HK40090714A - Sulfur-containing isoindoline derivative, and preparation method therefor and medical use thereof - Google Patents

Description

Sulfur-containing isoindoline derivatives, their preparation methods and their pharmaceutical applications

Technical Field

This disclosure pertains to the pharmaceutical field and relates to a sulfur-containing isoindoline derivative, its preparation method, and its pharmaceutical application. In particular, this disclosure relates to the sulfur-containing isoindoline derivative of general formula (I), its preparation method, pharmaceutical compositions containing the derivative, and its use as a cereblon modulator in the treatment of multiple myeloma.

Background Technology

Multiple myeloma (MM) is a malignant tumor with main symptoms including hypercalcemia, kidney damage, anemia, and bone disease. MM is the second most common hematologic malignancy after non-Hodgkin's lymphoma, affecting 4–6 people per 100,000 people globally each year, and approximately 1.6 people per 100,000 people in China each year. Current treatment methods mainly include drug therapy and autologous stem cell transplantation.

Currently, there are four main classes of drugs widely used in clinical practice: lenalidomide immunomodulators, proteasome inhibitors, hormones, and monoclonal antibodies. Drugs in clinical research stages include bispecific antibodies, ADCs, and CAR-T therapy. These drugs have different mechanisms of action, and combination therapy often achieves better efficacy. Clinically, dual, triple, or even quadruple therapy is commonly used, typically combining immunomodulators, proteasome inhibitors, and hormones, sometimes with the addition of antibodies. Lenalidomide is the most commonly used immunomodulator, used in first-line treatment, maintenance therapy after stem cell transplantation, and second- and third-line treatment after relapse. Its sales reached $9.7 billion in 2018/2019. The entire MM market is also considerable and growing rapidly, due to continuous improvements in the diagnosis and treatment of MM, leading to longer patient survival and extended treatment durations. The MM market is projected to reach $33 billion by 2022, with immunomodulators, represented by lenalidomide, still accounting for the largest share.

The mechanism of action of immunomodulators (IMiDs) in treating multiple myeloma (MM) is primarily based on the fact that IMiD drugs bind to the Cerebrolysin B (CRBN) protein, activating the E3 ligase activity of CRBN, which then selectively binds to the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3). This leads to the rapid ubiquitination and degradation of Ikaros and Aiolos. Downregulation of Ikaros/Aiolos results in downregulation of c-Myc, followed by downregulation of IRF4, ultimately inhibiting myeloma cell growth and inducing apoptosis. Furthermore, IKZF3 can inhibit the transcription of IL-2 and TNF cytokines in T/NK cells. IKZF3 degradation relieves this inhibition, promoting the release of these cytokines and thus exerting an immunomodulatory effect. Clinical trials have also shown a correlation between the clinical benefits of IMiD drugs and the level of CRBN expression. Knocking down CRBN in lenalidomide-sensitive cell lines (OPM2 and KMS18) revealed the loss of lenalidomide's inhibitory activity on cell growth, leading to drug resistance. The level of CRBN knockdown was correlated with the degree of drug resistance. In cell proliferation experiments, reducing the expression level of CRBN in cells (U266-CRBN60 and U266-CRBN75) reduced the inhibitory activity of both lenalidomide and pomalidomide on cell growth.

Currently approved IMiD drugs include thalidomide, lenalidomide, and pomalidomide, all from Celgene (now merged with BMS). The binding affinity of the three compounds to CRBN increases sequentially, hence the clinical dosage decreases accordingly. The primary indication for all three compounds is multidisciplinary disease (MM). Thalidomide and lenalidomide also have other indications, especially lenalidomide, which can be used to treat myelodysplastic syndromes (MDS). Regarding side effects, lenalidomide and pomalidomide exhibit similar effects, with significant myelosuppression, a target-related toxicity. Thalidomide has some other side effects, such as sedation, constipation, and neurological side effects.

All IMiDs' adipicimide moiety binds to a hydrophobic bag defined by three tryptophan residues in CRBN (called the "thalidomide binding bag"). Conversely, the phthalimide/isoindolone ring is exposed to the solvent and alters the molecular surface of CRBN, thereby modulating substrate recognition. Different IMiDs lead to significant modifications on the CRBN molecular surface and different substrate recognition preferences. Therefore, modifications to IMiDs may lead to the degradation of other transcription factors, causing unwanted toxic side effects. This mode of action of IMiDs is also known as a molecular glue, vividly describing the binding effect of this small molecule on two protein substrates.

Because the median survival for multiple myeloma is currently over five years, this prolonged survival has led to a high proportion of patients developing resistance to currently marketed drugs such as lenalidomide and pomalidomide, severely reducing the effectiveness of these treatments. Therefore, we envision developing more active drug molecules to overcome drug resistance while minimizing the toxic side effects of these compounds.

Published patent applications for Cereblon modifiers include WO2008115516A2, WO2011100380A1, WO2019226770A1, WO2019014100A1 and WO2020064002A1, etc.

Summary of the Invention

The purpose of this disclosure is to provide a compound of general formula (I) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, mixture thereof, or pharmaceutically acceptable salt thereof:

in:

Ring A is aryl or heteroaryl;

Ring B is a cycloalkyl or heterocyclic group;

Y is _CH2 or C(O);

^R1 may be the same or different, and each is independently selected from hydrogen, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro and hydroxy;

R ² is selected from hydrogen atom, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein each of the alkyl, alkenyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl groups is independently and optionally substituted by one or more substituents selected from halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups;

R ³ may be the same or different, and each is independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro and hydroxy;

R ⁴ is selected from hydrogen atom, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein each of the alkyl, alkenyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally substituted by one or more substituents selected from halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

^R5 and ^R6 may be the same or different, and each is independently selected from hydrogen, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclic, aryl and heteroaryl.

n is 0, 1, 2, or 3;

p is 0, 1, 2, 3 or 4;

q is 0, 1, or 2; and

t can be 0, 1, 2 or 3.

In some preferred embodiments of this disclosure, the compound represented by general formula (I) or its tautomers, meso compounds, racemates, enantiomers, diastereomers, mixtures thereof, or pharmaceutically acceptable salts thereof are compounds represented by general formula (I-1) or their tautomers, meso compounds, racemates, enantiomers, diastereomers, mixtures thereof, or pharmaceutically acceptable salts thereof:

in:

Rings A, B, Y, ^R1 to ^R6 , n, p, q and t are as defined in general formula (I).

In some preferred embodiments of this disclosure, the compound represented by general formula (I) or its tautomers, meso compounds, racemates, enantiomers, diastereomers, mixtures thereof, or pharmaceutically acceptable salts thereof are compounds represented by general formula (I-2) or their tautomers, meso compounds, racemates, enantiomers, diastereomers, mixtures thereof, or pharmaceutically acceptable salts thereof:

in:

Rings A, B, Y, ^R1 to ^R6 , n, p, q and t are as defined in general formula (I).

In some preferred embodiments of this disclosure, the compound represented by general formula (I) or its tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, are compounds represented by general formula (II) or their tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:

in:

Rings A, B, Y, ^R1 to ^R4 , n, p, and t are as defined in general formula (I).

In some preferred embodiments of this disclosure, the compound represented by general formula (I) or general formula (II), or its tautomers, meso compounds, racemates, enantiomers, diastereomers, mixtures thereof, or pharmaceutically acceptable salts thereof, are compounds represented by general formula (II-1) or general formula (II-2), or their tautomers, meso compounds, racemates, enantiomers, diastereomers, mixtures thereof, or pharmaceutically acceptable salts thereof:

in:

Rings A, B, Y, ^R1 to ^R4 , n, p and t are as defined in general formula (II).

In some embodiments of this 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 a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or 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.

In some embodiments of this 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 a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from ^R3 and p as defined in general formula (I).

In some embodiments of this 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 tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein ring B is a 3- to 8-membered heterocyclic group; preferably, ring B is selected from piperidinyl, pyrrolidinyl, and N-heterocyclic butyl; more preferably, ring B is a 6-membered heterocyclic group; most preferably, ring B is piperidinyl.

In some embodiments of this 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, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt, wherein J is 0 or 1, and k is 0 or 1; preferably, R ^4a and R ^4b may be the same or different, and each is independently selected from hydrogen, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently optionally substituted by one or more substituents selected from halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups; and r is 0, 1, or 2.

In some preferred embodiments of this disclosure, the compound represented by general formula (I) or general formula (II), or its tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, are compounds represented by general formula (IIG), or their tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:

in:

^G1 , ^G2 and ^G3 may be the same or different, and each may be a carbon atom or a nitrogen atom independently;

R ^4a and R ^4b may be the same or different, and each is independently selected from hydrogen, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently optionally substituted by one or more substituents selected from halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

r is 0, 1, or 2;

J is either 0 or 1;

k is 0 or 1;

Y, ^R1 to ^R3 , n and p are as defined in general formula (I).

In some preferred embodiments of this disclosure, the compound represented by general formula (I), general formula (I-1), general formula (II), general formula (II-1) or general formula (IIG), or its tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, are compounds represented by general formula (IIG-1), or their tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:

in:

^G1 , ^G2 and ^G3 may be the same or different, and each may be a carbon atom or a nitrogen atom independently;

R ^4a and R ^4b may be the same or different, and each is independently selected from hydrogen, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently optionally substituted by one or more substituents selected from halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

r is 0, 1, or 2;

J is either 0 or 1;

k is 0 or 1;

Y, ^R1 to ^R3 , n and p are as defined in general formula (I).

In some preferred embodiments of this disclosure, the compound represented by general formula (I), general formula (I-2), general formula (II), general formula (II-2) or general formula (IIG), or a tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by general formula (IIG-2), or a tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

in:

^G1 , ^G2 and ^G3 may be the same or different, and each may be a carbon atom or a nitrogen atom independently;

R ^4a and R ^4b may be the same or different, and each is independently selected from hydrogen, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently optionally substituted by one or more substituents selected from halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

r is 0, 1, or 2;

J is either 0 or 1;

k is 0 or 1;

Y, ^R1 to ^R3 , n and p are as defined in general formula (I).

In some preferred embodiments of this disclosure, the compound represented by general formula (IIG), general formula (IIG-1) or general formula (IIG-2), or its tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein ^G2 is a nitrogen atom and ^G1 and ^G3 are carbon atoms; or ^G1 is a nitrogen atom and ^G2 and ^G3 are carbon atoms; or ^G1 , ^G2 , and ^G3 are all carbon atoms; or ^G2 and ^G3 are both nitrogen atoms and ^G1 is a carbon atom.

In some preferred embodiments of this disclosure, the compound represented by general formula (I), general formula (II), or general formula (IIG), or a tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by general formula (III), or a tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

in:

R ^4a and R ^4b may be the same or different, and each is independently selected from hydrogen, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently optionally substituted by one or more substituents selected from halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

r is 0, 1, or 2;

Y, ^R1 to ^R3 , n and p are as defined in general formula (I).

In some preferred embodiments of this disclosure, the compounds represented by general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (IIG), general formula (IIG-1), or general formula (III), or their tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, are compounds represented by general formula (III-1), or their tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:

in:

Y, ^R1 to ^R3 , ^R4a , ^R4b , r, n and p are as defined in general formula (III).

In some preferred embodiments of this disclosure, the compounds represented by general formula (I), general formula (I-2), general formula (II), general formula (II-2), general formula (IIG), general formula (IIG-2), or general formula (III), or their tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, are compounds represented by general formula (III-2), or their tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:

in:

Y, ^R1 to ^R3 , ^R4a , ^R4b , r, n and p are as defined in general formula (III).

In some preferred embodiments of this disclosure, the compound represented by general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1), general formula (II-2), general formula (IIG), general formula (IIG-1), general formula (IIG-2), general formula (III), general formula (III-1) or general formula (III-2), or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Y is _CH2 .

In some preferred embodiments of this disclosure, the compounds 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 their tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or their pharmaceutically acceptable salts, wherein ^R4 is the same or different and is each independently selected from hydrogen atoms, halogens, _C1-6 alkyl groups, 3- to 8-membered cycloalkyl groups, 3- to 8-membered heterocyclic groups, 6- to 10-membered aryl groups, and 5- to 10-membered heteroaryl groups, wherein the 3- to 8-membered cycloalkyl groups, 3- to 8-membered heterocyclic groups, 6- to 10-membered aryl groups, and 5- to 10-membered heteroaryl groups are each independently optionally selected from halogens, _C1-6 alkyl groups, _C2-6 alkenyl groups, _C2-6 alkoxy groups, _C1-6 halogenated C1-6 alkyl groups, and halogenated _C1-6 alkyl groups. It is substituted by one or more of the following substituents: _1-6 alkoxy, cyano, amino, nitro, hydroxy, and _C1-6 hydroxyalkyl.

In some preferred embodiments of this disclosure, the compounds represented by 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, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or their pharmaceutically acceptable salts, wherein R ^4a is selected from 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclic, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl, wherein each of the 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclic, 6- to ₁₀ -membered aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by one or more substituents selected from halogen, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkoxy, halo _{- C1-6} alkyl, halo-C1-6 alkoxy, cyano, amino, nitro, hydroxy, and _C1-6 hydroxyalkyl; R ^R4b may be the same or different, and each is independently selected from hydrogen atoms, halogens, _C1-6 alkyl groups and 3 to 8-membered cycloalkyl groups; preferably, ^R4a is a hydrogen atom and ^R4b is a hydrogen atom.

In some preferred embodiments of this 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, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or their pharmaceutically acceptable salts, wherein ^R1 is the same or different, and each is independently selected from hydrogen atoms, halogens and _C1-6 alkyl groups; preferably, ^R1 is a hydrogen atom.

In some embodiments of this disclosure, the compound represented by general formula (I), general formula (I-1), general formula (I-2), general formula (II), general formula (II-1), general formula (II-2), general formula (IIG), general formula (IIG-1), general formula (IIG-2), general formula (III), general formula (III-1) or general formula (III-2), or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ^R2 is selected from hydrogen atoms, _C1-6 alkyl groups and 3- to 8-membered cycloalkyl groups; preferably, ^R2 is a hydrogen atom.

In some embodiments of this 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, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or their pharmaceutically acceptable salts, wherein ^R3 is the same or different and is each independently selected from hydrogen atoms, halogens and _C1-6 alkyl groups.

In some embodiments of this 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, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or their pharmaceutically usable salts, wherein ^R3 is the same or different, and each is independently a hydrogen atom or a halogen; preferably a hydrogen atom.

In some embodiments of this disclosure, the compound represented by general formula (I), general formula (I-1) or general formula (I-2) or its tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically usable salt, wherein q is 0 or 1; preferably q is 0.

In some embodiments of this 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, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or their pharmaceutically acceptable salts, wherein n is 0 or 1.

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

In some embodiments of this 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, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically usable salt, wherein t is 0, 1 or 2.

In some embodiments of this disclosure, the compound represented by 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, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt, wherein r is 0 or 1.

In some embodiments of this disclosure, the compound represented by general formula (III), general formula (III-1) or general formula (III-2) or its tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein: Y is _CH2 ; ^R1 are the same or different and are each independently selected from hydrogen atoms, halogens and _C1-6 alkyl groups; ^R2 is a hydrogen atom; ^R3 are the same or different and are each independently a hydrogen atom or a halogen; ^R4a is ^R4b is a hydrogen atom; n is 0 or 1; p is 0 or 1; and r is 1.

Table A lists typical compounds disclosed herein, including but not limited to:

Another aspect of this disclosure relates to compounds of general formula (IA) or their tautomers, meso compounds, racemates, enantiomers, diastereomers, mixtures thereof, or salts thereof.

in:

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

Ring B is a heterocyclic group; preferably a 3- to 8-membered heterocyclic group; more preferably a piperidinyl, pyrrolidinyl, or N-heterocyclic butyl group;

^R2 to ^R6 , p, q and t are as defined in general formula (I).

Another aspect of this disclosure relates to compounds of general formula (IIA) or their tautomers, meso compounds, racemates, enantiomers, diastereomers, mixtures thereof, or salts thereof.

in:

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

Ring B is a heterocyclic group; preferably a 3- to 8-membered heterocyclic group; more preferably a piperidinyl, pyrrolidinyl, or N-heterocyclic butyl group;

^R2 to ^R4 , p and t are as defined in general formula (II).

Another aspect of this disclosure relates to compounds of general formula (IIGA) or their tautomers, meso compounds, racemates, enantiomers, diastereomers, mixtures thereof, or salts thereof.

in:

^G1 , ^G2 , ^G3 , ^R2 , ^R3 , ^R4a , ^R4b , J, k, p, and r are as defined in general formula (IIG).

Another aspect of this disclosure relates to compounds of general formula (IIIA) or their tautomers, meso compounds, racemates, enantiomers, diastereomers, mixtures thereof, or salts thereof.

in:

^R2 , ^R3 , ^R4a , ^R4b , p and r are as defined in general formula (III).

Typical intermediate compounds disclosed herein include, but are not limited to:

Another aspect of this disclosure relates to compounds of general formula (IC) or their tautomers, meso compounds, racemates, enantiomers, diastereomers, mixtures thereof, or salts thereof.

in:

^Rm is a _C1-6 alkyl group; preferably tert-butyl.

Rings A, B, Y, ^R1 to ^R6 , n, p, q and t are as defined in general formula (I).

Another aspect of this disclosure relates to compounds of general formula (I-1C) or their tautomers, meso compounds, racemates, enantiomers, diastereomers, mixtures thereof, or salts thereof.

in:

^Rm is a _C1-6 alkyl group; preferably tert-butyl.

Rings A, B, Y, ^R1 to ^R6 , n, p, q and t are as defined in general formula (I-1).

Another aspect of this disclosure relates to compounds of general formula (IIC) or their tautomers, meso compounds, racemates, enantiomers, diastereomers, mixtures thereof, or salts thereof.

in:

^Rm is a _C1-6 alkyl group; preferably tert-butyl.

Rings A, B, Y, ^R1 to ^R4 , n, p and t are as defined in general formula (II).

Another aspect of this disclosure relates to compounds of general formula (II-1C) or their tautomers, meso compounds, racemates, enantiomers, diastereomers, mixtures thereof, or salts thereof.

in:

^Rm is a _C1-6 alkyl group; preferably tert-butyl.

Rings A, B, Y, ^R1 to ^R4 , n, p and t are as defined in general formula (II-1).

Another aspect of this disclosure relates to compounds of general formula (IIGC) or their tautomers, meso compounds, racemates, enantiomers, diastereomers, mixtures thereof, or salts thereof.

in:

^Rm is a _C1-6 alkyl group; preferably tert-butyl.

^G1 , ^G2 , ^G3 , Y, ^R1 to ^R3 , ^R4a , ^R4b , J, k, r, n and p are as defined in general formula (IIG).

Another aspect of this disclosure relates to compounds of general formula (IIGC-1) or their tautomers, meso compounds, racemates, enantiomers, diastereomers, mixtures thereof, or salts thereof.

in:

^Rm is a _C1-6 alkyl group; preferably tert-butyl.

^G1 , ^G2 , ^G3 , Y, ^R1 to ^R3 , ^R4a , ^R4b , J, k, r, n and p are as defined in general formula (IIG-1).

Another aspect of this disclosure relates to compounds of general formula (IIIC) or their tautomers, meso compounds, racemates, enantiomers, diastereomers, mixtures thereof, or salts thereof.

in:

^Rm is a _C1-6 alkyl group; preferably tert-butyl.

Y, ^R1 to ^R3 , ^R4a , ^R4b , r, n and p are as defined in general formula (III).

Another aspect of this disclosure relates to compounds of general formula (III-1C) or their tautomers, meso compounds, racemates, enantiomers, diastereomers, mixtures thereof, or salts thereof.

in:

^Rm is a _C1-6 alkyl group; preferably tert-butyl.

Y, ^R1 to ^R3 , ^R4a , ^R4b , r, n and p are as defined in general formula (III-1).

Typical intermediate compounds disclosed herein include, but are not limited to:

Another aspect of this disclosure relates to a method for preparing a compound of general formula (I) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

A compound of general formula (IA) reacts with a compound of general formula (IB) to give a compound of general formula (I).

in:

Rings A, B, Y, ^R1 to ^R6 , n, p, q and t are as defined in general formula (I).

Another aspect of this disclosure relates to a method for preparing a compound of general formula (I) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

Compounds of general formula (IC) undergo intramolecular ring-closure reactions to give compounds of general formula (I).

in:

^Rm is a _C1-6 alkyl group; preferably tert-butyl.

Rings A, B, Y, ^R1 to ^R6 , n, p, q and t are as defined in general formula (I).

Another aspect of this disclosure relates to a method for preparing a compound of general formula (I-1) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

Compounds of general formula (I-1C) undergo intramolecular ring-closure reactions to give compounds of general formula (I-1).

in:

^Rm is a _C1-6 alkyl group; preferably tert-butyl.

Rings A, B, Y, ^R1 to ^R6 , n, p, q and t are as defined in general formula (I-1).

Another aspect of this disclosure relates to a method for preparing a compound of general formula (I-2) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

A compound of general formula (I) or its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or its pharmaceutically usable salts, are prepared by chiral resolution to obtain a single-configuration compound of general formula (I-2), or its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or its pharmaceutically usable salts;

in:

^Rm is a _C1-6 alkyl group; preferably tert-butyl.

Rings A, B, Y, ^R1 to ^R6 , n, p, q and t are as defined in general formula (I).

Another aspect of this disclosure relates to a method for preparing a compound of general formula (II) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

Compounds of general formula (IIA) react with compounds of general formula (IB) to give compounds of general formula (II).

in:

Rings A, B, Y, ^R1 to ^R4 , n, p and t are as defined in general formula (II).

Another aspect of this disclosure relates to a method for preparing a compound of general formula (II) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

Compounds of general formula (IIC) undergo intramolecular ring-closure reactions to give compounds of general formula (II).

in:

^Rm is a _C1-6 alkyl group; preferably tert-butyl.

Rings A, B, Y, ^R1 to ^R4 , n, p and t are as defined in general formula (II).

Another aspect of this disclosure relates to a method for preparing a compound of general formula (II-1) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

Compounds of general formula (II-1C) undergo intramolecular ring-closure reactions to give compounds of general formula (II-1).

in:

^Rm is a _C1-6 alkyl group; preferably tert-butyl.

Rings A, B, Y, ^R1 to ^R4 , n, p and t are as defined in general formula (II).

Another aspect of this disclosure relates to a method for preparing a compound of general formula (II-2) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

A compound of general formula (II) or its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or its pharmaceutically usable salts, are prepared by chiral resolution to obtain a single-configuration compound of general formula (II-2), or its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or its pharmaceutically usable salts;

in:

^Rm is a _C1-6 alkyl group; preferably tert-butyl.

Rings A, B, Y, ^R1 to ^R4 , n, p and t are as defined in general formula (II).

Another aspect of this disclosure relates to a method for preparing a compound of general formula (IIG) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

Compounds of general formula (IIGA) react with compounds of general formula (IB) to give compounds of general formula (IIG).

in:

^G1 , ^G2 , ^G3 , Y, ^R1 to ^R3 , ^R4a , ^R4b , J, k, n, p and r are as defined in general formula (IIG).

Another aspect of this disclosure relates to a method for preparing a compound of general formula (IIG) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

Compounds of general formula (IIGC) undergo intramolecular ring-closure reactions to give compounds of general formula (IIG).

in:

^Rm is a _C1-6 alkyl group; preferably tert-butyl.

^G1 , ^G2 , ^G3 , Y, ^R1 to ^R3 , ^R4a , ^R4b , J, k, n, p and r are as defined in general formula (IIG).

Another aspect of this disclosure relates to a method for preparing a compound of general formula (IIG-1) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

Compounds of general formula (IIGC-1) undergo intramolecular ring-closure reactions to give compounds of general formula (IIG-1).

in:

^Rm is a _C1-6 alkyl group; preferably tert-butyl.

^G1 , ^G2 , ^G3 , Y, ^R1 to ^R3 , ^R4a , ^R4b , J, k, n, p and r are as defined in general formula (IIG-1).

Another aspect of this disclosure relates to a method for preparing a compound of general formula (IIG-2) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

A compound of general formula (IIG) or its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or its pharmaceutically usable salts, is prepared by chiral resolution to obtain a single-configuration compound of general formula (IIG-2), or its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or its pharmaceutically usable salts;

in:

^Rm is a _C1-6 alkyl group; preferably tert-butyl.

^G1 , ^G2 , ^G3 , Y, ^R1 to ^R3 , ^R4a , ^R4b , J, k, n, p and r are as defined in general formula (IIG).

Another aspect of this disclosure relates to a method for preparing a compound of general formula (III) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

Compounds of general formula (IIIA) react with compounds of general formula (IB) to give compounds of general formula (III).

in:

Y, ^R1 to ^R3 , ^R4a , ^R4b , n, p and r are as defined in general formula (III).

Another aspect of this disclosure relates to a method for preparing a compound of general formula (III) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

Compounds of general formula (IIIC) undergo intramolecular ring-closure reactions to give compounds of general formula (III).

in:

^Rm is a _C1-6 alkyl group; preferably tert-butyl.

Y, ^R1 to ^R3 , ^R4a , ^R4b , n, p and r are as defined in general formula (III).

Another aspect of this disclosure relates to a method for preparing a compound of general formula (III-1) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

Compounds of general formula (III-1C) undergo intramolecular ring-closure reactions to give compounds of general formula (III-1).

in:

^Rm is a _C1-6 alkyl group; preferably tert-butyl.

Y, ^R1 to ^R3 , ^R4a , ^R4b , n, p and r are as defined in general formula (III-1).

Another aspect of this disclosure relates to a method for preparing a compound of general formula (III-2) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

A compound of general formula (III) or its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or its pharmaceutically usable salts, are prepared by chiral resolution to obtain a single-configuration compound of general formula (III-2), or its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or its pharmaceutically usable salts;

in:

^Rm is a _C1-6 alkyl group; preferably tert-butyl.

Y, ^R1 to ^R3 , ^R4a , ^R4b , n, p and r are as defined in general formula (III).

Another aspect of this disclosure relates to a pharmaceutical composition comprising 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 thereof, or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

This disclosure further relates to the use of compounds of 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, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or their pharmaceutically acceptable salts or pharmaceutical compositions comprising the thereof, in the preparation of medicaments for the treatment and/or prevention of diseases associated with CRBN protein.

This disclosure further relates to the use of compounds of 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, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of medicaments for the treatment and/or prevention of cancer, angiogenesis-related conditions, pain, macular degeneration or related syndromes, skin diseases, lung diseases, asbestos-related diseases, parasitic diseases, immunodeficiency diseases, CNS diseases, CNS damage, atherosclerosis or related conditions, sleep disorders or related conditions, infectious diseases, hemoglobinopathies or related conditions, or TNFα-related conditions; preferably, in the preparation of medicaments for the treatment and/or prevention of cancer or CNS damage.

This disclosure also relates to a method of treating and/or preventing diseases associated with CRBN protein, comprising administering to a desired patient 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 a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof.

This disclosure also relates to a method 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, preferably a method for treating and/or preventing cancer or CNS damage, comprising administering to a desired patient 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 a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the thereof.

This disclosure further relates to a compound of 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 a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof, for use as a medicament.

This disclosure further relates to compounds of 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 tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, for the treatment and/or prevention of diseases associated with CRBN protein.

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

This disclosure further relates to compounds of 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 tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, for the treatment and/or prevention of cancer, angiogenesis-related conditions, pain, macular degeneration or related syndromes, skin diseases, lung diseases, asbestos-related diseases, parasitic diseases, immunodeficiency diseases, CNS diseases, CNS injuries, atherosclerosis or related conditions, sleep disorders or related conditions, infectious diseases, hemoglobinopathies or related conditions, or TNFα-related conditions; preferably cancer or CNS injuries.

The cancers described in this disclosure are selected from leukemia, myeloma, lymphoma, melanoma, skin cancer, liver cancer, kidney cancer, lung cancer, nasopharyngeal carcinoma, 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 carcinoma, brain tumors, CNS cancers, astrocytomas, and gliomas; preferably, the liver cancer is hepatocellular carcinoma; the colorectal cancer is colon cancer or rectal cancer; the sarcoma is osteosarcoma or soft tissue sarcoma; and the glioma is glioblastoma. The leukemias described are preferably chronic lymphocytic leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and piloblastic leukemia. The lymphomas described are preferably small lymphocytic lymphoma, marginal zone lymphoma, follicular lymphoma, mantle cell lymphoma, non-Hodgkin lymphoma (NHL), lymphoplasmacytic lymphoma, extranodal marginal zone lymphoma, T-cell lymphoma, B-cell lymphoma, and diffuse large B-cell lymphoma. The myelomas described are preferably multiple myeloma (MM) and myelodysplastic syndrome (MDS). The cancers described in this disclosure include primary or metastatic cancers. The cancers described in this disclosure also include those that are refractory or resistant to chemotherapy or radiotherapy. More preferably, the multiple myelomas are relapsed, refractory, or resistant. Most preferably, the multiple myelomas are refractory or resistant to lenalidomide or pomalidomide.

Examples of CNS diseases include, but are not limited to, the diseases described in U.S. Publication No. US2005/0143344A1, published June 30, 2005, the contents of which are incorporated herein by reference. Specific examples include, but are not limited to, amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, and other neuroimmunological diseases such as Tourette syndrome, delusions, or short-term disturbances of consciousness, or amnesia, or diffuse memory impairment that occurs in the absence of other central nervous system damage.

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

Diseases related to angiogenesis include, but are not limited to, inflammatory diseases, autoimmune diseases, viral diseases, genetic diseases, allergic diseases, bacterial diseases, ocular neovascularization, choroidal neovascularization, retinal neovascularization, and iridochromia (angiosynostosis). Preferably, these include, but are not limited to, arthritis, endometriosis, Crohn's disease, heart failure, severe heart failure, kidney injury, endotoxemia, toxic shock syndrome, osteoarthritis, retroviral replication, wasting diseases, meningitis, silica-induced fibrosis, asbestos-induced fibrosis, veterinary diseases, malignant tumor-related hypercalcemia, stroke, circulatory shock, periodontitis, gingivitis, megaloblastic anemia, refractory anemia, and 5q deletion syndrome.

The active compounds can be formulated into forms suitable for administration via any appropriate route, using one or more pharmaceutically acceptable carriers through conventional methods. Therefore, the active compounds of this disclosure can be formulated into various dosage forms for oral administration, injection (e.g., intravenous, intramuscular, or subcutaneous), inhalation, or insufflation. The compounds of this 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.

As a general guideline, the active compound is preferably expressed in a unit dose manner, or in a manner that allows the patient to self-administer a single dose. The unit dose of the disclosed compound or composition may be expressed as a tablet, capsule, sachet, bottled liquid, powder, granule, lozenge, suppository, regenerated powder, or liquid formulation. Suitable unit doses may range from 0.1 to 1000 mg.

In addition to the active compound, the pharmaceutical compositions disclosed herein may contain one or more excipients selected from the following: fillers (diluents), binders, wetting agents, disintegrants, or excipients. Depending on the method of administration, the composition may contain 0.1 to 99% by weight of the active compound.

Tablets contain an active ingredient and non-toxic, pharmaceutically acceptable excipients suitable for tablet preparation, used for mixing. These excipients may be inert excipients, granulating agents, disintegrants, binders, and lubricants. These tablets may be uncoated or coated using known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thus providing sustained release over a longer period.

Oral formulations can also be provided using soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or in which the active ingredient is mixed with a water-soluble carrier or an oil solvent.

Aqueous suspensions contain active substances and excipients suitable for preparing aqueous suspensions, used for mixing. These excipients are suspending agents, dispersing agents, 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 sweeteners.

Oil suspensions are prepared by suspending the active ingredient in vegetable or mineral oil. Oil suspensions may contain thickeners. Sweeteners and flavoring agents mentioned above may be added to provide palatable formulations. These compositions may be preserved by adding antioxidants.

The pharmaceutical compositions disclosed herein may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, a mineral oil, or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsion may also contain sweeteners, flavoring agents, preservatives, and antioxidants. Such formulations may also contain modifiers, preservatives, colorants, and antioxidants.

The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous solutions. Acceptable solvents or media that can be used include 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, which can be injected into the patient's bloodstream via local large-volume injection. Alternatively, the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the compounds disclosed herein. To maintain such a constant concentration, a continuous intravenous delivery device can be used. An example of such a device is the Deltec CADD-PLUS™ 5400 intravenous infusion pump.

The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous or oil suspensions for intramuscular and subcutaneous administration. These suspensions may be formulated using suitable dispersants or wetting agents and suspending agents as described above, according to known techniques. The sterile injectable formulations may also be sterile injectable solutions or suspensions prepared in parenteral-acceptable, non-toxic diluents or solvents. Furthermore, sterile fixative oils may be conveniently used as solvents or suspension media. For this purpose, any blended fixative oil may be used. Additionally, fatty acids may also be used to prepare injectable formulations.

The disclosed compounds can be administered in suppository form for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable, non-irritating excipient that is solid at normal temperatures but liquid in the rectum, and thus dissolves in the rectum to release the drug.

The compounds disclosed herein can be administered by adding water to prepare water-soluble dispersible powders and granules. These pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersant or wetting agent, a suspending agent, or one or more preservatives.

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 activity of the specific compound used, the patient's age, the patient's weight, the patient's health status, the patient's behavior, the patient's diet, the timing of administration, the route of administration, the rate of excretion, the combination of drugs, the severity of the disease, etc.; in addition, the optimal treatment mode, such as the treatment pattern, the daily dosage of the compound, or the type of medicinal salt can be validated based on conventional treatment protocols.

Terminology Explanation

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

The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched 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 their various branched isomers, etc. More preferably, lower alkyl groups containing 1 to 6 carbon atoms are used. 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, etc. Alkyl groups can be substituted or unsubstituted, and when substituted, they can be substituted at any usable connection point. The substituents are preferably selected independently from one or more substituents chosen from the D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclicoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl groups.

The term "alkylene" refers to a saturated straight-chain or branched aliphatic hydrocarbon group, which is a residue derived from the same carbon atom or two different carbon atoms of a parent alkane by removing two hydrogen atoms. It is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, and more preferably alkylene groups containing 1 to 6 carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylene ( _-CH2- ), 1,1-ethylene (-CH( _CH3 )-), 1,2-ethylene _{(-CH2CH2 )} -, _1,1 -propylene (-CH( _CH2CH3 )-), 1,2-propylene ( _-CH2CH ( _{CH3 )} -), 1,3-propylene ( _{-CH2CH2CH2- )} , and _{1,4 -} butylene _{( -CH2CH2CH2CH2-} ). The alkylene group can be substituted or unsubstituted. When substituted, it can be substituted at any usable linker. The substituent is preferably selected independently from one or more substituents selected from alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclic alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocyclic alkoxy, cycloalkylthio, heterocyclic alkylthio, and oxo.

The term "alkenyl" refers to an alkyl compound containing at least one carbon-carbon double bond in its molecule, wherein the definition of alkyl is as described above. Alkenyl groups can be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups, independently selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

The term "alkynyl" refers to an alkyl compound containing at least one carbon-carbon triple bond in its molecule, wherein the definition of alkyl is as described above. The alkynyl group can be substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms (which may be specific points or ranges of any 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 (e.g., 3, 4, 5, 6, 7 and 8), more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups.

The term "spirocycloalkyl" refers to a 5- to 20-membered polycyclic group that shares a single carbon atom (called a spiro atom) between its rings, and may contain one or more double bonds. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Spirocycloalkyl groups are classified as monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl groups based on the number of shared spiro atoms between the rings, with monospirocycloalkyl and bispirocycloalkyl groups being preferred. More preferably, it is a 3/5-membered, 3/6-membered, 4/4-membered, 4/5-membered, 4/6-membered, 5/5-membered, or 5/6-membered monospirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups include:

The term "fused cycloalkyl" refers to a 5- to 20-membered polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 3-/4-membered, 3-/5-membered, 3-/6-membered, 4-/4-membered, 4-/5-membered, 4-/6-membered, 5-/4-membered, 5-/5-membered, 5-/6-membered, 6-/3-membered, 6-/4-membered, 6-/5-membered, and 6-/6-membered bicyclic alkyl. Non-limiting examples of fused cycloalkyl groups include:

The term "bridged cycloalkyl" refers to a 5- to 20-membered polycyclic carbon group in which any two rings share two non-directly bonded carbon atoms, and may contain one or more double bonds. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Depending on the number of rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

The cycloalkyl ring comprises a cycloalkyl group (including monocyclic, spirocyclic, fused, and bridged rings) fused to an aryl, heteroaryl, or heterocyclic alkyl ring as described above, wherein the ring attached to the parent structure is a cycloalkyl group, and non-limiting examples include, etc.; preferably.

The cycloalkyl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is preferably selected independently from one or more substituents selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl.

The term "alkoxy" refers to -O-(alkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from D atoms, halogens, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclic oxy groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups.

The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent comprising 3 to 20 ring atoms, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), but excluding the ring portion of -O-O-, -O-S-, or -S-S-, and the remaining ring atoms are carbon. Preferably, it comprises 3 to 12 ring atoms, wherein 1 to 4 (e.g., 1, 2, 3, and 4) are heteroatoms; more preferably, it comprises 3 to 8 ring atoms (e.g., 3, 4, 5, 6, 7, and 8), wherein 1 to 3 are heteroatoms (e.g., 1, 2, and 3); even more preferably, it comprises 3 to 6 ring atoms, wherein 1 to 3 are heteroatoms; most preferably, it comprises 5 or 6 ring atoms, wherein 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include oxobutyl, pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and homopiperazinyl. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups.

The term "spiroheterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which one or more ring atoms share a single atom (called a spiro atom), wherein the sulfur may optionally be oxidized (i.e., forming a sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds. Preferably, it is 6 to 14-membered, more preferably 7 to 10-membered (e.g., 7, 8, 9, or 10-membered). Spiroheterocyclic groups are classified into monospirocyclic, bispirocyclic, or polyspirocyclic groups according to the number of shared spiro atoms between rings, with monospirocyclic and bispirocyclic groups being preferred. More preferably, it is a 3/5-membered, 3/6-membered, 4/4-membered, 4/5-membered, 4/6-membered, 5/5-membered, or 5/6-membered monospirocyclic group. Non-limiting examples of spirocyclic groups include:

The term "fused heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system. 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, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, and 6-membered/6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

The term "bridged heterocyclic group" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two non-directly connected atoms. It may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Depending on the number of rings, it can be classified as 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:

The heterocyclic ring comprises a heterocyclic group (including monocyclic, spirocyclic, fused heterocyclic, and bridged heterocyclic rings) fused to an aryl, heteroaryl, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples include:

wait.

The heterocyclic group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is preferably selected independently from one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclicoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl.

The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic) group having a conjugated π-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring comprises an aryl ring fused to a heteroaryl, heterocyclic, or cycloalkyl ring as described above, wherein the ring attached to the parent structure is an aryl ring, and non-limiting examples include:

The aryl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is preferably selected independently from one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl.

The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10-membered (e.g., 5, 6, 7, 8, 9, or 10-membered), more preferably 5- or 6-membered, such as furanyl, thiophene, pyridinyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring comprises a heteroaryl group fused to an aryl, heterocyclic, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include:

The heteroaryl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is preferably selected independently from one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl.

The aforementioned cycloalkyl, heterocyclic, aryl, and heteroaryl residues include residues derived from removing one hydrogen atom from a parent carbon atom, or residues derived from removing two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent, namely "divalent cycloalkyl", "divalent heterocyclic", "aryl", and "heteroaryl".

In the chemical structure of the compounds described in this disclosure, a bond indicates an unspecified configuration; that is, if chiral isomers exist in the chemical structure, the bond can be or simultaneously contain two configurations.

Furthermore, the compounds and intermediates of this disclosure may also exist in different tautomer forms, and all such forms are included within the scope of this disclosure. The terms "tautomer" or "tautomer form" refer to structural isomers of different energies that can interconvert via low energy barriers. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton transfer, such as keto-enol and imine-enamine isomerization. An example of a lactam-lactamimide equilibrium is between A and B as shown below.

All compounds in this disclosure can be classified as type A or type B. All tautomers are within the scope of this disclosure. The nomenclature of compounds does not exclude any tautomers.

On the other hand, the compounds disclosed herein can exist in specific geometric or stereoisomeric forms. This disclosure envisions all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this disclosure. Optically active (R)- and (S)- isomers, as well as D and L isomers, can be prepared by chiral synthesis or with chiral reagents or other conventional techniques. If an enantiomer of a compound of this disclosure is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, wherein the resulting diastereomer mixture is isolated and the auxiliary group is cleaved to provide a 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), it forms a salt of the diastereomer with a suitable optically active acid or base, and then the diastereomer is resolved by conventional methods known in the art, and the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomers is typically accomplished by using chromatography with a chiral stationary phase, optionally combined with chemical derivatization (e.g., from amines to carbamates).

The term "amino protecting group" is used to protect the amino group by a group that is easily removed, so that the amino group remains unchanged when other parts of the molecule react. Non-limiting examples include (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butoxycarbonyl, acetyl, benzyl, allyl, and p-methoxybenzyl. These groups may optionally be replaced by 1-3 substituents selected from halogens, alkoxy groups, or nitro groups. The amino protecting group is preferably (trimethylsilyl)ethoxymethyl and tert-butoxycarbonyl.

The term “hydroxyl protecting group” is a suitable group known in the art for the protection of hydroxyl groups, see “Protective Groups in Organic Synthesis”, ^5th Ed. TW Greene & P. GMWuts for hydroxyl protecting groups. As an example, preferably, the hydroxyl protecting group can be a (C _1-10 alkyl or aryl) ₃ -silyl, such as triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, etc.; it can be a C _1-10 alkyl or substituted alkyl, preferably alkoxy or aryl-substituted alkyl, more preferably C _1-6 alkoxy-substituted C _1-6 alkyl or phenyl-substituted C _1-6 alkyl, most preferably C _1-4 alkoxy-substituted C _1-4 alkyl, such as methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, etc.; it can be a (C _1-10 alkyl or aryl) acyl, such as formyl, acetyl, benzoyl, p-nitrobenzoyl, etc.; it can be a (C _1-6 alkyl or 6 to 10 aryl) sulfonyl; or it can be a (C _1-6 alkoxy or 6 to 10 aryloxy) carbonyl. The hydroxyl protecting group is preferably p-nitrobenzoyl.

The term "heterocyclic alkyl" refers to an alkyl group that is substituted with one or more heterocyclic groups, wherein the heterocyclic group and the alkyl group are as defined above.

The term “heteroarylalkyl” refers to an alkyl group that is substituted with one or more heteroaryl groups, wherein the heteroaryl and alkyl groups are as defined above.

The term “cycloalkyloxy” refers to cycloalkyl-O-, where the cycloalkyl group is as defined above.

The term “heterocyclic oxy group” refers to the heterocyclic group -O-, where the heterocyclic group is as defined above.

The term "aryloxy group" refers to aryl-O-, where the aryl group is as defined above.

The term “heteroaryloxy” refers to heteroaryl-O-, where the heteroaryl group is as defined above.

The term "alkylthio" refers to alkyl-S-, where the alkyl group is as defined above.

The term "halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

The term "haloalkoxy" refers to an alkoxy group that is substituted by one or more halogens, wherein the alkoxy group is as defined above.

The term “deuterated alkyl” refers to an alkyl group that is replaced by one or more deuterium atoms, wherein the alkyl group is as defined above.

The term "hydroxyalkyl" refers to an alkyl group that is replaced by one or more hydroxyl groups, wherein the alkyl group is as defined above.

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

The term "hydroxyl group" refers to -OH.

The term "thiol" refers to -SH.

The term "amino" refers to _-NH2 .

The term "cyano" refers to -CN.

The term "nitro" refers to _-NO2 .

The term "oxo" or "oxo" refers to "=O".

The term "carbonyl" refers to C=O.

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

The term "carboxylic acid ester group" refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O)O-, where alkyl and cycloalkyl are as defined above.

The compounds disclosed herein include other isotope derivatives. The term "isotope derivative" refers to a compound whose structure differs only in the presence of one or more isotopically enriched atoms. For example, compounds having the structure of this disclosure, in which hydrogen is replaced by "deuterium" or "tritium," or fluorine is replaced by ^18F -fluorine labeling ( ^18F isotope), or carbon atoms are replaced by ^11C- , ^13C- , or ^14C -enriched carbon ( ^11C- , ^13C- , or ^14C -carbon labeling; ^11C- , ^13C- , or ^14C -isotope), are all within the scope of this disclosure. Such compounds can be used, for example, as analytical tools or probes in biological assays, or as in vivo diagnostic imaging tracers for diseases, or as tracers for pharmacodynamic, pharmacokinetic, or receptor studies. In the deuterated form of the compound, each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize the deuterated form of the compound by referring to relevant literature. Commercially available deuterated starting materials can be used to prepare deuterated compounds, or they can be synthesized using conventional techniques with deuterating reagents, including but not limited to deuterated boranes, trideuterated borane tetrahydrofuran solutions, deuterated lithium aluminum hydride, deuterated iodoethane, and deuterated iodomethane. Deuterated compounds typically retain activity comparable to their undeuterated counterparts, and deuteration at certain sites can result in better metabolic stability, thus providing certain therapeutic advantages.

"Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility or absence of the event or environment. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may but does not have to be present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

"Substituted" refers to one or more hydrogen atoms in a group, preferably 1 to 5, more preferably 1 to 3 hydrogen atoms, which are independently substituted by the corresponding number of substituents. Those skilled in the art can determine possible or impossible substitutions without much effort (through experimentation or theory). For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

"Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically/pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically/pharmacologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity.

"Pharmacologically acceptable salts" refer to salts of the compounds disclosed herein that are safe and effective in mammalian use and possess the intended biological activity. Salts can be prepared separately during the final isolation and purification of the compounds, or by reacting suitable groups with suitable bases or acids. 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 both inorganic and organic acids.

As used herein, unless otherwise stated, the term "prevention" means the treatment or administration to patients, particularly those at risk of cancer and/or other conditions described herein, prior to the onset of symptoms. The term "prevention" includes the suppression or relief of symptoms of a specific disease. In some embodiments, patients with a family history of the disease are particularly candidates for a preventative approach. Furthermore, patients with a history of symptom recurrence are also potential candidates for prevention. In this regard, the term "prevention" may be used interchangeably with the term "preventative treatment."

For the purposes of pharmaceuticals or pharmacologically active agents, the term "therapeutic effective amount" refers to a sufficient quantity of a drug or agent that is non-toxic but achieves the desired effect. The determination of the effective amount varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. The appropriate effective amount in a given case can be determined by a person skilled in the art based on routine testing.

As used herein, the term "pharmaceutically acceptable" means that these compounds, materials, compositions, and/or dosage forms are suitable for contact with patient tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, within reasonable medical judgment, have a reasonable benefit/risk ratio, and are effective for their intended use.

As used herein, the singular forms of “a,” “an,” and “the” include plural references, and vice versa, unless the context clearly indicates otherwise.

When the term "about" is applied to parameters such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As those skilled in the art will understand, when a parameter is not critical, figures are usually given for illustrative purposes only and not as limitations.

The method for synthesizing the compounds disclosed herein

In order to achieve the purpose of this disclosure, the following technical solution is adopted:

Option 1

The present disclosure discloses a method for preparing a compound of formula (I), or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps:

Compounds of general formula (IA) and (IB) react under basic conditions to give a compound of general formula (I).

in:

Rings A, B, Y, ^R1 to ^R6 , n, p, q and t are as defined in general formula (I).

Option 2

The present disclosure discloses a method for preparing a compound of formula (I), or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps:

Compounds of general formula (IA) and (ID) react under basic conditions to give a compound of general formula (IC).

Compounds of general formula (IC) undergo intramolecular ring-closure reactions under acidic conditions to give compounds of general formula (I).

in:

^Rm is a _C1-6 alkyl group; preferably tert-butyl.

Rings A, B, Y, ^R1 to ^R6 , n, p, q and t are as defined in general formula (I).

Option 3

The present disclosure discloses a method for preparing a compound of formula (I-1) or its tautomers, meso compounds, racemates, enantiomers, diastereomers, mixtures thereof, or pharmaceutically acceptable salts thereof, comprising the following steps:

Compounds of general formula (IA) and (I-1D) react under basic conditions to give a compound of general formula (I-1C).

Compounds of general formula (I-1C) undergo intramolecular ring-closure reactions under acidic conditions to give compounds of general formula (I-1).

in:

^Rm is a _C1-6 alkyl group; preferably tert-butyl.

Rings A, B, Y, ^R1 to ^R6 , n, p, q and t are as defined in general formula (I-1).

Option 4

The present disclosure discloses a method for preparing the compound of formula (I-2) or its tautomers, meso compounds, racemates, enantiomers, diastereomers, mixtures thereof, or pharmaceutically acceptable salts thereof, comprising the following steps:

A compound of general formula (I) or its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or its pharmaceutically usable salts, are prepared by chiral resolution to obtain a single-configuration compound of general formula (I-2), or its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or its pharmaceutically usable salts;

in:

^Rm is a _C1-6 alkyl group; preferably tert-butyl.

Rings A, B, Y, ^R1 to ^R6 , n, p, q and t are as defined in general formula (I).

Option 5

The present disclosure discloses a method for preparing a compound of formula (II) or its tautomers, meso compounds, racemates, enantiomers, diastereomers, mixtures thereof, or pharmaceutically acceptable salts thereof, comprising the following steps:

Compounds of general formula (IIA) and (IB) react under basic conditions to give compounds of general formula (II).

in:

Rings A, B, Y, ^R1 to ^R4 , n, p and t are as defined in general formula (II).

Option Six

The present disclosure discloses a method for preparing a compound of formula (II) or its tautomers, meso compounds, racemates, enantiomers, diastereomers, mixtures thereof, or pharmaceutically acceptable salts thereof, comprising the following steps:

Compounds of general formula (IIA) and (ID) react under basic conditions to give compounds of general formula (IIC).

Compounds of general formula (IIC) undergo intramolecular ring-closure reactions under acidic conditions to give compounds of general formula (II).

in:

^Rm is a _C1-6 alkyl group; preferably tert-butyl.

Rings A, B, Y, ^R1 to ^R4 , n, p and t are as defined in general formula (II).

Option 7

The present disclosure discloses a method for preparing a compound of general formula (II-1) or its tautomers, meso compounds, racemates, enantiomers, diastereomers, mixtures thereof, or pharmaceutically acceptable salts thereof, comprising the following steps:

Compounds of general formula (IIA) and (I-1D) react under basic conditions to give compounds of general formula (II-1C).

Compounds of general formula (II-1C) undergo intramolecular cyclization under acidic conditions to give compounds of general formula (II-1).

in:

^Rm is a _C1-6 alkyl group; preferably tert-butyl.

Rings A, B, Y, ^R1 to ^R4 , n, p and t are as defined in general formula (II-1).

Option 8

The present disclosure discloses a method for preparing a compound of formula (II-2) or its tautomers, meso compounds, racemates, enantiomers, diastereomers, mixtures thereof, or pharmaceutically acceptable salts thereof, comprising the following steps:

A compound of general formula (II) or its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or its pharmaceutically usable salts, are prepared by chiral resolution to obtain a single-configuration compound of general formula (II-2), or its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or its pharmaceutically usable salts;

in:

^Rm is a _C1-6 alkyl group; preferably tert-butyl.

Rings A, B, Y, ^R1 to ^R4 , n, p and t are as defined in general formula (II).

Option Nine

The present disclosure includes a method for preparing a compound of formula (IIG) or its tautomers, meso compounds, racemates, enantiomers, diastereomers, mixtures thereof, or pharmaceutically acceptable salts thereof, comprising the following steps:

Compounds of general formula (IIGA) and compounds of general formula (IB) react under basic conditions to give compounds of general formula (IIG).

in:

^G1 , ^G2 , ^G3 , Y, ^R1 to ^R3 , ^R4a , ^R4b , J, k, n, p and r are as defined in general formula (IIG).

Option 10

The present disclosure includes a method for preparing a compound of formula (IIG) or its tautomers, meso compounds, racemates, enantiomers, diastereomers, mixtures thereof, or pharmaceutically acceptable salts thereof, comprising the following steps:

Compounds of general formula (IIGC) undergo intramolecular ring-closure reactions under acidic conditions to yield compounds of general formula (IIG).

in:

^Rm is a _C1-6 alkyl group; preferably tert-butyl.

^G1 , ^G2 , ^G3 , Y, ^R1 to ^R3 , ^R4a , ^R4b , J, k, n, p and r are as defined in general formula (IIG).

Option 11

The present disclosure discloses a method for preparing a compound of general formula (IIG-1) or its tautomers, meso compounds, racemates, enantiomers, diastereomers, mixtures thereof, or pharmaceutically acceptable salts thereof, comprising the following steps:

Compounds of general formula (IIGC-1) undergo intramolecular ring-closure reactions under acidic conditions to give compounds of general formula (IIG-1).

in:

^Rm is a _C1-6 alkyl group; preferably tert-butyl.

^G1 , ^G2 , ^G3 , Y, ^R1 to ^R3 , ^R4a , ^R4b , J, k, n, p and r are as defined in general formula (IIG-1).

Option Twelve

The present disclosure discloses a method for preparing a compound of general formula (IIG-2) or its tautomers, meso compounds, racemates, enantiomers, diastereomers, mixtures thereof, or pharmaceutically acceptable salts thereof, comprising the following steps:

A compound of general formula (IIG) or its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or its pharmaceutically usable salts, is prepared by chiral resolution to obtain a single-configuration compound of general formula (IIG-2), or its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or its pharmaceutically usable salts;

in:

^Rm is a _C1-6 alkyl group; preferably tert-butyl.

^G1 , ^G2 , ^G3 , Y, ^R1 to ^R3 , ^R4a , ^R4b , J, k, n, p and r are as defined in general formula (IIG).

Option Thirteen

The present disclosure discloses a method for preparing a compound of formula (III) or its tautomers, meso compounds, racemates, enantiomers, diastereomers, mixtures thereof, or pharmaceutically acceptable salts thereof, comprising the following steps:

Compounds of general formula (IIIA) and (IB) react under basic conditions to give compounds of general formula (III).

in:

Y, ^R1 to ^R3 , ^R4a , ^R4b , n, p and r are as defined in general formula (III).

Option Fourteen

The present disclosure discloses a method for preparing a compound of formula (III) or its tautomers, meso compounds, racemates, enantiomers, diastereomers, mixtures thereof, or pharmaceutically acceptable salts thereof, comprising the following steps:

Compounds of general formula (IIIA) and (ID) react under basic conditions to give compounds of general formula (IIIC).

Compounds of general formula (IIIC) undergo intramolecular ring-closure reactions under acidic conditions to yield compounds of general formula (III).

in:

^Rm is a _C1-6 alkyl group; preferably tert-butyl.

Y, ^R1 to ^R3 , ^R4a , ^R4b , n, p and r are as defined in general formula (III).

Option Fifteen

The present disclosure discloses a method for preparing a compound of formula (III-1) or its tautomers, meso compounds, racemates, enantiomers, diastereomers, mixtures thereof, or pharmaceutically acceptable salts thereof, comprising the following steps:

Compounds of general formula (IIIA) and (I-1D) react under basic conditions to give compounds of general formula (III-1C).

Compounds of general formula (III-1C) undergo intramolecular ring-closure reactions under acidic conditions to give compounds of general formula (III-1).

in:

^Rm is a _C1-6 alkyl group; preferably tert-butyl.

Y, ^R1 to ^R3 , ^R4a , ^R4b , n, p and r are as defined in general formula (III-1).

Option Sixteen

The present disclosure discloses a method for preparing a compound of formula (III-2) or its tautomers, meso compounds, racemates, enantiomers, diastereomers, mixtures thereof, or pharmaceutically acceptable salts thereof, comprising the following steps:

A compound of general formula (III) or its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or its pharmaceutically usable salts, are prepared by chiral resolution to obtain a single-configuration compound of general formula (III-2), or its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or its pharmaceutically usable salts;

in:

^Rm is a _C1-6 alkyl group; preferably tert-butyl.

Y, ^R1 to ^R3 , ^R4a , ^R4b , n, p and r are as defined in general formula (III).

The reagents providing alkaline conditions in the above synthesis schemes include organic and inorganic bases. The organic bases include, but are not limited to: triethylamine, N,N-diisopropylethylamine, n-butyllithium, diisopropylaminolithium, 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; potassium carbonate is preferred.

The reagents providing acidic conditions in the above synthesis schemes 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 selected from p-toluenesulfonic acid, p-toluenesulfonic acid monohydrate, and benzenesulfonic acid.

The above reaction is preferably carried out in a solvent, which 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.

Attached Figure Description

Figure 1: Efficacy data of compound 6 and control CC-92480 against NCI-H929 xenografts in CB-17SCID mice.

Figure 2: Effects of compound 6 and control CC-92480 on body weight of CB-17SCID mice.

Detailed Implementation

The following embodiments are used to further describe this disclosure, but these embodiments are not intended to limit the scope of this disclosure.

Example

The structure of the compounds was determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). NMR shifts (δ) are given in units of ^10⁻⁶ (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer or a Bruker AVANCE NEO 500M, with deuterated dimethyl sulfoxide (DMSO- _d₆ ), deuterated chloroform ( _CDCl₃ ), and deuterated methanol ( _CD₃OD ) as solvents, and tetramethylsilane (TMS) as the internal standard.

MS measurements were performed using an Agilent 1200/1290 DAD-6110/6120 Quadrupole MS LC-MS system (manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS), a Waters ACQuity UPLC-QD/SQD system (manufacturer: Waters, MS model: Waters ACQuity Qda Detector/Waters SQ Detector), or a THERMO Ultimate 3000-Q Exactive system (manufacturer: THERMO, MS model: THERMO Q Exactive).

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

Chiral HPLC analysis was performed using an Agilent 1260 DAD high-performance liquid chromatograph.

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

Chiral preparation was performed using a Shimadzu LC-20AP preparative chromatograph.

The CombiFlash rapid preparation system uses the CombiFlash Rf200 (TELEDYNE ISCO).

Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.15 mm to 0.2 mm, and the diameter of the silica gel plates used for thin-layer chromatography separation and purification products is 0.4 mm to 0.5 mm.

Silica gel column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

The average inhibition rate and _IC50 value of the kinase were determined using a NovoStar microplate reader (BMG GmbH, Germany).

The known starting materials disclosed herein can be synthesized using or in accordance with methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, AccelaChemBio Inc., Shanghai Bid Pharmaceutical, and Darui Chemicals.

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

Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

A hydrogen atmosphere refers to a reaction flask connected to a hydrogen balloon with a volume of approximately 1L.

The pressurized hydrogenation reaction was performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

The microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.

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

Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃～30℃.

The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent used in the reaction, the eluent system for column chromatography used to purify the compounds, and the developing solvent system for TLC included: A: dichloromethane/methanol system; B: n-hexane/ethyl acetate system. The volume ratio of the solvent was adjusted according to the polarity of the compounds, and small amounts of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

Example 1

4-(4-((4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)oxy)methyl)phenyl)thio)piperidin-1-yl)-3-fluorobenzonitrile1

first step

4-((4-formylphenyl)thio)piperidine-1-carboxylic acid tert-butyl ester 1b

4-Mercaptopril-1-carboxylic acid tert-butyl ester 1a (2.05 g, 9.44 mmol, Bio-Dextrose), 4-fluorobenzaldehyde (1.17 g, 9.44 mmol), and potassium carbonate (2.86 g, 20.71 mmol) were added to N,N-dimethylformamide (40 mL). The reaction mixture was heated to 120 °C and reacted overnight. After the reaction was complete, the reaction mixture was diluted with water (200 mL) and 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 using eluent system B to give title compound 1b (2.66 g, yield: 88%).

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

Step 2

4-(piperidin-4-ylthio)benzaldehyde hydrochloride 1c

Compound 1b (2.66 g, 8.28 mmol) was dissolved in 20 mL of 4 M hydrogen chloride solution of 1,4-dioxane, and the mixture was stirred for about 3 hours. The reaction mixture was filtered, and the filter cake was washed with ethyl acetate (3 mL × 3) and allowed to air dry to give compound 1c. The crude product was used directly in the next reaction.

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

Step 3

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

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

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

Step 4

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

Compound 1d (150 mg, 0.44 mmol) was added to methanol (8 mL) under ice bath conditions, followed by potassium borohydride (29 mg, 0.53 mmol). The reaction mixture was reacted under ice bath conditions for 2 hours. The reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated sodium chloride aqueous solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system B to give the title compound 1e (150 mg, yield: 99%).

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

Step 5

4-(4-((4-(bromomethyl)phenyl)thio)piperidin-1-yl)-3-fluorobenzonitrile 1f

Compound 1e (150 mg, 0.43 mmol) was added to dichloromethane (8 mL) under ice bath conditions, followed by the addition of triphenylphosphine (150 mg, 0.57 mmol) and carbon tetrabromide (189 mg, 0.57 mmol). The reaction was carried out under ice bath conditions for 20 minutes, then allowed to rise to room temperature for 2 hours. The reaction mixture was concentrated, and the residue was purified by column chromatography using eluent system B to give the title compound 1f (120 mg, yield: 68%).

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

Step 6

4-(4-((4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)oxy)methyl)phenyl)thio)piperidin-1-yl)-3-fluorobenzonitrile1

1 g (25 mg, 0.096 mmol, Jiangsu Aikon Biopharmaceutical R&D Co., Ltd.) of 3-(4-hydroxy-1-oxoisoindoline-2-yl)piperidine-2,6-dione and 27 mg (0.096 mmol) of anhydrous potassium carbonate were added to 3 mL of N,N-dimethylacetamide, followed by compound 1f (38 mg, 0.093 mmol). The reaction mixture was reacted for 16 hours. After filtration, the reaction solution was subjected to high performance liquid chromatography (Waters 2767-SQ Detecor 2, elution system: 10 mmol/L ammonium bicarbonate aqueous solution and acetonitrile, acetonitrile gradient: 55%-70%, flow rate: 30 mL/min) to obtain title compound 1 (16 mg, yield 28%).

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

¹ H NMR (400MHz, DMSO-d ₆ )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).

Example 2

4-(4-((4-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)oxy)methyl)phenyl)thio)piperidin-1-yl)-3-fluorobenzonitrile 2

2-(2,6-dioxadiazine-3-yl)-4-hydroxyisoindoline-1,3-dione 2a (30 mg, 0.113 mmol, Bio-Pharmaceutical) 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 carried out for 16 hours. After filtration, the reaction solution was prepared by high performance liquid chromatography (Waters 2767-SQDetecor2, elution system: 10 mmol/L ammonium bicarbonate aqueous solution and acetonitrile, acetonitrile gradient: 55%-75%, flow rate: 30 mL/min) to obtain title compound 2 (30 mg, yield 68%).

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

¹ H NMR (500MHz, DMSO-d ₆ )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).

Example 3

(S)-4-(4-((4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)phenyl)thio)piperidin-1-yl)-3-fluorobenzonitrile3

first step

(S)-5-amino-4-(4-((4-(((1-(4-cyano-2-fluorophenyl)piperidin-4-yl)thio)benzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxovalerate tert-butyl ester 3b

(S)-5-amino-4-(4-hydroxy-1-oxoisoindoline-2-yl)-5-oxovalerate 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), compound 1f (350 mg, 0.863 mmol) was added, and the reaction was carried out 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, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography with eluent system B to give title compound 3b (500 mg, yield: 88%).

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

Step 2

(S)-4-(4-((4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)phenyl)thio)piperidin-1-yl)-3-fluorobenzonitrile3

Compound 3b (500 mg, 0.758 mmol) was added to acetonitrile (30 mL), followed by p-toluenesulfonic acid monohydrate (187 mg, 0.983 mmol). The mixture was stirred at 85 °C for 10 hours. The solvent was removed from the reaction mixture under reduced pressure, water (20 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed successively with saturated sodium bicarbonate solution (20 mL) and saturated sodium chloride solution (20 mL), then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was then subjected to 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 give title compound 3 (30 mg, yield: 7%, ee: 99.6%). Chiral HPLC analysis: retention time 31.81 min, chiral purity: 99.6% (column: Chiralpak IE 150*4.6mm, 5μm; column temperature: 35℃, flow rate: 1.0mL/min, mobile phase: n-hexane/ethanol/diethylamine = 20/80/0.08 (v/v/v)).

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

¹ H NMR (500MHz, DMSO-d ₆ )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).

Example 4

(S)-4-(4-((4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)-2-fluorophenyl)thio)piperidin-1-yl)-3-fluorobenzonitrile4

first step

4-((2-fluoro-4-formylphenyl)thio)piperidine-1-carboxylic acid tert-butyl ester 4b

Compound 1a (600 mg, 2.76 mmol), 3,4-difluorobenzaldehyde 4a (470 mg, 3.3 mmol), and potassium carbonate (954 mg, 6.90 mmol) were added to N,N-dimethylformamide (12 mL). The reaction mixture was heated to 80 °C and reacted for 2 hours. The reaction mixture was diluted with water (200 mL) and 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 using eluent system B to give title compound 4b (920 mg, yield: 98%).

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

Step 2

3-Fluoro-4-(piperidin-4-ylthio)benzaldehyde trifluoroacetate 4c

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

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

Step 3

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

Compound 4c (960 mg, 2.72 mmol), 3,4-difluorobenzonitrile (756 mg, 5.43 mmol, Bio-Pharmaceutical), and potassium carbonate (1.50 g, 10.86 mmol) were added to N,N-dimethylformamide (12 mL), and the reaction mixture was heated to 80 °C and reacted overnight. Water (50 mL) was added to the reaction mixture, 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 using eluent system B to give the title compound 4d (890 mg, yield: 91%).

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

Step 4

3-Fluoro-4-(4-((2-Fluoro-4-(hydroxymethyl)phenyl)thio)piperidin-1-yl)benzonitrile 4e

Compound 4d (260 mg, 0.725 mmol) was added to methanol (8 mL) under ice bath conditions, followed by sodium borohydride (55 mg, 1.45 mmol). The reaction mixture was stirred under ice bath conditions for 1 hour. The reaction solution was quenched with saturated ammonium chloride solution (10 mL) and then extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system B to give the title compound 4e (250 mg, yield: 96%).

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

Step 5

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

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

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

Step 6

(S)-5-amino-4-(4-((4-(((1-(4-cyano-2-fluorophenyl)piperidin-4-yl)thio)-3-fluorobenzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxovalerate tert-butyl ester 4g

Compound 3a (56 mg, 0.169 mmol) and anhydrous potassium carbonate (42 mg, 0.307 mmol) were added to N,N-dimethylformamide (3 mL), followed by compound 4f (65 mg, 0.153 mmol). The reaction mixture was reacted for 1 hour. The reaction solution was poured into ice water (20 mL) and 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 give the title compound 4 g (95 mg, yield: 91%).

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

Step 7

(S)-4-(4-((4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)-2-fluorophenyl)thio)piperidin-1-yl)-3-fluorobenzonitrile4

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

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

¹ H NMR (500MHz, DMSO-d ₆ )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),

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

Example 5

(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

Using the synthetic route of compound 4 in Example 4, wherein the starting compound 3,4-difluorobenzaldehyde was replaced with the starting compound 2,4-difluorobenzaldehyde, title compound 5 (90 mg) was obtained.

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

¹ H NMR (500MHz, DMSO-d ₆ )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,1H),2 .61-2.54(m,1H),2.46-2.41(m,1H),2.02-1.94(m,3H),1.70-1.59(m,2H).

Example 6

(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

first step

4-((5-formylpyridin-2-yl)thio)piperidine-1-carboxylic acid tert-butyl ester 6b

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 mixture was heated to 80 °C and reacted for 1 hour. The reaction mixture was diluted with water (30 mL) and 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 using eluent system B to give title compound 6b (1.0 g, yield: 96%).

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

Step 2

6-(piperidin-4-ylthio)nicotinaldehyde trifluoroacetate 6c

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

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

Step 3

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

Compound 6c (760 mg, 2.94 mmol), 3,4-difluorobenzonitrile (817 mg, 5.87 mmol), and potassium carbonate (1.22 g, 8.81 mmol) were added to N,N-dimethylformamide (15 mL), and the reaction mixture was heated to 80 °C and reacted overnight. Water (50 mL) was added to the reaction mixture, 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 using eluent system B to give the title compound 6d (850 mg, yield: 84%).

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

Step 4

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

Compound 6d (600 mg, 1.76 mmol) was added to methanol (10 mL) under ice bath conditions, followed by the slow addition of sodium borohydride (133 mg, 3.51 mmol). The reaction mixture was reacted for 1 hour. The reaction solution was quenched with water (10 mL) and then extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system B to give the title compound 6e (580 mg, yield: 96%).

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

Step 5

4-(4-((5-(bromomethyl)pyridin-2-yl)thio)piperidin-1-yl)-3-fluorobenzonitrile 6f

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

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

Step 6

(S)-5-amino-4-(4-((6-((1-(4-cyano-2-fluorophenyl)piperidin-4-yl)thio)pyridin-3-yl)methoxy)-1-oxoisoindolin-2-yl)-5-oxovalerate tert-butyl ester 6g

Compound 3a (82 mg, 0.246 mmol) and anhydrous potassium carbonate (65 mg, 0.468 mmol) were added to N,N-dimethylformamide (3 mL), followed by compound 6f (95 mg, 0.244 mmol). The reaction mixture was reacted for 2 hours. The reaction solution was poured into ice water (10 mL) and 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 give the title compound 6 g (145 mg, yield: 94%).

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

Step 7

(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

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

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

¹ H 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).

Example 6’

(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′

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

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

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

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

¹ H NMR (500MHz, DMSO-d ₆ ): 10.97(s,1H),8.59(s,1H),7.78(dd,1H),7.68(d,1H),7.56(d,1H),7.5 0(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).

Example 7

(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

Using the synthetic route of compound 4 in Example 4, wherein the starting compound 3,4-difluorobenzaldehyde was replaced with the starting compound 2-chloropyrimidine-5-carboxaldehyde, the title compound 7 (38 mg) was obtained.

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

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).

Example 8

(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-fluorobenzonitrile8

Using the synthetic route of compound 4 in Example 4, wherein the starting compound 3,4-difluorobenzaldehyde was replaced with the starting compound 2-fluoropyridine-5-carboxaldehyde, and the compound 3a in step six was replaced with (S)-5-amino-4-(6-fluoro-4-hydroxy-1-oxoisoindoline-2-yl)-5-oxovalerate tert-butyl ester (prepared by the method disclosed in Example 7 on page 99 of the specification in patent application "WO2019040274A1"), title compound 8 (33 mg) was obtained.

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

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).

Example 9

(S)-4-(4-((6-(((2-(2,6-dioxopiridine-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)pyridin-3-yl)thio)piperidine-1-yl)-3-fluorobenzonitrile 9

Using the synthetic route of compound 4 in Example 4, wherein the starting compound 3,4-difluorobenzaldehyde was replaced with the starting compound 5-fluoropyridine-2-carboxaldehyde, title compound 9 (45 mg) was obtained.

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

^1H 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).

Example 10

(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

Using the synthetic route of compound 4 in Example 4, wherein the starting compound 3,4-difluorobenzaldehyde was replaced with the starting compound 2,3,4-trifluorobenzaldehyde, title compound 10 (63 mg) was obtained.

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

¹ H NMR (500MHz, DMSO-d ₆ ): 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),4.40(d,1H),4 .25(d,1H),3.67-3.46(m,3H),3.06-2.82(m,3H),2.64-2.56(m,1H),2.46-2.37(m,1H),2.07-1.90(m,3H),1.73-1.56(m,2H).

Example 11

(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

Using the synthetic route of compound 4 in Example 4, wherein the starting compound 3,4-difluorobenzaldehyde was replaced with the starting compound 2,4,5-trifluorobenzaldehyde, title compound 11 (70 mg) was obtained.

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

¹ H NMR (500MHz, DMSO-d ₆ ): 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,1H),3.72-3 .61(m,1H),3.58-3.46(m,2H),3.07-2.96(m,2H),2.95-2.83(m,1H),2.6 5-2.56(m,1H),2.44-2.38(m,1H),2.09-1.90(m,3H),1.74-1.58(m,2H).

Example 12

(S)-4-(4-((4-(((2-(2,6-dioxopiridine-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)-2,6-difluorophenyl)thio)piperidine-1-yl)-3-fluorobenzonitrile 12

Using the synthetic route of compound 4 in Example 4, wherein the starting compound 3,4-difluorobenzaldehyde was replaced with the starting compound 3,4,5-trifluorobenzaldehyde, title compound 12 (20 mg) was obtained.

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

¹ H NMR (500MHz, DMSO-d ₆ ): δ10.99(s,1H),7.67(dd,1H),7.54(dd,1H),7.50(t,1H),7.43-7.33(m ,3H),7.29(d,1H),7.11(t,1H),5.31(s,2H),5.13(dd,1H),4.50(d,1H), 4.34(d,1H),3.58-3.42(m,2H),3.40-3.34(m,1H),3.01-2.84(m,3H),2. 68-2.55(m,1H),2.46-2.35(m,1H),2.05-1.85(m,3H),1.65-1.52(m,2H).

Example 13

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

Using the synthetic route of compound 4 in Example 4, wherein the starting compound 3,4-difluorobenzaldehyde was replaced with the starting compound 6-fluoro-2-methyl-3-pyridinecarboxaldehyde, title compound 13 (60 mg) was obtained.

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

¹ H NMR (500MHz, DMSO-d ₆ ): 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).

Example 14

(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

Using the synthetic route of compound 4 in Example 4, wherein the starting compound 3,4-difluorobenzaldehyde was replaced with the starting compound 3-chloro-4-fluorobenzaldehyde, title compound 14 (22 mg) was obtained.

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

¹ H NMR (500MHz, DMSO-d ₆ ): 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),4.43(d,1H),4 .28(d,1H),3.71-3.61(m,1H),3.58-3.47(m,2H),3.08-2.98(m,2H),2.96-2.85(m ,1H),2.66-2.54(m,1H),2.46-2.37(m,1H),2.12-1.93(m,3H),1.75-1.60(m,2H).

Example 15

4-(3-((5-(((2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)oxy)methyl)pyridin-2-yl)thio)pyrrolidine-1-yl)-3-fluorobenzonitrile 15

Using the synthetic route of compound 4 in Example 4, wherein starting compound 1a (4-mercaptopril-1-carboxylic acid tert-butyl ester) was replaced with 3-mercaptopril-1-carboxylic acid tert-butyl ester, and starting compound 3,4-difluorobenzaldehyde was replaced with starting compound 2-fluoropyridine-5-carboxaldehyde, title compound 15 (39 mg) was obtained.

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

^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),4.49-4.3 6(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).

Example 16

(S)-4-(3-((4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)phenyl)thio)azacyclobutane-1-yl)-3-fluorobenzonitrile 16

Using the synthetic route of compound 4 in Example 4, wherein starting compound 1a (4-mercaptopril-1-carboxylic acid tert-butyl ester) was replaced with 3-mercaptoazacyclobutane-1-carboxylic acid tert-butyl ester, and starting compound 3,4-difluorobenzaldehyde was replaced with starting compound 4-fluorobenzaldehyde, title compound 16 (15 mg) was obtained.

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

¹ H NMR (500MHz, DMSO-d ₆ ): 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).

Example 17

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

first step

4-((6-fluoro-5-formylpyridin-2-yl)thio)piperidine-1-carboxylic acid tert-butyl ester 17b

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 the reaction was carried out for 2 hours. The reaction solution was diluted with water (200 mL), and 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 using eluent system B to give title compound 17b (1.0 g, 42% yield).

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

Step 2

4-((6-fluoro-5-(hydroxymethyl)pyridin-2-yl)thio)piperidine-1-carboxylic acid tert-butyl ester 17c

Compound 17b (1.0 g, 2.94 mmol) was dissolved in a mixed solvent of tetrahydrofuran (20 mL) and methanol (2 mL). Sodium borohydride (223 mg, 5.90 mmol) was slowly added under ice bath conditions, and the reaction was allowed to proceed for 2 hours. The reaction mixture was quenched with water (50 mL) and then extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system B to give the title compound 17c (910 mg, 90% yield).

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

Step 3

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

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

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

Step 4

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

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

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

Step 5

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

Compound 17e (310 mg, 0.86 mmol) was added to dichloromethane (10 mL), along with triphenylphosphine (360 mg, 1.37 mmol) and carbon tetrabromide (455 mg, 1.37 mmol), and the reaction was allowed to proceed for 12 hours. The reaction mixture was diluted with water (50 mL), extracted with dichloromethane (30 mL × 3), and the organic phases were combined. The mixture was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system B to give the title compound 17f (340 mg, 93% yield).

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

Step 6

(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-oxovalerate tert-butyl ester 17g

Compound 3a (268 mg, 0.80 mmol) and anhydrous potassium carbonate (223 mg, 1.61 mmol) were added to N,N-dimethylformamide (10 mL), followed by compound 17f (340 mg, 0.80 mmol). The reaction mixture was reacted for 1 hour. The reaction solution was poured into ice water (20 mL) and 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 give the title compound 17 g (540 mg, yield: 99%).

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

Step 7

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

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

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

¹ H NMR (500MHz, DMSO-d ₆ )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,1H),4.00-3 .88(m,1H),3.58-3.45(m,2H),3.16-3.04(dd,2H),2.98-2.84(m,1H),2.66-2.55( m,1H),2.48-2.35(m,1H),2.23-2.12(m,2H),2.08-1.92(m,1H),1.82-1.70(m,2H).

Example 18

(S)-4-(4-((4-(((2-(2,6-dioxopiridine-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)-3,5-difluorophenyl)thio)piperidine-1-yl)-3-fluorobenzonitrile 18

Using the synthetic route of compound 17 in Example 17, the starting compound 2,6-difluoropyridine-3-carboxaldehyde was replaced with the starting compound 2,4,6-trifluorobenzaldehyde to obtain title compound 18 (27 mg).

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

¹ H NMR (500MHz, DMSO-d ₆ ): 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).

Biological evaluation

Test Example 1: Biological Evaluation of NCI-H929 Proliferation Experiment

The following method was used to determine the inhibitory activity of the disclosed compound on the proliferation of NCI-H929 cells. The experimental method is briefly described below.

NCI-H929 cells (ATCC, CRL-9068) were cultured in complete medium containing 10% fetal bovine serum (Corning, 35-076-CV) and 0.05 mM 2-mercaptoethanol (Sigma, M3148) in RPMI 1640 medium (Hyclone, SH30809.01). On day 1, NCI-H929 cells were seeded at a density of 6000 cells/well in 96-well plates using complete medium, with 100 μL of cell suspension per well. Simultaneously, 10 μL of serially diluted test compounds prepared in complete medium were added to each well. The compounds were first dissolved in DMSO at an initial concentration of 10 mM, and then serially diluted 5-fold to a total of 9 concentrations. The blank control was 100% DMSO. Then, 5 μL of the DMSO-dissolved compound was added to 95 μL of complete medium, resulting in a 20-fold dilution of the compound. Finally, 10 μL of the compound diluted in complete culture medium was added to each well of the cell suspension, resulting in nine concentration points with a 5-fold serial dilution starting from 50 μM. A blank control containing 0.5% DMSO was included. The plates were incubated at 37°C in a 5% CO2 cell culture incubator for 5 days. On the sixth day, the 96-well cell culture plates were removed, and 50 μL of luminescent cell activity assay reagent (Promega, G7573) was added to each well. After incubation at room temperature for 10 minutes, the luminescence signal values were read using a multi-functional microplate reader (PerkinElmer, EnVision2015). The _IC50 values of the compound's inhibitory activity were calculated using Graphpad Prism software, as shown in Table 1.

Table 1. _IC50 values of the disclosed compounds for inhibiting the proliferation of NCI-H929 cells.

compound <![CDATA[IC₅₀(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

Conclusion: The compound disclosed herein exhibits excellent activity in inhibiting the proliferation of NCI-H929 cells.

Test Example 2: Efficacy Test

1. Experimental Objective

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

2. Experimental reagents

Compound of Example 6;

Comparative example CC-92480 (see compound 2 in WO2019014100A1, synthesized according to the method disclosed therein).

Compound 6 and control example CC-92480 were prepared with 5% DMSO + 20% PEG400 + 70% (10% TPGS) + 5% (1% HPMC K100LV).

3. Experimental methods and materials

3.1 Laboratory animals and their housing conditions

Thirty female CB-17 SCID mice were purchased from Beijing Vital River Laboratory Animal Co., Ltd. (Certificate No.: 20170011006049, SCXK(沪)2017-0011). They weighed approximately 19g at the time of purchase. Five mice were housed per cage, with a 12/12-hour light/dark cycle, a constant temperature of 23±1℃, and a humidity of 50-60%. They had free access to food and water.

3.2 Grouping of animals:

After acclimatization, CB-17 SCID rats were grouped as follows:

Note: qd means once a day; i.g means by gavage.

3.3 Experimental Methods:

Thirty female CB-17SCID mice were subcutaneously injected with 5 × ^10⁶ NCI-H929 cells/mouse/100 μL (containing 50 μL Matrigel) in the right rib area. After 10 days, when the tumor volume of the tumor-bearing mice reached approximately 200 ^mm³ , the mice were randomly divided into three groups according to tumor volume and body weight: solvent control group, CC-92480-1mpk, and compound-1mpk (Example 6), with seven mice in each group. The day of grouping was designated as Day 0 (D0), and the drug was administered once daily by gavage for a total of 11 days (Table 2). The tumor volume of the tumor-bearing mice was measured twice a week using calipers, and the body weight was measured using a balance, and the data were recorded. When the tumor volume reached 2000 ^mm³ , or most tumors ruptured, or the body weight decreased by 20%, the tumor-bearing animals were euthanized as the experimental endpoint.

3.4 Data Statistics

All data were plotted and statistically analyzed using Excel and GraphPad Prism 5 software.

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

The relative tumor proliferation rate T/C (%) = (TT ₀ )/(CC ₀ )×100 (%), where: T and C are the tumor volumes of the treatment group and the control group at the end of the experiment; T ₀ and C ₀ are the tumor volumes at the beginning of the experiment.

Tumor inhibition rate TGI (%) = 1 - T/C (%). When TGI (%) exceeds 100%, the specific value will not be displayed, but only >100% will be used.

Tumor regression (%) = [( _T0 - T)/ _T0 ] × 100 (%).

4. Results

The efficacy data of compound CC-92480 and control compound CC-92480 against NCI-H929 xenografts in CB-17SCID mice are shown in Table 2 and Figure 1 below.

The effects of compound 6 and control CC-92480 on body weight of CB-17SCID mice are shown in Figure 2.

Table 2. Efficacy of the disclosed compounds against NCI-H929 xenografts in CB-17SCID mice.

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

5. Conclusion

In Example 6, the compound was administered once daily, starting 10 days after tumor cell transplantation. Significant tumor regression occurred after 11 days of administration. The calculated tumor inhibition rate was >100%, and the tumor regression rate was 88%, showing a statistically significant difference compared to the same dose of CC-92480 at the experimental endpoint (p < 0.05). Furthermore, the administration had no effect on mouse body weight. Under the same conditions, the tumor regression rate of the control group CC-92480 was 34%.

Test Example 3: Pharmacokinetic Evaluation

1. Overview

Using mice as test animals, the plasma drug concentrations at different time points after oral administration of the compound of Example 6 and the control CC-92480 were determined by LC/MS/MS. The pharmacokinetic behavior of this compound in mice was investigated to evaluate its pharmacokinetic characteristics.

2. Test Plan

2.1 Test Drugs

Compound of Example 6 and Control Example CC-92480.

2.2 Experimental Animals

Eighteen female mice were purchased from Vital River Laboratory Animal Co., Ltd., Animal Production License No.: SCXK(沪)2017-0005.

2.3 Drug Preparation

Weigh the compound from Example 6, add 5% by volume of DMSO and 5% Tween 80 (Shanghai Titan Technology Co., Ltd.) to dissolve it, and then add 90% physiological saline to prepare a clear solution of 0.1 mg/mL.

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

2.4 Administration

Nine mice were administered the compound of Example 6 by gavage at a dose of 2 mg/kg and an administration volume of 0.2 mL/10 g.

Nine mice were administered the control compound CC-92480 by gavage at a dose of 2 mg/kg and an administration volume of 0.2 mL/10 g.

3. Operation

Mice were administered compound 6 (Example 6) and control CC-92480 via gavage. Blood samples of 0.2 mL (3 animals per time point) were collected before administration and at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours after administration. The samples were placed in EDTA-K2 anticoagulant tubes, centrifuged at 10000 rpm for 1 minute (4°C), and plasma was separated within 1 hour and stored at -20°C for analysis. The blood collection and centrifugation processes were performed under ice bath conditions.

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

4. Pharmacokinetic Parameter Results

The pharmacokinetic parameters of the compounds disclosed herein are shown in Table 3 below.

Table 3 Pharmacokinetic parameters of the compounds disclosed herein

Conclusion: The compound disclosed in this study exhibits good pharmacokinetic absorption and has advantages in pharmacokinetic properties.

Test Example 4: Evaluation of the plasma stability of the disclosed compounds

1. Abstract

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

2. Test Plan

2.1 Test Drugs

Compound of Example 6 and Control Example CC-92480.

2.2 Test plasma

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

2.3 Preparation of Compound Solutions

Weigh a certain amount of the compound from Example 6 and add DMSO to prepare a 30 mM stock solution. Take a certain volume of the stock solution and dilute it with DMSO to prepare a 1600 μM solution I. Then take a certain volume of the 1600 μM solution I and dilute it with 50% methanol to prepare a 16 μM working solution II. Prepare the 30 mM stock solution, 1600 μM solution I', and 16 μM working solution II' of CC-92480 using the above method.

2.4 Sample incubation

Take 5 μL of the working solution of 16 μM compound from Example 6 and control example CC-92480, and add them to 75 μL of plasma to bring the final concentration of the compound to 1 μM. Incubate the samples in a 37°C water bath for 0, 15, 30, 60, 90, 120, and 180 minutes. After incubation, add 240 μL of acetonitrile containing the internal standard, then shake at 800 rpm for 10 minutes, centrifuge at 3700 rpm at 4°C for 20 minutes, and analyze the supernatant using LC-MS with an injection volume of 2 μL.

3. Results

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

Table 4. Stability data of the disclosed compounds in monkey plasma.

serial number <![CDATA[T_1/2(min)/monkey]]> Example 6 806 CC-92480 199

Conclusion: The disclosed compound has a stability advantage in monkey plasma.

Claims (34)

1. A compound of general formula (IIG) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, mixture thereof, or pharmaceutically acceptable salt thereof: in: Y is _CH2 or C(O); ^R1 may be the same or different, and each is independently selected from hydrogen atoms, halogens and _C1-6 alkyl groups; ^R2 is a hydrogen atom; ^G1 , ^G2 and ^G3 may be the same or different, and each is independently a carbon atom or a nitrogen atom; ^R3 may be the same or different, and each is independently selected from hydrogen atoms, halogens and _C1-6 alkyl groups; R ^4a is a 6- to 10-membered aryl group, wherein the 6- to 10-membered aryl group is optionally substituted by one or more substituents selected from halogen, _C1-6 alkyl, _C1-6 alkoxy, halo- _C1-6 alkyl and cyano; R ^4b may be the same or different, and each is independently selected from hydrogen atoms, halogens and _C1-6 alkyl groups; r is 0, 1, or 2; J is either 0 or 1; k is 0 or 1; n is 0, 1, 2, or 3; p can be 0, 1, 2, 3, or 4. 2. The compound of general formula (IIG) according to claim 1, or a tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is of general formula (IIG-1) or general formula (IIG-2), or a tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof: in: ^G1 , ^G2 , ^G3 , Y, ^R1 to ^R3 , ^R4a , ^R4b , J, k, n, p and r as defined in claim 1. 3. The compound of formula (IIG) according to claim 1, or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ^G2 is a nitrogen atom and ^G1 and ^G3 are carbon atoms; or G1 is ^a nitrogen atom and G2 and ^G3 are carbon atoms; or ^G1 , ^{G2 ,} and ^G3 are all carbon atoms; or ^G2 and ^G3 are both nitrogen atoms and ^G1 is a carbon atom. 4. The compound of general formula (IIG) according to claim 1, or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically usable salt thereof, wherein ^G2 is a nitrogen atom and ^G1 and ^G3 are carbon atoms. 5. The compound of general formula (IIG) according to claim 1, or a tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is of general formula (III), or a tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof: in: r is 0, 1, or 2; Y, ^R1 to ^R3 , ^R4a , ^R4b , n and p are as defined in claim 1. 6. The compound of general formula (IIG) according to claim 1, or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is of general formula (III-1) or general formula (III-2), or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof: in: Y, ^R1 to ^R3 , ^R4a , ^R4b , r, n and p are as defined in claim 1. 7. The compound of general formula (IIG) according to claim 1, or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Y is _CH2 . 8. The compound of general formula (IIG) according to claim 1, or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically usable salt thereof, wherein ^R4a is a hydrogen atom and ^R4b is a hydrogen atom. 9. The compound of general formula (IIG) according to claim 1, or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically usable salt thereof, wherein ^R1 is a hydrogen atom. 10. The compound of general formula (IIG) according to claim 1, or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically usable salt thereof, wherein ^R3 are the same or different and are each independently a hydrogen atom or a halogen. 11. The compound of general formula (IIG) according to claim 1, or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically usable salt thereof, wherein ^R3 is a hydrogen atom. 12. The compound of general formula (IIG) according to claim 1, or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1. 13. The compound of general formula (IIG) according to claim 1, or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2. 14. The compound of general formula (IIG) according to claim 1, or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein r is 0 or 1. 15. The compound of general formula (IIG) according to claim 1, or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, selected from the following compounds: 16. A compound of general formula (IIGA) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, mixture thereof, or salt thereof. in: ^G1 , ^G2 , ^G3 , ^R2 , ^R3 , ^R4a , ^R4b , J, k, p, and r are as defined in claim 1. 17. The compound of general formula (IIGA) according to claim 16, or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, mixture thereof, or salt thereof, selected from the group consisting of: 18. A compound of general formula (IIGC) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, mixture thereof, or salt thereof. in: R ^m is a _C1-6 alkyl group; ^G1 , ^G2 , ^G3 , Y, ^R1 to ^R3 , ^R4a , ^R4b , J, k, r, n and p as defined in claim 1. 19. The compound of general formula (IIGC) according to claim 18, or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a salt thereof, wherein ^Rm is tert-butyl. 20. The compound according to claim 18, or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, mixture thereof, or salt thereof, wherein the compound is selected from the following compounds: 21. A method for preparing a compound of general formula (IIG) according to claim 1, or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising: Compounds of general formula (IIGA) react with compounds of general formula (IB) to give compounds of general formula (IIG). in: ^G1 , ^G2 , ^G3 , Y, ^R1 to ^R3 , ^R4a , ^R4b , J, k, n, p and r as defined in claim 1. 22. A method for preparing a compound of general formula (IIG) according to claim 1, or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising: Compounds of general formula (IIGC) undergo intramolecular ring-closure reactions to give compounds of general formula (IIG). in: R ^m is a _C1-6 alkyl group; ^G1 , ^G2 , ^G3 , Y, ^R1 to ^R3 , ^R4a , ^R4b , J, k, n, p and r as defined in claim 1. 23. The method of claim 22, wherein ^Rm is tert-butyl. 24. A pharmaceutical composition comprising a compound according to any one of claims 1 to 15, or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients. 25. Use of the compound of any one of claims 1 to 15, or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 24, in the preparation of a medicament for the treatment and/or prevention of diseases associated with CRBN protein. 26. Use of the compound or tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 24, in the preparation of a medicament for the treatment and/or prevention of cancer, angiogenesis-related conditions, pain, macular degeneration or related syndromes, skin diseases, lung diseases, asbestos-related diseases, parasitic diseases, immunodeficiency diseases, CNS diseases, CNS injuries, atherosclerosis or related conditions, sleep disorders or related conditions, infectious diseases, hemoglobinopathies or related conditions, or TNFα-related conditions. 27. Use of the compound of any one of claims 1 to 15, or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 24, in the preparation of a medicament for the treatment and/or prevention of cancer or CNS damage. 28. The use according to claim 26 or 27, wherein the cancer is selected from leukemia, myeloma, lymphoma, melanoma, skin cancer, liver cancer, kidney cancer, lung cancer, nasopharyngeal carcinoma, 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 carcinoma, 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 lenalidomide- or pomalidomide-resistant. 33. The use according to claim 28, wherein the lymphoma is selected from 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 angiogenesis-related diseases are selected from arthritis, endometriosis, Crohn's disease, heart failure, severe heart failure, kidney injury, endotoxemia, toxic shock syndrome, osteoarthritis, retroviral replication, wasting diseases, meningitis, silica-induced fibrosis, asbestos-induced fibrosis, veterinary diseases, malignant tumor-related hypercalcemia, stroke, circulatory shock, periodontitis, gingivitis, megaloblastic anemia, refractory anemia, and 5q deletion syndrome.