CN114456173A

CN114456173A - Fused ring group substituted cycloheximide derivatives, preparation method thereof and application thereof in medicines

Info

Publication number: CN114456173A
Application number: CN202111317092.2A
Authority: CN
Inventors: 贾敏强; 陈刚; 郭沛骅; 杨方龙; 贺峰; 陶维康
Original assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Current assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Priority date: 2020-11-10
Filing date: 2021-11-09
Publication date: 2022-05-10
Anticipated expiration: 2041-11-09
Also published as: CN114456173B

Abstract

The disclosure relates to fused ring group substituted cycloheximide derivatives, a preparation method thereof and application thereof in medicine. Specifically, the disclosure relates to a fused ring group substituted cycloheximide derivative shown as a general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, and an application of the derivative as a therapeutic agent, in particular an application of the derivative as a Cereblan regulator in the field of treatment of multiple myeloma.

Description

Fused ring group substituted cycloheximide derivatives, preparation method thereof and application thereof in medicines

Technical Field

The disclosure belongs to the field of medicines, and relates to a fused ring group substituted cycloheximide derivative, a preparation method thereof and application thereof in medicines. In particular to a fused ring group substituted cycloheximide derivative shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, and application of the derivative as a Cereblon regulator in the field of treating multiple myeloma.

Background

MM (multiple myeloma) is a malignant tumor, and its major symptoms include hypercalcemia, kidney damage, anemia, and bone disease. MM is the second most common hematological malignancy second to non-hodgkin lymphoma, with 4-6 per 100,000 worldwide per year, about 1.6 per 100,000 per year in china, and the current treatment is mainly drug therapy and autologous stem cell transplantation therapy. The currently widely used drugs in clinic mainly comprise four main classes, namely, an immunomodulator of a diamine type, a proteasome inhibitor, a hormone type and a monoclonal antibody; the drugs in clinical research stage include double antibody, ADC, CAR-T, etc. The action mechanisms of the medicines are different, the combination can achieve better curative effect, and the clinical application generally adopts dual, triple or even quadruple medicines, generally combines immunomodulators, proteasome inhibitors and hormones, and sometimes adds antibodies. Lenalidomide is the most commonly used immunomodulator, and is used in first-line therapy, maintenance therapy after stem cell transplantation and second-third-line therapy after relapse. The drug is sold at 2018/2019 in the market at $ 97 billion. In addition, the entire MM market is quite substantial and growing rapidly due to the continuing improvement and sophistication of MM diagnosis and treatment, longer patient survival and corresponding extended dosing time. The MM market is expected to reach a scale of $ 330 billion in 2022, with the largest proportion still being immunomodulatory agents represented by lenalidomide.

Immunomodulators IMiDs (immunomodulators) mainly have the action mechanism that after the IMiDs are combined with Cereblon (CRBN) protein, E3 ligase activity of CRBN is activated, and further the IMiDs are selectively combined with transcription factors Ikaros (IKZF1) and Aiolos (IKZF 3); thereby causing Ikaros and Aiolos to ubiquitinate and degrade rapidly. Downregulation of Ikaros/Aiolos leads to downregulation of c-Myc, followed by IRF4 downregulation, ultimately leading to inhibition of myeloma cell growth and apoptosis. In addition, the IKZF3 can inhibit the transcription of IL2 and TNF cytokines in T/NK cells, and after the IKZF3 is degraded, the inhibition can be relieved, so that the release of the cytokines is promoted, and the immunoregulation effect is realized. Clinical trials also indicate that clinical benefit of IMiDs drugs is also correlated with the level of CRBN expression. Upon knockdown of CRBN in lenalidomide-sensitive cell lines (OPM2 and KMS18), lenalidomide was found to have lost cell growth inhibitory activity, resulting in drug resistance, with the level of CRBN knockdown correlating with the degree of drug resistance; in cell proliferation experiments, the expression level of CRBN in cells is reduced (U266-CRBN60 and U266-CRBN75), and the activities of lenalidomide and pomalidomide for inhibiting cell growth are reduced.

Currently approved IMiDs drugs on the market are thalidomide, lenalidomide and pomalidomide, all from Celgene (currently incorporated by BMS). The binding force of the three compounds and CRBN is sequentially enhanced, so that the clinical dosage is sequentially reduced. The main indications for the three compounds are MM, thalidomide and lenalidomide but also other indications, in particular lenalidomide, which can be used to treat myelodysplastic syndrome (MDS). In the aspect of side effect, the lenalidomide and pomalidomide have similar performance and obvious bone marrow suppression effect, and the side effect is toxicity related to a target; thalidomide has other side effects such as sedation, constipation, neurological side effects, and the like.

The adipimide moieties of all IMiDs bind to a hydrophobic pocket defined by the three tryptophan residues in CRBN (termed the "thalidomide binding pocket"). In contrast, the phthalimide/isoindolone ring is exposed to the solvent and alters the molecular surface of CRBN, thereby modulating substrate recognition; different imids result in significant modification of the surface of the CRBN molecule, and the preference for substrate recognition is also different. Thus, modifications to IMiDs may lead to degradation of other transcription factors, causing unwanted toxic side effects. This mode of action of IMiDs, also known as molecular glue, is figuratively expressed as the binding of this small molecule to two protein substrates.

Because the median survival time of the current multiple myeloma is more than five years, the prolongation of the survival time leads most patients to have higher-proportion drug resistance to the currently marketed drugs such as lenalidomide and pomalidomide, so that the treatment effect of the drugs is seriously reduced. We therefore envisage the development of more active drug molecules to overcome the problem of drug resistance whilst minimising the toxic side effects of such compounds.

Published Cereblan modulator patent applications include WO2008115516A2, WO2011100380A1, WO2019226770A1, WO2019014100A1, and WO2020064002A1, among others.

Disclosure of Invention

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

wherein:

w is a carbon atom or a nitrogen atom;

ring a is aryl or heteroaryl;

y is CH₂Or C (O);

z is oxygen atom or NH;

G¹、G²、G³and G⁴Are the same or different and are each independently CR⁸Or a nitrogen atom;

ring B is aryl or heteroaryl;

R¹selected from the group consisting of hydrogen atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxyalkyl groups, cyano groups, amino groups and hydroxyl groups;

each R is²The same or different, and each is independently selected from the group consisting of hydrogen atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R³and R⁴Are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, and an alkyl group;

each R is⁵Are the same or different and are each independently selected from the group consisting of hydrogen atom, halogenAn alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl and heterocyclyl group, wherein the alkyl, alkoxy, cycloalkyl and heterocyclyl group are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

each R is⁶The same or different, and each is independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxyl, cycloalkyl, and heterocyclyl;

each R is⁷Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, -S (O)₂R⁹、-S(O)₂NR¹⁰R¹¹Cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R^7aselected from cyano, -S (O)₂R⁹、-S(O)₂NR¹⁰R¹¹Amino, heterocyclyl, aryl and heteroaryl, wherein said heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

each R is⁸The same or different, and each is independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxyl, cycloalkyl, and heterocyclyl;

R⁹selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, and heterocyclyl;

R¹⁰and R¹¹Are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclic group;

n is 0, 1,2 or 3;

p is 0, 1,2 or 3;

q is 0, 1,2, 3 or 4; and is

t is 0, 1,2, 3 or 4.

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

wherein:

ring A, ring B, Y, Z, G¹、G²、G³、G⁴、W、R¹～R⁷、R^7aN, p, q and t are as defined in formula (I).

In some embodiments of the present disclosure, the compound of formula (I) or formula (I-1) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring a is 6-to 10-membered aryl or 5-to 10-membered heteroaryl; preferably phenyl or 5 or 6 membered heteroaryl; more preferably phenyl or imidazolyl.

In some embodiments of the disclosure, the compound of formula (I) or formula (I-1) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Y is CH₂。

In some embodiments of the disclosure, the compound of formula (I) or formula (I-1) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Z is an oxygen atom.

In some embodiments of the disclosure, the compound of formula (I) or formula (I-1) or a tautomer, racemate, enantiomer, or diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein W is a nitrogen atom.

In some embodiments of the disclosure, the compound of formula (I) or formula (I-1) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is³And R⁴Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C_1-6An alkyl group; preferably, R³And R⁴Is a hydrogen atom.

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

wherein:

W¹and W²Are the same or different and are each independently CR⁵Or a nitrogen atom;

ring B, G¹、G²、G³、G⁴、R¹、R²、R⁵、R⁶、R⁷、R^7aN, q and t are as defined in formula (I).

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

wherein:

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

wherein:

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

wherein:

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III), formula (II-1) or formula (III-1), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein G is¹、G²、G³And G⁴Are all CR⁸；R⁸As defined in formula (I).

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III), formula (II-1) or formula (III-1), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein G is¹、G²、G³And G⁴Are all CR⁸(ii) a Each R is⁸Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C_1-6An alkyl group; preferably, R⁸Is a hydrogen atom.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III), formula (II-1), or formula (III-1), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring B is 6-to 10-membered aryl or 5-to 10-membered heteroaryl; preferably, ring B is phenyl or 5 or 6 membered heteroaryl; more preferably, ring B is phenyl.

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

wherein:

R¹、R²、R⁵、R⁶、R⁷、R⁹、R¹⁰、R¹¹n, q and t are as defined in formula (I).

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

wherein:

R^7aselected from cyano, -S (O)₂R⁹、-S(O)₂NR¹⁰R¹¹Amino, heterocyclyl, aryl and heteroaryl, wherein said heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II-1), formula (IIaa-1), formula (III) or formula (III-1), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of^7aSelected from cyano, -S (O)₂R⁹、-S(O)₂NR¹⁰R¹¹And 3 to 8 membered heterocyclyl; r⁹、R¹⁰And R¹¹As defined in formula (I); preferably, R^7aIs cyano.

In some preferred embodiments of the present disclosure, the compound of formula (II), formula (II-1), formula (IIaa) or formula (IIaa-1), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, whereinW¹Is a nitrogen atom, W²Is CR⁵，R⁵Is a hydrogen atom or C_1-6An alkyl group; or W²Is a nitrogen atom, W¹Is CR⁵，R⁵Is a hydrogen atom or C_1-6An alkyl group; or W¹And W²Are all nitrogen atoms.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II-1), formula (IIaa-1), formula (III) or formula (III-1), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of¹Is a hydrogen atom or C_1-6An alkyl group; preferably, R¹Is a hydrogen atom.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II-1), formula (IIaa-1), formula (III) or formula (III-1), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein each R is selected from the group consisting of²Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C_1-6An alkyl group; preferably, each R²Are the same or different and are each independently a hydrogen atom or a halogen.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II-1), formula (IIaa-1), formula (III) or formula (III-1), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein n is 0; or each R²Are identical or different and are each independently halogen or C_1-6Alkyl, and n is 1,2 or 3; preferably, n is 0; or R²Is halogen and n is 1.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II-1), formula (IIaa-1), formula (III) or formula (III-1), or a tautomer, racemate, enantiomer, or diastereomer thereofAn enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein each R⁵And R⁶Are the same or different and are each independently a hydrogen atom or C_1-6An alkyl group; preferably, each R⁵And R⁶Is a hydrogen atom.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II-1), formula (III) or formula (III-1), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein p and q are both 0; or each R⁵And R⁶Are the same or different and are each independently C_1-6Alkyl, and p and q are the same or different and are each independently 1 or 2; preferably, p and q are both 0.

In some preferred embodiments of the present disclosure, the compound of formula (IIaa) or formula (IIaa-1), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein q is 0; or each R⁶Are the same or different and are each independently C_1-6Alkyl, and q is 1 or 2; preferably, q is 0.

In some embodiments of the disclosure, the compound of formula (I), formula (II-1), formula (IIaa-1), formula (III) or formula (III-1) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein each R is R, wherein R is R, and R, and R, and R, and R⁷Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkyl, C_1-6Haloalkoxy, cyano, amino, nitro, hydroxy and C_1-6A hydroxyalkyl group; preferably, each R⁷Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C_1-6An alkyl group.

In some embodiments of the present disclosure, the compound of formula (I), formula (II-1), formula (IIaa-1), formula (III) or formula (III-1)A compound or tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein t is 0; or each R⁷Are the same or different and are each independently selected from halogen, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkyl, C_1-6Haloalkoxy, cyano, amino, nitro, hydroxy and C_1-6Hydroxyalkyl, and t is 1,2 or 3; preferably, t is 0; or each R⁷Are identical or different and are each independently halogen or C_1-6Alkyl, and t is 1 or 2.

In some embodiments of the present disclosure, the compound of formula (I) or formula (I-1) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring a is phenyl or imidazolyl; ring B is phenyl or 5 or 6 membered heteroaryl; y is CH₂(ii) a Z is an oxygen atom; w is a nitrogen atom; g¹、G²、G³And G⁴Are all CR⁸(ii) a Each R is⁸Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C_1-6An alkyl group; r¹Is a hydrogen atom or C_1-6An alkyl group; n is 0 or each R²Are identical or different and are each independently halogen or C_1-6Alkyl, and n is 1,2 or 3; r³And R⁴Is a hydrogen atom; p and q are both 0, or each R⁵And R⁶Are the same or different and are each independently C_1-6Alkyl, and p and q are the same or different and are each independently 1 or 2; t is 0 or each R⁷Are identical or different and are each independently halogen or C_1-6Alkyl, and t is 1 or 2; r is^7aIs cyano.

In some embodiments of the disclosure, the compound of formula (II) or formula (II-1) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein W is¹Is a nitrogen atom, W²Is CR⁵(ii) a Or W²Is a nitrogen atom, W¹Is CR⁵；R⁵Is a hydrogen atom or C_1-6An alkyl group; or W¹And W²Are all nitrogen atoms; ring B is phenyl; g¹、G²、G³And G⁴Are all CR⁸(ii) a Each R is⁸Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C_1-6An alkyl group; r¹Is a hydrogen atom or C_1-6An alkyl group; n is 0 or each R²Are identical or different and are each independently halogen or C_1-6Alkyl, and n is 1,2 or 3; q is 0; t is 0 or each R⁷Are identical or different and are each independently halogen or C_1-6Alkyl, and t is 1 or 2; r^7aIs cyano.

In some embodiments of the disclosure, the compound of formula (IIaa) or formula (IIaa-1) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein W is¹Is a nitrogen atom, W²Is CR⁵(ii) a Or W²Is a nitrogen atom, W¹Is CR⁵；R⁵Is a hydrogen atom or C_1-6An alkyl group; or W¹And W²Are all nitrogen atoms; r¹Is a hydrogen atom or C_1-6An alkyl group; n is 0 or each R²Are identical or different and are each independently halogen or C_1-6Alkyl, and n is 1,2 or 3; q is 0; t is 0 or each R⁷Are identical or different and are each independently halogen or C_1-6Alkyl, and t is 1 or 2; r^7aIs cyano.

Table a typical compounds of the present disclosure include, but are not limited to:

another aspect of the present disclosure relates to compounds of formula (IA), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

R^mis C_1-6An alkyl group; preferably tert-butyl;

Another aspect of the present disclosure relates to compounds of formula (IA-1), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

R^mis C_1-6An alkyl group; preferably tert-butyl;

ring A, ring B, Y, Z, G¹、G²、G³、G⁴、W、R¹～R⁷、R^7aN, p, q and t are as defined in the general formula (I-1).

Another aspect of the present disclosure relates to compounds of formula (IIA) or formula (IIIA), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

R^mis C_1-6An alkyl group; preferably tert-butyl;

ring B, G¹、G²、G³、G⁴、W¹、W²、R¹、R²、R⁶、R⁷、R^7aN, q and t are as defined in formula (II); r⁵And p is as defined in formula (III).

Another aspect of the present disclosure relates to compounds of formula (IIA-1) or formula (IIIA-1), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

R^mis C_1-6An alkyl group; preferably tert-butyl;

ring B, G¹、G²、G³、G⁴、W¹、W²、R¹、R²、R⁶、R⁷、R^7aN, q and t are as defined in the general formula (II-1); r⁵And p is as defined in the general formula (III-1).

Another aspect of the present disclosure relates to compounds of formula (IIaaA), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

R^mis C_1-6An alkyl group;preferably tert-butyl;

W¹、W²、R¹、R²、R⁶、R⁷、R^7an, q and t are as defined in formula (IIaa).

Another aspect of the present disclosure relates to a compound of formula (IIaaA-1), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

R^mis C_1-6An alkyl group; preferably tert-butyl;

W¹、W²、R¹、R²、R⁶、R⁷、R^7an, q and t are as defined in the general formula (IIaa-1).

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

another aspect of the present disclosure relates to a method of preparing a compound of formula (I), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:

subjecting a compound of formula (IA), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, to an intramolecular ring closure reaction to give a compound of formula (I), or a tautomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

R^mis C_1-6An alkyl group; preferably tert-butyl;

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

subjecting a compound of formula (IA-1), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, to an intramolecular ring closure reaction to obtain a compound of formula (I-1), or a tautomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

R^mis C_1-6An alkyl group; preferably tert-butyl;

Another aspect of the present disclosure relates to a method of preparing a compound of formula (II) or formula (III), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:

subjecting a compound of formula (IIA), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, to an intramolecular ring closure reaction to obtain a compound of formula (II), or a tautomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof, or

Subjecting a compound of formula (IIIA), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, to an intramolecular ring closure reaction to obtain a compound of formula (III), or a tautomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

R^mis C_1-6An alkyl group; preferably tert-butyl;

Another aspect of the present disclosure relates to a method of preparing a compound of formula (II-1) or formula (III-1), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:

subjecting the compound of formula (IIA-1), or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt to intramolecular ring closure reaction to obtain the compound of formula (II-1), or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt, or

Subjecting the compound of formula (IIIA-1), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, to an intramolecular ring closure reaction to obtain the compound of formula (III-1), or the tautomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

R^mis C_1-6An alkyl group; preferably tert-butyl;

Another aspect of the present disclosure relates to a method of preparing a compound of formula (IIaa), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:

subjecting a compound of formula (IIaaA), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, to an intramolecular ring closure reaction to give a compound of formula (IIaa), or a tautomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

R^mis C_1-6An alkyl group; preferably a tert-butyl group;

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

subjecting a compound of the general formula (IIaaA-1), or a tautomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, to an intramolecular cyclization reaction to obtain a compound of the general formula (IIaa-1), or a tautomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

R^mis C_1-6An alkyl group; preferably tert-butyl;

Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of the present disclosure represented by formula (I), formula (II-1), formula (IIaa-1), formula (III-1), or table a, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

The disclosure further relates to the use of a compound of formula (I), formula (II-1), formula (IIaa-1), formula (III-1) or Table A, or a tautomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for the treatment and/or prevention of a disease associated with CRBN protein.

The present disclosure further relates to compounds of formula (I), formula (II-1), formula (IIaa-1), formula (III-1) or Table A or tautomers, racemates, enantiomers, diastereomers or mixtures thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for the treatment and/or prevention of cancer, a disorder associated with angiogenesis, pain, macular degeneration or a related syndrome, a skin disease, a pulmonary disease, an asbestos-related disease, a parasitic disease, an immunodeficiency disease, a CNS injury, atherosclerosis or a related disorder, a sleep disorder or a related disorder, an infectious disease, a hemoglobinopathy or a related disorder, polycythemia vera, or a TNF α related disorder; preferably, for the manufacture of a medicament for the treatment and/or prevention of cancer or CNS damage.

The present disclosure also relates to a method for treating and/or preventing a disease associated with CRBN protein, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (II-1), formula (IIaa-1), formula (III-1) or table a or a tautomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure also relates to a method for the treatment and/or prevention of cancer, a condition associated with angiogenesis, pain, macular degeneration or a related syndrome, a skin disease, a lung disease, an asbestos-related disease, a parasitic disease, an immunodeficiency disease, a CNS injury, atherosclerosis or a related condition, a sleep disorder or a related condition, an infectious disease, a hemoglobinopathy or a related condition, polycythemia vera or a TNF α related condition, preferably a method for the treatment and/or prevention of cancer or a CNS injury, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (II-1), formula (IIaa-1), formula (III-1) or table a, or a tautomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure further relates to a compound of formula (I), formula (II-1), formula (IIaa-1), formula (III-1) or table a or a tautomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same, for use as a medicament.

The present disclosure further relates to compounds of formula (I), formula (II-1), formula (IIaa-1), formula (III-1) or table a or tautomers, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in the treatment and/or prevention of diseases associated with CRBN proteins.

The present disclosure further relates to compounds of formula (I), formula (II-1), formula (IIaa-1), formula (III-1) or table a or tautomers, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in the treatment and/or prevention of cancer, angiogenesis-related disorders, pain, macular degeneration or related syndromes, skin disorders, pulmonary disorders, asbestos-related diseases, parasitic diseases, immunodeficiency disorders, CNS diseases, CNS injury, atherosclerosis or related disorders, sleep disorders or related disorders, infectious diseases, hemoglobinopathies or related disorders, polycythemia vera or TNF α related disorders; cancer or CNS damage is preferred.

The cancer described in the present disclosure is selected from leukemia, myeloma, lymphoma, melanoma, skin cancer, liver cancer, kidney cancer, lung cancer, nasopharyngeal cancer, gastric cancer, esophageal cancer, colorectal cancer, gallbladder cancer, cholangiocarcinoma, chorioepithelial cancer, pancreatic cancer, pediatric tumor, cervical cancer, ovarian cancer, breast cancer, bladder cancer, urothelial cancer, ureteral tumor, prostate cancer, seminoma, testicular tumor, head and neck squamous cell carcinoma, endometrial cancer, thyroid cancer, sarcoma, osteoma, neuroblastoma, neuroendocrine cancer, brain tumor, CNS cancer, and glioma; preferably, the liver cancer is hepatocellular carcinoma; the colorectal cancer is colon cancer or rectal cancer; the sarcoma is osteosarcoma or soft tissue sarcoma; the glioma is a glioblastoma or astrocytoma.

The leukemia described in the present disclosure is preferably chronic lymphocytic leukemia, Acute Lymphocytic Leukemia (ALL), Acute Myeloid Leukemia (AML), Chronic Myeloid Leukemia (CML), and hairy cell leukemia, preferably small lymphocytic lymphoma, marginal zone lymphoma, follicular lymphoma, mantle cell lymphoma, non-hodgkin's lymphoma (NHL), lymphoplasmacytic lymphoma, extranodal marginal zone lymphoma, T-cell lymphoma, B-cell lymphoma, and diffuse large B-cell lymphoma; the myeloma is preferably Multiple Myeloma (MM) and myelodysplastic syndrome (MDS). The cancer described in the present disclosure includes primary or metastatic cancer. Cancers of the present disclosure also include those that are refractory or resistant to chemotherapy or radiation therapy. More preferably, the multiple myeloma is relapsed, refractory or resistant. Most preferably, the multiple myeloma is refractory or resistant to lenalidomide or pomalidomide.

Examples of CNS disorders include, but are not limited to, those described in U.S. publication No. US20050143344a1, published at 30/6/2005, the contents of which are incorporated herein by reference. Specific examples include, but are not limited to, amyotrophic lateral sclerosis, alzheimer's disease, parkinson's disease, huntington's disease, multiple sclerosis, and other neuroimmune disorders such as Tourette syndrome, delusions, or disturbances of consciousness that occur in a very short time, and amnesia, or scattered memory impairment that occurs when other central nervous system impairments are not present.

Examples of CNS injuries and related syndromes include, but are not limited to, the diseases described in U.S. publication No. US20060122228a1, published on 8.6.2006, the contents of which are incorporated herein by reference. Specific examples include, but are not limited to, CNS injury/impairment 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, postconcussion syndrome, contusion laceration, subdural hematoma, epidermal hematoma, post-traumatic epilepsy, chronic vegetative state, complete SCI, incomplete SCI, acute SCI, subacute SCI, chronic SCI, central spinal syndrome, spinal hemisection syndrome, anterior cord syndrome, conus medullaris syndrome, cauda equina syndrome, neurogenic shock, spinal shock, altered levels of consciousness, headache, nausea, vomiting, hypomnesis, vertigo, diplopia, blurred vision, mood swings, sleep disorders, irritability, inability to concentrate, nervousness, behavioral disorders, cognitive deficits, and epilepsy.

Angiogenesis-related diseases include, but are not limited to, inflammatory diseases, autoimmune diseases, viral diseases, genetic diseases, allergic diseases, bacterial diseases, ocular neovascular diseases, choroidal neovascular diseases, retinal neovascular diseases, and rubeosis iridis (atrial horn neovascularization). Preferably including but not limited to arthritis, endometriosis, crohn's disease, heart failure, severe heart failure, kidney damage, endotoxemia, toxic shock syndrome, osteoarthritis, retroviral replication, wasting disease, meningitis, silica-induced fibrosis, asbestos-induced fibrosis, veterinary disease, malignancy-associated hypercalcemia, stroke, circulatory shock, periodontitis, gingivitis, megaloblastic anemia, refractory anemia, and 5q deficiency syndrome.

The active compounds may be formulated in a form suitable for administration by any suitable route, using one or more pharmaceutically acceptable carriers to formulate compositions of the disclosure by conventional methods. Thus, the active compounds of the present disclosure may be formulated in a variety of dosage forms for oral administration, injection (e.g., intravenous, intramuscular, or subcutaneous), inhalation, or insufflation. The compounds of the present disclosure may also be formulated in sustained release 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 guide, the active compound is preferably administered in a unit dose or in a manner such that the patient can self-administer it in a single dose. The unit dose of a compound or composition of the present disclosure may be expressed in the form of a tablet, capsule, cachet, bottled liquid, powder, granule, lozenge, suppository, reconstituted powder, or liquid. A suitable unit dose may be 0.1 to 1000 mg.

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

Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be inert excipients, granulating agents, disintegrating agents, binding agents and lubricating agents. These tablets may be uncoated or they may be coated by known techniques which mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.

Oral formulations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or wherein the active ingredient is mixed with a water soluble carrier or an oil vehicle.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.

Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, or in a mineral oil. The oil suspension may contain a thickener. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of antioxidants.

The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, or a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. Such formulations may also contain a demulcent, a preservative, a colorant and an antioxidant.

The pharmaceutical compositions of the present disclosure may be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles or solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase, and the injection or microemulsion may be injected into the bloodstream of a patient by local mass injection. Alternatively, it may be desirable to administer the solution and microemulsion in a manner that maintains a constant circulating concentration of the disclosed compounds. To maintain such a constant concentration, a continuous intravenous delivery device may be used. An example of such a device is an intravenous pump model Deltec CADD-PLUS. TM.5400.

The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous or oleaginous suspensions for intramuscular and subcutaneous administration. The suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally-acceptable, non-toxic diluent or solvent. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. Any blend fixed oil may be used for this purpose. In addition, fatty acids can also be prepared into injections.

The compounds of the present disclosure may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and therefore will melt in the rectum to release the drug.

Dispersible powders and granules of the compounds of the present disclosure can be administered by the addition of water to prepare an aqueous suspension. These pharmaceutical compositions may be prepared by mixing the active ingredient with dispersing or wetting agents, suspending agents, or one or more preservatives.

As is well known to those skilled in the art, the dosage of a drug administered depends on a variety of factors, including, but not limited to: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs and the severity of the disease, etc.; in addition, the optimal treatment regimen, such as mode of treatment, daily amount of compound or type of pharmaceutically acceptable salt, can be verified according to conventional treatment protocols.

Description of the terms

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

The term "alkyl" refers to a saturated straight or branched aliphatic hydrocarbon group having 1 to 20 (e.g., 1,2, 3, 4, 5,6,7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C)_1-20Alkyl), preferably an alkyl group containing 1 to 12 carbon atoms (i.e., C)_1-12Alkyl), more preferably an alkyl group having 1 to 6 carbon atoms (i.e., C)_1-6Alkyl groups). Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 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-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, and mixtures thereof,2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 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-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof, and the like. Most preferably lower alkyl having 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl and the like. The alkyl group may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachment, the substituents preferably being selected from one or more of a D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkylene" refers to a divalent alkyl group, wherein alkyl is as defined above, having 1 to 20 (e.g., 1,2, 3, 4, 5,6,7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C)_1-20Alkylene). The alkylene group is preferably an alkylene group (i.e., C) having 1 to 12 (e.g., 1,2, 3, 4, 5,6,7,8, 9, 10, 11, and 12) carbon atoms_1-12Alkylene), more preferably alkylene having 1 to 6 carbon atoms (i.e., C)_1-6Alkylene). Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH)₂-), 1-ethylidene (-CH (CH)₃) -), 1, 2-ethylene (-CH)₂CH₂) -, 1-propylene (-CH (CH)₂CH₃) -), 1, 2-propylene (-CH)₂CH(CH₃) -), 1, 3-propylene (-Si-), and their useCH₂CH₂CH₂-) 1, 4-butylene (-CH₂CH₂CH₂CH₂-) and the like. The alkylene group may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachment, the substituents preferably being selected from one or more of alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio and oxo.

The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above, preferably an alkenyl (i.e., C) group having 2 to 12 (e.g., 2,3, 4, 5,6,7,8, 9, 10, 11, or 12) carbon atoms_2-12Alkenyl). The alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (i.e., C)_2-6Alkenyl). Non-limiting examples include: ethenyl, propenyl, isopropenyl, butenyl, and the like. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably selected from the group consisting of a hydrogen atom, an alkyl group, an alkoxy group, a halogen, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group.

The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is defined above and has an alkynyl (i.e., C) group of 2 to 12 (e.g., 2,3, 4, 5,6,7,8, 9, 10, 11, or 12) carbon atoms_2-12Alkynyl). The alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (i.e., C)_2-6Alkynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably selected from the group consisting of hydrogen atoms, alkyl groups, alkoxy groups, halogens, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups.

The term "alkoxy" refers to-O- (alkyl), wherein alkyl is as defined above. Non-limiting examples include: methoxy, ethoxy, propoxy, and butoxy, and the like. Alkoxy groups may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachment, with the substituents preferably being selected from one or more of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 (e.g., 3, 4, 5,6,7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., 3 to 20 membered cycloalkyl groups), preferably 3 to 12 carbon atoms (i.e., 3 to 12 membered cycloalkyl groups) (either at a particular point or optionally between two points, e.g., 3, 4, 5,6,7,8, 9, 10, 11, and 12 ring atoms, 4 to 11 ring atoms, 6 to 12 ring atoms, etc.), preferably 3 to 8 (e.g., 3, 4, 5,6,7, and 8) carbon atoms (i.e., 3 to 8 membered cycloalkyl groups), more preferably 3 to 6 carbon atoms (i.e., 3 to 6 membered cycloalkyl groups). Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spirocycloalkyl, fused ring alkyl, and bridged cycloalkyl groups.

The term "spirocycloalkyl" refers to a 5 to 20 membered polycyclic group sharing one carbon atom (referred to as a spiro atom) between monocyclic rings, which may contain one or more double bonds. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). Spirocycloalkyl groups are classified as mono-or polyspirocycloalkyl (e.g., a bispyridyl cycloalkyl group), preferably mono-and bispyridyl, depending on the number of spiro atoms shared between rings. More preferably 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, 5-membered/6-membered, 6-membered/4-membered, 6-membered/5-membered or 6-membered/6-membered spirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

the term "fused cyclic alkyl" refers to a 5 to 20 membered all carbon 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 of the rings may contain one or more double bonds. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). Polycyclic fused alkyl groups such as bicyclic, tricyclic, tetracyclic, etc. may be divided according to the number of constituent rings, and bicyclic or tricyclic groups are preferred, and 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/3-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 5-membered/7-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered, or 7-membered/6-membered bicycloalkyl groups are more preferred. Non-limiting examples of fused ring alkyl groups include:

the term "bridged cycloalkyl" refers to a 5 to 20 membered all carbon polycyclic group in which any two rings share two carbon atoms not directly attached, which may contain one or more double bonds. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). They may be classified into bicyclic, tricyclic, tetracyclic, etc. polycyclic bridged cycloalkyl groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic bridged cycloalkyl groups, and more preferably bicyclic or tricyclic bridged cycloalkyl groups. Non-limiting examples of bridged cycloalkyl groups include:

the cycloalkyl ring includes a cycloalkyl ring (including monocyclic, spiro, fused and bridged rings) fused to an aryl, heteroaryl or heterocycloalkyl ring as described above, wherein the ring(s) attached to the parent structure are cycloalkyl, non-limiting examples of which include indanyl

Tetrahydronaphthyl

And benzocycloheptalkyl

Etc.; preference is given to

Cycloalkyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, the substituents preferably being selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent comprising from 3 to 20 ring atoms, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e., form a sulfoxide or sulfone), but which does not include the cyclic portion of-O-, -O-S-or-S-, the remaining ring atoms being carbon. Preferably 3 to 12 (e.g., 3, 4, 5,6,7,8, 9, 10, 11, or 12) ring atoms, of which 1-4 (e.g., 1,2, 3, and 4) are heteroatoms (i.e., 3-to 12-membered heterocyclyl); more preferably 3 to 8 ring atoms (e.g., 3, 4, 5,6,7, and 8), wherein 1-3 are heteroatoms (e.g., 1,2, and 3) (i.e., 3-to 8-membered heterocyclyl); more preferably 3 to 6 ring atoms, of which 1-3 are heteroatoms (i.e. 3 to 6 membered heterocyclyl); most preferably 5 or 6 ring atoms, of which 1 to 3 are heteroatoms (i.e. a 5 or 6 membered heterocyclyl group). Non-limiting examples of monocyclic heterocyclyl groups include oxetanyl, pyrrolidinyl, tetrahydropyranyl, 1, 2.3.6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocyclic groups include spirocyclic heterocyclic groups, fused ring heterocyclic groups, and bridged heterocyclic groups.

The term "spiroheterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group sharing one atom (referred to as a spiro atom) between monocyclic rings, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e., form a sulfoxide or sulfone), the remaining ring atoms being carbon. It may contain one or more double bonds. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). Spiro heterocyclic groups are classified into a mono-spiro heterocyclic group or a multi-spiro heterocyclic group (e.g., a double-spiro heterocyclic group), preferably a mono-spiro heterocyclic group and a double-spiro heterocyclic group, according to the number of spiro atoms shared between rings. More preferably 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, 5-membered/6-membered or 6-membered/6-membered mono spiroheterocyclyl. Non-limiting examples of spiro heterocyclic groups include:

the term "fused heterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system, one or more of the rings may contain one or more double bonds, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e. to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). They may be classified into bicyclic, tricyclic, tetracyclic, etc. polycyclic fused heterocyclic groups according to the number of constituting rings, 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/3-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/7-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered/6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

the term "bridged heterocyclyl" refers to a 5 to 14 membered polycyclic heterocyclic group in which any two rings share two atoms not directly attached, which may contain one or more double bonds, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e., to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). They may be classified into bicyclic, tricyclic, tetracyclic, etc. polycyclic bridged heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic, or tetracyclic bridged heterocyclic groups, and more preferably bicyclic or tricyclic bridged heterocyclic groups. Non-limiting examples of bridged heterocyclic groups include:

the heterocyclyl ring includes a heterocyclyl (including monocyclic, spiroheterocyclic, fused heterocyclic and bridged heterocyclic) fused to an aryl, heteroaryl or cycloalkyl ring as described above, wherein the ring to which the parent structure is attached is a heterocyclyl, non-limiting examples of which include:

and the like.

The heterocyclyl group may be substituted or unsubstituted and when substituted may be substituted at any available point of attachment, the substituents preferably being selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (fused polycyclic is a ring sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl. Such aryl rings include those wherein the aryl ring as described above is fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:

aryl groups may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachment, with the substituents preferably being selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 (e.g., 1,2, 3, and 4) heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl is preferably 5 to 10 membered (e.g. 5,6,7,8, 9 or 10 membered), more preferably 5 or 6 membered heteroaryl, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl and the like. The heteroaryl ring includes a heteroaryl fused to an aryl, heterocyclyl or cycloalkyl ring as described above, wherein the ring joined together with the parent structure is a heteroaryl ring, non-limiting examples of which include:

heteroaryl groups may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachment, with the substituents preferably being selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The above-mentioned cycloalkyl, heterocyclyl, aryl and heteroaryl groups include residues derived from the parent ring atom by removal of one hydrogen atom, or residues derived from the parent ring atom by removal of two hydrogen atoms from the same ring atom or two different ring atoms, i.e., "cycloalkylene", "heterocyclylene", "arylene" and "heteroarylene".

The term "amino protecting group" refers to a group that is easily removed by introduction onto an amino group in order to keep the amino group unchanged during the reaction at other sites of the molecule. Non-limiting examples include: tert-butyldimethylsilyl (TBS), (trimethylsilyl) ethoxymethyl (SEM), tetrahydropyranyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), acetyl, benzyl, allyl, and p-methoxybenzyl, and the like. These groups may be optionally substituted with 1 to 3 substituents selected from halogen, alkoxy or nitro. The amino protecting groups are preferably (trimethylsilyl) ethoxymethyl and tert-butoxycarbonyl.

The term "hydroxyl-protecting group" is a suitable group for hydroxyl protection known in the art, see the literature ("Protective Groups in Organic Synthesis", 5)^Th Ed.T.W.Greene&P.g.m.wuts) for blocking or protecting the hydroxyl group while reacting on other functional groups of the compound. Non-limiting examples include: trimethylsilyl (TMS), Triethylsilyl (TES), Triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl, methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-Tetrahydropyranyl (THP), formyl, acetyl, benzoyl, p-nitrobenzoyl and the like.

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

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

The term "cycloalkyloxy" refers to cycloalkyl-O-wherein cycloalkyl is as defined above.

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

The term "alkylthio" refers to an alkyl-S-group wherein alkyl is as defined above.

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

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

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

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

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

The term "hydroxy" refers to-OH.

The term "mercapto" refers to-SH.

The term "amino" refers to the group-NH₂。

The term "cyano" refers to — CN.

The term "nitro" means-NO₂。

The term "oxo" refers to "═ O".

The term "carbonyl" refers to C ═ O.

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

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

The compounds of the present disclosure include other isotopic derivatives. The term "isotopic derivative" refers to a compound that differs in structure only in the presence of one or more isotopically enriched atoms. For example, having the structure of the present disclosure, replacing hydrogen with "deuterium" or "tritium", or¹⁸F-fluorine labeling: (¹⁸Isotope of F) instead of fluorine, or with¹¹C-，¹³C-, or¹⁴C-enriched carbon (C¹¹C-，¹³C-, or¹⁴C-carbon labeling;¹¹C-，¹³c-, or¹⁴C-isotopes) instead of carbon atoms are within the scope of the present disclosure. Such compounds are useful as analytical tools or probes in, for example, biological assays, or as tracers for in vivo diagnostic imaging of disease, or as tracers for pharmacodynamic, pharmacokinetic or receptor studies. Wherein deuteriumThe compounds in their cyclized form are such that each available hydrogen atom attached to a carbon atom may be independently replaced by a deuterium atom. The person skilled in the art is able to synthesize the deuterated forms of the compounds with reference to the relevant literature. Commercially available deuterated starting materials can be used in preparing the deuterated forms of the compounds, or they can be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated boranes, trideuteroborane in tetrahydrofuran, deuterated lithium aluminum hydrides, deuterated iodoethanes, and deuterated iodomethanes, among others. Deuterations can generally retain activity comparable to non-deuterated compounds and can achieve better metabolic stability when deuterated at certain specific sites, thereby achieving certain therapeutic advantages.

The compounds of the disclosure may exist in specific stereoisomeric forms. The term "stereoisomers" refers to isomers that are identical in structure but differ in the arrangement of the atoms in space. It includes cis and trans (or Z and E) isomers, (-) -and (+) -isomers, (R) -and (S) -enantiomers, diastereomers, (D) -and (L) -isomers, tautomers, atropisomers, conformers, and mixtures thereof (e.g., racemates, mixtures of diastereomers). Additional asymmetric atoms may be present in substituents in the compounds of the present disclosure. All such stereoisomers, as well as mixtures thereof, are included within the scope of the present disclosure. Optically active (-) -and (+) -isomers, (R) -and (S) -enantiomers, and (D) -and (L) -isomers can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. An isomer of a compound of the present disclosure may be prepared by asymmetric synthesis or chiral auxiliary, or, when a basic functional group (e.g., amino group) or an acidic functional group (e.g., carboxyl group) is contained in a molecule, a diastereoisomeric salt is formed with an appropriate optically active acid or base, and then diastereoisomeric resolution is performed by a conventional method known in the art to obtain a pure isomer. Furthermore, separation of enantiomers and diastereomers is typically accomplished by chromatography.

In the chemical structure of the compounds described in the present disclosure, a bond

Denotes an unspecified configuration, i.e. a bond if a chiral isomer is present in the chemical structure

Can be that

Or

Or at the same time contain

And

two configurations.

The compounds of the present disclosure may exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to a structural isomer that exists in equilibrium and is readily converted from one isomeric form to another. It includes all possible tautomers, i.e. in the form of a single isomer or in the form of a mixture of said tautomers in any ratio. Non-limiting examples include: keto-enol, imine-enamine, lactam-lactim, and the like. An example of a lactam-lactam equilibrium is between a and B as shown below:

when referring to pyrazolyl, it is understood to include any one of the following two structures or a mixture of two tautomers:

all tautomeric forms are within the scope of the disclosure, and the naming of the compounds does not exclude any tautomers.

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

"substituted" means that one or more, preferably 1 to 5, more preferably 1 to 3, hydrogen atoms in the group are independently substituted with a corresponding number of substituents. Those skilled in the art are able to ascertain (by experiment or theory) without undue effort, substitutions that are possible or impossible. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.

"pharmaceutical composition" means a mixture containing one or more compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.

By "pharmaceutically acceptable salt" is meant a salt of a compound of the present disclosure which is safe and effective for use in the body of a mammal and which has the requisite biological activity. Salts may be prepared separately during the final isolation and purification of the compound, or by reacting the appropriate group with an appropriate base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.

As used herein, unless otherwise specified, the term "preventing" refers to treating or administering a compound provided herein, with or without other active compounds, to a patient, especially at risk of cancer and/or other conditions described herein, prior to the onset of symptoms. The term "prevention" includes inhibition or alleviation of the symptoms of a particular disease. In certain embodiments, patients with a family history of disease are particularly candidates for prophylactic regimens. In addition, patients with a history of symptom recurrence are also potential candidates for prophylaxis. In this regard, the term "prevention" may be used interchangeably with the term "prophylactic treatment".

The term "therapeutically effective amount" with respect to a drug or pharmacologically active agent refers to a sufficient amount of the drug or agent that is non-toxic but achieves the desired effect. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient and also on the particular active substance, and an appropriate effective amount in an individual case can be determined by a person skilled in the art according to routine tests.

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

As used herein, the singular forms "a," "an," and "the" include plural references and vice versa unless the context clearly dictates otherwise.

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

Synthesis of the Compounds of the disclosure

In order to achieve the purpose of the present disclosure, the present disclosure adopts the following technical solutions:

scheme one

The invention discloses a method for preparing a compound shown in a general formula (I), or a tautomer, a racemate, an enantiomer, a diastereoisomer, a mixture form or a pharmaceutically acceptable salt form thereof,the method comprises the following steps:

reacting a compound of formula (IB), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, with a compound of formula (IC), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, under basic conditions to give a compound of formula (IA), or a tautomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof,

carrying out intramolecular ring closure reaction on a compound of the general formula (IA) or a tautomer, a racemate, an enantiomer, a diastereomer or a mixture form or a pharmaceutically acceptable salt thereof under acidic conditions to obtain a compound of the general formula (I) or a tautomer, a racemate, an enantiomer, a diastereomer or a mixture form or a pharmaceutically acceptable salt thereof,

wherein:

x is halogen, preferably Cl or Br;

R^mis C_1-6An alkyl group; preferably tert-butyl;

Scheme two

The preparation method of the compound shown in the general formula (I-1) or the tautomer, the racemate, the enantiomer, the diastereomer or the mixture form or the pharmaceutically acceptable salt form comprises the following steps:

reacting a compound of formula (IB), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, with a compound of formula (I-1C), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, under basic conditions to give a compound of formula (IA-1), or a tautomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof,

subjecting a compound of the general formula (IA-1), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, to intramolecular ring closure under acidic conditions to give a compound of the general formula (I-1), or a tautomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

x is halogen, preferably Cl or Br;

R^mis C_1-6An alkyl group; preferably tert-butyl;

Scheme three

The preparation method of the compound shown in the general formula (II) or the general formula (III), or the tautomer, the racemate, the enantiomer, the diastereomer, or the mixture thereof, or the pharmaceutically acceptable salt thereof, comprises the following steps:

the compound of the general formula (IIA), or a tautomer, a racemate, an enantiomer, a diastereomer, a mixture form or a pharmaceutically acceptable salt thereof undergoes an intramolecular ring closure reaction under acidic conditions to obtain the compound of the general formula (II), or the tautomer, the racemate, the enantiomer, the diastereomer, the mixture form or the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable salt thereof

Carrying out intramolecular ring closure reaction on a compound of the general formula (IIIA) or a tautomer, a racemate, an enantiomer, a diastereoisomer or a mixture form or a pharmaceutically acceptable salt thereof under an acidic condition to obtain a compound of the general formula (III) or a tautomer, a racemate, an enantiomer, a diastereoisomer or a mixture form or a pharmaceutically acceptable salt thereof,

wherein:

R^mis C_1-6An alkyl group; preferably tert-butyl;

ring B, G¹、G²、G³、G⁴、W¹、W²、R¹、R²、R⁵、R⁶、R⁷、R^7aN, q and t are as defined in formula (II); r⁵And p is as defined in formula (III).

Scheme four

The preparation method of the compound shown in the general formula (IIaa) or the tautomer, the racemate, the enantiomer, the diastereomer or the mixture form or the pharmaceutically acceptable salt form comprises the following steps:

subjecting a compound of formula (IIaaA), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, to intramolecular ring closure under acidic conditions to give a compound of formula (IIaa), or a tautomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

R^mis C_1-6An alkyl group; preferably tert-butyl;

Scheme five

The preparation method of the compound shown in the general formula (IIaa-1) or the tautomer, the racemate, the enantiomer, the diastereomer or the mixture thereof or the pharmaceutically acceptable salt thereof comprises the following steps:

subjecting a compound of the general formula (IIaaA-1), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, to intramolecular ring closure under acidic conditions to obtain a compound of the general formula (IIaa-1), or a tautomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

R^mis C_1-6An alkyl group; preferably tert-butyl;

The reagents in the above synthesis schemes that provide basic conditions include organic bases including, but not limited to, triethylamine, N-diisopropylethylamine, N-butyllithium, lithium diisopropylamide, sodium acetate, potassium acetate, sodium tert-butoxide, or potassium tert-butoxide, and inorganic bases including, but not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, anhydrous cesium carbonate, sodium hydroxide, lithium hydroxide monohydrate, lithium hydroxide, and potassium hydroxide; preferably selected from cesium carbonate, anhydrous cesium carbonate and potassium carbonate.

Reagents that provide acidic conditions in the above synthetic schemes include, but are not limited to, p-toluenesulfonic acid monohydrate, benzenesulfonic acid, anhydrous benzenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, sulfuric acid, hydrochloric acid, nitric acid, and trifluoroacetic acid; preferably benzenesulfonic acid or anhydrous benzenesulfonic acid.

The above reaction is preferably carried out in a solvent including, but 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-dimethylformamide, N-dimethylacetamide, and a mixture thereof.

Detailed Description

The following examples are presented to further illustrate the present disclosure, but are not intended to limit the scope of the present disclosure.

Examples

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift (. delta.) at 10^-6The units in (ppm) are given. NMR was measured using a Bruker AVANCE-400 nuclear magnetic instrument or Bruker AVANCE NEO 500M in deuterated dimethyl sulfoxide (DMSO-d)₆) Deuterated chloroform (CDCl)₃) Deuterated methanol (CD)₃OD), internal standard Tetramethylsilane (TMS).

MS was measured using an Agilent 1200/1290DAD-6110/6120Quadrupole MS LC MS (manufacturer: Agilent, MS model: 6110/6120Quadrupole MS), waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS model: waters ACQuity Qda Detector/waters SQ Detector), THERMO Ultratate 3000-Q active (manufacturer: THERMO, MS model: THERMO Q active).

High Performance Liquid Chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 HPLC.

Chiral HPLC assay using Agilent 1260DAD HPLC.

High performance liquid phase preparation Waters 2545-2767, Waters 2767-SQ Detector 2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs were used.

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

The CombiFlash rapid preparation instrument uses CombiFlash Rf200(TELEDYNE ISCO).

The thin layer chromatography silica gel plate adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.

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

Average inhibition rate of kinase and IC₅₀The values were determined with a NovoStar microplate reader (BMG, Germany).

Known starting materials of the present disclosure may be synthesized using or according to methods known in the art, or may be purchased from companies such as ABCR GmbH & co.kg, Acros Organics, Aldrich Chemical Company, J & K, shao distal Chemical technology (Accela ChemBio Inc), shanghai bici medicine, dary chemicals, and the like.

In the examples, the reaction can be carried out in an argon atmosphere or a nitrogen atmosphere, unless otherwise specified.

An argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to a balloon of argon or nitrogen with a volume of about 1L.

The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L.

The pressure hydrogenation reaction used a hydrogenation apparatus of Parr 3916EKX type and a hydrogen generator of Qinglan QL-500 type or a hydrogenation apparatus of HC2-SS type.

The hydrogenation reaction was usually evacuated and charged with hydrogen and repeated 3 times.

A CEM Discover-S908860 type microwave reactor was used for the microwave reaction.

In the examples, the solution means an aqueous solution unless otherwise specified.

In the examples, the reaction temperature is, unless otherwise specified, from 20 ℃ to 30 ℃ at room temperature.

The monitoring of the progress of the reaction in the examples employed Thin Layer Chromatography (TLC), a developing solvent used for the reaction, a system of eluents for column chromatography used for purifying compounds and a developing solvent system for thin layer chromatography including: a: a dichloromethane/methanol system; b: n-hexane/ethyl acetate system. The volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of basic or acidic reagents such as triethylamine and acetic acid can be added for adjustment.

Example 1

(S) -4- (3- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) oxy) methyl) phenyl) -5, 6-dihydroimidazo [1,2-a ] pyrazin-7 (8H) -yl) -3-fluorobenzonitrile 1

First step of

3- (4-formylphenyl) -5, 6-dihydroimidazo [1,2-a ] pyrazine-7 (8H) -carboxylic acid tert-butyl ester 1b

4-formylphenylboronic acid (260mg,1.73mmol, J & K), 3-bromo-5, 6-dihydroimidazo [1,2-a ] pyrazine-7 (8H) -carboxylic acid tert-butyl ester 1a (400mg,1.32mmol, shanghai bi-de-kogaku) and anhydrous sodium carbonate (323mg,3.04mmol) were added to a mixture of ethylene glycol dimethyl ether and water (12mL, V/V ═ 5:1), followed by bis (triphenylphosphine) palladium dichloride (93mg, 0.13mmol), nitrogen substitution 3 times, and the reaction mixture was heated to 85 ℃ for reaction overnight. The reaction solution was diluted with water (200mL), followed by extraction with ethyl acetate (100 mL. times.3), the organic phases were combined, washed with saturated sodium chloride solution (100mL), dried, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system A to give the title compound 1b (350mg, purity: 70%, yield: 57%). MS M/z (ESI) 328.1[ M +1 ].

Second step of

4- (5,6,7, 8-Tetrahydroimidazo [1,2-a ] pyrazin-3-yl) benzaldehyde hydrochloride 1c

Compound 1b (350mg,1.06mmol) was dissolved in dichloromethane (10mL), and a 4M solution of hydrogen chloride in 1, 4-dioxane (2.2mL) was added dropwise under ice-bath to react for 4 hours. The reaction was concentrated under reduced pressure to give the title compound 1c, which was used directly in the next reaction.

MS m/z(ESI):228.1[M+1]。

The third step

3-fluoro-4- (3- (4-formylphenyl) -5, 6-dihydroimidazo [1,2-a ] pyrazin-7 (8H) -yl) benzonitrile 1d

Compound 1c (240mg,0.64mmol), 4-bromo-3-fluorobenzonitrile (255mg,1.2 mmol)7mmol, Shanghai Biao medicine), potassium phosphate anhydrous (540mg,2.54mmol), 2-dicyclohexyl-phosphorus-2 ',6' -diisopropoxy-1, 1' -biphenyl (Ruphos) (60mg,0.128mmol), tris (dibenzylideneacetone) dipalladium (Pd)₂(dba)₃) (58mg,0.063mmol) was added to 1, 4-dioxane (10mL), nitrogen gas was purged 3 times, and the reaction mixture was heated to 100 ℃ for overnight reaction. The reaction solution was diluted with water (50mL), followed by extraction with ethyl acetate (50 mL. times.3), the organic phases were combined, washed with saturated sodium chloride solution (100 mL. times.2), then dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography with eluent system A to give the title compound 1d (60mg, purity: 80%, yield: 22%).

MS m/z(ESI):347.2[M+1]。

The fourth step

3-fluoro-4- (3- (4- (hydroxymethyl) phenyl) -5, 6-dihydroimidazo [1,2-a ] pyrazin-7 (8H) -yl) benzonitrile 1e

Compound 1d (60mg,0.138mmol) was added to a mixture of methanol and dichloromethane (6mL, V/V ═ 5:1) under ice bath, and potassium borohydride (10mg,0.185mmol) was slowly added, followed by reaction for 2 hours under ice bath. The reaction solution was diluted with water (20mL), extracted with dichloromethane (20 mL. times.6), the organic phases were combined, washed with saturated sodium chloride solution (20mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography with eluent system A to give the title compound 1e (32mg, yield: 67%).

MS m/z(ESI):349.1[M+1]。

The fifth step

4- (3- (4- (chloromethyl) phenyl) -5, 6-dihydroimidazo [1,2-a ] pyrazin-7 (8H) -yl) -3-fluorobenzonitrile 1f

Compound 1e (30mg,0.086mmol) was added to dichloromethane (3mL) under ice-bath, triethylamine (44mg,0.43mmol) and methanesulfonyl chloride (29mg,0.25mmol) were added in this order, and the reaction was stirred under ice-bath for 20 minutes and then warmed to room temperature and stirred for 6 hours. The reaction mixture was diluted with water (20mL), extracted with dichloromethane (20 mL. times.3), combined with the organic phase, washed with saturated sodium chloride solution (20mL), and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate under reduced pressure gave crude compound 1f (31mg), which was used directly in the next reaction.

MS m/z(ESI):367.1[M+1]。

The sixth step

(S) -5-amino-4- (4- ((4- (7- (4-cyano-2-fluorophenyl) -5,6,7, 8-tetrahydroimidazo [1,2-a ] pyrazin-3-yl) benzyl) oxy) -1-oxoisoindolin-2-yl) -5-oxopentanoic acid tert-butyl ester 1h

Compound 1f (31mg,0.067mmol), (S) -5-amino-4- (4-hydroxy-1-oxoisoindolin-2-yl) -5-oxopentanic acid tert-butyl ester 1g (27mg,0.081mmol, prepared by the well-known method "Journal of Medicinal Chemistry,2020,63(13), 6648-propan 6676") was added to N, N-dimethylformamide (3mL), anhydrous cesium carbonate (44mg,0.135mmol), sodium iodide (10mg,0.066mmol) was added at room temperature, and the mixture was heated to 50 ℃ for reaction for 6 hours. The reaction solution was diluted with water (20mL) and extracted with ethyl acetate (20 mL. times.3). The organic phases were combined, washed with saturated sodium chloride solution (20mL), dried, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography with eluent system A to give the title compound 1h (44mg, purity: 60%, yield: 59%).

MS m/z(ESI):665.2[M+1]。

Seventh step

Compound 1h (44mg,0.040mmol), dry benzenesulphonic acid (12mg,0.075mmol) was added to acetonitrile (3mL) and heated to 85 ℃ for 16 h. The reaction solution was concentrated under reduced pressure, and the crude product of the residue was prepared by high performance liquid chromatography (Waters 2767-SQ Detector 2, elution: 10mmol/L aqueous solution of ammonium hydrogencarbonate and acetonitrile, gradient of acetonitrile: 30% -50%, flow rate: 30ml/min) to obtain the title compound 1(10mg, yield: 42%, ee: 96.4%). Chiral HPLC analysis retention time 14.16 min, chiral purity: 96.4% (column: CHIRALPAK IH-3, 4.6 × 150mM, 3 μm, column temperature: 25 ℃, flow rate: 1.0mL/min, mobile phase: 5mM ammonium acetate solution/acetonitrile 55/45 (v/v)).

MS m/z(ESI):591.2[M+1]。

¹H NMR(500MHz,DMSO-d₆):δ10.98(s,1H),7.81(d,1H),7.63(d,1H),7.60-7.53(m,4H),7.51(t,1H),7.35(t,2H),7.29(t,1H),7.15(s,1H),5.30(s,2H),5.12(dd,1H),4.56(s,2H),4.46(d,1H),4.29(d,1H),4.20(t,2H),3.72(t,2H),2.98-2.82(m,1H),2.67-2.55(m,1H),2.47-2.36(m,1H),2.07-1.92(m,1H)。

Example 2

(S) -4- (3- (4- (((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-4-yl) oxy) methyl) phenyl) -5, 6-dihydroimidazo [1,5-a ] pyrazin-7 (8H)) -yl) -3-fluorobenzonitrile 2

First step of

3-bromo-5, 6,7, 8-tetrahydroimidazo [1,5-a ] pyrazine hydrochloride 2b

3-bromo-5, 6-dihydroimidazo [1,5-a ] pyrazine-7 (8H) -carboxylic acid tert-butyl ester 2a (1.0g,3.31mmol) was dissolved in a mixed solution of dichloromethane and methanol (12mL, V/V ═ 1: 1). A4M solution of hydrogen chloride in dioxane (12mL) was added under ice-cooling and the reaction was slowly returned to room temperature for 4 hours. The reaction was concentrated under reduced pressure to give the title compound 2b, which was used directly in the next reaction.

Second step of

4- (3-bromo-5, 6-dihydroimidazo [1,5-a ] pyrazin-7 (8H) -yl) -3-fluorobenzonitrile 2c

Compound 2b (220mg,1.02mmol), 4-bromo-3-fluorobenzonitrile (409mg,2.05mmol), potassium phosphate (868mg,4.09mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (RuPhos Pd G3) (128mg,0.153mmol) were dissolved in dioxane (8mL), purged with nitrogen three times, stirred at room temperature for 10 minutes, and then warmed to 95 ℃ for 20 hours. The reaction solution was diluted with water (50mL), extracted with ethyl acetate (50 mL. times.3), the organic phases were combined, washed with saturated sodium chloride solution (50mL), dried over anhydrous sodium sulfate of the organic phase, filtered, the filtrate was concentrated under reduced pressure, and purified by column chromatography using eluent system A to give the title compound 2c (170mg, yield: 51%).

MS m/z(ESI):321.0[M+1]，323.0[M+3]。

The third step

3-fluoro-4- (3- (4-formylphenyl) -5, 6-dihydroimidazo [1,5-a ] pyrazin-7 (8H) -yl) benzonitrile 2d

Compound 2c (260mg,0.810mmol), 4-formylphenylboronic acid (242.8mg,1.62mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (89mg,0.121mmol) and anhydrous sodium carbonate (257mg,2.43mmol) were dissolved in a mixed solution of 1, 4-dioxane and water (10mL, V/V ═ 4:1), nitrogen was purged three times, and the temperature was raised to 85 ℃ for 16 hours. The reaction solution was diluted with water (50mL), extracted with ethyl acetate (50 mL. times.3), the organic phases were combined, washed with saturated sodium chloride solution (50mL), dried over anhydrous sodium sulfate of the organic phase, filtered, the filtrate was concentrated under reduced pressure, and purified by column chromatography using eluent system A to give the title compound 2d (241mg, yield: 85%).

MS m/z(ESI):346.9[M+1]。

The fourth step

3-fluoro-4- (3- (4- (hydroxymethyl) phenyl) -5, 6-dihydroimidazo [1,5-a ] pyrazin-7 (8H) -yl) benzonitrile 2e

Compound 2d (220mg,0.635mmol) was dissolved in tetrahydrofuran (6mL) and sodium borohydride (72mg,1.91mmol) was added slowly under ice bath for 30 min. The reaction was quenched by the addition of saturated ammonium chloride solution (30mL), followed by extraction with ethyl acetate (50 mL. times.3), and the organic phases were combined, washed with saturated sodium chloride solution (50mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by column chromatography with eluent system A to give the title compound 2e (155mg, yield: 70%).

MS m/z(ESI):349.2[M+1]。

The fifth step

4- (3- (4- (bromomethyl) phenyl) -5, 6-dihydroimidazo [1,5-a ] pyrazin-7 (8H) -yl) -3-fluorobenzonitrile 2f

Compound 2e (50mg,0.144mmol) was dissolved in methylene chloride (3mL), and triphenylphosphine (75mg,0.287mmol) and carbon tetrabromide (95mg,0.287mmol) were added in this order to react for 1 hour. The reaction solution was concentrated under reduced pressure, and purified by column chromatography using eluent system A to give the title compound 2f (45mg, yield: 76%).

MS m/z(ESI):411.0[M+1],413.1[M+3]。

Sixth step (S) -5-amino-4- (4- ((4- (7- (4-cyano-2-fluorophenyl) -5,6,7, 8-tetrahydroimidazo [1,5-a ] pyrazin-3-yl) benzyl)

Oxy) -6-fluoro-1-oxoisoindolin-2-yl) -5-oxopentanoic acid tert-butyl ester 2h

Compound 2f (60mg,0.146mmol) and 2g (67mg,0.190mmol, prepared by the method disclosed in patent application "WO 2019040274A1, page 99, example 7") of tert-butyl (S) -5-amino-4- (6-fluoro-4-hydroxy-1-oxoisoindol-2-yl) -5-oxovalerate were dissolved in N, N-dimethylformamide (5mL), and potassium carbonate (40mg,0.292mmol) was added and reacted for 1 hour. The reaction was quenched by the addition of saturated ammonium chloride solution (20mL), followed by extraction with ethyl acetate (20 mL. times.3), and the organic phases were combined, washed with saturated sodium chloride solution (20mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by column chromatography with eluent system A to give the title compound 2h (80mg, yield: 80%).

MS m/z(ESI):683.2[M+1]。

Seventh step

Compound 2h (80mg,0.117mmol) was dissolved in acetonitrile (3mL), benzenesulfonic acid (46mg,0.293mmol) was added, and the mixture was heated to 80 ℃ for reaction for 16 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was prepared by high performance liquid chromatography (Gilson GX-281, mobile phase: 10mmol/L aqueous solution of ammonium hydrogencarbonate and acetonitrile, gradient of acetonitrile: 45% to 55%, flow rate: 30mL/min) to obtain the title compound 2(11mg, yield: 15%).

MS m/z(ESI):609.2[M+1]。

¹H NMR(500MHz,DMSO-d₆):δ10.98(s,1H),7.87-7.72(m,3H),7.66-7.51(m,3H),7.37-7.31(m,1H),7.26(t,1H),7.17-7.10(m,1H),6.95(s,1H),5.33(s,2H),5.12(dd,1H),4.61(s,2H),4.43(d,1H),4.35-4.16(m,3H),3.69(t,2H),2.98-2.83(m,1H),2.66-2.56(m,1H),2.46-2.40(m,1H),2.06-1.97(m,1H)。

Example 3

(S) -4- (3- (4- (((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-4-yl) oxy) methyl) phenyl) -5, 6-dihydroimidazo [1,2-a ] pyrazin-7 (8H) -yl) -3-fluorobenzonitrile 3

Using the synthetic route for Compound 1 in example 1, the starting compound, tert-butyl (S) -5-amino-4- (4-hydroxy-1-oxoisoindolin-2-yl) -5-oxovalerate, 1g, was replaced with tert-butyl (S) -5-amino-4- (6-fluoro-4-hydroxy-1-oxoisoindol-2-yl) -5-oxopentanoate, 2g, to afford the title compound, 3(21 mg). MS M/z (ESI) 609.2[ M +1 ].

¹H NMR(500MHz,DMSO-d₆):δ10.99(s,1H),7.81(d,1H),7.70-7.43(m,5H),7.38-7.24(m,2H),7.22-7.02(m,2H),5.31(s,2H),5.12(dd,1H),4.56(s,2H),4.42(d,1H),4.31-4.10(m,3H),3.73(t,2H),2.95-2.82(m,1H),2.64-2.55(m,1H),2.47-2.38(m,1H),2.04-1.90(m,1H)。

Test example:

biological evaluation

The present disclosure is further described and explained below in conjunction with test examples, but these examples are not meant to limit the scope of the present disclosure.

Test example 1NCI-H929 biological evaluation of proliferation assay

The following methods were used to determine the inhibitory activity of the compounds of the present disclosure on NCI-H929 cell proliferation. The experimental method is briefly described as follows:

NCI-H929 cells (ATCC, CRL-9068) were cultured in complete medium, RPMI1640 medium (Hyclone, SH30809.01) containing 10% fetal bovine serum (Corning, 35-076-CV) and 0.05mM 2-mercaptoethanol (Sigma, M3148). The first day of the experiment, H929 cells were seeded in 96-well plates using complete medium at a density of 6000 cells/well, 100. mu.L of cell suspension per well, while 10. mu.L of test compound diluted in complete medium was added per well, the compound was first dissolved in DMSO at an initial concentration of 10mM, serially diluted in a 5-fold concentration gradient for a total of 9 concentration pointsBlank control was 100% DMSO. Another 5. mu.L of the compound dissolved in DMSO was added to 95. mu.L of complete medium, i.e., the compound was diluted 20-fold with complete medium. Finally, 10. mu.L of each well of compound diluted in complete medium was added to the cell suspension, i.e.the final concentration of compound was 9 concentration points with 5-fold gradient dilution starting from 50. mu.M, a blank containing 0.5% DMSO was set and placed at 37 ℃ and 5% CO₂The cell incubator was incubated for 5 days. On the sixth day, 96-well cell culture plates were removed and 50. mu.L of each well was added

The reagent for measuring the activity of a luminescent cell (Promega, G7573) was left at room temperature for 10 minutes, and then the luminescence signal value was read using a multi-functional microplate reader (Perkinelmer, EnVision2015), and the IC of the inhibitory activity of the compound was calculated using Graphpad Prism software₅₀The values are shown in Table 1.

TABLE 1 Activity of the compounds of this disclosure to inhibit NCI-H929 cell proliferation.

Compound (I)	IC₅₀(nM)
		1	0.06
2	0.29
		3	0.62

And (4) conclusion: the compound disclosed by the invention has good activity of inhibiting the proliferation of NCI-H929 cells.

Claims

1. A compound of formula (I), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

w is a carbon atom or a nitrogen atom;

ring a is aryl or heteroaryl;

y is CH₂Or C (O);

z is oxygen atom or NH;

ring B is aryl or heteroaryl;

each R is⁵Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl andheterocyclyl, wherein said alkyl, alkoxy, cycloalkyl and heterocyclyl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

n is 0, 1,2 or 3;

p is 0, 1,2 or 3;

q is 0, 1,2, 3 or 4; and is

t is 0, 1,2, 3 or 4.

2. The compound of the general formula (I), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to claim 1, which is a compound of the general formula (I-1), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

ring A, ring B, Y, Z, G¹、G²、G³、G⁴、W、R¹～R⁷、R^7aN, p, q and t are as defined in claim 1.

3. A compound of formula (I) according to claim 1 or2, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring a is phenyl or 5-or 6-membered heteroaryl; preferably phenyl or imidazolyl.

4. A compound of general formula (I) according to any one of claims 1 to 3, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Y is CH₂。

5. The compound of general formula (I) according to any one of claims 1 to 4, wherein Z is an oxygen atom, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

6. A compound of general formula (I) according to any one of claims 1 to 5, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is³And R⁴Is a hydrogen atom.

7. The compound of formula (I), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 and 3 to 6, which is a compound of formula (II) or (III), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

ring B, G¹、G²、G³、G⁴、R¹、R²、R⁵、R⁶、R⁷、R^7aN, q and t are as defined in claim 1.

8. A compound of general formula (I) according to any one of claims 1 to 7, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein G¹、G²、G³And G⁴Are all CR⁸；R⁸Is a hydrogen atom.

9. A compound of general formula (I) according to any one of claims 1 to 8, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring B is phenyl or 5-or 6-membered heteroaryl; preferably, ring B is phenyl.

10. The compound of the general formula (I), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 9, which is a compound of the general formula (IIaa) or (IIaa-1), or a tautomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

R¹、R²、R⁵、R⁶、R⁷、R⁹、R¹⁰、R¹¹n, q and t are as defined in claim 1.

11. A compound of general formula (I) according to any one of claims 1 to 10, or a tautomer, racemate, or pair thereofAn enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R^7aSelected from cyano, -S (O)₂R⁹、-S(O)₂NR¹⁰R¹¹And 3 to 8 membered heterocyclyl; r⁹、R¹⁰And R¹¹As defined in claim 1.

12. A compound of general formula (I) according to any one of claims 7 to 11, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein W is¹Is a nitrogen atom, W²Is CR⁵，R⁵Is a hydrogen atom or C_1-6An alkyl group; or W²Is a nitrogen atom, W¹Is CR⁵，R⁵Is a hydrogen atom or C_1-6An alkyl group; or W¹And W²Are all nitrogen atoms.

13. The compound of general formula (I) according to any one of claims 1 to 12, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R¹Is a hydrogen atom or C_1-6An alkyl group.

14. The compound of general formula (I), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 13, wherein each R is²Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C_1-6An alkyl group.

15. The compound of general formula (I) according to any one of claims 1 to 14, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein each R is⁵And R⁶Are the same or different and are each independently a hydrogen atom or C_1-6An alkyl group.

16. The compound of general formula (I) according to any one of claims 1 to 15, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein each R is⁷Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkyl, C_1-6Haloalkoxy, cyano, amino, nitro, hydroxy and C_1-6A hydroxyalkyl group.

17. A compound of general formula (I), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 16, selected from the group consisting of:

18. a compound of formula (IA), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

R^mis C_1-6An alkyl group; preferably tert-butyl;

ring A, ring B, Y, Z, G¹、G²、G³、G⁴、W、R¹～R⁷、R^7a、n、p, q and t are as defined in claim 1.

19. The compound of claim 18, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

20. a process for the preparation of a compound of formula (I) according to claim 1, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:

wherein:

R^mis C_1-6An alkyl group; preferably tert-butyl;

21. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 17, or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

22. Use of a compound of general formula (I) according to any one of claims 1 to 17 or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 21, for the preparation of a medicament for the treatment and/or prevention of a disease associated with CRBN proteins.

23. Use of a compound of general formula (I) according to any one of claims 1 to 17 or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 21, for the preparation of a medicament for the treatment and/or prevention of cancer, a disorder related to angiogenesis, pain, macular degeneration or a related syndrome, a skin disease, a lung disease, an asbestos-related disease, a parasitic disease, an immunodeficiency disorder, a CNS disease, CNS injury, atherosclerosis or a related disorder, a sleep disorder or a related disorder, an infectious disease, a hemoglobinopathy or a related disorder, polycythemia vera or a TNF α -related disorder; preferably, for the manufacture of a medicament for the treatment and/or prevention of cancer or CNS damage.

24. The use of claim 23, wherein the cancer is selected from the group consisting of leukemia, myeloma, lymphoma, melanoma, skin cancer, liver cancer, kidney cancer, lung cancer, nasopharyngeal cancer, gastric cancer, esophageal cancer, colorectal cancer, gallbladder cancer, bile duct cancer, chorioepithelial cancer, pancreatic cancer, pediatric tumors, cervical cancer, ovarian cancer, breast cancer, bladder cancer, urothelial cancer, ureteral tumors, prostate cancer, seminoma, testicular tumors, head and neck squamous cell carcinoma, endometrial cancer, thyroid cancer, sarcoma, osteoma, neuroblastoma, neuroendocrine cancer, brain tumor, CNS cancer, and glioma; preferably, the liver cancer is hepatocellular carcinoma; the colorectal cancer is colon cancer or rectal cancer; the sarcoma is osteosarcoma or soft tissue sarcoma; the glioma is a glioblastoma or astrocytoma.

25. The use according to claim 24, wherein the myeloma is preferably Multiple Myeloma (MM) and myelodysplastic syndrome (MDS); preferably, the multiple myeloma is relapsed, refractory or resistant.

26. The use of claim 25, wherein the multiple myeloma is lenalidomide or pomalidomide refractory or resistant.