Sulfur-containing isoindoline derivatives, preparation methods thereof and their medical applications

Abstract

The present disclosure relates to sulfur-containing isoindoline derivatives, preparation methods thereof and their applications in medicine. Specifically, the present disclosure relates to a sulfur-containing isoindoline derivative represented by general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative and its use as a therapeutic agent, in particular, its use as a Cereblon modulator in the field of treating multiple myeloma. #imgabs0#

Description

Technical Field

[0001] The present disclosure belongs to the field of medicine, and relates to a sulfur-containing isoindoline derivative, a preparation method thereof, and its application in medicine. In particular, the present disclosure relates to a sulfur-containing isoindoline derivative represented by general formula (I), a preparation method thereof, and a pharmaceutical composition containing the derivative, and its use as a Cereblon modulator in the field of treating multiple myeloma. Background Art

[0002] Multiple myeloma (MM) is a malignant tumor with major symptoms including hypercalcemia, kidney damage, anemia and bone disease. MM is the second most common hematological malignancy after non-Hodgkin's lymphoma, with 4 to 6 cases per 100,000 people worldwide and about 1.6 cases per 100,000 people in China. The current treatment methods are mainly drug therapy and autologous stem cell transplantation.

[0003] At present, there are four major categories of drugs widely used in clinical practice, namely, immunomodulators of the amide class, proteasome inhibitors, hormones, and monoclonal antibodies. Drugs in the clinical research stage include bispecific antibodies, ADC, CAR-T, etc. These drugs have different mechanisms of action, and combined use can often achieve better therapeutic effects. Clinically, dual, triple, or even quadruple drugs are generally used, generally immunomodulators, proteasome inhibitors and hormones are used in combination, and antibodies are sometimes added. Among them, lenalidomide is the most commonly used immunomodulator, which is used for first-line treatment, maintenance treatment after stem cell transplantation, and second- and third-line treatment after relapse. The drug had sales of US$9.7 billion in 2018 / 2019. In addition, the entire MM market is also considerable and growing rapidly. This is due to the continuous improvement and perfection of the diagnosis and treatment of MM, longer survival of patients, and correspondingly longer medication time. It is estimated that the MM market will reach a scale of US$33 billion in 2022, of which the largest share is still immunomodulators represented by lenalidomide.

[0004] The mechanism of action of immunomodulators (IMiDs) in the treatment of MM is that after IMiD drugs bind to Cereblon (CRBN) protein, they activate the E3 ligase activity of CRBN, and then selectively bind to transcription factors Ikaros (IKZF1) and Aiolos (IKZF3); this leads to rapid ubiquitination and degradation of Ikaros and Aiolos. Downregulation of Ikaros / Aiolos leads to downregulation of c-Myc, followed by downregulation of IRF4, and finally leads to inhibition of myeloma cell growth and apoptosis. In addition, IKZF3 can also inhibit the transcription of IL2 and TNF cytokines in T / NK cells. After IKZF3 degradation, this inhibition can be relieved to promote the release of these cytokines and play an immunomodulatory role. Clinical trials have also shown that the clinical benefits of IMiD drugs are also correlated with the level of CRBN expression. After knocking down CRBN in cell lines sensitive to lenalidomide (OPM2 and KMS18), it was found that the activity of lenalidomide in inhibiting cell growth disappeared, and drug resistance was produced. The level of CRBN knockdown was correlated with the degree of drug resistance. In the cell proliferation experiment, the expression level of CRBN in the cells was reduced (U266-CRBN60 and U266-CRBN75), and the activity of lenalidomide and pomalidomide in inhibiting cell growth was reduced.

[0005] The IMiD drugs that have been approved for marketing include thalidomide, lenalidomide and pomalidomide, all of which are from Celgene (currently merged with BMS). The binding ability of the three compounds to CRBN increases successively, so the clinical dosage decreases successively. The main indications of the three compounds are MM. Thalidomide and lenalidomide have other indications, especially lenalidomide, which can be used to treat myelodysplastic syndrome (MDS). In terms of side effects, lenalidomide and pomalidomide have similar performances and have obvious bone marrow suppression, which is a target-related toxicity; thalidomide has some other side effects, such as sedation, constipation, neurological side effects, etc.

[0006] The adipimide portion of all IMiDs binds to a hydrophobic pocket defined by three tryptophan residues in CRBN, known as the "thalidomide binding pocket." In contrast, the phthalimide / isoindolone ring is exposed to the solvent and changes the molecular surface of CRBN, thereby regulating substrate recognition. Different IMiDs lead to distinct modifications of the CRBN molecular surface and different preferences for substrate recognition. Therefore, modifications to IMiDs may lead to the degradation of other transcription factors and cause unnecessary toxic side effects. This mode of action of IMiDs is also known as molecular glue, which vividly describes the bonding effect of this small molecule on two protein substrates.

[0007] Since the median survival of multiple myeloma is more than five years, the extended survival makes most patients have a high rate of drug resistance to currently marketed drugs such as lenalidomide and pomalidomide, which seriously reduces the therapeutic effect of such drugs. Therefore, we envision developing drug molecules with better activity to overcome the problem of drug resistance, while minimizing the toxic side effects of such compounds.

[0008] Published patent applications for Cereblon regulators include WO2008115516A2, WO2011100380A1, WO2019226770A1, WO2019014100A1 and WO2020064002A1, among others. Summary of the invention

[0009] The object of the present disclosure is to provide a compound represented by general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

[0010]

[0011] in:

[0012] Ring A is an aryl group or a heteroaryl group;

[0013] Ring B is a cycloalkyl group or a heterocyclic group;

[0014] Y is CH2 or C(O);

[0015] R 1 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro and hydroxyl;

[0016] R 2 is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0017] R 3 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro and hydroxyl;

[0018] R 4Selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic radical, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl;

[0019] R 5 and R 6 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0020] n is 0, 1, 2 or 3;

[0021] p is 0, 1, 2, 3 or 4;

[0022] q is 0, 1, or 2; and

[0023] t is 0, 1, 2, or 3.

[0024] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by the general formula (I-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof:

[0025]

[0026] in:

[0027] Ring A, Ring B, Y, R 1 To R 6 , n, p, q and t are as defined in the general formula (I).

[0028] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by the general formula (I-2) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof:

[0029]

[0030] in:

[0031] Ring A, Ring B, Y, R 1 To R 6 , n, p, q and t are as defined in the general formula (I).

[0032] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by the general formula (II) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof:

[0033]

[0034] in:

[0035] Ring A, Ring B, Y, R 1 To R 4 , n, p and t are as defined in the general formula (I).

[0036] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (II) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by the general formula (II-1) or the general formula (II-2) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0037]

[0038] in:

[0039] Ring A, Ring B, Y, R 1 To R 4 , n, p and t are as defined in the general formula (II).

[0040] In some embodiments of the present disclosure, the 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) or its tautomer, racemate, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl or a 5- to 6-membered heteroaryl group; preferably selected from phenyl, pyridyl and pyrimidinyl.

[0041] In some embodiments of the present disclosure, the compound represented by the 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 tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein Selected from R 3 and p are as defined in the general formula (I).

[0042] In some embodiments of the present disclosure, the compound represented by the 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 tautomer, mesomorph, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring B is a 3- to 8-membered heterocyclic group; preferably, ring B is selected from piperidinyl, pyrrolidinyl and N-heterocyclobutyl; more preferably, ring B is a 6-membered heterocyclic group; most preferably, ring B is piperidinyl.

[0043] In some embodiments of the present disclosure, the compound represented by the 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 tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein for J is 0 or 1, k is 0 or 1; preferably, for R 4a and R 4b are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; and r is 0, 1 or 2.

[0044] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (II) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by the general formula (IIG) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0045]

[0046] in:

[0047] G 1 , G 2 and G 3 are the same or different and are each independently a carbon atom or a nitrogen atom;

[0048] R 4a and R 4b are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0049] r is 0, 1, or 2;

[0050] J is 0 or 1;

[0051] k is 0 or 1;

[0052] Y, R 1 To R 3 , n and p are as defined in the general formula (I).

[0053] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), general formula (I-1), general formula (II), general formula (II-1) or general formula (IIG) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by the general formula (IIG-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0054]

[0055] in:

[0056] G 1 , G 2 and G 3 are the same or different and are each independently a carbon atom or a nitrogen atom;

[0057] R 4a and R 4bare the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0058] r is 0, 1, or 2;

[0059] J is 0 or 1;

[0060] k is 0 or 1;

[0061] Y, R 1 To R 3 , n and p are as defined in the general formula (I).

[0062] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), general formula (I-2), general formula (II), general formula (II-2) or general formula (IIG) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by the general formula (IIG-2) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0063]

[0064] in:

[0065] G 1 , G 2 and G 3 are the same or different and are each independently a carbon atom or a nitrogen atom;

[0066] R 4a and R 4b are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0067] r is 0, 1, or 2;

[0068] J is 0 or 1;

[0069] k is 0 or 1;

[0070] Y, R 1 To R 3 , n and p are as defined in the general formula (I).

[0071] In some preferred embodiments of the present disclosure, the compound represented by the general formula (IIG), the general formula (IIG-1) or the general formula (IIG-2) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein 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 are all carbon atoms; or G 2 and G 3 All are nitrogen atoms, G 1 For carbon atoms.

[0072] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II) or general formula (IIG) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by the general formula (III) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof:

[0073]

[0074] in:

[0075] R 4a and R 4b are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0076] r is 0, 1, or 2;

[0077] Y, R 1 To R 3 , n and p are as defined in the general formula (I).

[0078] In some preferred embodiments of the present disclosure, the compound represented by the 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) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by the general formula (III-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0079]

[0080] in:

[0081] Y, R 1 To R 3 , R 4a , R 4b , r, n and p are as defined in the general formula (III).

[0082] In some preferred embodiments of the present disclosure, the compound represented by the 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) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by the general formula (III-2) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof:

[0083]

[0084] in:

[0085] Y, R 1 To R 3 , R 4a , R 4b , r, n and p are as defined in the general formula (III).

[0086] In some preferred embodiments of the present disclosure, the 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) or general formula (III-2) or their tautomers, racemates, racemates, enantiomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein Y is CH2.

[0087] In some preferred embodiments of the present disclosure, the compound represented by the 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 tautomer, mesomer, racemate, enantiomer, diastereoisomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 4 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 alkyl, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl, wherein the 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl are each independently selected from halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, cyano, amino, nitro, hydroxyl and C 1-6 The hydroxyalkyl group is substituted by one or more substituents.

[0088] In some preferred embodiments of the present disclosure, the compound represented by the general formula (IIG), general formula (IIG-1), general formula (IIG-2), general formula (III), general formula (III-1) or general formula (III-2) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 4a 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl, wherein the 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl are each independently selected from halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, cyano, amino, nitro, hydroxyl and C 1-6The hydroxyalkyl group is substituted by one or more substituents; R 4b are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 alkyl and 3 to 8 membered cycloalkyl; preferably, R 4a for R 4b A hydrogen atom.

[0089] In some preferred embodiments of the present disclosure, the compound represented by the 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 its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or pharmaceutically acceptable salt thereof, wherein R 1 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 Alkyl; preferably, R 1 A hydrogen atom.

[0090] In some embodiments of the present disclosure, the compound represented by the 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 its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 2 Selected from hydrogen atoms, C 1-6 alkyl and 3 to 8 membered cycloalkyl; preferably, R 2 A hydrogen atom.

[0091] In some embodiments of the present disclosure, the compound represented by the 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 its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 3 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 alkyl.

[0092] In some embodiments of the present disclosure, the compound represented by the 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 its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 3 are the same or different and are each independently a hydrogen atom or a halogen; preferably a hydrogen atom.

[0093] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (I-1) or general formula (I-2) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein q is 0 or 1; preferably q is 0.

[0094] In some embodiments of the present disclosure, the 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) or general formula (III-2) or their tautomers, racemates, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein n is 0 or 1.

[0095] In some embodiments of the present disclosure, the 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) or general formula (III-2) or their tautomers, racemates, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein p is 0, 1 or 2.

[0096] In some embodiments of the present disclosure, the compound represented by the 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 tautomer, racemate, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein t is 0, 1 or 2.

[0097] In some embodiments of the present disclosure, the compound represented by the general formula (IIG), general formula (IIG-1), general formula (IIG-2), general formula (III), general formula (III-1) or general formula (III-2) or its tautomer, racemate, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein r is 0 or 1.

[0098] In some embodiments of the present disclosure, the compound represented by the general formula (III), the general formula (III-1) or the general formula (III-2) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: Y is CH2; R 1 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 Alkyl; 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 for R 4b is a hydrogen atom; n is 0 or 1; p is 0 or 1; and r is 1.

[0099] Table A Typical compounds of the present disclosure include, but are not limited to:

[0100]

[0101]

[0102]

[0103]

[0104]

[0105]

[0106]

[0107]

[0108]

[0109]

[0110]

[0111]

[0112]

[0113]

[0114]

[0115]

[0116]

[0117] Another aspect of the present disclosure relates to a compound represented by general formula (IA) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a salt thereof,

[0118]

[0119] in:

[0120] Ring A is selected from phenyl, pyridyl and pyrimidinyl; preferably phenyl;

[0121] Ring B is a heterocyclic group; preferably a 3- to 8-membered heterocyclic group; more preferably a piperidinyl group, a pyrrolidinyl group or an N-heterocyclobutyl group;

[0122] R 2 To R 6 , p, q and t are as defined in the general formula (I).

[0123] Another aspect of the present disclosure relates to a compound represented by general formula (IIA) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a salt thereof,

[0124]

[0125] in:

[0126] Ring A is selected from phenyl, pyridyl and pyrimidinyl; preferably phenyl;

[0127] Ring B is a heterocyclic group; preferably a 3- to 8-membered heterocyclic group; more preferably a piperidinyl group, a pyrrolidinyl group or an N-heterocyclobutyl group;

[0128] R 2 To R 4 , p and t are as defined in the general formula (II).

[0129] Another aspect of the present disclosure relates to a compound represented by the general formula (IIGA) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a salt thereof,

[0130]

[0131] in:

[0132] G 1 , G 2 , G 3 , R 2 , R 3 , R 4a , R 4b , J, k, p and r are as defined in Formula (IIG).

[0133] Another aspect of the present disclosure relates to a compound represented by general formula (IIIA) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a salt thereof,

[0134]

[0135] in:

[0136] R 2 , R 3 , R 4a , R 4b , p and r are as defined in the general formula (III).

[0137] Typical intermediate compounds of the present disclosure include, but are not limited to:

[0138]

[0139]

[0140]

[0141] Another aspect of the present disclosure relates to a compound represented by the general formula (IC) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a salt thereof,

[0142]

[0143] in:

[0144] R m C 1-6 Alkyl; preferably tert-butyl;

[0145] Ring A, Ring B, Y, R 1 To R 6 , n, p, q and t are as defined in the general formula (I).

[0146] Another aspect of the present disclosure relates to a compound represented by general formula (I-1C) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a salt thereof,

[0147]

[0148] in:

[0149] R m C 1-6 Alkyl; preferably tert-butyl;

[0150] Ring A, Ring B, Y, R 1 To R 6 , n, p, q and t are as defined in the general formula (I-1).

[0151] Another aspect of the present disclosure relates to a compound represented by the general formula (IIC) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a salt thereof,

[0152]

[0153] in:

[0154] R m C 1-6 Alkyl; preferably tert-butyl;

[0155] Ring A, Ring B, Y, R 1 To R 4 , n, p and t are as defined in the general formula (II).

[0156] Another aspect of the present disclosure relates to a compound represented by the general formula (II-1C) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a salt thereof,

[0157]

[0158] in:

[0159] R m C 1-6 Alkyl; preferably tert-butyl;

[0160] Ring A, Ring B, Y, R 1 To R 4 , n, p and t are as defined in the general formula (II-1).

[0161] Another aspect of the present disclosure relates to a compound represented by the general formula (IIGC) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a salt thereof,

[0162]

[0163] in:

[0164] R m C1-6 Alkyl; preferably tert-butyl;

[0165] G 1 , G 2 , G 3 , Y, R 1 To R 3 , R 4a , R 4b , J, k, r, n and p are as defined in Formula (IIG).

[0166] Another aspect of the present disclosure relates to a compound represented by the general formula (IIGC-1) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a salt thereof,

[0167]

[0168] in:

[0169] R m C 1-6 Alkyl; preferably tert-butyl;

[0170] G 1 , G 2 , G 3 , Y, R 1 To R 3 , R 4a , R 4b , J, k, r, n and p are as defined in the general formula (IIG-1).

[0171] Another aspect of the present disclosure relates to a compound represented by general formula (IIIC) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a salt thereof,

[0172]

[0173] in:

[0174] R m C 1-6 Alkyl; preferably tert-butyl;

[0175] Y, R 1 To R 3 , R 4a , R 4b , r, n and p are as defined in the general formula (III).

[0176] Another aspect of the present disclosure relates to a compound represented by the general formula (III-1C) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a salt thereof,

[0177]

[0178] in:

[0179] R m C 1-6 Alkyl; preferably tert-butyl;

[0180] Y, R 1 To R 3 , R 4a , R 4b , r, n and p are as defined in the general formula (III-1).

[0181] Typical intermediate compounds of the present disclosure include, but are not limited to:

[0182]

[0183]

[0184]

[0185]

[0186]

[0187]

[0188]

[0189] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

[0190]

[0191] The compound of general formula (IA) reacts with the compound of general formula (IB) to obtain the compound of general formula (I),

[0192] in:

[0193] Ring A, Ring B, Y, R 1 To R 6 , n, p, q and t are as defined in the general formula (I).

[0194] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

[0195]

[0196] The compound of general formula (IC) undergoes an intramolecular ring-closing reaction to obtain a compound of general formula (I),

[0197] in:

[0198] R m C 1-6 Alkyl; preferably tert-butyl;

[0199] Ring A, Ring B, Y, R 1 To R 6 , n, p, q and t are as defined in the general formula (I).

[0200] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

[0201]

[0202] The compound of general formula (I-1C) undergoes an intramolecular ring-closing reaction to obtain a compound of general formula (I-1),

[0203] in:

[0204] R m C 1-6 Alkyl; preferably tert-butyl;

[0205] Ring A, Ring B, Y, R 1 To R 6 , n, p, q and t are as defined in the general formula (I-1).

[0206] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I-2) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

[0207]

[0208] The compound of general formula (I) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof is prepared by chiral resolution to obtain a single configuration compound represented by general formula (I-2), or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof;

[0209] in:

[0210] R m C1-6 Alkyl; preferably tert-butyl;

[0211] Ring A, Ring B, Y, R 1 To R 6 , n, p, q and t are as defined in the general formula (I).

[0212] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

[0213]

[0214] The compound of general formula (IIA) reacts with the compound of general formula (IB) to obtain the compound of general formula (II),

[0215] in:

[0216] Ring A, Ring B, Y, R 1 To R 4 , n, p and t are as defined in the general formula (II).

[0217] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

[0218]

[0219] The compound of general formula (IIC) undergoes an intramolecular ring-closing reaction to obtain a compound of general formula (II),

[0220] in:

[0221] R m C 1-6 Alkyl; preferably tert-butyl;

[0222] Ring A, Ring B, Y, R 1 To R 4 , n, p and t are as defined in the general formula (II).

[0223] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

[0224]

[0225] The compound of general formula (II-1C) undergoes an intramolecular ring-closing reaction to obtain a compound of general formula (II-1),

[0226] in:

[0227] R m C 1-6 Alkyl; preferably tert-butyl;

[0228] Ring A, Ring B, Y, R 1 To R 4 , n, p and t are as defined in the general formula (II).

[0229] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II-2) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

[0230]

[0231] The compound of general formula (II) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof is prepared 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 pharmaceutically acceptable salt thereof;

[0232] in:

[0233] R m C 1-6 Alkyl; preferably tert-butyl;

[0234] Ring A, Ring B, Y, R 1 To R 4 , n, p and t are as defined in the general formula (II).

[0235] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IIG) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

[0236]

[0237] The compound of general formula (IIGA) reacts with the compound of general formula (IB) to obtain the compound of general formula (IIG),

[0238] in:

[0239] G 1 , G 2 , G 3, Y, R 1 To R 3 , R 4a , R 4b , J, k, n, p and r are as defined in Formula (IIG).

[0240] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IIG) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

[0241]

[0242] The compound of general formula (IIGC) undergoes an intramolecular ring-closing reaction to obtain a compound of general formula (IIG),

[0243] in:

[0244] R m C 1-6 Alkyl; preferably tert-butyl;

[0245] G 1 , G 2 , G 3 , Y, R 1 To R 3 , R 4a , R 4b , J, k, n, p and r are as defined in Formula (IIG).

[0246] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IIG-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

[0247]

[0248] The compound of the general formula (IIGC-1) undergoes an intramolecular ring-closing reaction to obtain a compound of the general formula (IIG-1),

[0249] in:

[0250] R m C 1-6 Alkyl; preferably tert-butyl;

[0251] G 1 , G 2 , G 3 , Y, R 1 To R 3 , R 4a , R 4b, J, k, n, p and r are as defined in the general formula (IIG-1).

[0252] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IIG-2) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

[0253]

[0254] The compound of the general formula (IIG) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt is prepared by chiral resolution to obtain a single configuration compound represented by the general formula (IIG-2), or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt;

[0255] in:

[0256] R m C 1-6 Alkyl; preferably tert-butyl;

[0257] G 1 , G 2 , G 3 , Y, R 1 To R 3 , R 4a , R 4b , J, k, n, p and r are as defined in Formula (IIG).

[0258] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

[0259]

[0260] The compound of general formula (IIIA) reacts with the compound of general formula (IB) to obtain the compound of general formula (III),

[0261] in:

[0262] Y, R 1 To R 3 , R 4a , R 4b , n, p and r are as defined in the general formula (III).

[0263] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

[0264]

[0265] The compound of general formula (IIIC) undergoes an intramolecular ring-closing reaction to obtain a compound of general formula (III),

[0266] in:

[0267] R m C 1-6 Alkyl; preferably tert-butyl;

[0268] Y, R 1 To R 3 , R 4a , R 4b , n, p and r are as defined in the general formula (III).

[0269] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

[0270]

[0271] The compound of general formula (III-1C) undergoes an intramolecular ring-closing reaction to obtain a compound of general formula (III-1),

[0272] in:

[0273] R m C 1-6 Alkyl; preferably tert-butyl;

[0274] Y, R 1 To R 3 , R 4a , R 4b , n, p and r are as defined in the general formula (III-1).

[0275] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III-2) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

[0276]

[0277] The compound of general formula (III) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof is prepared 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 pharmaceutically acceptable salt thereof;

[0278] in:

[0279] R m C 1-6 Alkyl; preferably tert-butyl;

[0280] Y, R 1 To R 3 , R 4a , R 4b , n, p and r are as defined in the general formula (III).

[0281] Another aspect of the present disclosure relates to a pharmaceutical composition, which contains a compound of the present disclosure represented by the general formula (I), (I-1), (I-2), (II), (II-1), (II-2), (IIG), (IIG-1), (IIG-2), (III), (III-1), (III-2) or Table A, or its tautomer, mesoform, racemate, enantiomer, diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0282] The present disclosure further relates to the use of compounds shown in 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 their tautomers, mesomorphs, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the same in the preparation of drugs for treating and / or preventing diseases associated with CRBN protein.

[0283] The present disclosure further relates to the use of compounds of formula (I), (I-1), (I-2), (II), (II-1), (II-2), (IIG), (IIG-1), (IIG-2), (III), (III-1), (III-2) or shown in Table A, or their tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the same in the preparation of medicaments for treating and / or preventing cancer, angiogenesis-related disorders, pain, macular degeneration or related syndromes, skin diseases, lung diseases, asbestos-related diseases, parasitic diseases, immunodeficiency diseases, CNS diseases, CNS damage, atherosclerosis or related disorders, sleep disorders or related disorders, infectious diseases, hemoglobinopathies or related disorders, or TNFα-related disorders; preferably, use in the preparation of medicaments for treating and / or preventing cancer or CNS damage.

[0284] The present disclosure also relates to a method for treating and / or preventing diseases associated with CRBN protein, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), (I-1), (I-2), (II), (II-1), (II-2), (IIG), (IIG-1), (IIG-2), (III), (III-1), (III-2) or shown in Table A, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0285] The present disclosure also relates to a method for treating and / or preventing cancer, angiogenesis-related disorders, pain, macular degeneration or related syndromes, skin diseases, lung diseases, asbestos-related diseases, parasitic diseases, immunodeficiency diseases, CNS diseases, CNS damage, atherosclerosis or related disorders, sleep disorders or related disorders, infectious diseases, hemoglobinopathies or related disorders, or TNFα-related disorders, preferably a method for treating and / or preventing cancer or CNS damage, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of 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 Table A, or its tautomers, racemates, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same.

[0286] The present disclosure further relates to a compound of 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 Table A, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt or pharmaceutical composition containing the same, which is used as a drug.

[0287] The present disclosure further relates to compounds shown in 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 their tautomers, racemates, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the same, which are used to treat and / or prevent diseases associated with CRBN protein.

[0288] The CRBN protein-related diseases described in the present disclosure are selected from cancer, angiogenesis-related disorders, pain, macular degeneration or related syndromes, skin diseases, lung diseases, asbestos-related diseases, parasitic diseases, immunodeficiency diseases, CNS diseases, CNS damage, atherosclerosis or related disorders, sleep disorders or related disorders, infectious diseases, hemoglobinopathies or related disorders, or TNFα-related disorders; preferably cancer or CNS damage.

[0289] The present disclosure further relates to compounds shown in formula (I), (I-1), (I-2), (II), (II-1), (II-2), (IIG), (IIG-1), (IIG-2), (III), (III-1), (III-2) or Table A, or their tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the same, for use in treating and / or preventing cancer, angiogenesis-related disorders, pain, macular degeneration or related syndromes, skin diseases, lung diseases, asbestos-related diseases, parasitic diseases, immunodeficiency diseases, CNS diseases, CNS damage, atherosclerosis or related disorders, sleep disorders or related disorders, infectious diseases, hemoglobinopathies or related disorders, or TNFα-related disorders; preferably cancer or CNS damage.

[0290] The cancer described in the present disclosure is selected from leukemia, myeloma, lymphoma, melanoma, skin cancer, liver cancer, kidney cancer, lung cancer, nasopharyngeal cancer, gastric 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, seminoma, testicular tumors, head and neck tumors, head and neck squamous cell carcinoma, endometrial cancer, thyroid cancer, sarcoma, osteoma, neuroblastoma, neuroendocrine cancer, brain tumor, CNS cancer, 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; the glioma is glioblastoma. The leukemia is preferably chronic lymphocytic leukemia, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML) and hairy cell leukemia, the lymphoma is preferably small lymphocytic lymphoma, marginal zone lymphoma, follicular lymphoma, mantle cell lymphoma, non-Hodgkin's lymphoma (NHL), lymphoplasmacytic lymphoma, extranodal marginal zone lymphoma, T cell lymphoma, B cell lymphoma and diffuse large B cell lymphoma; the myeloma is preferably multiple myeloma (MM) and myelodysplastic syndrome (MDS). The cancer described in the present disclosure includes primary or metastatic cancer. The cancer described in the present disclosure also includes refractory or resistant to chemotherapy or radiotherapy. More preferably, the multiple myeloma is relapsed, refractory or resistant. Most preferably, the multiple myeloma is refractory or resistant to lenalidomide or pomalidomide.

[0291] Examples of CNS diseases include, but are not limited to, those described in U.S. Publication No. US2005 / 0143344A1, published on June 30, 2005, the contents of which 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 neuroimmune diseases such as Tourette syndrome, delusions, or disturbances of consciousness that occur over a short period of time, or amnesia, or scattered memory impairment that occurs when other central nervous system damage is not present.

[0292] Examples of CNS injuries and related syndromes include, but are not limited to, diseases described in U.S. Publication No. US2006 / 0122228A1, published on June 8, 2006, the contents of which are incorporated herein by reference. Specific examples include, but are not limited to, CNS injuries / impairments and related syndromes including, but are not limited to, primary brain injury, secondary brain injury, traumatic brain injury, focal brain injury, diffuse axonal injury, craniocerebral injury, concussion, post-concussive syndrome, cerebral contusion, subdural hematoma, epidermal hematoma, post-traumatic epilepsy, chronic autonomic state, complete SCI, incomplete SCI, acute SCI, subacute SCI, chronic SCI, central cord syndrome, hemisection of the cord syndrome, anterior cord syndrome, conus medullaris syndrome, cauda equina syndrome, neurogenic shock, spinal shock, altered level of consciousness, headache, nausea, vomiting, memory loss, vertigo, diplopia, blurred vision, emotional instability, sleep disorders, irritability, inability to concentrate, nervousness, behavioral disorders, cognitive deficits, and epilepsy.

[0293] Diseases associated with angiogenesis include, but are not limited to, inflammatory diseases, autoimmune diseases, viral diseases, genetic diseases, allergic diseases, bacterial diseases, ocular neovascular diseases, choroidal neovascular diseases, retinal neovascular diseases, and rubeosis iridis (angle neovascularization). Preferably, include, but are not limited to, arthritis, endometriosis, Crohn's disease, heart failure, severe heart failure, renal injury, endotoxemia, toxic shock syndrome, osteoarthritis, retroviral replication, wasting diseases, meningitis, silica-induced fibrosis, asbestos-induced fibrosis, veterinary diseases, hypercalcemia associated with malignancy, stroke, circulatory shock, periodontitis, gingivitis, macrocytic anemia, refractory anemia, and 5q deletion syndrome.

[0294] The active compound can be prepared into a form suitable for administration by any appropriate route, and the composition of the present disclosure can be prepared by conventional methods using one or more pharmaceutically acceptable carriers. Therefore, the active compound of the present disclosure can be formulated into various dosage forms for oral administration, injection (e.g., intravenous, intramuscular or subcutaneous) administration, inhalation or insufflation administration. The compounds of the present disclosure can also be formulated into dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges or syrups.

[0295] As a general guide, the active compound is preferably in a unit dose form, or in a form that a patient can self-administer in a single dose. The unit dose of the disclosed compound or composition can be expressed in tablets, capsules, cachets, bottled liquids, powders, granules, lozenges, suppositories, reconstituted powders or liquid preparations. Suitable unit doses can be 0.1 to 1000 mg.

[0296] The pharmaceutical composition of the present disclosure may contain one or more excipients in addition to the active compound, and the excipients are selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients, etc. Depending on the administration method, the composition may contain 0.1 to 99% by weight of the active compound.

[0297] Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for preparing tablets. These excipients may be inert excipients, granulating agents, disintegrants, binders and lubricants. These tablets may be uncoated or may be coated by known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release effect over a longer period of time.

[0298] Oral preparations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or wherein the active ingredient is mixed with a water-soluble carrier or an oily vehicle.

[0299] Aqueous suspensions contain the active substance and excipients suitable for preparing aqueous suspensions for mixing. Such excipients are suspending agents, dispersants or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweetening agents.

[0300] Oil suspensions can be prepared by suspending the active ingredient in a vegetable oil, or a mineral oil. The oil suspension may contain a thickener. The above-mentioned sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions may be preserved by adding an antioxidant.

[0301] Pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, or a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsions may also contain sweeteners, flavoring agents, preservatives, and antioxidants. Such preparations may also contain a demulcent, a preservative, a coloring agent, and an antioxidant.

[0302] The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous solutions. Acceptable vehicles or solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable formulation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase. The injection or microemulsion may be injected into the patient's bloodstream by local mass injection. Alternatively, it is preferred that the solution and microemulsion be administered in a manner that maintains a constant circulating concentration of the disclosed compound. To maintain such a constant concentration, a continuous intravenous drug delivery device may be used. An example of such a device is the Deltec CADD-PLUS.TM.5400 intravenous injection pump.

[0303] Pharmaceutical compositions of the present disclosure can be in the form of sterile injection water or oil suspension for intramuscular and subcutaneous administration. The suspension can be prepared by known techniques with the above-mentioned suitable dispersants or wetting agents and suspending agents. Sterile injection preparations can also be sterile injection solutions or suspensions prepared in parenteral acceptable non-toxic diluents or solvents. In addition, sterile fixed oils can be conveniently used as solvents or suspension media. For this purpose, any blended fixed oils can be used. In addition, fatty acids can also be used to prepare injections.

[0304] The disclosed compounds 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 which is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.

[0305] The compounds of the present disclosure can be administered by preparing water-suspended dispersible powders and granules by the addition of water. These pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersing or wetting agent, a suspending agent, or one or more preservatives.

[0306] As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to the following factors: the activity of the specific compound used, the age of the patient, the weight of the patient, the health status of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, the severity of the disease, etc.; in addition, the best treatment method such as the mode of treatment, the daily dosage of the compound or the type of pharmaceutically acceptable salt can be verified according to traditional treatment regimens.

[0307] Terminology

[0308] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0309] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, and more preferably an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably independently selected from one or more substituents of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0310] The term "alkylene" refers to a saturated straight or branched aliphatic hydrocarbon group, which is a residue derived from the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkane, and is a straight or branched group containing 1 to 20 carbon atoms, preferably 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, and more preferably 1 to 6 carbon atoms. Non-limiting examples of alkylene 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-), and the like. The alkylene group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably independently selected from one or more substituents of alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio and oxo.

[0311] The term "alkenyl" refers to an alkyl compound containing at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above. Alkenyl may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0312] The term "alkynyl" refers to an alkyl compound containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above. Alkynyl may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0313] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms (which can be a specific point or an interval consisting of two points, such as 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 (such as 3, 4, 5, 6, 7 and 8), more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyls include cycloalkyls of spiro rings, condensed rings and bridged rings.

[0314] The term "spirocycloalkyl" refers to a polycyclic group of 5 to 20 yuan, a carbon atom (called spiral atom) shared between monocyclic rings, which may contain one or more double bonds. Preferably, it is 6 to 14 yuan, more preferably 7 to 10 yuan (e.g., 7, 8, 9 or 10 yuan). According to the number of spiral atoms shared between rings, the spirocycloalkyl is divided into a single spiral cycloalkyl, a double spiral cycloalkyl or a multi-spirocycloalkyl, preferably a single spiral cycloalkyl and a double spiral cycloalkyl. More preferably, it is 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiral cycloalkyl. Non-limiting examples of spirocycloalkyl include:

[0315]

[0316] The term "condensed cycloalkyl" refers to 5 to 20 yuan, and each ring in the system shares a pair of adjacent carbon atoms with other rings in the system. All carbon polycyclic groups, wherein one or more rings can contain one or more double bonds. Preferably 6 to 14 yuan, more preferably 7 to 10 yuan (such as 7,8,9 or 10 yuan). According to the number of the composition ring, dicyclo, tricyclo, tetracycle or polycyclic condensed cycloalkyl can be divided, preferably dicyclo or tricyclo, more preferably 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan and 6 yuan / 6 yuan of dicycloalkyl. The limiting examples of condensed cycloalkyl include:

[0317]

[0318] The term "bridged cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, and which may contain one or more double bonds. Preferably, it is 6 to 14 members, and more preferably, it is 7 to 10 members (e.g., 7, 8, 9, or 10 members). According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl, preferably a bicyclic, tricyclic, or tetracyclic, more preferably a bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include:

[0319]

[0320] The cycloalkyl ring includes a cycloalkyl group as described above (including a monocyclic ring, a spirocyclic ring, a condensed ring and a bridged ring) fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, non-limiting examples include etc.; preferred

[0321] The cycloalkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably independently selected from one or more substituents of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0322] The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy and butoxy. Alkoxy can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, which are independently selected from D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0323] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent containing 3 to 20 ring atoms, one or more of which are heteroatoms selected from nitrogen, oxygen and sulfur, the sulfur being optionally oxo-substituted (i.e. forming a sulfoxide or sulfone), but excluding the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms being carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 (e.g. 1, 2, 3 and 4) are heteroatoms; more preferably, it contains 3 to 8 ring atoms (e.g. 3, 4, 5, 6, 7 and 8), of which 1-3 are heteroatoms (e.g. 1, 2 and 3); more preferably, it contains 3 to 6 ring atoms, of which 1-3 are heteroatoms; most preferably, it contains 5 or 6 ring atoms, of which 1-3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyls include oxetanyl, pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls.

[0324] The term "spiro heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 20 members, one atom (called spiral atom) shared between monocyclic rings, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, and the sulfur may be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds. It is preferably 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members). According to the number of spiral atoms shared between rings, the spiral heterocyclic group is divided into a monospiro heterocyclic group, a bispiro heterocyclic group or a polyspiro heterocyclic group, preferably a monospiro heterocyclic group and a bispiro heterocyclic group. It is more preferably a 3-yuan / 5-yuan, 3-yuan / 6-yuan, 4-yuan / 4-yuan, 4-yuan / 5-yuan, 4-yuan / 6-yuan, 5-yuan / 5-yuan or 5-yuan / 6-yuan monospiro heterocyclic group. Non-limiting examples of spiral heterocyclic groups include:

[0325]

[0326] The term "fused heterocyclic radical" refers to 5 to 20 yuan, each ring in the system shares a pair of adjacent atoms with other rings in the system. The polycyclic heterocyclic group, one or more rings may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, and the sulfur may be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is 6 to 14 yuan, more preferably 7 to 10 yuan (e.g., 7, 8, 9 or 10 yuan). According to the number of the composition ring, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic radical, preferably a bicyclic or tricyclic, more preferably 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan and 6 yuan / 6 yuan bicyclic fused heterocyclic radical. Non-limiting examples of fused heterocyclic radicals include:

[0327]

[0328] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 14 members, any two rings sharing two atoms that are not directly connected, which may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, the sulfur may be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

[0329]

[0330] The heterocyclic ring includes a heterocyclic group as described above (including a monocyclic, spiro heterocyclic, fused heterocyclic and bridged heterocyclic) fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, non-limiting examples of which include:

[0331] wait.

[0332] The heterocyclyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably independently selected from one or more substituents of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0333] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring that shares adjacent carbon atom pairs) group with a conjugated π electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring includes an aryl ring as described above fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and its non-limiting examples include:

[0334]

[0335] The aryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably independently selected from one or more substituents of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0336] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl is preferably 5 to 10 yuan (e.g., 5, 6, 7, 8, 9, or 10 yuan), more preferably 5 yuan or 6 yuan, such as furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring includes a heteroaryl fused to an aryl, heterocyclyl, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples thereof include:

[0337]

[0338]

[0339] The heteroaryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably independently selected from one or more substituents of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0340] The above-mentioned cycloalkyl, heterocyclic, aryl and heteroaryl groups include residues derived from a parent carbon atom by removing one hydrogen atom, or residues derived from the same carbon atom or two different carbon atoms of the parent by removing two hydrogen atoms, i.e., "divalent cycloalkyl", "divalent heterocyclic", "arylene" and "heteroarylene".

[0341] In the chemical structures of the compounds disclosed herein, the bond Indicates that the configuration is not specified, that is, if there are chiral isomers in the chemical structure, the bond Can be or include both Two configurations.

[0342] In addition, the compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also referred to as prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. An example of a lactam-lactim equilibrium is between A and B as shown below.

[0343]

[0344] All compounds in the present disclosure can be drawn as either Form A or Form B. All tautomeric forms are within the scope of the present disclosure. The naming of the compounds does not exclude any tautomers.

[0345] On the other hand, the compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All of these isomers and their mixtures are included within the scope of the present 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. If one enantiomer of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereoisomer salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art, and then the pure enantiomers are recovered. In addition, the separation of enantiomers and diastereomers is usually achieved by using chromatography, which uses a chiral stationary phase and is optionally combined with a chemical derivatization method (such as the formation of carbamates from amines).

[0346] The term "amino protecting group" is to protect the amino group with a group that is easy to remove in order to keep the amino group unchanged when other parts of the molecule react. Non-limiting examples include (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butyloxycarbonyl, acetyl, benzyl, allyl and p-methoxybenzyl. These groups can be optionally substituted with 1-3 substituents selected from halogen, alkoxy or nitro. The amino protecting group is preferably (trimethylsilyl)ethoxymethyl and tert-butyloxycarbonyl.

[0347] The term "hydroxy protecting group" refers to a group known in the art as being suitable for protecting a hydroxy group, see the literature ("Protective Groups in Organic Synthesis", 5 Th Ed.TWGreene & P.GMWuts) in the hydroxyl protecting group. As an example, preferably, the hydroxyl protecting group can be (C 1-10 alkyl or aryl) 3 silyl, for example: triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, etc.; it can be C 1-10 Alkyl or substituted alkyl, preferably alkoxy or aryl substituted alkyl, more preferably C 1-6 Alkoxy substituted C 1-6Alkyl or phenyl substituted C 1-6 Alkyl, most preferably C 1-4 Alkoxy substituted C 1-4 Alkyl, for example: methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, etc.; can be (C 1-10 alkyl or aromatic) acyl, such as formyl, acetyl, benzoyl, p-nitrobenzoyl, etc.; can be (C 1-6 alkyl or 6 to 10 membered aryl) sulfonyl; it may also be (C 1-6 The hydroxy protecting group is preferably a p-nitrobenzoyl group.

[0348] The term "heterocyclylalkyl" refers to an alkyl group substituted with one or more heterocyclyl groups, wherein heterocyclyl and alkyl are as defined above.

[0349] The term "heteroarylalkyl" refers to an alkyl group substituted with one or more heteroaryl groups, wherein heteroaryl and alkyl are as defined above.

[0350] The term "cycloalkyloxy" refers to a cycloalkyl-O- group in which cycloalkyl is as defined above.

[0351] The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.

[0352] The term "aryloxy" refers to an aryl-O- group in which aryl is as defined above.

[0353] The term "heteroaryloxy" refers to heteroaryl-O-, wherein heteroaryl is as defined above.

[0354] The term "alkylthio" refers to an alkyl-S- group in which alkyl is as defined above.

[0355] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0356] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0357] The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.

[0358] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

[0359] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0360] The term "hydroxy" refers to -OH.

[0361] The term "thiol" refers to -SH.

[0362] The term "amino" refers to -NH2.

[0363] The term "cyano" refers to -CN.

[0364] The term "nitro" refers to -N02.

[0365] The term "oxo" or "oxo" refers to "=0".

[0366] The term "carbonyl" refers to C=O.

[0367] The term "carboxy" refers to -C(O)OH.

[0368] The term "carboxylate" refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O)O-, wherein alkyl and cycloalkyl are as defined above.

[0369] The compounds of the present disclosure include other isotopic derivatives. The term "isotopic derivative" refers to a compound whose structure differs only in the presence of one or more isotopically enriched atoms. For example, a compound having a structure of the present disclosure, with "deuterium" or "tritium" replacing hydrogen, or with 18 F-fluorine labeling ( 18 F isotope) instead of fluorine, or with 11 C-, 13 C-or 14 C-enriched carbon ( 11 C-, 13 C-or 14 C-carbon labeling; 11 C-, 13 C-or 14 Compounds in which a carbon atom is replaced by a C-isotope) are within the scope of the present disclosure. Such compounds can be used as analytical tools or probes in biological assays, for example, or can be used as in vivo diagnostic imaging tracers for diseases, or as tracers for pharmacodynamics, pharmacokinetics or receptor studies. The deuterated form of the compound is that each available hydrogen atom connected to the carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize deuterated forms of compounds with reference to relevant literature. Commercially available deuterated starting materials can be used when preparing deuterated forms of compounds, or they can be synthesized using deuterated reagents using conventional techniques, and deuterated reagents include but are not limited to deuterated borane, trideuterated borane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated iodoethane and deuterated iodomethane, etc. Deuterated substances can generally retain activity comparable to undeuterated compounds, and when deuterated at certain specific sites, better metabolic stability can be achieved, thereby obtaining certain therapeutic advantages.

[0370] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0371] "Substituted" means that one or more hydrogen atoms, preferably 1 to 5, more preferably 1 to 3 hydrogen atoms in the group are replaced independently by a corresponding number of substituents. Those skilled in the art can determine possible or impossible substitutions (by experiment or theory) without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0372] "Pharmaceutical composition" means a mixture containing one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

[0373] "Pharmaceutically acceptable salts" refer to salts of the disclosed compounds that are safe and effective for use in mammals and have the desired biological activity. Salts can be prepared separately during the final isolation and purification of the compounds, or by reacting a suitable group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids and organic acids.

[0374] As used herein, unless otherwise indicated, the term "prevention" refers to the use of compounds provided herein with or without other active compounds for treatment or administration to patients, especially those at risk for cancer and / or other conditions described herein, before the onset of symptoms. The term "prevention" includes the suppression or alleviation of the symptoms of a particular disease. In certain embodiments, patients with a family history of the disease are particularly candidates for preventive regimens. In addition, patients with a history of symptom recurrence are also potential candidates for prevention. In this regard, the term "prevention" can be used interchangeably with the term "preventive treatment".

[0375] With respect to a drug or pharmacologically active agent, the term "therapeutically effective amount" refers to a sufficient amount of the drug or agent that is non-toxic but can achieve the desired effect. The determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the specific active substance. The appropriate effective amount in each case can be determined by a person skilled in the art based on routine experiments.

[0376] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with patient tissues without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio, and effective for the intended use.

[0377] As used herein, the singular form of "a," "an," and "the" include plural references and vice versa unless the context clearly dictates otherwise.

[0378] When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As will be understood by those skilled in the art, when a parameter is not critical, numbers are generally given only for illustrative purposes and not for limitation.

[0379] Synthesis method of the disclosed compound

[0380] In order to achieve the purpose of this disclosure, this disclosure adopts the following technical solutions:

[0381] Solution 1

[0382] The method for preparing the compound represented by the general formula (I) of the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, comprises the following steps:

[0383]

[0384] The compound of general formula (IA) and the compound of general formula (IB) react under alkaline conditions to obtain a compound of general formula (I),

[0385] in:

[0386] Ring A, Ring B, Y, R 1 To R 6 , n, p, q and t are as defined in the general formula (I).

[0387] Solution 2

[0388] The method for preparing the compound represented by the general formula (I) of the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, comprises the following steps:

[0389]

[0390] The compound of general formula (IA) reacts with the compound of general formula (ID) under alkaline conditions to obtain a compound of general formula (IC),

[0391] The compound of general formula (IC) undergoes an intramolecular ring-closing reaction under acidic conditions to obtain a compound of general formula (I).

[0392] in:

[0393] R m C 1-6 Alkyl; preferably tert-butyl;

[0394] Ring A, Ring B, Y, R 1 To R 6 , n, p, q and t are as defined in the general formula (I).

[0395] Option 3

[0396] The present invention discloses a method for preparing a compound represented by general formula (I-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0397]

[0398] The compound of general formula (IA) and the compound of general formula (I-1D) react under alkaline conditions to obtain a compound of general formula (I-1C),

[0399] The compound of general formula (I-1C) undergoes an intramolecular ring-closing reaction under acidic conditions to obtain a compound of general formula (I-1),

[0400] in:

[0401] R m C 1-6 Alkyl; preferably tert-butyl;

[0402] Ring A, Ring B, Y, R 1 To R 6 , n, p, q and t are as defined in the general formula (I-1).

[0403] Option 4

[0404] The present invention discloses a method for preparing a compound represented by general formula (I-2) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0405]

[0406] The compound of general formula (I) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof is prepared by chiral resolution to obtain a single configuration compound represented by general formula (I-2), or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof;

[0407] in:

[0408] R m C 1-6 Alkyl; preferably tert-butyl;

[0409] Ring A, Ring B, Y, R 1 To R 6 , n, p, q and t are as defined in the general formula (I).

[0410] Option 5

[0411] The method for preparing the compound represented by the general formula (II) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, comprises the following steps:

[0412]

[0413] The compound of general formula (IIA) and the compound of general formula (IB) react under alkaline conditions to obtain a compound of general formula (II),

[0414] in:

[0415] Ring A, Ring B, Y, R 1 To R 4 , n, p and t are as defined in the general formula (II).

[0416] Option 6

[0417] The method for preparing the compound represented by the general formula (II) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, comprises the following steps:

[0418]

[0419] The compound of general formula (IIA) and the compound of general formula (ID) react under alkaline conditions to obtain a compound of general formula (IIC),

[0420] The compound of general formula (IIC) undergoes an intramolecular ring-closing reaction under acidic conditions to obtain a compound of general formula (II).

[0421] in:

[0422] R m C 1-6 Alkyl; preferably tert-butyl;

[0423] Ring A, Ring B, Y, R 1 To R 4 , n, p and t are as defined in the general formula (II).

[0424] Option 7

[0425] The present invention discloses a method for preparing a compound represented by general formula (II-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0426]

[0427] The compound of general formula (IIA) and the compound of general formula (I-1D) react under alkaline conditions to obtain a compound of general formula (II-1C),

[0428] The compound of general formula (II-1C) undergoes an intramolecular ring-closing reaction under acidic conditions to obtain a compound of general formula (II-1),

[0429] in:

[0430] R m C 1-6 Alkyl; preferably tert-butyl;

[0431] Ring A, Ring B, Y, R 1 To R 4 , n, p and t are as defined in the general formula (II-1).

[0432] Option 8

[0433] The present invention discloses a method for preparing a compound represented by general formula (II-2) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0434]

[0435] The compound of general formula (II) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof is prepared 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 pharmaceutically acceptable salt thereof;

[0436] in:

[0437] Rm C 1-6 Alkyl; preferably tert-butyl;

[0438] Ring A, Ring B, Y, R 1 To R 4 , n, p and t are as defined in the general formula (II).

[0439] Option 9

[0440] The method for preparing the compound represented by the general formula (IIG) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, comprises the following steps:

[0441]

[0442] The compound of general formula (IIGA) reacts with the compound of general formula (IB) under alkaline conditions to obtain a compound of general formula (IIG),

[0443] in:

[0444] G 1 , G 2 , G 3 , Y, R 1 To R 3 , R 4a , R 4b , J, k, n, p and r are as defined in Formula (IIG).

[0445] Plan 10

[0446] The method for preparing the compound represented by the general formula (IIG) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, comprises the following steps:

[0447]

[0448] The compound of general formula (IIGC) undergoes an intramolecular ring-closing reaction under acidic conditions to obtain a compound of general formula (IIG).

[0449] in:

[0450] R m C 1-6 Alkyl; preferably tert-butyl;

[0451] G 1 , G 2 , G 3 , Y, R 1 To R 3 , R 4a , R4b , J, k, n, p and r are as defined in Formula (IIG).

[0452] Plan 11

[0453] The present invention discloses a method for preparing a compound represented by general formula (IIG-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0454]

[0455] The compound of general formula (IIGC-1) undergoes an intramolecular ring-closing reaction under acidic conditions to obtain a compound of general formula (IIG-1).

[0456] in:

[0457] R m C 1-6 Alkyl; preferably tert-butyl;

[0458] G 1 , G 2 , G 3 , Y, R 1 To R 3 , R 4a , R 4b , J, k, n, p and r are as defined in the general formula (IIG-1).

[0459] Plan 12

[0460] The present invention discloses a method for preparing a compound represented by the general formula (IIG-2) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0461]

[0462] The compound of the general formula (IIG) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt is prepared by chiral resolution to obtain a single configuration compound represented by the general formula (IIG-2), or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt;

[0463] in:

[0464] R m C 1-6 Alkyl; preferably tert-butyl;

[0465] G 1 , G 2, G 3 , Y, R 1 To R 3 , R 4a , R 4b , J, k, n, p and r are as defined in Formula (IIG).

[0466] Plan 13

[0467] The present invention discloses a method for preparing a compound represented by general formula (III) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0468]

[0469] The compound of general formula (IIIA) reacts with the compound of general formula (IB) under alkaline conditions to obtain a compound of general formula (III),

[0470] in:

[0471] Y, R 1 To R 3 , R 4a , R 4b , n, p and r are as defined in the general formula (III).

[0472] Scheme 14

[0473] The method for preparing the compound represented by the general formula (III) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, comprises the following steps:

[0474]

[0475] The compound of general formula (IIIA) and the compound of general formula (ID) react under alkaline conditions to obtain a compound of general formula (IIIC),

[0476] The compound of general formula (IIIC) undergoes an intramolecular ring-closing reaction under acidic conditions to obtain a compound of general formula (III),

[0477] in:

[0478] R m C 1-6 Alkyl; preferably tert-butyl;

[0479] Y, R 1 To R 3 , R 4a , R 4b , n, p and r are as defined in the general formula (III).

[0480] Plan 15

[0481] The present invention discloses a method for preparing a compound represented by general formula (III-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0482]

[0483] The compound of general formula (IIIA) and the compound of general formula (I-1D) react under alkaline conditions to obtain a compound of general formula (III-1C),

[0484] The compound of general formula (III-1C) undergoes an intramolecular ring-closing reaction under acidic conditions to obtain a compound of general formula (III-1),

[0485] in:

[0486] R m C 1-6 Alkyl; preferably tert-butyl;

[0487] Y, R 1 To R 3 , R 4a , R 4b , n, p and r are as defined in the general formula (III-1).

[0488] Scheme 16

[0489] The present invention discloses a method for preparing a compound represented by general formula (III-2) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0490]

[0491] The compound of general formula (III) or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof is prepared 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 pharmaceutically acceptable salt thereof;

[0492] in:

[0493] R m C 1-6 Alkyl; preferably tert-butyl;

[0494] Y, R 1 To R 3 , R4a , R 4b , n, p and r are as defined in the general formula (III).

[0495] The reagents providing alkaline conditions in the above synthesis scheme include organic bases and inorganic bases, the organic bases include but are not limited to: triethylamine, N,N-diisopropylethylamine, n-butyl lithium, 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; preferably potassium carbonate.

[0496] The reagents providing acidic conditions in the above synthesis scheme 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.

[0497] The above reaction is preferably carried out in a solvent, and the solvent used includes but is 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 DESCRIPTION OF THE DRAWINGS

[0498] Figure 1 : The efficacy data of the compound of Example 6 and the control example CC-92480 on NCI-H929 transplanted tumors in CB-17SCID mice.

[0499] Figure 2 : Effects of the compound of Example 6 and the control example CC-92480 on the body weight of CB-17 SCID mice. DETAILED DESCRIPTION

[0500] The following embodiments are used to further describe the present disclosure, but these embodiments are not intended to limit the scope of the present disclosure.

[0501] Example

[0502] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10 -6 The unit of (ppm) is given. NMR measurements were performed using a Bruker AVANCE-400 nuclear magnetic spectrometer or a Bruker AVANCENEO 500M, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD) as the measurement solvent, and tetramethylsilane (TMS) as the internal standard.

[0503] MS was measured using Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS LC / 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 THERMOUltimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0504] High performance liquid chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC1200VWD and Waters HPLC e2695-2489.

[0505] Chiral HPLC analysis was performed using an Agilent 1260 DAD high performance liquid chromatograph.

[0506] High performance liquid chromatography was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.

[0507] Chiral preparations were performed using a Shimadzu LC-20AP preparative chromatograph.

[0508] The CombiFlash rapid preparation instrument used Combiflash Rf200 (TELEDYNE ISCO).

[0509] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15mm-0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm.

[0510] Silica gel column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier.

[0511] Average kinase inhibition rate and IC 50 The values ​​were determined using NovoStar microplate reader (BMG, Germany).

[0512] The known starting materials disclosed herein can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, AccelaChemBio Inc, Shanghai Bid Pharmaceuticals, Darui Chemicals and other companies.

[0513] Unless otherwise specified in the examples, the reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0514] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1L.

[0515] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

[0516] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or a HC2-SS hydrogenator.

[0517] The hydrogenation reaction is usually carried out by evacuating the vacuum, filling with hydrogen, and repeating the operation three times.

[0518] The microwave reaction was carried out using a CEM Discover-S 908860 microwave reactor.

[0519] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0520] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0521] The reaction progress in the embodiment is monitored by thin layer chromatography (TLC), and the developing solvent used in the reaction, the eluent system of column chromatography used for purifying the compound and the developing solvent system of thin layer chromatography include: A: dichloromethane / methanol system; B: n-hexane / ethyl acetate system. The volume ratio of the solvent is adjusted according to the polarity of the compound, and can also be adjusted by adding a small amount of alkaline or acidic reagents such as triethylamine and acetic acid.

[0522] Example 1

[0523] 4-(4-((4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)phenyl)thio)piperidin-1-yl)-3-fluorobenzonitrile 1

[0524]

[0525] first step

[0526] tert-Butyl 4-((4-Formylphenyl)thio)piperidine-1-carboxylate 1b

[0527] 4-mercaptopiperidine-1-carboxylic acid tert-butyl ester 1a (2.05 g, 9.44 mmol, Bidex Pharmaceuticals), 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 solution was heated to 120°C and reacted overnight. After the reaction was completed, the reaction solution was diluted with water (200 mL), then extracted with ethyl acetate (100 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (100 mL), the organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with eluent system B to obtain the title compound 1b (2.66 g, yield: 88%).

[0528] MS m / z(ESI):266.1[M-55].

[0529] Step 2

[0530] 4-(Piperidin-4-ylthio)benzaldehyde hydrochloride 1c

[0531] Compound 1b (2.66 g, 8.28 mmol) was dissolved in 4M hydrogen chloride solution of 1,4-dioxane (20 mL) and stirred for about 3 hours. The reaction solution was filtered, and the filter cake was rinsed with ethyl acetate (3 mL × 3) and dried naturally to obtain the title compound 1c. The crude product was directly used for the next step.

[0532] MS m / z(ESI):221.8[M+1].

[0533] Step 3

[0534] 3-Fluoro-4-(4-((4-formylphenyl)thio)piperidin-1-yl)benzonitrile 1d

[0535] Compound 1c (1.89 g, 7.33 mmol), 3,4-difluorobenzonitrile (1.07 g, 7.70 mmol, Bidex Pharmaceuticals) and potassium carbonate (4.05 g, 29.33 mmol) were added to N,N-dimethylacetamide (15 mL), and the reaction solution was heated to 120°C for overnight reaction. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL×3). The organic phases were combined and washed with saturated sodium chloride solution (50 mL×3). The organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography with eluent system B to obtain the title compound 1d (2.2 g, yield: 93%).

[0536] MS m / z(ESI):341.0[M+1].

[0537] Step 4

[0538] 3-Fluoro-4-(4-((4-(hydroxymethyl)phenyl)thio)piperidin-1-yl)benzonitrile 1e

[0539] Compound 1d (150 mg, 0.44 mmol) was added to methanol (8 mL) under ice bath, potassium borohydride (29 mg, 0.53 mmol) was added, and the mixture was reacted under ice bath for 2 hours. The reaction solution was diluted with water (20 mL), and then extracted with ethyl acetate (30 mL×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 with eluent system B to obtain the title compound 1e (150 mg, yield: 99%).

[0540] MS m / z(ESI):343.1[M+1].

[0541] Step 5

[0542] 4-(4-((4-(Bromomethyl)phenyl)thio)piperidin-1-yl)-3-fluorobenzonitrile 1f

[0543] Under ice bath, compound 1e (150 mg, 0.43 mmol) was added to dichloromethane (8 mL), triphenylphosphine (150 mg, 0.57 mmol) and carbon tetrabromide (189 mg, 0.57 mmol) were added in sequence, and the mixture was reacted under ice bath for 20 minutes, and then warmed to room temperature for 2 hours. The reaction solution was concentrated, and the residue was purified by column chromatography with eluent system B to obtain the title compound 1f (120 mg, yield: 68%).

[0544] MS m / z(ESI): 405.0[M+1]; 407.0[M+3].

[0545] Step 6

[0546] 4-(4-((4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)phenyl)thio)piperidin-1-yl)-3-fluorobenzonitrile 1

[0547] 1 g of 3-(4-hydroxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione (25 mg, 0.096 mmol, Jiangsu Aikang Biopharmaceutical Research and Development Co., Ltd.) 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, and the reaction was carried out for 16 hours. After filtering the reaction solution, it was subjected to high performance liquid chromatography preparation (Waters 2767-SQ Detecor 2, elution system: 10 mmol / L aqueous solution of ammonium bicarbonate and acetonitrile, acetonitrile gradient: 55%-70%, flow rate: 30 mL / min) to obtain the title compound 1 (16 mg, yield 28%).

[0548] MS m / z(ESI):585.1[M+1].

[0549] 1 H NMR (400MHz, 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).

[0550] Example 2

[0551] 4-(4-((4-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)methyl)phenyl)thio)piperidin-1-yl)-3-fluorobenzonitrile 2

[0552]

[0553] 2-(2,6-Dioxopiperidin-3-yl)-4-hydroxyisoindoline-1,3-dione 2a (30 mg, 0.113 mmol, Bidex Pharmaceuticals) and anhydrous potassium carbonate (21 mg, 0.152 mmol) were added to N,N-dimethylacetamide (3 mL), and compound 1f (30 mg, 0.074 mmol) was added. The reaction was allowed to react for 16 hours. The reaction solution was filtered and purified by high performance liquid chromatography (Waters 2767-SQDetecor2, elution system: 10 mmol / L aqueous solution of ammonium bicarbonate and acetonitrile, acetonitrile gradient: 55%-75%, flow rate: 30 mL / min) to obtain the title compound 2 (30 mg, yield 68%).

[0554] MS m / z(ESI):599.1[M+1].

[0555] 1 H NMR (500MHz, 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).

[0556] Example 3

[0557] (S)-4-(4-((4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)phenyl)thio)piperidin-1-yl)-3-fluorobenzonitrile 3

[0558]

[0559] first step

[0560] (S)-tert-Butyl 5-amino-4-(4-((4-((1-(4-cyano-2-fluorophenyl)piperidin-4-yl)thio)benzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate 3b

[0561] (S)-5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoic acid tert-butyl ester 3a (318 mg, 0.951 mmol, prepared by the 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), and compound 1f (350 mg, 0.863 mmol) was added and reacted for 16 hours. The reaction solution was poured into ice water (20 mL), then extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (20 mL × 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 the title compound 3b (500 mg, yield: 88%).

[0562] MS m / z(ESI):659.2[M+1].

[0563] Step 2

[0564] (S)-4-(4-((4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)phenyl)thio)piperidin-1-yl)-3-fluorobenzonitrile 3

[0565] Compound 3b (500 mg, 0.758 mmol) was added to acetonitrile (30 mL), p-toluenesulfonic acid monohydrate (187 mg, 0.983 mmol) was added, and the mixture was stirred at 85°C for 10 hours. The reaction solution was decompressed to remove the solvent, water (20 mL) was added, and then extracted with ethyl acetate (30 mL×3). The organic phases were combined, washed with saturated sodium bicarbonate solution (20 mL) and saturated sodium chloride solution (20 mL) in sequence, and then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was prepared by high performance liquid chromatography (Waters 2767-SQ Detecor 2, elution system: 10 mmol / L ammonium bicarbonate aqueous solution 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% (chromatographic 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)).

[0566] MS m / z(ESI):585.2[M+1].

[0567] 1 H NMR (500MHz, 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).

[0568] Example 4

[0569] (S)-4-(4-((4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)-2-fluorophenyl)thio)piperidin-1-yl)-3-fluorobenzonitrile

[0570]

[0571]

[0572] first step

[0573] tert-Butyl 4-((2-fluoro-4-formylphenyl)thio)piperidine-1-carboxylate 4b

[0574] 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 solution was heated to 80°C for 2 hours. The reaction solution was diluted with water (200 mL), then extracted with ethyl acetate (100 mL×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 with eluent system B to obtain the title compound 4b (920 mg, yield: 98%).

[0575] MS m / z(ESI):283.9[M-55].

[0576] Step 2

[0577] 3-Fluoro-4-(piperidin-4-ylthio)benzaldehyde trifluoroacetate 4c

[0578] Compound 4b (920 mg, 2.71 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (2 mL) was slowly added under ice bath, and the reaction was continued for 1 hour. The reaction solution was concentrated and dried to obtain the title compound 4c, and the crude product was directly used in the next step without purification.

[0579] MS m / z(ESI):239.9[M+1].

[0580] Step 3

[0581] 3-Fluoro-4-(4-((2-fluoro-4-formylphenyl)thio)piperidin-1-yl)benzonitrile 4d

[0582] Compound 4c (960 mg, 2.72 mmol), 3,4-difluorobenzonitrile (756 mg, 5.43 mmol, Bidex Pharmaceuticals) and potassium carbonate (1.50 g, 10.86 mmol) were added to N,N-dimethylformamide (12 mL), and the reaction solution was heated to 80°C for overnight reaction. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography with eluent system B to obtain the title compound 4d (890 mg, yield: 91%).

[0583] MS m / z(ESI):358.9[M+1].

[0584] Step 4

[0585] 3-Fluoro-4-(4-((2-fluoro-4-(hydroxymethyl)phenyl)thio)piperidin-1-yl)benzonitrile 4e

[0586] Compound 4d (260 mg, 0.725 mmol) was added to methanol (8 mL) under ice bath, sodium borohydride (55 mg, 1.45 mmol) was added, and the reaction was stirred under ice bath for 1 hour. The reaction solution was quenched with saturated ammonium chloride solution (10 mL), then extracted with ethyl acetate (30 mL×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 with eluent system B to give the title compound 4e (250 mg, yield: 96%).

[0587] MS m / z(ESI):360.9[M+1].

[0588] Step 5

[0589] 4-(4-((4-(bromomethyl)-2-fluorophenyl)thio)piperidin-1-yl)-3-fluorobenzonitrile 4f

[0590] Compound 4e (250 mg, 0.694 mmol) was added to dichloromethane (5 mL), followed by triphenylphosphine (237 mg, 0.901 mmol) and carbon tetrabromide (299 mg, 0.901 mmol), and the mixture was reacted for 1 hour. The reaction solution was concentrated, and the residue was purified by column chromatography using eluent system B to obtain the title compound 4f (130 mg, yield: 44%).

[0591] MS m / z(ESI): 423.0[M+1]; 425.0[M+3].

[0592] Step 6

[0593] (S)-5-amino-4-(4-((4-((1-(4-cyano-2-fluorophenyl)piperidin-4-yl)thio)-3-fluorobenzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoic acid tert-butyl ester 4g

[0594] Compound 3a (56 mg, 0.169 mmol) and anhydrous potassium carbonate (42 mg, 0.307 mmol) were added to N, N-dimethylformamide (3 mL), and compound 4f (65 mg, 0.153 mmol) was added to react for 1 hour. The reaction solution was poured into ice water (20 mL), then extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (20 mL × 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 the title compound 4g (95 mg, yield: 91%).

[0595] MS m / z(ESI):677.0[M+1].

[0596] Step 7

[0597] (S)-4-(4-((4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)-2-fluorophenyl)thio)piperidin-1-yl)-3-fluorobenzonitrile

[0598] Compound 4g (50 mg, 0.074 mmol) was added to acetonitrile (6 mL), and benzenesulfonic acid (17 mg, 0.096 mmol) was added at room temperature, and the mixture was reacted at 80°C for 12 hours. The solvent was removed from the reaction solution under reduced pressure, and the residue was subjected to high performance liquid chromatography (Waters 2767-SQ Detecor 2, elution system: 1 / 1000 volume of trifluoroacetic acid aqueous solution and acetonitrile, acetonitrile gradient: 50%-67%, flow rate: 30 mL / min) to obtain the title compound 4 (13 mg, yield: 29%).

[0599] MS m / z(ESI):603.2[M+1].

[0600] 1 H NMR (500MHz, DMSO-d6) δ10.99 (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),

[0601] 2.46-2.41 (m, 1H), 2.03-1.96 (m, 3H), 1.67-1.57 (m, 2H).

[0602] Example 5

[0603] (S)-4-(4-((4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)-3-fluorophenyl)thio)piperidin-1-yl)-3-fluorobenzonitrile 5

[0604]

[0605] The synthetic route of compound 4 in Example 4 was adopted, wherein the raw material compound 3,4-difluorobenzaldehyde was replaced by the raw material compound 2,4-difluorobenzaldehyde, to prepare the title compound 5 (90 mg).

[0606] MS m / z(ESI):603.1[M+1].

[0607] 1 H NMR(500MHz,DMSO-d6)δ10.98(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,1 H),2.61-2.54(m,1H),2.46-2.41(m,1H),2.02-1.94(m,3H),1.70-1.59(m,2H).

[0608] Example 6

[0609] (S)-4-(4-((5-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)pyridin-2-yl)thio)piperidin-1-yl)-3-fluorobenzonitrile 6

[0610]

[0611]

[0612] first step

[0613] tert-Butyl 4-((5-formylpyridin-2-yl)thio)piperidine-1-carboxylate 6b

[0614] Compound 1a (700 mg, 3.22 mmol), 6-fluoropyridine-3-carboxaldehyde 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 solution was heated to 80°C for 1 hour. The reaction solution was diluted with water (30 mL), then extracted with ethyl acetate (40 mL×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 with eluent system B to obtain the title compound 6b (1.0 g, yield: 96%).

[0615] MS m / z(ESI):267.1[M-55].

[0616] Step 2

[0617] 6-(Piperidin-4-ylthio)nicotinaldehyde trifluoroacetate 6c

[0618] Compound 6b (950 mg, 2.95 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (2 mL) was slowly added under ice bath, and the reaction was carried out for 1 hour. The reaction solution was concentrated and dried to obtain the title compound 6c, and the crude product was directly used in the next step without purification.

[0619] MS m / z(ESI):223.1[M+1].

[0620] Step 3

[0621] 3-Fluoro-4-(4-(((5-formylpyridin-2-yl)thio)piperidin-1-yl)benzonitrile 6d

[0622] 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 solution was heated to 80°C for overnight reaction. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with eluent system B to obtain the title compound 6d (850 mg, yield: 84%).

[0623] MS m / z(ESI):342.1[M+1].

[0624] Step 4

[0625] 3-Fluoro-4-(4-((5-(hydroxymethyl)pyridin-2-yl)thio)piperidin-1-yl)benzonitrile 6e

[0626] Under ice bath, compound 6d (600 mg, 1.76 mmol) was added to methanol (10 mL), sodium borohydride (133 mg, 3.51 mmol) was slowly added, and the reaction was continued for 1 hour. The reaction solution was quenched with water (10 mL), and then extracted with ethyl acetate (30 mL×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 with eluent system B to obtain the title compound 6e (580 mg, yield: 96%).

[0627] MS m / z(ESI):344.1[M+1].

[0628] Step 5

[0629] 4-(4-((5-(Bromomethyl)pyridin-2-yl)thio)piperidin-1-yl)-3-fluorobenzonitrile 6f

[0630] Compound 6e (200 mg, 0.582 mmol) was added to dichloromethane (6 mL), followed by triphenylphosphine (199 mg, 0.757 mmol) and carbon tetrabromide (251 mg, 0.757 mmol), and the mixture was reacted for 2 hours. The reaction solution was concentrated, and the residue was purified by column chromatography using eluent system B to obtain the title compound 6f (190 mg, yield: 80%).

[0631] MS m / z(ESI): 406.0[M+1]; 408.0[M+3].

[0632] Step 6

[0633] (S)-5-amino-4-(4-((6-((1-(4-cyano-2-fluorophenyl)piperidin-4-yl)thio)pyridin-3-yl)methoxy)-1-oxoisoindolin-2-yl)-5-oxopentanoic acid tert-butyl ester 6 g

[0634] Compound 3a (82 mg, 0.246 mmol) and anhydrous potassium carbonate (65 mg, 0.468 mmol) were added to N, N-dimethylformamide (3 mL), and compound 6f (95 mg, 0.244 mmol) was added to react for 2 hours. The reaction solution was poured into ice water (10 mL), and then extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (20 mL × 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 the title compound 6g (145 mg, yield: 94%).

[0635] MS m / z(ESI):660.2[M+1].

[0636] Step 7

[0637] (S)-4-(4-((5-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)pyridin-2-yl)thio)piperidin-1-yl)-3-fluorobenzonitrile 6

[0638] Compound 6g (60 mg, 0.091 mmol) was added to acetonitrile (5 mL), and benzenesulfonic acid (16 mg, 0.091 mmol) was added at room temperature, and the mixture was reacted at 80°C for 8 hours. The solvent was removed from the reaction solution under reduced pressure, and the residue was subjected to high performance liquid chromatography (Gilson GX-281, elution system: 10 mmol / L aqueous solution of ammonium bicarbonate and acetonitrile, acetonitrile gradient: 60%-80%, flow rate: 30 mL / min) to obtain the title compound 6 (42 mg, yield: 78%).

[0639] MS m / z(ESI):586.4[M+1].

[0640] 1H NMR (500MHz, DMSO-d6): δ10.98(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).

[0641] Example 6

[0642] (R)-4-(4-((5-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)pyridin-2-yl)thio)piperidin-1-yl)-3-fluorobenzonitrile 6′

[0643]

[0644] Compound 6 (500 mg, 0.853 mmol) was dissolved in tetrahydrofuran (30 mL), and a saturated aqueous sodium carbonate solution (30 mL) was added. After the addition was completed, the mixture was stirred vigorously for 1.5 hours. The reaction solution was separated, and the organic phase was diluted with dichloromethane (120 mL), washed with a saturated ammonium chloride solution (20 mL) and a saturated sodium chloride solution (20 mL) in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of the title compound 6'a (chiral HPLC showed that the content of compound 6' was 42.8%).

[0645] The obtained crude product 6'a was subjected to chiral preparation (separation conditions: chiral preparation column CHIRALPAK IE 20*250 mm (Daicel); mobile phase: n-hexane and ethanol, ethanol gradient: 80%; flow rate: 20 mL / min), and the obtained preparation solution was concentrated under reduced pressure in a water bath at less than 20°C to obtain the title compound 6' (25 mg) with a yield of 5.0%.

[0646] MS m / z(ESI):586.1[M+1].

[0647] Chiral HPLC analysis: retention time 24.426 minutes, chiral purity: 100% (chromatographic column: CHIRALPAK IE150*4.6mm, 5um; mobile phase: n-hexane / ethanol = 20 / 80 (v / v))

[0648] 1 H NMR (500MHz, 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).

[0649] Example 7

[0650] (S)-4-(4-((5-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)pyrimidin-2-yl)thio)piperidin-1-yl)-3-fluorobenzonitrile 7

[0651]

[0652] The synthetic route of compound 4 in Example 4 was adopted, wherein the raw material compound 3,4-difluorobenzaldehyde was replaced by the raw material compound 2-chloropyrimidine-5-carboxaldehyde, to prepare the title compound 7 (38 mg).

[0653] MS m / z(ESI):587.2[M+1].

[0654] 1 H NMR (500MHz, DMSO-d6): δ10.97(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).

[0655] Example 8

[0656] (S)-4-(4-((5-(((2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)oxy)methyl)pyridin-2-yl)thio)piperidin-1-yl)-3-fluorobenzonitrile 8

[0657]

[0658] The synthetic route of compound 4 in Example 4 was adopted, wherein the raw material compound 3,4-difluorobenzaldehyde was replaced by the raw material compound 2-fluoropyridine-5-carboxaldehyde, and the compound 3a in step six was replaced by (S)-5-amino-4-(6-fluoro-4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoic acid tert-butyl ester (prepared by the method disclosed in Example 7 on page 99 of the specification of patent application WO2019040274A1), to obtain the title compound 8 (33 mg).

[0659] MS m / z(ESI):604.1[M+1].

[0660] 1 H NMR (500MHz, DMSO-d6): δ10.99(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).

[0661] Example 9

[0662] (S)-4-(4-((6-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)pyridin-3-yl)thio)piperidin-1-yl)-3-fluorobenzonitrile 9

[0663]

[0664] The synthetic route of compound 4 in Example 4 was adopted, wherein the starting compound 3,4-difluorobenzaldehyde was replaced by the starting compound 5-fluoropyridine-2-carboxaldehyde, to prepare the title compound 9 (45 mg).

[0665] MS m / z(ESI):586.3[M+1].

[0666] 1 H NMR (500MHz, DMSO-d6): δ10.99(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).

[0667] Example 10

[0668] (S)-4-(4-((4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)-2,3-difluorophenyl)thio)piperidin-1-yl)-3-fluorobenzonitrile 10

[0669]

[0670] The synthetic route of compound 4 in Example 4 was adopted, wherein the starting compound 3,4-difluorobenzaldehyde was replaced by the starting compound 2,3,4-trifluorobenzaldehyde, to prepare the title compound 10 (63 mg).

[0671] MS m / z(ESI):621.1[M+1].

[0672] 1 H NMR (500MHz, DMSO-d6): δ10.98(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),4.4 0(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).

[0673] Embodiment 11

[0674] (S)-4-(4-((4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)-2,5-difluorophenyl)thio)piperidin-1-yl)-3-fluorobenzonitrile 11

[0675]

[0676] The synthetic route of compound 4 in Example 4 was adopted, wherein the starting compound 3,4-difluorobenzaldehyde was replaced by the starting compound 2,4,5-trifluorobenzaldehyde, to prepare the title compound 11 (70 mg).

[0677] MS m / z(ESI):621.1[M+1].

[0678] 1 H NMR (500MHz, DMSO-d6): δ10.98(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,1 H),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).

[0679] Example 12

[0680] (S)-4-(4-((4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)-2,6-difluorophenyl)thio)piperidin-1-yl)-3-fluorobenzonitrile 12

[0681]

[0682] The synthetic route of compound 4 in Example 4 was adopted, wherein the starting compound 3,4-difluorobenzaldehyde was replaced by the starting compound 3,4,5-trifluorobenzaldehyde, to prepare the title compound 12 (20 mg).

[0683] MS m / z(ESI):621.1[M+1].

[0684] 1H NMR (500MHz, DMSO-d6): δ10.99(s,1H),7.67(dd,1H),7.54(dd,1H),7.50(t,1 H),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).

[0685] Example 13

[0686] (S)-4-(4-((5-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)-6-methylpyridin-2-yl)thio)piperidin-1-yl)-3-fluorobenzonitrile 13

[0687]

[0688] The synthetic route of compound 4 in Example 4 was adopted, wherein the starting compound 3,4-difluorobenzaldehyde was replaced by the starting compound 6-fluoro-2-methyl-3-pyridinecarboxaldehyde, to prepare the title compound 13 (60 mg).

[0689] MS m / z(ESI):600.2[M+1].

[0690] 1 H NMR (500MHz, DMSO-d6): δ10.97(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).

[0691] Embodiment 14

[0692] (S)-4-(4-((2-chloro-4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)phenyl)thio)piperidin-1-yl)-3-fluorobenzonitrile 14

[0693]

[0694] The synthetic route of compound 4 in Example 4 was adopted, wherein the starting compound 3,4-difluorobenzaldehyde was replaced by the starting compound 3-chloro-4-fluorobenzaldehyde, to prepare the title compound 14 (22 mg).

[0695] MS m / z(ESI):618.9[M+1].

[0696] 1 H NMR (500MHz, DMSO-d6): δ10.98(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),4.4 3(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).

[0697] Embodiment 15

[0698] 4-(3-((5-(((2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)pyridin-2-yl)thio)pyrrolidin-1-yl)-3-fluorobenzonitrile 15

[0699]

[0700] The synthetic route of compound 4 in Example 4 was adopted, wherein the raw material compound 1a (tert-butyl 4-mercaptopiperidine-1-carboxylate) was replaced by tert-butyl 3-mercaptopyrrolidine-1-carboxylate, and the raw material compound 3,4-difluorobenzaldehyde was replaced by the raw material compound 2-fluoropyridine-5-carboxaldehyde, to obtain the title compound 15 (39 mg).

[0701] MS m / z(ESI):572.3[M+1].

[0702] 1H NMR (500MHz, DMSO-d6): δ10.97(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).

[0703] Example 16

[0704] (S)-4-(3-((4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)phenyl)thio)azetidin-1-yl)-3-fluorobenzonitrile 16

[0705]

[0706] The synthetic route of compound 4 in Example 4 was adopted, wherein the raw material compound 1a (tert-butyl 4-mercaptopiperidine-1-carboxylate) was replaced by tert-butyl 3-mercaptoazetidine-1-carboxylate, and the raw material compound 3,4-difluorobenzaldehyde was replaced by the raw material compound 4-fluorobenzaldehyde, to obtain the title compound 16 (15 mg).

[0707] MS m / z(ESI):557.0[M+1].

[0708] 1 H NMR (500MHz, DMSO-d6): δ10.97(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).

[0709] Embodiment 17

[0710] (S)-4-(4-((5-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)-6-fluoropyridin-2-yl)thio)piperidin-1-yl)-3-fluorobenzonitrile 17

[0711]

[0712]

[0713] first step

[0714] tert-Butyl 4-((6-fluoro-5-formylpyridin-2-yl)thio)piperidine-1-carboxylate 17b

[0715] Compound 1a (1.5 g, 6.90 mmol), 2,6-difluoropyridine-3-carboxaldehyde 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 solution was diluted with water (200 mL), then extracted with ethyl acetate (100 mL×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 with eluent system B to obtain the title compound 17b (1.0 g, yield 42%).

[0716] MS m / z(ESI):285.0[M-55].

[0717] Step 2

[0718] Tert-butyl 4-((6-fluoro-5-(hydroxymethyl)pyridin-2-yl)thio)piperidine-1-carboxylate 17c

[0719] 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 slowly added under ice bath, and the reaction was continued for 2 hours. The reaction solution was quenched with water (50 mL), and then extracted with ethyl acetate (30 mL×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 with eluent system B to obtain the title compound 17c (910 mg, yield 90%).

[0720] MS m / z(ESI):287.0[M-55].

[0721] Step 3

[0722] (2-Fluoro-6-(piperidin-4-ylthio)pyridin-3-yl)methanol hydrochloride 17d

[0723] Compound 17c (910 mg, 2.66 mmol) was dissolved in dichloromethane (10 mL), and 4M hydrogen chloride solution in 1,4-dioxane (3 mL, 12 mmol) was added and reacted for 1 hour. The reaction solution was concentrated and dried to obtain the title compound 17d (625 mg), which was directly used in the next step.

[0724] MS m / z(ESI):243.1[M+1].

[0725] Step 4

[0726] 3-Fluoro-4-(4-((6-fluoro-5-(hydroxymethyl)pyridin-2-yl)thio)piperidin-1-yl)benzonitrile 17e

[0727] Compound 17d (625 mg, 2.24 mmol) was added to N,N-dimethylformamide (20 mL), 3,4-difluorobenzonitrile (312 mg, 2.24 mmol) and potassium carbonate (930 mg, 6.73 mmol) were added, and the reaction solution was heated to 80°C for 2 hours. The reaction solution was diluted with water (100 mL), extracted with ethyl acetate (100 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography with eluent system B to obtain the title compound 17e (400 mg, yield 50%).

[0728] MS m / z(ESI):362.0[M+1].

[0729] Step 5

[0730] 4-(4-((5-(bromomethyl)-6-fluoropyridin-2-yl)thio)piperidin-1-yl)-3-fluorobenzonitrile 17f

[0731] Compound 17e (310 mg, 0.86 mmol) was added to dichloromethane (10 mL), and triphenylphosphine (360 mg, 1.37 mmol) and carbon tetrabromide (455 mg, 1.37 mmol) were added, and the reaction was continued for 12 hours. The reaction solution was diluted with water (50 mL), extracted with dichloromethane (30 mL×3), and 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 with eluent system B to obtain the title compound 17f (340 mg, yield 93%).

[0732] MS m / z(ESI):423.9[M+1].

[0733] Step 6

[0734] (S)-5-amino-4-(4-((6-((1-(4-cyano-2-fluorophenyl)piperidin-4-yl)thio)-2-fluoropyridin-3-yl)methoxy)-1-oxoisoindolin-2-yl)-5-oxopentanoic acid tert-butyl ester 17g

[0735] Compound 3a (268 mg, 0.80 mmol) and anhydrous potassium carbonate (223 mg, 1.61 mmol) were added to N, N-dimethylformamide (10 mL), and compound 17f (340 mg, 0.80 mmol) was added to react for 1 hour. The reaction solution was poured into ice water (20 mL), and then extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (20 mL × 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 the title compound 17g (540 mg, yield: 99%).

[0736] MS m / z(ESI):678.2[M+1].

[0737] Step 7

[0738] (S)-4-(4-((5-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)-6-fluoropyridin-2-yl)thio)piperidin-1-yl)-3-fluorobenzonitrile 17

[0739] Compound 17g (540 mg, 0.80 mmol) was added to acetonitrile (20 mL), and benzenesulfonic acid (252 mg, 1.59 mmol) was added at room temperature, and the mixture was reacted at 80°C for 12 hours. The solvent was removed from the reaction solution under reduced pressure, and the residue was subjected to high performance liquid chromatography (Waters 2545-SQ Detecor 2, elution system: 10 mmol / L aqueous solution of ammonium bicarbonate and acetonitrile, acetonitrile gradient: 53%-95%, flow rate: 30 ml / min) to give the title compound 4 (270 mg, yield: 56%).

[0740] MS m / z(ESI):604.0[M+1].

[0741] 1H NMR(500MHz,DMSO-d6)δ10.98(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,1 H),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).

[0742] Embodiment 18

[0743] (S)-4-(4-((4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)-3,5-difluorophenyl)thio)piperidin-1-yl)-3-fluorobenzonitrile 18

[0744]

[0745] The synthetic route of compound 17 in Example 17 was adopted to prepare the title compound 18 (27 mg) by replacing the raw material compound 2,6-difluoropyridine-3-carboxaldehyde with the raw material compound 2,4,6-trifluorobenzaldehyde.

[0746] MS m / z(ESI):621.0[M+1].

[0747] 1 H NMR (500MHz, DMSO-d6): δ10.95(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).

[0748] Biological evaluation

[0749] Test Example 1 Biological Evaluation of NCI-H929 Proliferation Experiment

[0750] The following method is used to determine the inhibitory activity of the disclosed compounds on the proliferation of NCI-H929 cells. The experimental method is briefly described as follows.

[0751] NCI-H929 cells (ATCC, CRL-9068) were cultured with 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 seeded in a 96-well plate at a density of 6000 cells / well using complete medium, with 100 μL of cell suspension per well, and 10 μL of the compound to be tested prepared in complete medium was added to each well. The compound was first dissolved in DMSO, with an initial concentration of 10 mM, and a 5-fold concentration gradient was continuously diluted, with a total of 9 concentration points, and the blank control was 100% DMSO. Then 5 μL of the compound dissolved in DMSO was added to 95 μL of complete medium, i.e., the compound was diluted 20 times with complete medium. Finally, 10 μL of the compound diluted in complete medium was added to the cell suspension, i.e., the final concentration of the compound was 9 concentration points with a 5-fold gradient dilution starting from 50 μM, and a blank control containing 0.5% DMSO was set up. The cells were placed in a 37°C, 5% CO2 cell culture incubator and incubated for 5 days. On the sixth day, the 96-well cell culture plate was taken out and 50 μL of The luminescent cell activity detection reagent (Promega, G7573) was placed at room temperature for 10 minutes, and the luminescent signal value was read using a multi-function microplate reader (PerkinElmer, EnVision2015). The IC value of the inhibitory activity of the compound was calculated using Graphpad Prism software. 50 See Table 1 for values.

[0752] Table 1 IC of the compounds disclosed herein for inhibiting proliferation of NCI-H929 cells 50 value

[0753] Compound <![CDATA[IC 50 (nM)]]> 1 0.34 2 4.36 3 0.10 4 0.17 5 0.08 6 0.02 7 0.13 8 0.28 9 0.90 10 0.18 11 0.22 12 0.61 13 1.78 14 0.27 15 0.75 16 1.13 17 0.21 18 0.34

[0754] Conclusion: The disclosed compounds have good activity in inhibiting the proliferation of NCI-H929 cells.

[0755] Test Example 2: Drug Efficacy Test

[0756] 1. Purpose of the experiment

[0757] The effects of the compound of Example 6 and the control example CC-92480 on inhibiting the growth of human multiple myeloma cell NCI-H929 xenografts in CB-17 SCID mice were evaluated.

[0758] 2. Experimental drugs

[0759] Example 6 compound;

[0760] Comparative Example CC-92480 (see compound 2 in WO2019014100A1, synthesized according to the method disclosed therein)

[0761]

[0762] The compound of Example 6 and the control example CC-92480 were formulated with 5% DMSO + 20% PEG400 + 70% (10% TPGS) + 5% (1% HPMC K100LV).

[0763] 3. Experimental methods and materials

[0764] 3.1 Experimental animals and housing conditions

[0765] Thirty CB-17 SCID female mice were purchased from Beijing Weitong Lihua Experimental Animal Co., Ltd. (certificate number: 20170011006049, SCXK (Shanghai) 2017-0011). They weighed about 19 g when purchased and were raised 5 mice / cage with a 12 / 12 h light / dark cycle, a constant temperature of 23 ± 1 °C, and a humidity of 50-60%. They had free access to food and water.

[0766] 3.2 Animal Grouping:

[0767] After adaptive feeding, CB-17 SCID mice were divided into the following groups:

[0768]

[0769] Note: qd means administration once a day; ig means administration by intragastric administration.

[0770] 3.3 Experimental methods:

[0771] 5×10 NCI-H929 cells in the logarithmic growth phase were cultured 6 Cells / mouse / 100 μL (containing 50 μL Matrigel) were inoculated subcutaneously in the right rib of 30 female CB-17SCID mice. After 10 days, the tumor volume of the tumor-bearing mice reached 200 mm 3When the mice reached 2000 mm, they were randomly divided into 3 groups according to tumor volume and body weight: vehicle control group, CC-92480-1 mpk, and Example 6 compound-1 mpk, with 7 mice in each group. The day of grouping was set as Day 0 (D0), and oral administration began once a day for a total of 11 days (Table 2). The tumor volume of tumor-bearing mice was measured with a vernier caliper and the body weight was measured with a balance twice a week and the data were recorded. When the tumor volume reached 2000 mm 3 Or when most tumors ruptured or body weight decreased by 20%, tumor-bearing animals were euthanized as the experimental endpoint.

[0772] 3.4 Data Statistics

[0773] All data were graphed and statistically analyzed using Excel and GraphPad Prism 5 software.

[0774] The formula for calculating tumor volume (V) is: V = 1 / 2 × a × b 2 , where a and b represent length and width respectively.

[0775] Relative tumor proliferation rate T / C (%) = (T-T0) / (C-C0) × 100 (%), where: T and C are the tumor volumes of the treatment group and the control group at the end of the experiment; T0 and C0 are the tumor volumes at the beginning of the experiment.

[0776] Tumor inhibition rate TGI (%) = 1-T / C (%). When TGI (%) exceeds 100%, the specific value will not be displayed and will only be expressed as >100%.

[0777] Tumor regression (%) = [(T0-T) / T0] x 100 (%).

[0778] 4. Results

[0779] The efficacy data of the compound of Example 6 and the control example CC-92480 on NCI-H929 transplanted tumors in CB-17SCID mice are shown in Tables 2 and Figure 1 .

[0780] Effects of Example 6 Compound and Control Example CC-92480 on Body Weight of CB-17SCID Mice Figure 2 .

[0781] Table 2 Efficacy of the disclosed compounds on NCI-H929 transplanted tumors in CB-17 SCID mice

[0782]

[0783] Note: qd means administration once a day; po means oral administration.

[0784] 5. Conclusion

[0785] The compound of Example 6 was administered once a day 10 days after tumor cell transplantation. After 11 days of administration, the tumor volume was significantly reduced. The tumor inhibition rate was calculated to be >100%, and the tumor regression rate was 88%. At the end of the experiment, there was a statistical difference (p < 0.05) compared with the same dose of CC-92480, and the administration had no effect on the weight of the mice. Under the same conditions, the tumor regression rate of the control CC-92480 was 34%.

[0786] Test Example 3 Pharmacokinetic Evaluation

[0787] 1. Overview

[0788] Mice were used as test animals, and the drug concentrations in plasma at different times after oral administration of the compound of Example 6 and the control example CC-92480 were determined by LC / MS / MS. The pharmacokinetic behavior of the disclosed compound in mice was studied, and its pharmacokinetic characteristics were evaluated.

[0789] 2. Experimental plan

[0790] 2.1 Trial Drugs

[0791] Example 6 compound and comparative example CC-92480.

[0792] 2.2 Experimental animals

[0793] Eighteen female mice were purchased from Weitonglihua Experimental Animal Co., Ltd., with animal production license number: SCXK (Shanghai) 2017-0005.

[0794] 2.3 Drug preparation

[0795] The compound of Example 6 was weighed, and 5% volume of DMSO and 5% Tween 80 (Shanghai Titan Technology Co., Ltd.) were added to dissolve it, and then 90% physiological saline was added to prepare a 0.1 mg / mL clear solution.

[0796] The control example CC-92480 was weighed, 5% volume of DMSO and 5% Tween 80 (Shanghai Titan Technology Co., Ltd.) were added to dissolve it, and then 90% physiological saline was added to prepare a 0.1 mg / mL clear solution.

[0797] 2.4 Administration

[0798] The compound of Example 6 was administered to 9 mice by gavage at a dosage of 2 mg / kg and a dosing volume of 0.2 mL / 10 g.

[0799] The compound control example CC-92480 was administered to 9 mice by gavage at a dosage of 2 mg / kg and a dosing volume of 0.2 mL / 10 g.

[0800] 3. Operation

[0801] The compound of Example 6 and the control CC-92480 were administered to mice by gavage, and 0.2 mL of blood was collected before administration and 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours after administration (3 animals at each time point), placed in an EDTA-K2 anticoagulant tube, centrifuged at 10000 rpm for 1 minute (4°C), and plasma was separated within 1 hour and stored at -20°C for testing. The blood collection and centrifugation process were operated under ice bath conditions.

[0802] Determination of the content of the test compound in mouse plasma after administration of different drug concentrations: 25 μL of mouse plasma at each time point after administration was taken, 50 μL (100 ng / mL) of internal standard solution camptothecin (China National Institute for the Control of Biological Products) and 175 μL of acetonitrile were added, vortexed for 5 minutes, centrifuged for 10 minutes (3700 rpm), and 1 μL of the supernatant of the plasma sample was taken for LC / MS / MS (API4000 triple quadrupole tandem mass spectrometer, Applied Biosystems, USA; Shimadzu LC-30AD ultra-high performance liquid chromatography system, Shimadzu, Japan) analysis.

[0803] 4. Pharmacokinetic parameter results

[0804] The pharmacokinetic parameters of the disclosed compounds are shown in Table 3 below.

[0805] Table 3 Pharmacokinetic parameters of the disclosed compounds

[0806]

[0807] Conclusion: The disclosed compounds have good pharmacokinetic absorption and pharmacokinetic advantages.

[0808] Test Example 4 Evaluation of Plasma Stability of the Disclosed Compounds

[0809] 1. Summary

[0810] The stability of the compound of Example 6 and the control example CC-92480 was quantitatively determined by LC-MS / MS after incubation in monkey frozen plasma at 37°C for 0, 15, 30, 60, 120, 180, and 240 minutes, respectively.

[0811] 2. Experimental plan

[0812] 2.1 Trial Drugs

[0813] Example 6 compound and comparative example CC-92480.

[0814] 2.2 Experimental plasma

[0815] Monkey plasma was purchased from Shanghai Medicilon Biopharmaceutical Co., Ltd.

[0816] 2.3 Compound solution preparation

[0817] Weigh a certain amount of the compound of Example 6, add DMSO to prepare a 30mM stock solution, take a certain volume of the stock solution, dilute it with DMSO to a solution I with a concentration of 1600μM; then take a certain volume of the 1600μM solution I and dilute it with 50% methanol to a working solution II with a concentration of 16μM. Use the above method to prepare a 30mM stock solution, a 1600μM solution I' and a 16μM working solution II' of CC-92480.

[0818] 2.4 Sample incubation

[0819] Take 5 μL of the working solution of 16 μM compound of Example 6 and control CC-92480, respectively, and add them to 75 μL of plasma to make the final concentration of the compound 1 μM. The samples were incubated in a 37°C water bath for 0, 15, 30, 60, 90, 120, and 180 minutes. After the incubation, 240 μL of acetonitrile containing the internal standard was added, and then the shaker was shaken at 800 rpm for 10 minutes, and the centrifuge was centrifuged at 3700 rpm at 4°C for 20 minutes. The supernatant was analyzed by LC-MS, and the injection volume was 2 μL.

[0820] 3. Results

[0821] The conversion of the disclosed compounds in monkey plasma is shown in Table 4 below.

[0822] Table 4 Stability data of the disclosed compounds in monkey plasma

[0823] serial number <![CDATA[T 1 / 2 (min) / Monkey]]> Example 6 806 CC-92480 199

[0824] Conclusion: The disclosed compounds have stability advantages in monkey plasma.

Claims

1. A compound represented by the general formula (IIG) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof: in: Y is CH2 or C(O); R 1 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 alkyl; R 2 is a hydrogen atom; G 1 , G 2 and G 3 are the same or different and are each independently a carbon atom or a nitrogen atom; R 3 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 alkyl; R 4a is a 6- to 10-membered aryl group, wherein the 6- to 10-membered aryl group is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl and cyano are substituted with one or more substituents; R 4b are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 alkyl; r is 0, 1, or 2; J is 0 or 1; k is 0 or 1; n is 0, 1, 2 or 3; p is 0, 1, 2, 3 or 4.

2. The compound represented by the general formula (IIG) according to claim 1, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (IIG-1) or the general formula (IIG-2), or its tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof: in: G 1 , G 2 , G 3 , Y, R 1 To R 3 , R 4a , R 4b , J, k, n, p and r as defined in claim 1.

3. The compound represented by the general formula (IIG) according to claim 1, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein 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 are all carbon atoms; or G 2 and G 3 All are nitrogen atoms, G 1 For carbon atoms.

4. The compound represented by the general formula (IIG) according to claim 1, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein G 2 is a nitrogen atom, G 1 and G 3 For carbon atoms.

5. The compound represented by the general formula (IIG) according to claim 1, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (III) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof: in: r is 0, 1, or 2; Y, R 1 To R 3 , R 4a , R 4b , n and p are as defined in claim 1.

6. The compound represented by the general formula (IIG) according to claim 1, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (III-1) or the general formula (III-2), or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof: in: Y, R 1 To R 3 , R 4a , R 4b , r, n and p are as defined in claim 1.

7. The compound represented by the general formula (IIG) according to claim 1, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Y is CH2.

8. The compound represented by the general formula (IIG) according to claim 1, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 4a for R 4b A hydrogen atom.

9. The compound represented by the general formula (IIG) according to claim 1, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 1 A hydrogen atom.

10. The compound represented by the general formula (IIG) according to claim 1, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 3 are the same or different and are each independently a hydrogen atom or a halogen.

11. The compound represented by the general formula (IIG) according to claim 1, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 3 A hydrogen atom.

12. The compound represented by the general formula (IIG) according to claim 1, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1.

13. The compound represented by the general formula (IIG) according to claim 1, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein p is 0, 1 or 2.

14. The compound represented by the general formula (IIG) according to claim 1, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein r is 0 or 1.

15. The compound represented by the general formula (IIG) according to claim 1 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is selected from the following compounds:

16. A compound represented by the general formula (IIGA) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a salt thereof, in: G 1 , G 2 , G 3 , R 2 , R 3 , R 4a , R 4b , J, k, p and r are as defined in claim 1.

17. The compound represented by the general formula (IIGA) according to claim 16 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or salt thereof, which is selected from the following compounds:

18. A compound represented by the general formula (IIGC) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof, in: R m C 1-6 alkyl; G 1 , G 2 , G 3 , Y, R 1 To R 3 , R 4a , R 4b , J, k, r, n and p are as defined in claim 1.

19. The compound represented by the general formula (IIGC) according to claim 18, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or salt thereof, wherein R m It is tert-butyl.

20. The compound according to claim 18 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof, which is selected from the following compounds:

21. A method for preparing the compound represented by the general formula (IIG) according to claim 1 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising: The compound of general formula (IIGA) reacts with the compound of general formula (IB) to obtain the compound of general formula (IIG), in: G 1 , G 2 , G 3 , Y, R 1 To R 3 , R 4a , R 4b , J, k, n, p and r are as defined in claim 1.

22. A method for preparing the compound represented by the general formula (IIG) according to claim 1 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising: The compound of general formula (IIGC) undergoes an intramolecular ring-closing reaction to obtain a compound of general formula (IIG), in: R m C 1-6 alkyl; G 1 , G 2 , G 3 , Y, R 1 To R 3 , R 4a , R 4b , J, k, n, p and r are as defined in claim 1.

23. The method according to claim 22, wherein R m It is tert-butyl.

24. A pharmaceutical composition comprising a compound according to any one of claims 1 to 15 or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

25. Use of a compound according to any one of claims 1 to 15 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 24 in the preparation of a medicament for treating and / or preventing a disease associated with the CRBN protein.

26. Use of a compound according to any one of claims 1 to 15 or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or mixture form, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 24 in the preparation of a medicament 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 diseases, CNS diseases, CNS damage, atherosclerosis or related conditions, sleep disorders or related conditions, infectious diseases, hemoglobinopathies or related conditions, or TNFα-related conditions.

27. A compound according to any one of claims 1 to 15 or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or mixture form, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 24 for the preparation of a medicament for the treatment and / or prevention of cancer or CNS injury.

28. The method of claim 26 or 27, wherein the cancer is selected from the group consisting of leukemia, myeloma, lymphoma, melanoma, skin cancer, liver cancer, kidney cancer, lung cancer, nasopharyngeal cancer, gastric 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, seminoma, testicular tumors, head and neck tumors, head and neck squamous cell carcinoma, endometrial cancer, thyroid cancer, sarcoma, osteoma, neuroblastoma, neuroendocrine cancer, brain tumor, CNS cancer, astrocytoma and glioma.

29. The use according to claim 28, 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.

30. The use according to claim 28, wherein the myeloma is multiple myeloma (MM) and myelodysplastic syndrome (MDS).

31. The use according to claim 30, wherein the multiple myeloma is relapsed, refractory or resistant.

32. The use according to claim 30, wherein the multiple myeloma is refractory or resistant to lenalidomide or pomalidomide.

33. The method of claim 28, wherein the lymphoma is selected from the group consisting of 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.

34. The use according to claim 26, wherein the disease associated with angiogenesis is selected from arthritis, endometriosis, Crohn's disease, heart failure, severe heart failure, renal injury, endotoxemia, toxic shock syndrome, osteoarthritis, retroviral replication, wasting disease, meningitis, silica-induced fibrosis, asbestos-induced fibrosis, veterinary diseases, hypercalcemia associated with malignancy, stroke, circulatory shock, periodontitis, gingivitis, megaloblastic anemia, refractory anemia and 5q deletion syndrome.

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