a compound of general formula (IIG), Eventually, G 1 , G 2 , G 3 , Y, R 1 ~R 3 , R 4a , R 4b , J, k, n, p, and r are as defined in general formula (IIG).

[0164] Technical proposal 10 The compound represented by the general formula (IIG) relating to this disclosure, or its tautomers, meso compounds, racemic compounds, enantiomers, diastereomers, or mixtures thereof, or methods for preparing pharmaceutically acceptable salts thereof, are: [ka] The process includes the step of undergoing an intramolecular cyclization reaction of a compound of general formula (IIGC) under acidic conditions to obtain a compound of general formula (IIG), Eventually, R m C 1-6 It is an alkyl group, preferably a tert-butyl group, G 1 , G 2 , G 3 , Y, R 1 ~R 3 , R 4a , R 4b , J, k, n, p, and r are as defined in general formula (IIG).

[0165] Technical proposal 11 The compound represented by the general formula (IIG-1) relating to this disclosure, or its tautomers, meso compounds, racemic compounds, enantiomers, diastereomers, or mixtures thereof, or methods for preparing pharmaceutically acceptable salts thereof, are: [ka] The method includes the step of undergoing an intramolecular cyclization reaction of a compound of general formula (IIGC-1) under acidic conditions to obtain a compound of general formula (IIG-1), Eventually, R m C 1-6 It is an alkyl group, preferably a tert-butyl group, G 1 , G 2 , G 3 , Y, R 1 ~R 3 , R 4a , R 4b J, k, n, p, and r are as defined in general formula (IIG-1).

[0166] Technical proposal 12 The compound represented by the general formula (IIG-2) relating to this disclosure, or its tautomers, meso compounds, racemic compounds, enantiomers, diastereomers, or mixtures thereof, or methods for preparing pharmaceutically acceptable salts thereof, are: [ka] The method includes the step of preparing a compound of general formula (IIG) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, by chiral resolution to obtain a single-configuration compound represented by general formula (IIG-2), or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof. Eventually, R m C 1-6 It is an alkyl group, preferably a tert-butyl group, G1 , G 2 , G 3 , Y, R 1 ~R 3 , R 4a , R 4b , J, k, n, p, and r are as defined in general formula (IIG).

[0167] Technical proposal 13 The compound represented by general formula (III) relating to this disclosure, or its tautomers, meso compounds, racemic compounds, enantiomers, diastereomers, or mixtures thereof, or methods for preparing pharmaceutically acceptable salts thereof, are: [ka] The process includes the step of reacting a compound of general formula (IIIA) with a compound of general formula (IB) under basic conditions to obtain a compound of general formula (III), Eventually, Y, R 1 ~R 3 , R 4a , R 4b n, p, and r are as defined in general formula (III).

[0168] Technical proposal 14 The compound represented by general formula (III) relating to this disclosure, or its tautomers, meso compounds, racemic compounds, enantiomers, diastereomers, or mixtures thereof, or methods for preparing pharmaceutically acceptable salts thereof, are: [ka] The step involves reacting a compound of general formula (IIIA) with a compound of general formula (ID) under basic conditions to obtain a compound of general formula (IIIC), The method includes the step of undergoing an intramolecular cyclization reaction of a compound of general formula (IIIC) under acidic conditions to obtain a compound of general formula (III), Eventually, R m C 1-6 It is an alkyl group, preferably a tert-butyl group, Y, R 1 ~R3 , R 4a , R 4b n, p, and r are as defined in general formula (III).

[0169] Technical proposal 15 The compound represented by general formula (III-1) relating to this disclosure, or its tautomers, meso compounds, racemic compounds, enantiomers, diastereomers, or mixtures thereof, or methods for preparing pharmaceutically acceptable salts thereof, are: [ka] The process includes the step of reacting a compound of general formula (IIIA) with a compound of general formula (I-1D) under basic conditions to obtain a compound of general formula (III-1C), The method includes the step of undergoing an intramolecular cyclization reaction of a compound of general formula (III-1C) under acidic conditions to obtain a compound of general formula (III-1), Eventually, R m C 1-6 It is an alkyl group, preferably a tert-butyl group, Y, R 1 ~R 3 , R 4a , R 4b n, p, and r are as defined in general formula (III-1).

[0170] Technical proposal 16 The compound represented by general formula (III-2) relating to this disclosure, or its tautomers, meso compounds, racemic compounds, enantiomers, diastereomers, or mixtures thereof, or methods for preparing pharmaceutically acceptable salts thereof, are: [ka] The process includes the step of preparing a compound of general formula (III) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, by chiral resolution to obtain a single-configuration compound represented by general formula (III-2), or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof. Eventually, R m C 1-6 It is an alkyl group, preferably a tert-butyl group, Y, R 1 ~R 3 , R 4a , R 4b n, p, and r are as defined in general formula (III).

[0171] In the above-described synthesis technique, the reagents that provide basic conditions include organic bases and inorganic bases. The organic bases include, but are not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, sodium acetate, potassium acetate, sodium tert-butoxide, or potassium tert-butoxide. The inorganic bases include, but are not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide monohydrate, lithium hydroxide, and potassium hydroxide, with potassium carbonate being preferred.

[0172] In the above proposed synthesis technique, the reagents that provide acidic conditions include, but are not limited to, p-toluenesulfonic acid, p-toluenesulfonic acid monohydrate, benzenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, sulfuric acid, hydrochloric acid, nitric acid, and trifluoroacetic acid. Preferably, they are selected from p-toluenesulfonic acid, p-toluenesulfonic acid monohydrate, and benzenesulfonic acid.

[0173] The above reaction is preferably carried out in a solvent, and the solvents used include, but are not limited to, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, and mixtures thereof. [Brief explanation of the drawing]

[0174] [Figure 1] This shows the therapeutic efficacy data of the compound in Example 6 and the control example CC-92480 on NCI-H929 transplanted tumors in CB-17 SCID mice. [Figure 2] This shows the effect of the compound in Example 6 and the control example CC-92480 on the body weight of CB-17 SCID mice. [Modes for carrying out the invention]

[0175] The present disclosure will be further described below in accordance with the examples, but these examples are not intended to limit the scope of the present disclosure.

[0176] Examples The structure of the compound is determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The NMR displacement () is 10 -6 The results are expressed in units of ppm. A Bruker AVANCE-400 or Bruker AVANCE NEO 500M nuclear magnetic resonance spectrometer was used for the NMR measurements. The measurement solvents were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), and the internal standard was tetramethylsilane (TMS).

[0177] For MS measurements, the following liquid chromatograph mass spectrometers were used: Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS (Manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS), waters ACQuity UPLC-QD / SQD (Manufacturer: waters, MS model: waters ACQuity Qda Detector / waters SQ Detector), and THERMO Ultimate 3000-Q Exactive (Manufacturer: THERMO, MS model: THERMO Q Exactive).

[0178] High-performance liquid chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD, and Waters HPLC e2695-2489.

[0179] For chiral HPLC analysis, an Agilent 1260 DAD high-performance liquid chromatograph was used.

[0180] For preparative high-performance liquid chromatography, the following instruments were used: Waters 2545-2767 preparative chromatograph, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson GX-281.

[0181] For chiral preparative chromatography, a Shimadzu LC-20AP preparative chromatograph was used.

[0182] For the CombiFlash high-speed preparative chromatograph, the CombiFlash Rf200 (TELEDYNE ISCO) was used.

[0183] For thin-layer chromatography, Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates were used. The specifications for silica gel plates used in thin-layer chromatography (TLC) were 0.15 mm to 0.2 mm, and the specifications for the separation and purification of products by thin-layer chromatography were 0.4 mm to 0.5 mm.

[0184] In silica gel column chromatography, silica gel of 200-300 mesh size from Yantai Huanghai Silica Gel was commonly used as a vector.

[0185] Kinase mean inhibition rate and IC 50 A NovoStar microplate reader (BMG GmbH, Germany) was used to measure the values.

[0186] The known starting materials relating to this disclosure may be synthesized by employing or in accordance with methods known in the art, or may be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc., Shanghai Bide Pharmaceutical, and Dalui Chemicals.

[0187] Unless otherwise specified in the examples, the reactions can all be carried out in an argon or nitrogen atmosphere.

[0188] An argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen balloon with a capacity of approximately 1 L.

[0189] A hydrogen atmosphere refers to a reaction flask connected to a hydrogen balloon with a capacity of approximately 1 L.

[0190] For the pressurized hydrogenation reaction, a Parr 3916EKX type hydrogenator and either a QL-500 type hydrogen generator or an HC2-SS type hydrogenator were used.

[0191] The hydrogenation reaction typically involved repeating the process of evacuating the system and filling it with hydrogen three times.

[0192] A CEM Discover-S 908860 microwave reactor was used for the microwave reaction.

[0193] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0194] Unless otherwise specified in the examples, the reaction temperature is 20°C to 30°C at room temperature.

[0195] Thin-layer chromatography (TLC) was used to monitor the reaction progress in the examples. The developing solvent used in the reaction, the eluent system for column chromatography to purify the compound, and the developing solvent system for thin-layer chromatography included A: dichloromethane / methanol system and B: n-hexane / ethyl acetate system. The volume ratio of the solvents may be adjusted according to the polarity of the compound, or by adding small amounts of basic or acidic reagents such as triethylamine and acetic acid.

[0196] Example 1 4-(4-((4-(((2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-4-yl)oxy)methyl)phenyl)thio)piperidine-1-yl)-3-fluorobenzonitrile 1 [ka] [ka] Step 1 4-((4-formylphenyl)thio)piperidine-1-carboxylate tert-butyl 1b 4-mercaptopiperidine-1-carboxylate tert-butyl 1a (2.05 g, 9.44 mmol, Bi-de Pharmaceutical), 4-fluorobenzaldehyde (1.17 g, 9.44 mmol), and potassium carbonate (2.86 g, 20.71 mmol) were added to N,N-dimethylformamide (40 mL). The reaction mixture was heated to 120°C and allowed to react overnight. After the reaction was complete, the reaction mixture was diluted with water (200 mL), then extracted with ethyl acetate (100 mL x 3), the organic phases were combined, washed with saturated sodium chloride solution (100 mL), the organic phases were dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system B to obtain the title compound 1b (2.66 g, yield: 88%). MS m / z (ESI): 266.1 [M-55].

[0197] Step 2 4-(piperidine-4-ylthio)benzaldehyde hydrochloride 1c Compound 1b (2.66 g, 8.28 mmol) was dissolved in a 4 M hydrogen chloride solution of 1,4-dioxane (20 mL) and reacted with stirring for approximately 3 hours. The reaction mixture was filtered, the filter cake was rinsed with ethyl acetate (3 mL x 3), and air-dried to obtain the title compound 1c, and the crude product was used directly in the next reaction. MS m / z (ESI): 221.8 [M+1].

[0198] Step 3 3-Fluoro-4-(4-((4-formylphenyl)thio)piperidine-1-yl)benzonitrile 1d Compound 1c (1.89 g, 7.33 mmol), 3,4-difluorobenzonitrile (1.07 g, 7.70 mmol, Bi De Pharmaceutical), and potassium carbonate (4.05 g, 29.33 mmol) were added to N,N-dimethylacetamide (15 mL), and the reaction mixture was heated to 120°C and allowed to react overnight. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined and washed with saturated sodium chloride solution (50 mL x 3). The organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by column chromatography using eluent system B to obtain the title compound 1d (2.2 g, yield: 93%). MS m / z (ESI): 341.0 [M+1].

[0199] Step 4 3-Fluoro-4-(4-((4-(hydroxymethyl)phenyl)thio)piperidine-1-yl)benzonitrile 1e Compound 1d (150 mg, 0.44 mmol) was added to methanol (8 mL) under ice bath conditions, potassium borohydride (29 mg, 0.53 mmol) was added, and the mixture was reacted under ice bath conditions for 2 hours. The reaction solution was diluted with water (20 mL), then extracted with ethyl acetate (30 mL x 3), the organic phases were combined, washed with saturated sodium chloride aqueous solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system B to obtain the title compound 1e (150 mg, yield: 99%). MS m / z (ESI): 343.1 [M+1].

[0200] Step 5 4-(4-((4-(bromomethyl)phenyl)thio)piperidine-1-yl)-3-fluorobenzonitrile 1f Under ice bath conditions, compound 1e (150 mg, 0.43 mmol) was added to dichloromethane (8 mL), followed by triphenylphosphine (150 mg, 0.57 mmol) and tetrabromomethane (189 mg, 0.57 mmol). The mixture was reacted under ice bath conditions for 20 minutes, then the temperature was raised to room temperature and the reaction was continued for 2 hours. The reaction mixture was concentrated, and the residue was purified using eluent system B by column chromatography to obtain the title compound 1f (120 mg, yield: 68%). MS m / z (ESI):405.0[M+1];407.0[M+3].

[0201] Step 6 4-(4-((4-(((2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-4-yl)oxy)methyl)phenyl)thio)piperidine-1-yl)-3-fluorobenzonitrile 1 1 g (25 mg, 0.096 mmol, Jiangsu Aikang Biomedical Research and Development Co., Ltd.) of 3-(4-hydroxy-1-oxoisoindorin-2-yl)piperidine-2,6-dione and anhydrous potassium carbonate (27 mg, 0.096 mmol) were added to N,N-dimethylacetamide (3 mL), and compound 1f (38 mg, 0.093 mmol) was added. The mixture was reacted for 16 hours. After filtering the reaction mixture, preparative high-performance liquid chromatography (Waters 2767-SQ Detecor 2, eluent: aqueous solution of 10 mmol / L ammonium bicarbonate and acetonitrile, acetonitrile gradient: 55%~70%, flow rate: 30 mL / min) yielded the title compound 1 (16 mg, yield 28%). MS m / z (ESI): 585.1 [M+1]. 1H NMR (400 MHz, DMSO-d6) 10.99 (s, 1H), 7.69 (dd, 1H), 7.55 (dd, 1H), 7.52-7.43 (m, 5H), 7.37-7.29 (m, 2H), 7.13 (t, 1H), 5.25 (s, 2H), 5.12 (dd, 1H), 4.43 (d, 1H), 4.27 (d, 1H), 3.58-3.42 (m, 3H), 3.05-2.83 (m, 3H), 2.63-2.52 (m, 1H), 2.48-2.38 (m, 1H), 2.06-1.93 (m, 3H), 1.68-1.55 (m, 2H).

[0202] Example 2 4-(4-((4-(((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)methyl)phenyl)thio)piperidine-1-yl)-3-fluorobenzonitrile 2 [ka] [ka] 2-(2,6-dioxopiperidine-3-yl)-4-hydroxyisoindoline-1,3-dione 2a (30 mg, 0.113 mmol, Bi-De Pharmaceutical) and anhydrous potassium carbonate (21 mg, 0.152 mmol) were added to N,N-dimethylacetamide (3 mL), compound 1f (30 mg, 0.074 mmol) was added, and the mixture was reacted for 16 hours. After filtering the reaction mixture, preparative high-performance liquid chromatography (Waters 2767-SQ Detecor 2, eluent: aqueous solution of 10 mmol / L ammonium bicarbonate and acetonitrile, acetonitrile gradient: 55%~75%, flow rate: 30 mL / min) yielded the title compound 2 (30 mg, yield 68%). MS m / z (ESI): 599.1 [M+1]. 1H NMR (500 MHz, DMSO-d6) 11.13 (s, 1H), 7.84 (dd, 1H), 7.68 (dd, 1H), 7.60 (d, 1H), 7.55 (dd, 1H), 7.53-7.45 (m, 5H), 7.13 (t, 1H), 5.37 (s, 2H), 5.10 (dd, 1H), 3.60-3.44 (m, 3H), 3.06-2.82 (m, 3H), 2.65-2.55 (m, 1H), 2.54-2.45 (m, 1H), 2.10-1.95 (m, 3H), 1.68-1.54 (m, 2H).

[0203] Example 3 (S)-4-(4-((4-(((2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-4-yl)oxy)methyl)phenyl)thio)piperidine-1-yl)-3-fluorobenzonitrile 3 [ka] [ka]

[0204] Step 1 (S)-5-amino-4-(4-((4-((1-(4-cyano-2-fluorophenyl)piperidine-4-yl)thio)benzyl)oxy)-1-oxoisoindorin-2-yl)-5-oxopentanoate tert-butyl 3b (S)-5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate tert-butyl 3a (318 mg, 0.951 mmol, prepared by a known method "Journal of Medicinal Chemistry, 2020, 63(13), 6648-6676") and anhydrous potassium carbonate (239 mg, 1.729 mmol) were added to N,N-dimethylacetamide (8 mL), compound 1f (350 mg, 0.863 mmol) was added, and the mixture was reacted for 16 hours. The reaction mixture was placed in ice water (20 mL), then extracted with ethyl acetate (30 mL x 3), the organic phases were combined, washed with saturated sodium chloride solution (20 mL x 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography with eluent system B to obtain the title compound 3b (500 mg, yield: 88%). MS m / z (ESI): 659.2 [M+1].

[0205] Step 2 (S)-4-(4-((4-(((2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-4-yl)oxy)methyl)phenyl)thio)piperidine-1-yl)-3-fluorobenzonitrile 3 Compound 3b (500 mg, 0.758 mmol) was added to acetonitrile (30 mL), and p-toluenesulfonic acid monohydrate (187 mg, 0.983 mmol) was added. The mixture was stirred at 85°C for 10 hours. The solvent was removed from the reaction mixture under reduced pressure, water (20 mL) was added, and then the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined and washed sequentially with saturated sodium bicarbonate solution (20 mL) and saturated sodium chloride solution (20 mL). The mixture was then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was obtained by preparative high-performance liquid chromatography (Waters 2767-SQ Detecor 2, eluent: aqueous solution of 10 mmol / L ammonium bicarbonate and acetonitrile, acetonitrile gradient: 45%~60%, flow rate: 30 mL / min) to obtain the title compound 3 (30 mg, yield: 7%, ee: 99.6%). Chiral HPLC analysis: Retention time 31.81 minutes, chiral purity: 99.6% (Column: Chiralpak IE 150*4.6 mm, 5 μm, Column temperature: 35°C, Flow rate: 1.0 mL / min, Mobile phase: n-hexane / ethanol / diethylamine = 20 / 80 / 0.08 (v / v / v)). MS m / z (ESI): 585.2 [M+1]. 1 H NMR (500 MHz, DMSO-d6) 10.98 (s, 1H), 7.68 (dd, 1H), 7.55 (dd, 1H), 7.52-7.43 (m, 5H), 7.37-7.28 (m, 2H), 7.13 (t, 1H), 5.25 (s, 2H), 5.12 (dd, 1H), 4.43 (d, 1H), 4.27 (d, 1H), 3.58-3.42 (m, 3H), 3.05-2.84 (m, 3H), 2.63-2.54 (m, 1H), 2.48-2.37 (m, 1H), 2.06-1.93 (m, 3H), 1.68-1.55 (m, 2H).

[0206] Example 4 (S)-4-(4-((4-(((2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-4-yl)oxy)methyl)-2-fluorophenyl)thio)piperidine-1-yl)-3-fluorobenzonitrile 4 [ka] [ka]

[0207] Step 1 4-((2-fluoro-4-formylphenyl)thio)piperidine-1-carboxylate tert-butyl 4b Compound 1a (600 mg, 2.76 mmol), 3,4-difluorobenzaldehyde 4a (470 mg, 3.3 mmol), and potassium carbonate (954 mg, 6.90 mmol) were added to N,N-dimethylformamide (12 mL). The reaction mixture was heated to 80°C and reacted for 2 hours. The reaction mixture was diluted with water (200 mL), then extracted with ethyl acetate (100 mL x 3), the organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system B to obtain the title compound 4b (920 mg, yield: 98%). MS m / z (ESI): 283.9 [M-55].

[0208] Step 2 3-Fluoro-4-(piperidine-4-ylthio)benzaldehyde trifluoroacetate 4c Compound 4b (920 mg, 2.71 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (2 mL) was gradually added under an ice bath, and the mixture was reacted for 1 hour. The reaction mixture was concentrated and dried to obtain the title compound 4c, and the crude product was used directly in the next reaction without purification. MS m / z (ESI): 239.9 [M+1].

[0209] Step 3 3-Fluoro-4-(4-((2-Fluoro-4-Formylphenyl)thio)piperidine-1-yl)benzonitrile 4d Compound 4c (960 mg, 2.72 mmol), 3,4-difluorobenzonitrile (756 mg, 5.43 mmol, Bi De Pharmaceutical), and potassium carbonate (1.50 g, 10.86 mmol) were added to N,N-dimethylformamide (12 mL), and the reaction mixture was heated to 80°C and allowed to react overnight. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and the resulting residue was purified with eluent system B by column chromatography to obtain the title compound 4d (890 mg, yield: 91%). MS m / z (ESI): 358.9 [M+1].

[0210] Step 4 3-Fluoro-4-(4-((2-Fluoro-4-(Hydroxymethyl)phenyl)thio)piperidine-1-yl)benzonitrile 4e Under ice bath conditions, compound 4d (260 mg, 0.725 mmol) was added to methanol (8 mL), sodium borohydride (55 mg, 1.45 mmol) was added, and the reaction was stirred under ice bath conditions for 1 hour. The reaction mixture was quenched with saturated ammonium chloride solution (10 mL), then extracted with ethyl acetate (30 mL x 3), the organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system B to obtain the title compound 4e (250 mg, yield: 96%). MS m / z (ESI): 360.9 [M+1].

[0211] Step 5 4-(4-((4-(bromomethyl)-2-fluorophenyl)thio)piperidine-1-yl)-3-fluorobenzonitrile 4f Compound 4e (250 mg, 0.694 mmol) was added to dichloromethane (5 mL), followed by triphenylphosphine (237 mg, 0.901 mmol) and tetrabromomethane (299 mg, 0.901 mmol), and the mixture was reacted for 1 hour. The reaction mixture was concentrated, and the residue was purified by column chromatography using eluent system B to obtain the title compound 4f (130 mg, yield: 44%). MS m / z (ESI):423.0 [M+1];425.0 [M+3].

[0212] Step 6 (S)-5-amino-4-(4-((4-((1-(4-cyano-2-fluorophenyl)piperidine-4-yl)thio)-3-fluorobenzyl)oxy)-1-oxoisoindorin-2-yl)-5-oxopentanoate tert-butyl 4g Compound 3a (56 mg, 0.169 mmol) and anhydrous potassium carbonate (42 mg, 0.307 mmol) were added to N,N-dimethylformamide (3 mL), compound 4f (65 mg, 0.153 mmol) was added, and the mixture was reacted for 1 hour. The reaction mixture was placed in ice water (20 mL), then extracted with ethyl acetate (30 mL x 3), the organic phases were combined, washed with saturated sodium chloride solution (20 mL x 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified with eluent system B by column chromatography to obtain 4 g (95 mg, yield: 91%) of the title compound. MS m / z (ESI): 677.0 [M+1].

[0213] Step 7 (S)-4-(4-((4-(((2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-4-yl)oxy)methyl)-2-fluorophenyl)thio)piperidine-1-yl)-3-fluorobenzonitrile 4 Four g (50 mg, 0.074 mmol) of the compound was added to acetonitrile (6 mL), and benzenesulfonic acid (17 mg, 0.096 mmol) was added at room temperature. The mixture was reacted at 80°C for 12 hours. The solvent was removed from the reaction mixture under reduced pressure, and the resulting residue was obtained by preparative high-performance liquid chromatography (Waters 2767-SQ Detecor 2, eluent: aqueous solution of trifluoroacetic acid and acetonitrile, acetonitrile gradient: 50%~67%, flow rate: 30 mL / min) to obtain the title compound 4 (13 mg, yield: 29%). MS m / z (ESI): 603.2 [M+1]. 1 H NMR (500 MHz, DMSO-d6) δ 10.99 (s, 1H), 7.69 (dd, 1H), 7.62-7.53 (m, 2H), 7.50 (t, 1H), 7.43 (dd, 1H), 7.39-7.27 (m, 3H), 7.13 (t, 1H), 5.28 (s, 2H), 5.13 (dd, 1H), 4.46 (d, 1H), 4.30 (d, 1H), 3.53-3.48 (m, 3H), 3.01-2.88 (m, 3H), 2.65-2.56 (m, 1H), 2.46-2.41 (m, 1H), 2.03-1.96 (m, 3H), 1.67-1.57 (m, 2H).

[0214] Example 5 (S)-4-(4-((4-(((2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-4-yl)oxy)methyl)-3-fluorophenyl)thio)piperidine-1-yl)-3-fluorobenzonitrile 5 [ka] The synthesis route of compound 4 in Example 4 was adopted, and the starting compound 3,4-difluorobenzaldehyde was replaced with the starting compound 2,4-difluorobenzaldehyde to obtain the title compound 5 (90 mg). MS m / z (ESI): 603.1 [M+1]. 1 H NMR (500 MHz, DMSO-d6) δ 10.98 (s, 1H), 7.70 (dd, 1H), 7.60-7.48 (m, 3H), 7.42-7.31 (m, 3H), 7.27 (dd, 1H), 7.14 (t, 1H), 5.27 (s, 2H), 5.11 (dd, 1H), 4.39 (d, 1H), 4.23 (d, 1H), 3.68-3.62 (m, 1H), 3.56-3.49 (m, 2H), 3.01 (t, 2H), 2.95-2.87 (m, 1H), 2.61-2.54 (m, 1H), 2.46-2.41 (m, 1H), 2.02-1.94 (m, 3H), 1.70-1.59 (m, 2H).

[0215] Example 6 (S)-4-(4-((5-(((2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-4-yl)oxy)methyl)pyridine-2-yl)thio)piperidine-1-yl)-3-fluorobenzonitrile 6 [ka] [ka]

[0216] Step 1 4-((5-formylpyridine-2-yl)thio)piperidine-1-carboxylate tert-butyl 6b Compound 1a (700 mg, 3.22 mmol), 6-fluoropyridine-3-aldehyde 6a (443 mg, 3.54 mmol), and potassium carbonate (1.11 g, 8.05 mmol) were added to N,N-dimethylformamide (10 mL). The reaction mixture was heated to 80°C and reacted for 1 hour. The reaction mixture was diluted with water (30 mL), then extracted with ethyl acetate (40 mL x 3), the organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system B to obtain the title compound 6b (1.0 g, yield: 96%). MS m / z (ESI): 267.1 [M-55].

[0217] Step 2 6-(piperidine-4-ylthio)nicotinaldehyde trifluoroacetate 6c Compound 6b (950 mg, 2.95 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (2 mL) was gradually added under an ice bath, and the mixture was reacted for 1 hour. The reaction mixture was concentrated and dried to obtain the title compound 6c, and the crude product was used directly in the next reaction without purification. MS m / z (ESI): 223.1 [M+1].

[0218] Step 3 3-Fluoro-4-(4-(((5-Formylpyridine-2-yl)thio)piperidine-1-yl)benzonitrile 6d Compound 6c (760 mg, 2.94 mmol), 3,4-difluorobenzonitrile (817 mg, 5.87 mmol), and potassium carbonate (1.22 g, 8.81 mmol) were added to N,N-dimethylformamide (15 mL), and the reaction mixture was heated to 80°C and allowed to react overnight. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography using eluent system B to obtain the title compound 6d (850 mg, yield: 84%). MS m / z (ESI): 342.1 [M+1].

[0219] Step 4 3-Fluoro-4-(4-((5-(hydroxymethyl)pyridine-2-yl)thio)piperidine-1-yl)benzonitrile 6e Under ice bath conditions, compound 6d (600 mg, 1.76 mmol) was added to methanol (10 mL), and sodium borohydride (133 mg, 3.51 mmol) was gradually added, and the mixture was reacted for 1 hour. The reaction mixture was quenched with water (10 mL), then extracted with ethyl acetate (30 mL x 3), the organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system B to obtain the title compound 6e (580 mg, yield: 96%). MS m / z (ESI): 344.1 [M+1].

[0220] Step 5 4-(4-((5-(bromomethyl)pyridine-2-yl)thio)piperidine-1-yl)-3-fluorobenzonitrile 6f Compound 6e (200 mg, 0.582 mmol) was added to dichloromethane (6 mL), followed by triphenylphosphine (199 mg, 0.757 mmol) and tetrabromomethane (251 mg, 0.757 mmol), and the mixture was reacted for 2 hours. The reaction mixture was concentrated, and the residue was purified by column chromatography using eluent system B to obtain the title compound 6f (190 mg, yield: 80%). MS m / z (ESI):406.0 [M+1];408.0 [M+3].

[0221] Step 6 (S)-5-amino-4-(4-((6-((1-(4-cyano-2-fluorophenyl)piperidine-4-yl)thio)pyridine-3-yl)methoxy)-1-oxoisoindorin-2-yl)-5-oxopentanoate tert-butyl 6g Compound 3a (82 mg, 0.246 mmol) and anhydrous potassium carbonate (65 mg, 0.468 mmol) were added to N,N-dimethylformamide (3 mL), compound 6f (95 mg, 0.244 mmol) was added, and the mixture was reacted for 2 hours. The reaction mixture was placed in ice water (10 mL), then extracted with ethyl acetate (30 mL x 3), the organic phases were combined, washed with saturated sodium chloride solution (20 mL x 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system B to obtain 6 g (145 mg, yield: 94%) of the title compound. MS m / z (ESI): 660.2 [M+1].

[0222] Step 7 (S)-4-(4-((5-(((2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-4-yl)oxy)methyl)pyridine-2-yl)thio)piperidine-1-yl)-3-fluorobenzonitrile 6 Six g (60 mg, 0.091 mmol) of the compound was added to acetonitrile (5 mL), and benzenesulfonic acid (16 mg, 0.091 mmol) was added at room temperature. The mixture was reacted at 80°C for 8 hours. The solvent was removed from the reaction mixture under reduced pressure, and the resulting residue was subjected to preparative high-performance liquid chromatography (Gilson GX-281, eluent: aqueous solution of 10 mmol / L ammonium bicarbonate and acetonitrile, acetonitrile gradient: 60%~80%, flow rate: 30 mL / min) to obtain the title compound 6 (42 mg, yield: 78%). MS m / z (ESI): 586.4 [M+1]. 1 H NMR (500 MHz, DMSO-d6): δ 10.98 (s, 1H), 8.60 (s, 1H), 7.78 (dd, 1H), 7.69 (dd, 1H), 7.59-7.48 (m, 2H), 7.38-7.33 (m, 3H), 7.16 (t, 1H), 5.24 (s, 2H), 5.12 (dd, 1H), 4.42 (d, 1H), 4.26 (d, 1H), 4.07-3.99 (m, 1H), 3.56-3.48 (m, 2H), 3.13-3.03 (m, 2H), 2.96-2.87 (m, 1H), 2.63-2.55 (m, 1H), 2.46-2.38 (m, 1H), 2.21-2.12 (m, 2H), 2.02-1.94 (m, 1H), 1.82-1.70 (m, 2H).

[0223] Example 6' (R)-4-(4-((5-(((2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-4-yl)oxy)methyl)pyridine-2-yl)thio)piperidine-1-yl)-3-fluorobenzonitrile 6' [ka] [ka] Compound 6 (500 mg, 0.853 mmol) was dissolved in tetrahydrofuran (30 mL), saturated sodium carbonate aqueous solution (30 mL) was added, and the mixture was reacted for 1.5 hours with vigorous stirring after the addition was complete. The reaction mixture was separated, the organic phase was diluted with dichloromethane (120 mL), washed sequentially with saturated ammonium chloride solution (20 mL) and saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product of the title compound 6'a (which, according to chiral HPLC, contained 42.8% of compound 6'a).

[0224] The crude product of 6'a obtained was chiral preparatively (separation conditions: chiral preparative column CHIRALPAK IE 20*250 mm (Daicel), mobile phase: n-hexane and ethanol, ethanol gradient: 80%, flow rate: 20 mL / min), and the resulting preparative solution was concentrated under reduced pressure in a water bath below 20°C to obtain the title compound 6' (25 mg), with a yield of 5.0%. MS m / z (ESI): 586.1 [M+1]. Chiral HPLC analysis: Retention time 24.426 minutes, chiral purity: 100% (Column: CHIRALPAK IE 150*4.6 mm, 5 μm, Mobile phase: n-hexane / ethanol = 20 / 80 (v / v)) 1 H NMR (500 MHz, DMSO-d6): 10.97 (s, 1H), 8.59 (s, 1H), 7.78 (dd, 1H), 7.68 (d, 1H), 7.56 (d, 1H), 7.50 (t, 1H), 7.35 (t, 3H), 7.15 (t, 1H), 5.24 (s, 2H), 5.11 (dd, 1H), 4.41 (d, 1H), 4.25 (d, 1H), 4.02 (t, 1H), 3.51 (d, 2H), 3.07 (t, 2H), 2.91 (ddd, 1H), 2.60 - 2.55 (m, 1H), 2.43 (dd, 1H), 2.20 - 2.12 (m, 2H), 1.99 (s, 1H), 1.76 (tt, 2H).

[0225] Example 7 (S)-4-(4-((5-(((2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-4-yl)oxy)methyl)pyrimidine-2-yl)thio)piperidine-1-yl)-3-fluorobenzonitrile 7 [ka] The synthesis route of compound 4 in Example 4 was adopted, and the starting compound 3,4-difluorobenzaldehyde was replaced with the starting compound 2-chloropyrimidine-5-aldehyde to obtain the title compound 7 (38 mg). MS m / z (ESI): 587.2 [M+1]. 1 H NMR (500 MHz, DMSO-d6): δ 10.97 (s, 1H), 8.82 (s, 2H), 7.70 (dd, 1H), 7.57 (dd, 1H), 7.53 (t, 1H), 7.38 (t, 2H), 7.17 (t, 1H), 5.26 (s, 2H), 5.12 (dd, 1H), 4.44 (d, 1H), 4.27 (d, 1H), 3.99-3.92 (m, 1H), 3.58-3.47 (m, 2H), 3.14-3.04 (m, 2H), 2.96-2.87 (m, 1H), 2.64-2.56 (m, 1H), 2.44-2.37 (m, 1H), 2.26-2.15 (m, 2H), 2.03-1.96 (m, 1H), 1.85-1.75 (m, 2H).

[0226] Example 8 (S)-4-(4-((5-(((2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1-oxoisoindorin-4-yl)oxy)methyl)pyridine-2-yl)thio)piperidine-1-yl)-3-fluorobenzonitrile 8 [ka] The synthesis route of compound 4 in Example 4 was adopted, in which the starting compound 3,4-difluorobenzaldehyde was replaced with the starting compound 2-fluoropyridine-5-aldehyde, and compound 3a in step 6 was replaced with (S)-5-amino-4-(6-fluoro-4-hydroxy-1-oxoisoindorin-2-yl)-5-oxopentanoate tert-butyl (obtained by the method disclosed in "Example 7 on page 99 of the specification in patent application WO2019040274A1") to obtain the title compound 8 (33 mg). MS m / z (ESI): 604.1 [M+1]. 1 H NMR (500 MHz, DMSO-d6): δ 10.99 (s, 1H), 8.60 (d, 1H), 7.78 (dd, 1H), 7.70 (dd, 1H), 7.57 (dd, 1H), 7.39-7.31 (m, 2H), 7.20-7.11 (m, 2H), 5.25 (s, 2H), 5.11 (dd, 1H), 4.40 (d, 1H), 4.23 (d, 1H), 4.09-3.98 (m, 1H), 3.58-3.46 (m, 2H), 3.13-3.02 (m, 2H), 2.96-2.83 (m, 1H), 2.63-2.55 (m, 1H), 2.46-2.34 (m, 1H), 2.21-2.12 (m, 2H), 2.04-1.93 (m, 1H), 1.82-1.68 (m, 2H).

[0227] Example 9 (S)-4-(4-((6-(((2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-4-yl)oxy)methyl)pyridine-3-yl)thio)piperidine-1-yl)-3-fluorobenzonitrile 9 [ka] The synthesis route of compound 4 in Example 4 was adopted, and the starting compound 3,4-difluorobenzaldehyde was replaced with the starting compound 5-fluoropyridine-2-aldehyde to obtain the title compound 9 (45 mg). MS m / z (ESI): 586.3 [M+1]. 1 H NMR (500 MHz, DMSO-d6): δ 10.99 (s, 1H), 8.63 (d, 1H), 7.95 (dd, 1H), 7.68 (dd, 1H), 7.61-7.51 (m, 2H), 7.49 (t, 1H), 7.35 (d, 1H), 7.32 (d, 1H), 7.13 (t, 1H), 5.33 (s, 2H), 5.13 (dd, 1H), 4.47 (d, 1H), 4.32 (d, 1H), 3.65-3.45 (m, 3H), 3.05-2.85 (m, 3H), 2.68-2.55 (m, 1H), 2.44-2.35 (m, 1H), 2.07-1.93 (m, 3H), 1.71-1.55 (m, 2H).

[0228] Example 10 (S)-4-(4-((4-(((2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-4-yl)oxy)methyl)-2,3-difluorophenyl)thio)piperidine-1-yl)-3-fluorobenzonitrile 10 [ka] The synthesis route of compound 4 in Example 4 was adopted, and the starting compound 3,4-difluorobenzaldehyde was replaced with the starting compound 2,3,4-trifluorobenzaldehyde to obtain the title compound 10 (63 mg). MS m / z (ESI): 621.1 [M+1]. 1H NMR (500 MHz, DMSO-d6): δ 10.98 (s, 1H), 7.69 (dd, 1H), 7.58-7.48 (m, 2H), 7.47-7.33 (m, 4H), 7.13 (t, 1H), 5.35 (s, 2H), 5.12 (dd, 1H), 4.40 (d, 1H), 4.25 (d, 1H), 3.67-3.46 (m, 3H), 3.06-2.82 (m, 3H), 2.64-2.56 (m, 1H), 2.46-2.37 (m, 1H), 2.07-1.90 (m, 3H), 1.73-1.56 (m, 2H).

[0229] Example 11 (S)-4-(4-((4-(((2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-4-yl)oxy)methyl)-2,5-difluorophenyl)thio)piperidine-1-yl)-3-fluorobenzonitrile 11 [ka] The synthesis route of compound 4 in Example 4 was adopted, and the starting compound 3,4-difluorobenzaldehyde was replaced with 2,4,5-trifluorobenzaldehyde to obtain the starting compound and title compound 11 (70 mg). MS m / z (ESI): 621.1 [M+1]. 1 H NMR (500 MHz, DMSO-d6): δ 10.98 (s, 1H), 7.89 (dd, 1H), 7.63-7.46 (m, 4H), 7.42-7.32 (m, 2H), 7.14 (t, 1H), 5.27 (s, 2H), 5.12 (dd, 1H), 4.42 (d, 1H), 4.27 (d, 1H), 3.72-3.61 (m, 1H), 3.58-3.46 (m, 2H), 3.07-2.96 (m, 2H), 2.95-2.83 (m, 1H), 2.65-2.56 (m, 1H), 2.44-2.38 (m, 1H), 2.09-1.90 (m, 3H), 1.74-1.58 (m, 2H).

[0230] Example 12 (S)-4-(4-((4-(((2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-4-yl)oxy)methyl)-2,6-difluorophenyl)thio)piperidine-1-yl)-3-fluorobenzonitrile 12 [ka] The synthesis route of compound 4 in Example 4 was adopted, and the starting compound 3,4-difluorobenzaldehyde was replaced with the starting compound 3,4,5-trifluorobenzaldehyde to obtain the title compound 12 (20 mg). MS m / z (ESI): 621.1 [M+1]. 1 H NMR (500 MHz, DMSO-d6): δ 10.99 (s, 1H), 7.67 (dd, 1H), 7.54 (dd, 1H), 7.50 (t, 1H), 7.43-7.33 (m, 3H), 7.29 (d, 1H), 7.11 (t, 1H), 5.31 (s, 2H), 5.13 (dd, 1H), 4.50 (d, 1H), 4.34 (d, 1H), 3.58-3.42 (m, 2H), 3.40-3.34 (m, 1H), 3.01-2.84 (m, 3H), 2.68-2.55 (m, 1H), 2.46-2.35 (m, 1H), 2.05-1.85 (m, 3H), 1.65-1.52 (m, 2H).

[0231] Example 13 (S)-4-(4-((5-(((2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-4-yl)oxy)methyl)-6-methylpyridine-2-yl)thio)piperidine-1-yl)-3-fluorobenzonitrile 13 [ka] The synthesis route of compound 4 in Example 4 was adopted, and the starting compound 3,4-difluorobenzaldehyde was replaced with the starting compound 6-fluoro-2-methyl-3-pyridinealdehyde to obtain the title compound 13 (60 mg). MS m / z (ESI): 600.2 [M+1]. 1 H NMR (500 MHz, DMSO-d6): δ 10.97 (s, 1H), 7.78-7.63 (m, 2H), 7.61-7.47 (m, 2H), 7.44-7.30 (m, 2H), 7.24-7.07 (m, 2H), 5.24 (s, 2H), 5.11 (dd, 1H), 4.41 (d, 1H), 4.25 (d, 1H), 4.06-3.92 (m, 1H), 3.60-3.43 (m, 2H), 3.14-3.02 (m, 2H), 2.97-2.83 (m, 1H), 2.68-2.56 (m, 1H), 2.52 (s, 3H), 2.48-2.37 (m, 1H), 2.22-2.11 (m, 2H), 2.04-1.93 (m, 1H), 1.83-1.68 (m, 2H).

[0232] Example 14 (S)-4-(4-((2-chloro-4-(((2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-4-yl)oxy)methyl)phenyl)thio)piperidine-1-yl)-3-fluorobenzonitrile 14 [ka] The synthesis route of compound 4 in Example 4 was adopted, and the starting compound 3,4-difluorobenzaldehyde was replaced with the starting compound 3-chloro-4-fluorobenzaldehyde to obtain the title compound 14 (22 mg). MS m / z (ESI): 618.9 [M+1]. 1H NMR (500 MHz, DMSO-d6): δ 10.98 (s, 1H), 7.74-7.62 (m, 2H), 7.60 (d, 1H), 7.56 (dd, 1H), 7.53-7.44 (m, 2H), 7.35 (d, 1H), 7.32 (d, 1H), 7.14 (t, 1H), 5.25 (s, 2H), 5.12 (dd, 1H), 4.43 (d, 1H), 4.28 (d, 1H), 3.71-3.61 (m, 1H), 3.58-3.47 (m, 2H), 3.08-2.98 (m, 2H), 2.96-2.85 (m, 1H), 2.66-2.54 (m, 1H), 2.46-2.37 (m, 1H), 2.12-1.93 (m, 3H), 1.75-1.60 (m, 2H).

[0233] Example 15 4-(3-((5-(((2-((S)-2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-4-yl)oxy)methyl)pyridine-2-yl)thio)pyrrolidine-1-yl)-3-fluorobenzonitrile 15 [ka] The synthesis route of compound 4 in Example 4 was adopted, and starting material compound 1a (4-mercaptopiperidine-1-carboxylate tert-butyl) was replaced with 3-mercaptopyrrolidine-1-carboxylate tert-butyl, and starting material compound 3,4-difluorobenzaldehyde was replaced with starting material compound 2-fluoropyridine-5-aldehyde to obtain the title compound 15 (39 mg). MS m / z (ESI): 572.3 [M+1]. 1H NMR (500 MHz, DMSO-d6): δ 10.97 (s, 1H), 8.81 (d, 1H), 7.80 (dd, 1H), 7.58 (dd, 1H), 7.52 (t, 1H), 7.44 (dd, 1H), 7.42-7.32 (m, 3H), 6.79 (t, 1H), 5.25 (s, 2H), 5.11 (dd, 1H), 4.49-4.36 (m, 2H), 4.26 (d, 1H), 4.12-4.04 (m, 1H), 3.68-3.54 (m, 2H), 3.52-3.44 (m, 1H), 3.00-2.84 (m, 1H), 2.64-2.56 (m, 1H), 2.44-2.35 (m, 2H), 2.10-1.94 (m, 2H).

[0234] Example 16 (S)-4-(3-((4-(((2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-4-yl)oxy)methyl)phenyl)thio)azetidine-1-yl)-3-fluorobenzonitrile 16 [ka] The synthesis route of compound 4 in Example 4 was adopted, and starting material compound 1a (4-mercaptopiperidine-1-carboxylate tert-butyl) was replaced with 3-mercaptoazetidine-1-carboxylate tert-butyl, and starting material compound 3,4-difluorobenzaldehyde was replaced with starting material compound 4-fluorobenzaldehyde to obtain the title compound 16 (15 mg). MS m / z (ESI): 557.0 [M+1]. 1H NMR (500 MHz, DMSO-d6): δ 10.97 (s, 1H), 7.60 (dd, 1H), 7.54-7.42 (m, 4H), 7.37-7.27 (m, 4H), 6.62 (t, 1H), 5.24 (s, 2H), 5.12 (dd, 1H), 4.64-4.54 (m, 2H), 4.47-4.35 (m, 2H), 4.26 (d, 1H), 4.02-3.90 (m, 2H), 3.00-2.84 (m, 1H), 2.66-2.56 (m, 1H), 2.44-2.35 (m, 1H), 2.08-1.90 (m, 1H).

[0235] Example 17 (S)-4-(4-((5-(((2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-4-yl)oxy)methyl)-6-fluoropyridine-2-yl)thio)piperidine-1-yl)-3-fluorobenzonitrile 17 [ka] [ka]

[0236] Step 1 4-((6-fluoro-5-formylpyridine-2-yl)thio)piperidine-1-carboxylate tert-butyl 17b Compound 1a (1.5 g, 6.90 mmol), 2,6-difluoropyridine-3-aldehyde 17a (1.04 g, 7.27 mmol), and potassium carbonate (2.4 g, 17.36 mmol) were added to N,N-dimethylformamide (15 mL) and reacted for 2 hours. The reaction mixture was diluted with water (200 mL), then extracted with ethyl acetate (100 mL x 3), the organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system B to obtain the title compound 17b (1.0 g, yield 42%). MS m / z (ESI): 285.0 [M-55].

[0237] Step 2 4-((6-fluoro-5-(hydroxymethyl)pyridine-2-yl)thio)piperidine-1-carboxylate tert-butyl 17c Compound 17b (1.0 g, 2.94 mmol) was dissolved in a mixed solvent of tetrahydrofuran (20 mL) and methanol (2 mL), and sodium borohydride (223 mg, 5.90 mmol) was gradually added under an ice bath, and the reaction was allowed to proceed for 2 hours. The reaction mixture was quenched with water (50 mL), then extracted with ethyl acetate (30 mL x 3), the organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system B to obtain the title compound 17c (910 mg, 90% yield). MS m / z (ESI): 287.0 [M-55].

[0238] Step 3 (2-Fluoro-6-(piperidine-4-ylthio)pyridine-3-yl)methanol hydrochloride 17d Compound 17c (910 mg, 2.66 mmol) was dissolved in dichloromethane (10 mL), and a 4 M hydrogen chloride solution of 1,4-dioxane (3 mL, 12 mmol) was added. The mixture was reacted for 1 hour. The reaction mixture was concentrated and dried to obtain the title compound 17d (625 mg), which was then used in the next reaction. MS m / z (ESI): 243.1 [M+1].

[0239] Step 4 3-Fluoro-4-(4-((6-Fluoro-5-(hydroxymethyl)pyridine-2-yl)thio)piperidine-1-yl)benzonitrile 17e Compound 17d (625 mg, 2.24 mmol) was added to N,N-dimethylformamide (20 mL), and 3,4-difluorobenzonitrile (312 mg, 2.24 mmol) and potassium carbonate (930 mg, 6.73 mmol) were added. The reaction mixture was heated to 80°C and reacted for 2 hours. The reaction mixture was diluted with water (100 mL), extracted with ethyl acetate (100 mL x 3), the organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the resulting residue was purified with eluent system B by column chromatography to obtain the title compound 17e (400 mg, 50% yield). MS m / z (ESI): 362.0 [M+1].

[0240] Step 5 4-(4-((5-(bromomethyl)-6-fluoropyridine-2-yl)thio)piperidine-1-yl)-3-fluorobenzonitrile 17f Compound 17e (310 mg, 0.86 mmol) was added to dichloromethane (10 mL), triphenylphosphine (360 mg, 1.37 mmol) and tetrabromomethane (455 mg, 1.37 mmol) were added, and the mixture was reacted for 12 hours. The reaction mixture was diluted with water (50 mL), extracted with dichloromethane (30 mL x 3), the organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified using eluent system B by column chromatography to obtain the title compound 17f (340 mg, 93% yield). MS m / z (ESI): 423.9 [M+1].

[0241] Step 6 (S)-5-amino-4-(4-((6-((1-(4-cyano-2-fluorophenyl)piperidine-4-yl)thio)-2-fluoropyridine-3-yl)methoxy)-1-oxoisoindorin-2-yl)-5-oxopentanoate tert-butyl 17g Compound 3a (268 mg, 0.80 mmol) and anhydrous potassium carbonate (223 mg, 1.61 mmol) were added to N,N-dimethylformamide (10 mL), compound 17f (340 mg, 0.80 mmol) was added, and the mixture was reacted for 1 hour. The reaction mixture was placed in ice water (20 mL), then extracted with ethyl acetate (30 mL x 3), the organic phases were combined, washed with saturated sodium chloride solution (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system B to obtain 17 g (540 mg, yield: 99%) of the title compound. MS m / z (ESI): 678.2 [M+1].

[0242] Step 7 (S)-4-(4-((5-(((2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-4-yl)oxy)methyl)-6-fluoropyridine-2-yl)thio)piperidine-1-yl)-3-fluorobenzonitrile 17 17 g (540 mg, 0.80 mmol) of the compound was added to acetonitrile (20 mL), and benzenesulfonic acid (252 mg, 1.59 mmol) was added at room temperature. The mixture was reacted at 80°C for 12 hours. The solvent was removed from the reaction mixture under reduced pressure, and the resulting residue was obtained by preparative high-performance liquid chromatography (Waters 2545-SQ Detecor 2, eluent: aqueous solution of 10 mmol / L ammonium bicarbonate and acetonitrile, acetonitrile gradient: 53%~95%, flow rate: 30 mL / min) to obtain the title compound 4 (270 mg, yield: 56%). MS m / z (ESI): 604.0 [M+1]. 1H NMR (500 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.01 (t, 1H), 7.70 (dd, 1H), 7.57 (dd, 1H), 7.52 (t, 1H), 7.43-7.30 (m, 3H), 7.17 (t, 1H), 5.25 (s, 2H), 5.12 (dd, 1H), 4.39 (d, 1H), 4.24 (d, 1H), 4.00-3.88 (m, 1H), 3.58-3.45 (m, 2H), 3.16-3.04 (dd, 2H), 2.98-2.84 (m, 1H), 2.66-2.55 (m, 1H), 2.48-2.35 (m, 1H), 2.23-2.12 (m, 2H), 2.08-1.92 (m, 1H), 1.82-1.70 (m, 2H).

[0243] Example 18 (S)-4-(4-((4-(((2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-4-yl)oxy)methyl)-3,5-difluorophenyl)thio)piperidine-1-yl)-3-fluorobenzonitrile 18 [ka] The synthesis route of compound 17 in Example 17 was adopted, and the starting compound 2,6-difluoropyridine-3-aldehyde was replaced with the starting compound 2,4,6-trifluorobenzaldehyde to obtain the title compound 18 (27 mg). MS m / z (ESI): 621.0 [M+1]. 1H NMR (500 MHz, DMSO-d6): δ 10.95 (s, 1H), 7.70 (dd, 1H), 7.59-7.51 (m, 2H), 7.45 (d, 1H), 7.38 (d, 1H), 7.27 (d, 2H), 7.16 (t, 1H), 5.24 (dd, 2H), 5.09 (dd, 1H), 4.32 (d, 1H), 4.16 (d, 1H), 3.86-3.73 (m, 1H), 3.60-3.47 (m, 2H), 3.13-3.00 (m, 2H), 2.96-2.82 (m, 1H), 2.62-2.53 (m, 1H), 2.44-2.34 (m, 1H), 2.17-2.04 (m, 2H), 2.01-1.90 (m, 1H), 1.75-1.60 (m, 2H).

[0244] Biological evaluation Example 1: Biological evaluation of NCI-H929 proliferation experiment The following method is for measuring the inhibitory activity of the compounds relating to this disclosure on NCI-H929 cell proliferation. The experimental method is briefly described below.

[0245] NCI-H929 cells (ATCC, CRL-9068) were cultured in complete medium, i.e., RPMI1640 medium (Hyclone, SH30809.01) containing 10% fetal bovine serum (Corning, 35-076-CV) and 0.05 mM 2-mercaptoethanol (Sigma, M3148). On the first day of the experiment, NCI-H929 cells were inoculated into 96-well plates at a density of 6000 cells / well with complete medium, resulting in 100 μL of cell suspension per well. Simultaneously, 10 μL of the compound, prepared in complete medium and gradient-diluted, was added to each well. The compound was first dissolved in DMSO to an initial concentration of 10 mM, and then sequentially diluted in a 5-fold concentration gradient, resulting in a total of 9 concentration points. The blank control was 100% DMSO. Furthermore, 5 μL of the compound dissolved in DMSO was added to 95 μL of complete medium, i.e., the compound was diluted 20-fold with complete medium. Finally, 10 μL / well of the compound diluted in complete medium was added to the cell suspension, i.e., the final concentration of the compound was reduced from 50 μM to 9 concentration points through a 5-fold gradient dilution. A blank control containing 0.5% DMSO was set up, and the cells were incubated in a cell incubator at 37°C and 5% CO2 for 5 days. On day 6, the 96-well cell culture plate was removed, 50 μL of CellTiter-Glo® luminescence cell activity detection reagent (Promega, G7573) was added per well, and after 10 minutes at room temperature, the luminescence signal values ​​were read using a multifunctional microplate reader (PerkinElmer, EnVision2015), and the IC50 of the inhibitory activity of the compound was calculated using Graphpad Prism software. 50 The values ​​are shown in Table 1.

[0246] [Table 4] Conclusion: The compounds described herein have very good inhibitory activity against the proliferation of NCI-H929 cells.

[0247] Test Example 2: Efficacy Test 1. Objective of the experiment The inhibitory effects of the compound from Example 6 and the control compound CC-92480 on the growth of human multiple myeloma cell NCI-H929 transplanted tumors in CB-17 SCID mice were evaluated.

[0248] 2. Experimental drugs Compound of Example 6, Control example: CC-92480 (refer to compound 2 in WO2019014100A1, synthesized by the method disclosed therein) [ka] The compound in Example 6 and the control example CC-92480 were prepared using 5% DMSO + 20% PEG400 + 70% (10% TPGS) + 5% (1% HPMC K100LV).

[0249] 3. Experimental methods and materials 3.1 Laboratory animals and rearing conditions Thirty female CB-17 SCID mice were purchased from Beijing Weitong Lihua Laboratory Animals Co., Ltd. (certificate number: 20170011006049, SCXK (Shanghai) 2017-0011). At the time of purchase, each mouse weighed approximately 19 g. They were housed in cages of five, with a 12 / 12 hour light / dark cycle, a constant temperature of 23±1°C, and humidity of 50-60%. Water and food were provided freely.

[0250] 3.2 Classification of animals: After adaptive rearing of CB-17 SCID mice, they were divided into groups as follows. [Table 5]

[0251] 3.3 Experimental Method: 5 × 10⁶ NCI-H929 cells in the logarithmic growth phase 6 Thirty female CB-17 SCID mice were subcutaneously inoculated with 100 μL of cells / mouse (containing 50 μL of Matrigel) into the right rib region, and after 10 days, the tumor volume of the tumor-bearing mice was 200 mm². 3When the tumor volume reached a certain level, the mice were randomly divided into three groups based on tumor volume and body weight: a solvent control group, CC-92480-1 mpk, and compound-1 mpk of Example 6, with 7 mice per group. The day of group division was designated as Day 0 (D0), and intragastric administration was started once a day for a total of 11 days (Table 2). Tumor volume of the tumor-bearing mice was measured twice a week using calipers, and body weight was measured using a balance, and the data was recorded. When the tumor volume reached 2000 mm³... 3 The tumor-bearing animals were euthanized as the endpoint of the experiment if they reached a certain stage, if many tumors ruptured, or if their body weight decreased by 20%.

[0252] 3.4. Data Statistics All data was plotted and statistically analyzed using Excel and GraphPad Prism 5 software. The formula for calculating tumor volume (V) is V = 1 / 2 × a × b 2 Of these, a and b represent length and width, respectively. The relative tumor growth rate T / C (%) = (T - T0) / (C - C0) × 100, where T and C are the tumor volumes of the treatment group and control group at the end of the experiment, and T0 and C0 are the tumor volumes at the start of the experiment. The tumor inhibition rate (TGI) is calculated as TGI(%) = 1 - T / C(%). When TGI(%) exceeds 100%, a specific numerical value cannot be shown, and only the value >100% is indicated. Tumor regression (%)=[(T0-T) / T0]×100(%).

[0253] 4, results The therapeutic effects of the compound in Example 6 and the control compound CC-92480 on NCI-H929 transplanted tumors in CB-17 SCID mice are shown in Table 2 and Figure 1 below. The effects of the compound in Example 6 and the control compound CC-92480 on the body weight of CB-17 SCID mice are shown in Figure 2.

[0254] [Table 6]

[0255] 5. Conclusion The compound of Example 6 was administered once a day for a total of 11 days starting from 10 days after tumor cell transplantation. After administration, the tumor volume was significantly reduced. According to calculations, the tumor inhibition rate > 100%, the tumor regression rate was 88%, there was a statistically significant difference compared with CC-92480 at the same dose at the end point of the experiment (p < 0.05), and the administration had no effect on the mouse body weight. Under the same conditions, the tumor regression rate of the control CC-92480 was 34%.

[0256] Test Example 3 Pharmacokinetic Evaluation 1. Overview Using mice as test animals, the drug concentrations in plasma at different time points after intragastric administration of the compound of Example 6 and the control CC-92480 to mice were measured by the LC / MS / MS method. The pharmacokinetic behavior of the compound according to the present disclosure in the mouse body was studied, and its pharmacokinetic characteristics were evaluated.

[0257] 2. Test Plan 2.1 Test Drugs The compound of Example 6 and the control CC-92480.

[0258] 2.2 Test Animals 18 female mice, purchased from Vital River Laboratory Animal Technology Co., Ltd., with the animal production license number SCXK (Hu) 2017-0005.

[0259] 2.3 Preparation of Drugs Weighed the compound of Example 6, added 5% volume of DMSO and 5% Tween 80 (Shanghai Titan Technology Co., Ltd.) to dissolve it, and then added 90% physiological saline to prepare a clear solution of 0.1 mg / mL.

[0260] Weighed the control CC-92480, added 5% volume of DMSO and 5% Tween 80 (Shanghai Titan Technology Co., Ltd.) to dissolve it, and then added 90% physiological saline to prepare a clear solution of 0.1 mg / mL.

[0261] 2.4 Administration The compound from Example 6 was administered intragastricly to nine mice, with a dose of 2 mg / kg and a volume of 0.2 mL / 10 g in all cases.

[0262] Nine mice were administered CC-92480 intragastricly to control mice, with a dose of 2 mg / kg and a volume of 0.2 mL / 10 g in all cases.

[0263] 3, operation Mice were administered intragastricly with the compound from Example 6 and the control CC-92480. 0.2 mL of blood (from three animals at each time point) was collected before administration and at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours after administration. The blood was placed in an EDTA-K2 anticoagulation test tube, centrifuged at 10000 rpm for 1 minute (4°C), and the plasma was separated within 1 hour. The samples were then stored at -20°C for testing. The process from blood collection to centrifugation was performed under ice bath conditions.

[0264] The content of compounds awaiting measurement in the plasma of mice administered with different concentrations of the drug was measured as follows: 25 μL of mouse plasma was collected at each time point after administration, 50 μL (100 ng / mL) of the internal standard solution camptothecin (China Biochemical Inspection Institute) and 175 μL of acetonitrile were added, the mixture was vortexed for 5 minutes, and the mixture was centrifuged for 10 minutes (3700 rpm). 1 μL of the supernatant was taken from the plasma sample and analyzed using LC / MS / MS (API 4000 triple quadrupole tandem mass spectrometer, Applied Biosystems, USA; Shimadzu LC-30AD ultra-high-performance liquid chromatography system, Shimadzu, Japan).

[0265] 4. Results of pharmacokinetic parameters The pharmacokinetic parameters of the compounds related to this disclosure are shown in Table 3 below.

[0266] [Table 7] Conclusion: The compounds described herein exhibit good pharmacokinetic absorption and possess pharmacokinetic advantages.

[0267] Test Example 4: Evaluation of Plasma Stability of Compounds Related to This Disclosure 1. Summary The stability of the compound from Example 6 and the control CC-92480 was quantitatively measured by LC-MS / MS after incubation in cryopreserved monkey plasma at 37°C for 0, 15, 30, 60, 120, 180, and 240 minutes, respectively.

[0268] 2. Test Plan 2.1 Test reagent Compound from Example 6 and control example CC-92480.

[0269] 2.2 Test plasma The monkey plasma was purchased from Shanghai Meidixi Biomedical Co., Ltd.

[0270] 2.3 Preparation of compound solutions A fixed amount of the compound from Example 6 was weighed, and DMSO was added to prepare a 30 mM stock solution. A fixed volume of the stock solution was taken and diluted with DMSO to a 1600 μM solution I. A fixed volume of the 1600 μM solution I was then taken and diluted with 50% methanol to a 16 μM working solution II. Using the above method, a 30 mM stock solution, a 1600 μM solution I', and a 16 μM working solution II' of CC-92480 were prepared.

[0271] 2.4 Sample Incubation 16 μM of the compound from Example 6 and 5 μL of the working solution of CC-92480 from the control example were taken and added to 75 μL of plasma, respectively, to a final concentration of 1 μM of the compound. The samples were incubated in a water bath at 37°C for 0, 15, 30, 60, 90, 120, and 180 minutes. After incubation, 240 μL of acetonitrile containing an internal standard was added, followed by shaking at 800 rpm for 10 minutes, centrifugation at 3700 rpm at 4°C for 20 minutes, and analysis of the supernatant by LC-MS, which showed an injection volume of 2 μL.

[0272] 3, results The transformation of the compounds related to this disclosure in monkey plasma is shown in Table 4 below.

[0273] [Table 8] Conclusion: The compounds described herein exhibit stable advantages in monkey plasma.

Claims

1. A compound represented by general formula (IIG) or its tautomers, meso compounds, racemic compounds, enantiomers, diastereomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 Eventually, Y is CH ２ or C(O), R １ These are homologous or different, and each is independently selected from hydrogen atoms and halogens. R ２ It is a hydrogen atom, R ３ These are homologous or homologous, and each is independently selected from a hydrogen atom, a halogen, and a C1-6 alkyl group. G2 is a nitrogen atom, and G1 and G3 are carbon atoms, or G1 is a nitrogen atom, and G2 and G3 are carbon atoms, or G1, G2 and G3 are all carbon atoms, or G2 and G3 are all nitrogen atoms, and G1 is a carbon atom, R 4a is 【Chemistry 2】 And, R4b is a hydrogen atom, r is either 0 or 1, J is either 0 or 1. k is either 0 or 1, n is 0, 1, 2, or 3. p is 0, 1, 2, 3, or 4. Compounds represented by general formula (IIG) or their tautomers, meso compounds, racemic compounds, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof.

2. A compound represented by general formula (IIG-1) or general formula (IIG-2), or its tautomers, meso compounds, racemic compounds, enantiomers, diastereomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof. 【Transformation 3】 or 【Chemistry 4】 Eventually, G1, G2, G3, Y, R1 to R3, R4a, R4b, J, k, r, n, and p are as defined in claim 1. A compound represented by the general formula (IIG) as described in claim 1, or in the form of a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

3. R １ is a hydrogen atom, A compound represented by the general formula (IIG) as described in claim 1, or in the form of a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

4. the below described 【Transformation 5】 【Transformation 6】 【Transformation 7】 【Transformation 8】 【Chemistry 9】 Selected from the following compounds: A compound represented by the general formula (IIG) as described in claim 1, or in the form of a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

5. A method for preparing a compound represented by the general formula (IIG) described in claim 1, or a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, 【Chemistry 10】 This includes reacting a compound of general formula (IIGA) with a compound of general formula (IB) to obtain a compound of general formula (IIG), Eventually, G1, G2, G3, Y, R1 to R3, R4a, R4b, J, k, n, p, and r are as defined in claim 1. method.

6. A method for preparing a compound represented by the general formula (IIG) described in claim 1, or a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, 【Chemistry 11】 This includes an intramolecular cyclization reaction of a compound of general formula (IIGC) to obtain a compound of general formula (IIG), Eventually, R ｍ C １－６ It is an alkyl group, and G1, G2, G3, Y, R1 to R3, R4a, R4b, J, k, n, p, and r are as defined in claim 1. method.

7. A pharmaceutical composition comprising a compound represented by general formula (IIG) as described in any one of claims 1 to 4, or a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable vectors, diluents, or excipients.

8. A compound represented by general formula (IIG) as described in any one of claims 1 to 4, or in the form of a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 7, for use in the treatment and / or prevention of diseases related to the CRBN protein.

9. A compound represented by general formula (IIG) as described in any one of claims 1 to 4, or a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 7, for use in the treatment and / or prevention of cancer, angiogenesis-related conditions, pain, macular degeneration or related syndromes, skin diseases, lung diseases, asbestos-related diseases, parasitic diseases, immunodeficiency disorders, CNS diseases, CNS disorders, atherosclerosis or related conditions, sleep disorders or related conditions, infectious diseases, abnormal hemoglobin disorders or related conditions, or TNFα-related conditions.

10. The compound according to claim 9, wherein the cancer is selected from leukemia, myeloma, lymphoma, melanoma, skin cancer, liver cancer, kidney cancer, lung cancer, nasopharyngeal cancer, stomach cancer, esophageal cancer, colorectal cancer, gallbladder cancer, bile duct cancer, choriocarcinoma, pancreatic cancer, polycythemia vera, pediatric tumors, cervical cancer, ovarian cancer, breast cancer, bladder cancer, urothelial carcinoma, ureteral tumors, prostate cancer, seminomas, testicular tumors, head and neck tumors, head and neck squamous cell carcinoma, endometrial cancer, thyroid cancer, sarcoma, osteoma, neuroblastoma, neuroendocrine cancer, brain tumors, CNS cancer, astrocytoma, and glioma.

11. The compound according to claim 10, wherein the liver cancer is hepatocellular carcinoma, the colorectal cancer is colon cancer or rectal cancer, the sarcoma is osteosarcoma or soft tissue sarcoma, and the glioma is glioblastoma.

12. The compound according to claim 10, wherein the myeloma is multiple myeloma (MM) or myelodysplastic syndrome (MDS).

13. The compound according to claim 12, wherein the multiple myeloma is relapsed, refractory, or resistant.

14. The compound according to claim 12, wherein the multiple myeloma is refractory or resistant to lenalidomide or pomalidomide.

15. The compound according to claim 10, wherein the lymphoma is small lymphocytic lymphoma, marginal zone lymphoma, follicular lymphoma, mantle cell lymphoma, non-Hodgkin lymphoma (NHL), lymphoplasmacytic lymphoma, extranodal marginal zone lymphoma, T-cell lymphoma, B-cell lymphoma, or diffuse large B-cell lymphoma.

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