WO2022148358A1

WO2022148358A1 - Cyclohexadiimide derivative substituted by fused heterocyclyl, and preparation method therefor and pharmaceutical application thereof

Info

Publication number: WO2022148358A1
Application number: PCT/CN2022/070210
Authority: WO
Inventors: 贾敏强; 汤焕宇; 杨方龙; 贺峰; 陶维康
Original assignee: 江苏恒瑞医药股份有限公司; 上海恒瑞医药有限公司
Priority date: 2021-01-05
Filing date: 2022-01-05
Publication date: 2022-07-14
Also published as: CN116669736A; TW202241872A

Abstract

The present disclosure relates to a cyclohexadiimide derivative substituted by fused heterocyclyl, and a preparation method therefor and a pharmaceutical application thereof. Specifically, the present disclosure relates to a cyclohexadiimide derivative substituted by fused heterocyclyl and represented by general formula (I), a preparation method therefor, and a pharmaceutical composition comprising the derivative and a use thereof as a treatment agent, and particularly a use as a Cereblon adjustment agent in the field of multiple myeloma treatment.

Description

Condensed heterocyclic group substituted cyclohexanediimide derivative, its preparation method and its application in medicine

technical field

The present disclosure belongs to the field of medicine, and relates to a fused heterocyclic group-substituted cyclohexanediimide derivative, a preparation method thereof and its application in medicine. In particular, the present disclosure relates to a fused heterocyclyl-substituted cyclohexanediimide derivative represented by general formula (I), a method for its preparation and a pharmaceutical composition containing the derivative, and its use as a Cereblon modulator in the treatment of Use in the field of multiple myeloma.

Background technique

Multiple myeloma (MM) is a malignant tumor whose main symptoms include hypercalcemia, kidney damage, anemia and bone disease. MM is the second most common hematological malignancy after non-Hodgkin lymphoma, with 4 to 6 people per 100,000 people in the world and about 1.6 people per 100,000 people in China each year. The current treatment methods are mainly drug therapy and autologous stem cell transplantation. At present, there are four main categories of drugs widely used in clinical practice, namely, immunomodulators, proteasome inhibitors, hormones and monoclonal antibodies. Wait. The mechanisms of action of these drugs are different, and combined use can often achieve better efficacy. Clinically, double, triple, or even quadruple drugs are generally used, usually immunomodulators, proteasome inhibitors and hormones. Add antibody. Among them, lenalidomide is the most commonly used immunomodulator. Lenalidomide is used in first-line treatment, maintenance treatment after stem cell transplantation, and second- and third-line treatment after relapse. The drug had sales of $9.7 billion in 2018/2019. In addition, the entire MM market is also considerable and growing rapidly. This is due to the continuous improvement and perfection of the diagnosis and treatment of MM, and the patient's survival period is longer and the medication time is correspondingly prolonged. It is estimated that the MM market will reach a scale of US$33 billion in 2022, of which the largest proportion is still the immunomodulator represented by lenalidomide.

The mechanism of action of immunomodulators (IMiDs) in the treatment of MM is mainly that after IMiDs bind to Cereblon (CRBN) protein, it will activate the E3 ligase activity of CRBN, and then selectively interact with the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3). ) binding; resulting in rapid ubiquitination and degradation of Ikaros and Aiolos. Down-regulation of Ikaros/Aiolos results in down-regulation of c-Myc, followed by down-regulation of IRF4, and finally leads to myeloma cell growth inhibition and apoptosis. In addition, IKZF3 can also inhibit the transcription of IL2 and TNF cytokines in T/NK cells. After the degradation of IKZF3, this inhibition can be relieved to promote the release of these cytokines and play a role in immune regulation. Clinical trials have also shown that the clinical benefit of IMiDs drugs is also related to the level of CRBN expression. After knockdown of CRBN in lenalidomide-sensitive cell lines (OPM2 and KMS18), it was found that the activity of lenalidomide to inhibit cell growth disappeared, resulting in drug resistance. The level of CRBN knockdown was related to the degree of drug resistance; in cell proliferation In the experiment, reducing the expression level of CRBN in cells (U266-CRBN60 and U266-CRBN75), the activities of lenalidomide and pomalidomide in inhibiting cell growth were reduced.

The currently approved IMiDs drugs include thalidomide, lenalidomide and pomalidomide, all from Celgene (now merged by BMS). The binding force of these three compounds to CRBN increased in turn, so the clinical dosage decreased in turn. The main indication of these three compounds is MM, and thalidomide and lenalidomide can also treat other indications, especially lenalidomide, which can be used to treat myelodysplastic syndrome (MDS). In terms of side effects, lenalidomide and pomalidomide have similar performance and have obvious myelosuppressive effects, which are target-related toxicity; thalidomide has some other side effects, such as sedation, constipation, and neurological side effects. Wait.

The adipimide portion of all IMiDs binds to a hydrophobic pocket defined by three tryptophan residues in CRBN (called the "thalidomide binding pocket"). In contrast, the phthalimide/isoindolinone ring is exposed to the solvent and alters the molecular surface of CRBN, thereby regulating substrate recognition; different IMiDs lead to obvious modification of the molecular surface of CRBN, and the preference for substrate recognition is also different. Therefore, modification of IMiDs may lead to the degradation of other transcription factors, causing unnecessary toxic side effects. This mode of action of IMiDs, also known as molecular glue, visualizes the binding effect of this small molecule on two protein substrates.

Since the current median survival time of multiple myeloma is more than five years, the prolongation of survival time makes most patients resistant to the currently marketed drugs such as lenalidomide and pomalidomide. The treatment effect is severely reduced. Therefore, the inventors envisage developing drug molecules with better activity to overcome the problem of drug resistance while minimizing the toxic and side effects of such compounds.

Published patent applications for Cereblon modulators include WO2008115516A2, WO2011100380A1, WO2019226770A1, WO2019014100A1, and WO2020064002A1, among others.

SUMMARY OF THE INVENTION

The purpose of this disclosure is to provide a compound of general formula (I) or a pharmaceutically acceptable salt thereof:

in:

G ¹ , G ² and G ³ are the same or different, and are each independently CR ⁸ or a nitrogen atom;

Z is CR ^a R ^b or an oxygen atom;

R ^a and R ^b are the same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, and a haloalkyl group;

X is _CH or C(O);

Y is oxygen atom or NH;

Ring A is aryl or heteroaryl;

R ¹ is selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino and hydroxy;

R ² is the same or different at each occurrence and is each independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, Cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, One or more substituents of alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl replaced;

R ³ and R ⁴ are the same or different, and are each independently selected from hydrogen atoms, halogens, and alkyl groups;

R ⁵ is the same or different at each occurrence and is each independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, oxo, cyano, amino, nitro, hydroxy, Hydroxyalkyl, -C(O)OR ⁹ , -CONR ¹⁰ R ¹¹ , cycloalkyl and heterocyclyl, wherein said alkyl, alkoxy, cycloalkyl and heterocyclyl are each independently optionally One selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl or replaced by multiple substituents;

R ⁶ is the same or different at each occurrence and is each independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, Cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, One or more substituents of alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl replaced;

R ⁷ is selected from cyano, -S(O) ₂ R ⁹ and -S(O) ₂ NR ¹⁰ R ¹¹ ;

R ⁸ is the same or different at each occurrence and is each independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, Cycloalkyl and heterocyclyl;

^R9 is the same or different at each occurrence and is each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclyl group;

R ¹⁰ and R ¹¹ are the same or different at each occurrence and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclyl group;

n is 1, 2 or 3;

m is 0, 1, 2 or 3;

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

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

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

in:

Rings A, X, Y, Z, G ¹ , G ² , G ³ , R ¹ to R ⁷ , m, n, p and q are as defined in general formula (I).

In some embodiments of the present disclosure, the compound represented by the general formula (I), the general formula (I-1) or a pharmaceutically acceptable salt thereof is the compound represented by the general formula (I-1-1) or Its pharmaceutically acceptable salts:

in:

In some embodiments of the present disclosure, the compound represented by the general formula (I), the general formula (I-1) or a pharmaceutically acceptable salt thereof is the compound represented by the general formula (I-1-2) or Its pharmaceutically acceptable salts:

in:

In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (I-1), general formula (I-1-1), general formula (I-1-2) or A pharmaceutically acceptable salt thereof, wherein Y is an oxygen atom.

In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (I-1), general formula (I-1-1), general formula (I-1-2) or A pharmaceutically acceptable salt thereof, wherein R ³ and R ⁴ are both hydrogen atoms.

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

in:

Rings A, X, Z, G ¹ , G ² , G ³ , R ¹ , R ² , R ⁵ to R ⁷ , m, n, p and q are as defined in general formula (I).

In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (I-1), general formula (II) or a pharmaceutically acceptable salt thereof is general formula (II-1) The compound shown or a pharmaceutically acceptable salt thereof:

in:

In some embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (I-1-1), general formula (II), general formula (II-1) The compound shown or a pharmaceutically acceptable salt thereof is the compound represented by the general formula (II-1-1) or a pharmaceutically acceptable salt thereof:

in:

In some embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (I-1-2), general formula (II), general formula (II-1) are The compound shown or a pharmaceutically acceptable salt thereof is the compound represented by the general formula (II-1-2) or a pharmaceutically acceptable salt thereof:

in:

In some embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (I-1-1), general formula (I-1-2), general formula (II) , a compound represented by general formula (II-1), general formula (II-1-1), general formula (II-1-2) or a pharmaceutically acceptable salt thereof, wherein X is CH ₂ .

In some embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (I-1-1), general formula (I-1-2), general formula (II) , the compound represented by general formula (II-1), general formula (II-1-1), general formula (II-1-2) or a pharmaceutically acceptable salt thereof, wherein Z is CR ^a R ^b ; R ^a The same as R ^b , and each independently a hydrogen atom or a halogen; preferably, R ^a and R ^b are the same, and each independently a hydrogen atom or a fluorine atom.

In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (II) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof :

in:

Rings A, G ¹ , G ² , G ³ , R ¹ , R ² , R ⁵ to R ⁷ , m, n, p and q are as defined in general formula (I).

In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III) or its The pharmaceutically acceptable salt is the compound represented by the general formula (III-1) or a pharmaceutically acceptable salt thereof:

in:

In some embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (I-1-1), general formula (II), general formula (II-1), general formula The compound represented by formula (II-1-1), general formula (III), general formula (III-1) or a pharmaceutically acceptable salt thereof is the compound represented by general formula (III-1-1) or its pharmaceutically acceptable salt. Medicinal salt:

in:

In some embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (I-1-2), general formula (II), general formula (II-1), general formula The compound represented by formula (II-1-2), general formula (III), general formula (III-1) or a pharmaceutically acceptable salt thereof is the compound represented by general formula (III-1-2) or its pharmaceutically acceptable salt. Medicinal salt:

in:

In some embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (I-1-1), general formula (I-1-2), general formula (II) , general formula (II-1), general formula (II-1-1), general formula (II-1-2), general formula (III), general formula (III-1), general formula (III-1- 1) The compound represented by the general formula (III-1-2) or a pharmaceutically acceptable salt thereof, wherein G ¹ , G ² and G ³ are all CR ⁸ ; R ⁸ is a hydrogen atom.

In some embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (I-1-1), general formula (I-1-2), general formula (II) , general formula (II-1), general formula (II-1-1), general formula (II-1-2), general formula (III), general formula (III-1), general formula (III-1- 1), a compound represented by general formula (III-1-2) or a pharmaceutically acceptable salt thereof, wherein ring A is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group; preferably, ring A is benzene base.

In some embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (I-1-1), general formula (I-1-2), general formula (II) , general formula (II-1), general formula (II-1-1), general formula (II-1-2), general formula (III), general formula (III-1), general formula (III-1- 1) The compound represented by the general formula (III-1-2) or a pharmaceutically acceptable salt thereof, wherein R ¹ is a hydrogen atom.

In some embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (I-1-1), general formula (I-1-2), general formula (II) , general formula (II-1), general formula (II-1-1), general formula (II-1-2), general formula (III), general formula (III-1), general formula (III-1- 1) The compound represented by the general formula (III-1-2) or a pharmaceutically acceptable salt thereof, wherein R ² is a hydrogen atom.

In some embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (I-1-1), general formula (I-1-2), general formula (II) , general formula (II-1), general formula (II-1-1), general formula (II-1-2), general formula (III), general formula (III-1), general formula (III-1- 1) The compound represented by the general formula (III-1-2) or a pharmaceutically acceptable salt thereof, wherein p is 0, 1 or 2; preferably p is 0.

In some embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (I-1-1), general formula (I-1-2), general formula (II) , general formula (II-1), general formula (II-1-1), general formula (II-1-2), general formula (III), general formula (III-1), general formula (III-1- 1), a compound represented by the general formula (III-1-2) or a pharmaceutically acceptable salt thereof, wherein R ⁵ is the same or different at each occurrence, and each is independently a hydrogen atom or a C _1-6 alkyl group ; preferably, R ⁵ is a hydrogen atom.

In some embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (I-1-1), general formula (I-1-2), general formula (II) ), general formula (II-1), general formula (II-1-1), general formula (II-1-2), general formula (III), general formula (III-1), general formula (III-1 -1) The compound represented by the general formula (III-1-2) or a pharmaceutically acceptable salt thereof, wherein q is 0, 1 or 2; preferably, q is 1.

In some embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (I-1-1), general formula (I-1-2), general formula (II) ), general formula (II-1), general formula (II-1-1), general formula (II-1-2), general formula (III), general formula (III-1), general formula (III-1 -1), a compound represented by the general formula (III-1-2) or a pharmaceutically acceptable salt thereof, wherein R ⁶ is the same or different at each occurrence, and each is independently selected from hydrogen atom, halogen, C _{1 -6} alkyl, C _1-6 alkoxy, C _1-6 haloalkyl and C _1-6 haloalkoxy; preferably, R ⁶ is a halogen; more preferably, R ⁶ is a fluorine atom.

In some embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (I-1-1), general formula (I-1-2), general formula (II) ), general formula (II-1), general formula (II-1-1), general formula (II-1-2), general formula (III), general formula (III-1), general formula (III-1 -1), a compound represented by the general formula (III-1-2) or a pharmaceutically acceptable salt thereof, wherein R ⁷ is selected from cyano, -S(O) ₂ R ⁹ and -S(O) ₂ NR ¹⁰ R ¹¹ , wherein R ⁹ is a C _1-6 alkyl group, and both R ¹⁰ and R ¹¹ are hydrogen atoms; preferably, R ⁷ is a cyano group.

In some embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (I-1-1), general formula (I-1-2), general formula (II) , general formula (II-1), general formula (II-1-1), general formula (II-1-2), general formula (III), general formula (III-1), general formula (III-1- 1) The compound represented by the general formula (III-1-2) or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2.

In some embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (II), general formula (II-1), general formula (III) or general formula (III- The compound shown in 1), or a pharmaceutically acceptable salt thereof, wherein n is 2.

In some embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (I-1-1), general formula (I-1-2), general formula (II) , general formula (II-1), general formula (II-1-1), general formula (II-1-2), general formula (III), general formula (III-1), general formula (III-1- 1) The compound represented by the general formula (III-1-2) or a pharmaceutically acceptable salt thereof, wherein m is 0.

In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (I-1), general formula (II), general formula (II-1) or a pharmaceutically acceptable salt thereof, in

for

In some embodiments of the present disclosure, the compound represented by the general formula (I-1-1), the general formula (II-1-1) or a pharmaceutically acceptable salt thereof, wherein

for

In some embodiments of the present disclosure, the compound represented by the general formula (I-1-2), the general formula (II-1-2) or a pharmaceutically acceptable salt thereof, wherein

for

for

In some embodiments of the present disclosure, the compound represented by general formula (III), general formula (III-1) or a pharmaceutically acceptable salt thereof, wherein

for

In some embodiments of the present disclosure, the compound represented by the general formula (III-1-1) or a pharmaceutically acceptable salt thereof, wherein

for

In some embodiments of the present disclosure, the compound represented by the general formula (III-1-2) or a pharmaceutically acceptable salt thereof, wherein

for

for

In some embodiments of the present disclosure, the general formula (I), general formula (I-1), general formula (I-1-1), general formula (I-1-2), general formula (II) , general formula (II-1), general formula (II-1-1), general formula (II-1-2), general formula (III), general formula (III-1), general formula (III-1- 1), a compound represented by general formula (III-1-2) or a pharmaceutically acceptable salt thereof, wherein

for

R ⁶ is halogen; R ⁷ is cyano; preferably,

for

In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (I-1), general formula (I-1-1), general formula (I-1-2) or A pharmaceutically acceptable salt thereof, wherein G ¹ , G ² and G ³ are all CR ⁸ ; R ⁸ is a hydrogen atom; Z is CR ^a R ^b ; R ^a and R ^b are the same, and are each independently a hydrogen atom or a halogen ; X is CH ₂ ; Y is an oxygen atom; Ring A is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group; R ¹ is a hydrogen atom; R ² is a hydrogen atom; R ³ and R ⁴ are both hydrogen atoms ; R ⁵ is the same or different at each occurrence, and each is independently a hydrogen atom or a C _1-6 alkyl; R ⁶ is the same or different at each occurrence, and each is independently selected from a hydrogen atom, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl and C _1-6 haloalkoxy; R ⁷ is selected from cyano, -S(O) ₂ R ⁹ and -S(O) ₂ NR ¹⁰ R ¹¹ , wherein R ⁹ is a C _1-6 alkyl group, and both R ¹⁰ and R ¹¹ are hydrogen atoms; p is 0, 1 or 2; q is 0, 1 or 2; n is 1 or 2; m is 0.

In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (I-1) or a pharmaceutically acceptable salt thereof, wherein G ¹ , G ² and G ³ are all CR ⁸ R ⁸ is a hydrogen atom; Z is CR ^a R ^b ; R ^a and R ^b are the same, and are each independently a hydrogen atom or a halogen; X is CH ₂ ; Y is an oxygen atom; Ring A is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group; R ¹ is a hydrogen atom; R ² is a hydrogen atom; R ³ and R ⁴ are both hydrogen atoms; R ⁵ is the same or different at each occurrence, and is each independently a hydrogen atom or C _1-6 alkyl; R ⁶ is the same or different at each occurrence, and each is independently selected from hydrogen atom, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl and C _1-6 haloalkoxy; R ⁷ is selected from cyano, -S(O) ₂ R ⁹ and -S(O) ₂ NR ¹⁰ R ¹¹ , wherein R ⁹ is C _1-6 alkyl, R ¹⁰ and R ¹¹ are all hydrogen atoms; p is 0, 1 or 2; q is 0, 1 or 2; n is 2; m is 0.

In some embodiments of the present disclosure, the compound represented by general formula (II), general formula (II-1), general formula (II-1-1), general formula (II-1-2) or A pharmaceutically acceptable salt thereof, wherein G ¹ , G ² and G ³ are all CR ⁸ ; R ⁸ is a hydrogen atom; Z is CR ^a R ^b ; R ^a and R ^b are the same, and are each independently a hydrogen atom or fluorine Atom; X is CH ₂ ; Ring A is phenyl; R ¹ is a hydrogen atom; R ² is a hydrogen atom; R ⁵ is the same or different at each occurrence and is each independently a hydrogen atom or a C _1-6 alkyl group ; R ⁶ is the same or different at each occurrence and is each independently selected from a hydrogen atom, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl and C _1-6 haloalkane oxy; R ⁷ is cyano; p is 0, 1 or 2; q is 0, 1 or 2; n is 1 or 2;

In some embodiments of the present disclosure, the compound represented by general formula (II), general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein G ¹ , G ² and G ³ are all CR ⁸ ; R ⁸ is a hydrogen atom; Z is CR ^a R ^b ; R ^a and R ^b are the same, and are each independently a hydrogen atom or a fluorine atom; X is CH ₂ ; Ring A is a phenyl group; R ¹ is a hydrogen atom; R ² is a hydrogen atom; R ⁵ is the same or different at each occurrence, and each is independently a hydrogen atom or a C _1-6 alkyl; R ⁶ is the same or different at each occurrence, and each is independently selected from a hydrogen atom , halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl and C _1-6 haloalkoxy; R ⁷ is cyano; p is 0, 1 or 2; q is 0 , 1, or 2; n is 2; m is 0.

In some embodiments of the present disclosure, the compound represented by general formula (III), general formula (III-1), general formula (III-1-1), general formula (III-1-2) or A pharmaceutically acceptable salt thereof, wherein G ¹ , G ² and G ³ are all CR ⁸ ; R ⁸ is a hydrogen atom; Ring A is a phenyl group; R ¹ is a hydrogen atom; R ² is a hydrogen atom ^; appearing the same or different, and each independently is a hydrogen atom or a C _1-6 alkyl; R ⁶ is the same or different at each occurrence, and each is independently selected from a hydrogen atom, a halogen, a C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl and C _1-6 haloalkoxy; R ⁷ is cyano; p is 0, 1 or 2; q is 0, 1 or 2; n is 1 or 2 ; m is 0.

In some embodiments of the present disclosure, the compound represented by general formula (III), general formula (III-1) or a pharmaceutically acceptable salt thereof, wherein G ¹ , G ² and G ³ are all CR ⁸ R ⁸ is a hydrogen atom; Ring A is a phenyl group; R ¹ is a hydrogen atom; R ² is a hydrogen atom; R ⁵ is the same or different at each occurrence and is each independently a hydrogen atom or a C _1-6 alkyl group ; R ⁶ is the same or different at each occurrence and is each independently selected from a hydrogen atom, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl and C _1-6 haloalkane oxy; R ⁷ is cyano; p is 0, 1 or 2; q is 0, 1 or 2; n is 2;

In some embodiments of the present disclosure, the compound represented by general formula (III), general formula (III-1), general formula (III-1-1), general formula (III-1-2) or A pharmaceutically acceptable salt thereof, wherein G ¹ , G ² and G ³ are all CR ⁸ ; R ⁸ is a hydrogen atom; Ring A is a phenyl group; R ¹ is a hydrogen atom; R ⁵ is the same or different at each occurrence, and each independently a hydrogen atom or a C _1-6 alkyl group; R ⁶ is the same or different at each occurrence, and each is independently selected from a hydrogen atom, a halogen, a C _1-6 alkyl group, a C _1-6 alkoxy group R ⁷ is cyano; p is 0, ₁ or 2; q is 0, ₁ or 2; n is 1 or 2; m is 0.

In some embodiments of the present disclosure, the compound represented by general formula (III), general formula (III-1), general formula (III-1-1), general formula (III-1-2) or Its pharmaceutically acceptable salt, wherein G ¹ , G ² and G ³ are all CR ⁸ ; R ⁸ is a hydrogen atom;

for

R ¹ is a hydrogen atom; R ⁶ is a halogen; R ⁷ is a cyano group; p is 0; q is 1; n is 1 or 2;

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

Another aspect of the present disclosure relates to a compound of formula (IA) or a salt thereof,

in:

R ^m is C _1-6 alkyl; preferably, R ^m is tert-butyl;

Rings A, X, Y, Z, G ¹ , G ² , G ³ , R ¹ to R ⁷ , m, n, p and q are as defined for compounds of general formula (I).

Another aspect of the present disclosure relates to a compound represented by general formula (IA-1) or a salt thereof,

in:

R ^m is C _1-6 alkyl; preferably, R ^m is tert-butyl;

Rings A, X, Y, Z, G ¹ , G ² , G ³ , R ¹ to R ⁷ , m, n, p and q are as defined for compounds of general formula (I-1).

Another aspect of the present disclosure relates to a compound represented by the general formula (IA-1-1) or a salt thereof,

in:

R ^m is C _1-6 alkyl; preferably, R ^m is tert-butyl;

Rings A, X, Y, Z, G ¹ , G ² , G ³ , R ¹ to R ⁷ , m, n, p and q are as defined for the compound of general formula (I-1-1).

Another aspect of the present disclosure relates to a compound represented by the general formula (IA-1-2) or a salt thereof,

in:

R ^m is C _1-6 alkyl; preferably, R ^m is tert-butyl;

Rings A, X, Y, Z, G ¹ , G ² , G ³ , R ¹ to R ⁷ , m, n, p and q are as defined for compounds of general formula (I-1-2).

Another aspect of the present disclosure relates to a compound of general formula (IIA) or a salt thereof:

in:

R ^m is C _1-6 alkyl; preferably, R ^m is tert-butyl;

Rings A, X, Z, G ¹ , G ² , G ³ , R ¹ , R ² , R ⁵ to R ⁷ , m, n, p and q are as defined for compounds of general formula (II).

Another aspect of the present disclosure relates to a compound of general formula (IIA-1) or a salt thereof:

in:

R ^m is C _1-6 alkyl; preferably, R ^m is tert-butyl;

Rings A, X, Z, G ¹ , G ² , G ³ , R ¹ , R ² , R ⁵ to R ⁷ , m, n, p and q are as defined for compounds of general formula (II-1).

Another aspect of the present disclosure relates to a compound represented by the general formula (IIA-1-1) or a salt thereof:

in:

R ^m is C _1-6 alkyl; preferably, R ^m is tert-butyl;

Rings A, X, Z, G ¹ , G ² , G ³ , R ¹ , R ² , R ⁵ to R ⁷ , m, n, p and q are as defined in the compound of general formula (II-1-1).

Another aspect of the present disclosure relates to a compound of general formula (IIA-1-2) or a salt thereof:

in:

R ^m is C _1-6 alkyl; preferably, R ^m is tert-butyl;

Rings A, X, Z, G ¹ , G ² , G ³ , R ¹ , R ² , R ⁵ to R ⁷ , m, n, p and q are as defined for the compound of general formula (II-1-2).

Another aspect of the present disclosure relates to a compound of general formula (IIIA) or a salt thereof:

in:

R ^m is C _1-6 alkyl; preferably, R ^m is tert-butyl;

Rings A, G ¹ , G ² , G ³ , R ¹ , R ² , R ⁵ to R ⁷ , m, n, p and q are as defined for compounds of general formula (III).

Another aspect of the present disclosure relates to a compound represented by the general formula (IIIA-1) or a salt thereof:

in:

R ^m is C _1-6 alkyl; preferably, R ^m is tert-butyl;

Ring A, G ¹ , G ² , G ³ , R ¹ , R ² , R ⁵ to R ⁷ , m, n, p and q are as defined for compounds of general formula (III-1).

Another aspect of the present disclosure relates to a compound represented by the general formula (IIIA-1-1) or a salt thereof:

in:

R ^m is C _1-6 alkyl; preferably, R ^m is tert-butyl;

Ring A, G ¹ , G ² , G ³ , R ¹ , R ² , R ⁵ to R ⁷ , m, n, p and q are as defined for the compound of general formula (III-1-1).

Another aspect of the present disclosure relates to a compound of general formula (IIIA-1-2) or a salt thereof:

in:

R ^m is C _1-6 alkyl; preferably, R ^m is tert-butyl;

Ring A, G ¹ , G ² , G ³ , R ¹ , R ² , R ⁵ to R ⁷ , m, n, p and q are as defined for the compound of general formula (III-1-2).

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

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

The compound represented by the general formula (IA) or a salt thereof undergoes an intramolecular ring closure reaction to obtain the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof,

in:

R ^m is C _1-6 alkyl; preferably, R ^m is tert-butyl;

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

The compound represented by the general formula (IA-1) or a salt thereof undergoes an intramolecular ring closure reaction to obtain the compound represented by the general formula (I-1) or a pharmaceutically acceptable salt thereof,

in:

R ^m is C _1-6 alkyl; preferably, R ^m is tert-butyl;

Rings A, X, Y, Z, G ¹ , G ² , G ³ , R ¹ to R ⁷ , m, n, p and q are as defined in general formula (I-1).

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

The compound represented by the general formula (IA-1-1) or a salt thereof undergoes an intramolecular ring-closing reaction to obtain the compound represented by the general formula (I-1-1) or a pharmaceutically acceptable salt thereof,

in:

R ^m is C _1-6 alkyl; preferably, R ^m is tert-butyl;

Rings A, X, Y, Z, G ¹ , G ² , G ³ , R ¹ to R ⁷ , m, n, p and q are as defined in the general formula (I-1-1).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I-1-2) or a pharmaceutically acceptable salt thereof, the method comprising:

The compound represented by the general formula (IA-1-2) or a salt thereof undergoes an intramolecular ring-closing reaction to obtain the compound represented by the general formula (I-1-2) or a pharmaceutically acceptable salt thereof,

in:

R ^m is C _1-6 alkyl; preferably, R ^m is tert-butyl;

Rings A, X, Y, Z, G ¹ , G ² , G ³ , R ¹ to R ⁷ , m, n, p and q are as defined in the general formula (I-1-2).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II), or a pharmaceutically acceptable salt thereof, the method comprising:

The compound represented by the general formula (IIA) or a salt thereof undergoes an intramolecular ring closure reaction to obtain the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof,

in:

R ^m is C _1-6 alkyl; preferably, R ^m is tert-butyl;

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

The compound represented by the general formula (IIA-1) or a salt thereof undergoes an intramolecular ring closure reaction to obtain the compound represented by the general formula (II-1) or a pharmaceutically acceptable salt thereof,

in:

R ^m is C _1-6 alkyl; preferably, R ^m is tert-butyl;

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

The compound represented by the general formula (IIA-1-1) or a salt thereof undergoes an intramolecular ring closure reaction to obtain the compound represented by the general formula (II-1-1) or a pharmaceutically acceptable salt thereof,

in:

R ^m is C _1-6 alkyl; preferably, R ^m is tert-butyl;

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II-1-2) or a pharmaceutically acceptable salt thereof, the method comprising:

The compound represented by the general formula (IIA-1-2) or a salt thereof undergoes an intramolecular ring closure reaction to obtain the compound represented by the general formula (II-1-2) or a pharmaceutically acceptable salt thereof,

in:

R ^m is C _1-6 alkyl; preferably, R ^m is tert-butyl;

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:

The compound represented by the general formula (IIIA) or a salt thereof undergoes an intramolecular ring-closing reaction to obtain the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof,

in:

R ^m is C _1-6 alkyl; preferably, R ^m is tert-butyl;

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

The compound represented by the general formula (IIIA-1) or a salt thereof undergoes an intramolecular ring-closing reaction to obtain the compound represented by the general formula (III-1) or a pharmaceutically acceptable salt thereof,

in:

R ^m is C _1-6 alkyl; preferably, R ^m is tert-butyl;

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

The compound represented by the general formula (IIIA-1-1) or a salt thereof undergoes an intramolecular ring-closing reaction to obtain the compound represented by the general formula (III-1-1) or a pharmaceutically acceptable salt thereof,

in:

R ^m is C _1-6 alkyl; preferably, R ^m is tert-butyl;

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III-1-2) or a pharmaceutically acceptable salt thereof, the method comprising:

The compound represented by the general formula (IIIA-1-2) or a salt thereof undergoes an intramolecular ring-closing reaction to obtain the compound represented by the general formula (III-1-2) or a pharmaceutically acceptable salt thereof,

in:

R ^m is C _1-6 alkyl; preferably, R ^m is tert-butyl;

Another aspect of the present disclosure relates to a pharmaceutical composition comprising the general formula (I), the general formula (I-1), the general formula (I-1-1), the general formula (I- 1-2), general formula (II), general formula (II-1), general formula (II-1-1), general formula (II-1-2), general formula (III), general formula (III- 1), the compound shown in general formula (III-1-1), general formula (III-1-2) and the compound shown in Table A or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carrier, diluent or excipient.

The present disclosure further relates to general formula (I), general formula (I-1), general formula (I-1-1), general formula (I-1-2), general formula (II), general formula (II-1) ), general formula (II-1-1), general formula (II-1-2), general formula (III), general formula (III-1), general formula (III-1-1), general formula (III) - Use of the compounds shown in 1-2) and the compounds shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for the treatment and/or prevention of CRBN protein-related diseases.

The present disclosure further relates to general formula (I), general formula (I-1), general formula (I-1-1), general formula (I-1-2), general formula (II), general formula (II-1) ), general formula (II-1-1), general formula (II-1-2), general formula (III), general formula (III-1), general formula (III-1-1), general formula (III) The compound shown in -1-2) and the compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same are prepared for the treatment and/or prevention of cancer, angiogenesis-related disorders, pain, Macular degeneration or related syndrome, skin disease, lung disease, asbestos-related disease, parasitic disease, immunodeficiency disease, central nervous system (CNS) disease, CNS injury, atherosclerosis or related disorder, sleep disturbance or related disorder , use in a medicament for an infectious disease, hemoglobinopathies or related disorders or TNFα related disorders; preferably in 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 general formula (I), general formula (I-1), general formula (I-1- 1), general formula (I-1-2), general formula (II), general formula (II-1), general formula (II-1-1), general formula (II-1-2), general formula ( III), the compound represented by the general formula (III-1), the general formula (III-1-1), the general formula (III-1-2) and the compound shown in Table A or a pharmaceutically acceptable salt thereof, or containing its pharmaceutical composition.

The present disclosure also relates to a treatment and/or prevention of cancer, angiogenesis-related disorders, pain, macular degeneration or related syndromes, skin diseases, lung diseases, asbestos-related diseases, parasitic diseases, immunodeficiency diseases, CNS diseases , CNS damage, atherosclerosis or related disorders, sleep disorders or related disorders, infectious diseases, hemoglobinopathies or related disorders or TNFα related disorders, preferably a method for the treatment and/or prevention of cancer or CNS damage, which Including the administration of a therapeutically effective amount of general formula (I), general formula (I-1), general formula (I-1-1), general formula (I-1-2), general formula (II), general formula (I-1-2), general formula (II), general formula formula (II-1), general formula (II-1-1), general formula (II-1-2), general formula (III), general formula (III-1), general formula (III-1-1) , the compound represented by the general formula (III-1-2) and the compound represented by Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure further relates to a general formula (I), general formula (I-1), general formula (I-1-1), general formula (I-1-2), general formula (II), general formula (II) -1), general formula (II-1-1), general formula (II-1-2), general formula (III), general formula (III-1), general formula (III-1-1), general formula The compound shown in (III-1-2) and the compound shown in Table A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same, which are used as a medicine.

The present disclosure further relates to general formula (I), general formula (I-1), general formula (I-1-1), general formula (I-1-2), general formula (II), general formula (II-1) ), general formula (II-1-1), general formula (II-1-2), general formula (III), general formula (III-1), general formula (III-1-1), general formula (III) The compounds shown in -1-2) and the compounds shown in Table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, are used for the treatment and/or prevention of CRBN protein-related diseases.

The present disclosure further relates to general formula (I), general formula (I-1), general formula (I-1-1), general formula (I-1-2), general formula (II), general formula (II-1) ), general formula (II-1-1), general formula (II-1-2), general formula (III), general formula (III-1), general formula (III-1-1), general formula (III) The compound shown in -1-2) and the compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the treatment and/or prevention of cancer, angiogenesis-related disorders, pain, Macular degeneration or related syndromes, skin diseases, lung diseases, asbestos-related diseases, parasitic diseases, immunodeficiency diseases, CNS diseases, CNS damage, atherosclerosis or related conditions, sleep disorders or related conditions, infectious diseases, Hemoglobinopathies or related disorders or TNFα related disorders; preferably for the treatment and/or prevention of cancer or CNS damage.

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

The cancer described in this disclosure is selected from the group consisting of leukemia, myeloma, lymphoma, melanoma, skin cancer, liver cancer (eg, hepatocellular carcinoma), kidney cancer, lung cancer (eg, non-small cell lung cancer and small cell lung cancer), nasopharyngeal carcinoma cancer, gastric cancer, esophageal cancer (also known as esophageal cancer), colorectal cancer (such as colon and rectal cancer), gallbladder cancer, bile duct cancer, chorioepithelial cancer, pancreatic cancer, polycythemia vera, pediatric oncology, cervical cancer, Ovarian cancer, breast cancer, bladder cancer, urothelial cancer, ureteral tumor, prostate cancer, seminoma, testicular tumor, head and neck cancer, head and neck squamous cell carcinoma, endometrial cancer, thyroid cancer, sarcoma (such as osteosarcoma and soft tissue sarcomas), osteomas, neuroblastomas (i.e. neuroblastomas), neuroendocrine carcinomas, brain tumors, CNS carcinomas, astrocytomas and gliomas (e.g. glioblastomas); preferably, Said myeloma is preferably multiple myeloma (MM) and myelodysplastic syndrome (MDS); more preferably, said multiple myeloma is relapsed, refractory or resistant; most preferably Preferably, the multiple myeloma is lenalidomide or pomalidomide refractory or resistant.

The leukemia is preferably chronic lymphocytic leukemia, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML) and hairy cell leukemia, and the lymphoma is preferably Small lymphocytic lymphoma, marginal zone lymphoma, follicular lymphoma, mantle cell lymphoma, non-Hodgkin lymphoma (NHL), lymphoplasmacytic lymphoma, extranodal marginal zone lymphoma, T-cell lymphoma , B-cell lymphoma, and diffuse large B-cell lymphoma.

Cancers described in the present disclosure include primary or metastatic cancers. Cancers described in the present disclosure also include refractory or resistant to chemotherapy or radiation therapy.

Examples of CNS disorders include, but are not limited to, disorders described in US Publication No. 2005/0143344, published June 30, 2005, the contents of which are incorporated herein by reference. Specific examples include, but are not limited to, amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis and other neuroimmune diseases such as Tourette syndrome, delusions, Or disturbance of consciousness that occurs in a short period of time, and amnesia, or diffuse 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 disorders described in US Publication No. 2006/0122228, published June 8, 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 Injury, concussion, post-concussion syndrome, cerebral contusion, subdural hematoma, epidermal hematoma, post-traumatic epilepsy, chronic autonomic state, complete spinal cord injury (SCI), incomplete SCI, acute SCI, subcutaneous Acute SCI, chronic SCI, central spinal cord syndrome, hemisection cord syndrome, anterior cord syndrome, conus medullaris syndrome, cauda equina syndrome, neurogenic shock, spinal shock, altered level of consciousness, headache, nausea, vomiting, memory Depression, dizziness, diplopia, blurred vision, mood swings, sleep disturbances, irritability, inability to concentrate, neuroticism, behavioral disturbances, cognitive deficits, and epilepsy.

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

The active compounds can be formulated in a form suitable for administration by any suitable route, and the compositions of the present disclosure can be formulated by conventional methods using one or more pharmaceutically acceptable carriers. Accordingly, the active compounds of the present disclosure can be formulated in various dosage forms for oral administration, injection (eg, intravenous, intramuscular, or subcutaneous) administration, 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, injectable solutions, dispersible powders or granules, suppositories, lozenges or syrups.

As a general guide, the active compound is preferably presented in a unit dose or in a form that the patient can self-administer in a single dose. A unit dose of a compound or composition of the present disclosure may be expressed as a tablet, capsule, cachet, vial, powder, granule, lozenge, suppository, reconstituted powder, or liquid. A suitable unit dose may be 0.1 to 1000 mg.

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

Tablets contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients may be inert excipients, granulating agents, disintegrating agents, binders and lubricants. These tablets may be uncoated or they may be coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained release over an extended period of time.

Oral formulations can also be presented in soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or in which the active ingredient is mixed with a water-soluble or oily vehicle.

Aqueous suspensions contain the active substances in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents. The 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.

Oily suspensions can be formulated by suspending the active ingredient in vegetable or mineral oils. The oily suspensions may contain thickening agents. The aforementioned sweetening and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants.

The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oily phase can be vegetable oil, or mineral oil or a mixture thereof. Suitable emulsifying agents 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 coloring agent and an antioxidant.

The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous solutions. Among the acceptable vehicles or solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. A sterile injectable preparation can be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oily phase. The injectable solution or microemulsion can be injected into the bloodstream of a patient by local bulk injection. Alternatively, solutions and microemulsions are preferably administered in a manner that maintains a constant circulating concentration of the compounds of the present disclosure. To maintain this constant concentration, a continuous intravenous drug delivery device can be used. An example of such a device is the Deltec CADD-PLUS.TM.5400 IV pump.

The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous or oily suspensions for intramuscular and subcutaneous administration. This 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 non-toxic parenterally acceptable diluent or solvent. In addition, sterile fixed oils are conveniently employed as a solvent or suspending medium. For this purpose, any blending and fixing oil can be used. In addition, fatty acids are also available in the preparation of injectables.

The compounds of the present disclosure can 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.

The compounds of the present disclosure can be administered by the addition of water to prepare dispersible powders and granules for aqueous suspension. These pharmaceutical compositions can be prepared by admixing the active ingredient with a dispersing or wetting agent, suspending agent or one or more preservatives.

As is well known to those skilled in the art, the dosage of a drug to be administered depends on a variety of factors, including but not limited to the following factors: 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 , patient's diet, time of administration, mode of administration, rate of excretion, combination of drugs, severity of disease, etc.; in addition, optimal treatment mode such as mode of treatment, daily dose of compound or pharmaceutically acceptable salt Species can be verified against conventional treatment protocols.

Glossary

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 chain aliphatic hydrocarbon group having 1 to 20 (

eg

1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (ie C _1-20 alkyl). The alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (ie, a C _1-12 alkyl group), and more preferably an alkyl group having 1 to 6 carbon atoms (ie, a C _1-6 alkyl group). Non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2 -methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethyl pentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4- Ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3- Ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof, etc. Most preferably lower alkyl groups having 1 to 6 carbon atoms, non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl , n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3 -Methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl , 2,3-dimethylbutyl, etc. Alkyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents are preferably selected from the group consisting of D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkane One or more of oxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

The term "alkylene" refers to a divalent alkyl group, wherein the alkyl group is as defined above, having from 1 to 20 (eg, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (ie C _1-20 alkylene). The alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (ie, a C _1-12 alkylene group), and more preferably an alkylene group having 1 to 6 carbon atoms (ie, a C _1-6 alkylene group). ). Non-limiting examples of alkylene groups include, but are not limited to: methylene ( _-CH2- ), 1,1-ethylene (-CH( _CH3 )-), 1,2-ethylene (-CH ₂ CH ₂ )-, 1,1-propylene (-CH(CH ₂ CH ₃ )-), 1,2-propylene (-CH ₂ CH(CH ₃ )-), 1,3-propylene base (-CH ₂ CH ₂ CH ₂ -), 1,4-butylene (-CH ₂ CH ₂ CH ₂ CH ₂ -) and the like. Alkylene may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents are preferably selected from alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy group, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, ring One or more of alkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, and oxo.

The term "alkenyl" refers to an alkyl compound having at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above and has 2 to 12 (

eg

2, 3, 4, 5, 6, 7, 8 , 9, 10, 11 or 12) carbon atoms (ie C _2-12 alkenyl). The alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (ie, a C _2-6 alkenyl group). Non-limiting examples include: vinyl, propenyl, butenyl, pentenyl, hexenyl, and the like. Alkenyl can be substituted or unsubstituted, when substituted, the substituent is preferably selected from alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy , one or more of hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

The term "alkynyl" refers to an alkyl compound containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above and has 2 to 12 (

eg

2, 3, 4, 5, 6, 7, 8 , 9, 10, 11 or 12) carbon atoms (ie C _2-12 alkynyl). The alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (ie, a C _2-6 alkynyl group). 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 alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy , one or more of hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy. Alkoxy can be optionally substituted or unsubstituted, when substituted, the substituent is preferably selected from D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, hetero One or more of cyclooxy, 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 having 3 to 20 cycloalkyl rings (

eg

3, 4, 5, 6, 7, 8, 9, 10 , 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (ie 3 to 20 membered cycloalkyl), preferably 3 to 12 carbon atoms (ie 3 to 12 membered ring alkyl), more preferably 3 to 8 carbon atoms (ie 3 to 8 membered cycloalkyl), most preferably 3 to 6 carbon atoms (ie 3 to 6 membered cycloalkyl). Non-limiting examples of monocyclic cycloalkyl groups include: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptyl Alkenyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocycloalkyl groups, fused cycloalkyl groups, and bridged cycloalkyl groups.

The term "spirocycloalkyl" refers to a polycyclic group of 5 to 20 membered monocyclic rings sharing one carbon atom (called a spiro atom), which may contain one or more double bonds. Preferably 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan). According to the number of spiro atoms shared between the rings, spirocycloalkyl groups are divided into mono-spirocycloalkyl groups or multi-spirocycloalkyl groups (such as bis-spirocycloalkyl groups), preferably mono-spirocycloalkyl groups or double-spirocycloalkyl groups . More preferably 3 yuan/5 yuan, 3 yuan/6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 6 yuan/4 yuan, 6-membered/5-membered or 6-membered/6-membered monospirocycloalkyl. Non-limiting examples of spirocycloalkyl include:

The term "fused cycloalkyl" refers to an all-carbon polycyclic group in which an adjacent pair of carbon atoms is shared between 5- to 20-membered rings, one or more of which may contain one or more double bonds. Preferably 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan). According to the number of formed rings, it can be divided into bicyclic, tricyclic, tetracyclic and other polycyclic fused cycloalkyl groups, preferably bicyclic or tricyclic fused cycloalkyl groups, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered RMB, RMB 4/RMB 4, RMB 4/RMB 5, RMB 4/RMB 6, RMB 5/RMB 4, RMB 5/RMB 5, RMB 5/RMB 6, RMB 6/RMB 3, RMB 6/RMB 4, 6-membered/5-membered and 6-membered/6-membered bicyclic fused cycloalkyl. Non-limiting examples of fused cycloalkyl groups include:

The term "bridged cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members in which any two rings share two non-directly attached carbon atoms, which may contain one or more double bonds. Preferably 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic and other polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic bridged cycloalkyl groups, more preferably bicyclic or tricyclic bridged cycloalkyl groups. Non-limiting examples of bridged cycloalkyl include:

The cycloalkyl ring includes a cycloalkyl (including monocyclic, spiro, fused and bridged) as described above fused to an aryl, heteroaryl or heterocycloalkyl ring where it is attached to the parent structure Rings together are cycloalkyl, non-limiting examples include

etc.; preferred

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

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent having 3 to 20 (

eg

3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen, and sulfur, optionally oxo ( i.e. forming a sulfoxide or sulfone), but excluding ring moieties of -O-O-, -O-S- or -S-S-, the remaining ring atoms are carbon. It preferably has 3 to 12 ring atoms, of which 1 to 4 (eg 1, 2, 3 and 4) are heteroatoms (ie, a 3 to 12 membered heterocyclyl); more preferably has 3 to 8 ring atoms, wherein 1 to 3 are heteroatoms (eg 1, 2 and 3) (ie 3 to 8 membered heterocyclyl); more preferably 3 to 6 ring atoms, of which 1 to 3 are heteroatoms (ie 3 to 6 membered) heterocyclyl); most preferably contains 5 or 6 ring atoms, of which 1 to 3 are heteroatoms (ie 5 or 6 membered heterocyclyl). Non-limiting examples of monocyclic heterocyclyl groups include: pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpho olinyl, homopiperazinyl, etc. Polycyclic heterocyclyls include spiro heterocyclyls, fused heterocyclyls and bridged heterocyclyls.

The term "spiroheterocyclyl" refers to a 5- to 20-membered monocyclic polycyclic heterocyclic group sharing one atom (called a spiro atom), wherein one or more ring atoms are heterocyclic groups selected from nitrogen, oxygen and sulfur. atom, the sulfur may optionally be oxo (ie to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds. Preferably 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan). According to the number of spiro atoms shared between the rings, spiroheterocyclyl groups are classified into mono-spiroheterocyclyl groups or poly-spiroheterocyclyl groups (such as bis-spiroheterocyclyl groups), preferably mono-spiroheterocyclyl groups and bis-spiro-heterocyclyl groups . More preferably 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 monospiroheterocyclyl. Non-limiting examples of spiroheterocyclyl include:

The term "fused heterocyclic group" refers to a polycyclic heterocyclic group in which a 5- to 20-membered ring shares an adjacent pair of atoms, one or more of which may contain one or more double bonds, wherein one or more of the rings may contain one or more double bonds. The atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, which may be optionally oxo (ie, to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic fused heterocyclic groups, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/ 6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/3 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 5 yuan/7 yuan , 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 group. Non-limiting examples of fused heterocyclyl groups include:

The term "bridged heterocyclyl" refers to a polycyclic heterocyclic group of 5 to 14 members in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds in which one or more ring atoms To be selected from nitrogen, oxygen and sulfur, the sulfur may optionally be oxo (ie to form a sulfoxide or sulfone), the remaining ring atoms being carbon. Preferably 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic and other polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic bridged heterocyclic groups, more preferably bicyclic or tricyclic bridged heterocyclic groups. Non-limiting examples of bridged heterocyclyl groups include:

The heterocyclyl ring includes a heterocyclyl group (including monocyclic, spiroheterocycle, fused heterocycle and bridged heterocycle) as described above fused to an aryl, heteroaryl or cycloalkyl ring, wherein the The rings to which the structure is attached are heterocyclyl, non-limiting examples of which include:

Wait.

Heterocyclyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents are preferably selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy , one or more of 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 are rings that share adjacent pairs of carbon atoms) groups having a conjugated pi-electron system, preferably 6 to 10 membered , such as phenyl and naphthyl. The aryl ring includes an aryl ring as described above fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring linked to the parent structure is an aryl ring, non-limiting examples of which include :

Aryl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents are preferably selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, One or more of cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms (eg 1, 2, 3 and 4), 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5-10-membered (eg 5, 6, 7, 8, 9 or 10-membered), more preferably 5- or 6-membered, eg furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrole base, 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 linked to the parent structure is a heteroaryl ring, non-limiting examples of which include :

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

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

The term "amino protecting group" refers to a group introduced on an amino group that is easily removed in order to keep the amino group unchanged when other parts of the molecule are reacted. Non-limiting examples include: (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butoxycarbonyl (Boc), acetyl, p-toluenesulfonyl (Ts), benzyl, allyl and p-Methoxybenzyl, etc. These groups may be optionally substituted with 1-3 substituents selected from halogen, alkoxy or nitro.

The term "hydroxyl protecting group" refers to an easily removed group introduced on a hydroxy group, which is usually used to block or protect the hydroxy group while reacting on other functional groups of the compound. Non-limiting examples include: triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl, tert-butyl, C _1-6 alkoxy C _{1-6 alkyl substituted with phenyl or C 1-6} _alkyl substituted by phenyl (such as methoxymethyl (MOM) and ethoxyethyl, etc.), (C _1-10 alkyl or aryl) Acyl (such as: formyl, acetyl, benzoyl, p-nitrobenzoyl, etc.), (C _1-6 alkyl or 6- to 10-membered aryl) sulfonyl, (C _1-6 alkoxy or 6- to 10-membered aryloxy)carbonyl, allyl, 2-tetrahydropyranyl (THP) and the like.

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

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

The term "alkylthio" refers to alkyl-S-, 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 alkoxy 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 hydroxy 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 "thiol" refers to -SH.

The term "amino" refers to _-NH2 .

The term "cyano" refers to -CN.

The term "nitro" refers to _-NO2 .

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

The term "carbonyl" refers to C=O.

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

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

The compounds of the present disclosure may exist in specific stereoisomeric forms. The term "stereoisomer" refers to isomers that are structurally identical 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 isomers, (D)- and (L)-isomers, tautomers, atropisomers, conformers and mixtures thereof (e.g. racemates, mixtures of diastereomers) . Substituents in the compounds of the present disclosure may have additional asymmetric atoms. All such stereoisomers, as well as mixtures thereof, are included within the scope of this disclosure. Optically active (-)- and (+)-isomers, (R)- and (S)-enantiomers, and (D)- and (D)- and (+)-isomers can be prepared by chiral synthesis, chiral reagents, or other conventional techniques (L)-isomer. An isomer of a certain compound of the present disclosure can be prepared by asymmetric synthesis or chiral auxiliaries, or, when the molecule contains basic functional groups (such as amino groups) or acidic functional groups (such as carboxyl groups), with appropriate optical Active acids or bases form diastereomeric salts, which are then resolved by conventional methods known in the art to yield the pure isomers. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by chromatography.

In the chemical structure of the compound described in the present disclosure, the bond

Indicates an unspecified configuration, i.e. if a chiral isomer exists in the chemical structure, the bond

can be

or

or both

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, ie as a single isomer or as a mixture of said tautomers in any ratio. Non-limiting examples include: keto-enols, imine-enamines, lactam-lactams, and the like. An example of a lactam-lactam equilibrium is shown below:

When referring to pyrazolyl, it should be understood to include either one of the following two structures or a mixture of two tautomers:

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

The compounds of the present disclosure include all suitable isotopic derivatives of the compounds thereof. The term "isotopic derivative" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that can be incorporated into the compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, such as ² H (deuterium, D), respectively, ³ H (tritium, T), ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O, ¹⁸ O, ³² p, ³³ p, ³³ S, ³⁴ S, ³⁵ S, ³⁶ S, ¹⁸ F, ³⁶ Cl, ⁸² Br, ¹²³ I, ¹²⁴ I, ¹²⁵ I, ¹²⁹ I and ¹³¹ I, etc., preferably deuterium.

Compared with non-deuterated drugs, deuterated drugs have the advantages of reducing toxic and side effects, increasing drug stability, enhancing curative effect, and prolonging the biological half-life of drugs. All transformations of the isotopic composition of the compounds of the present disclosure, whether radioactive or not, are included within the scope of the present disclosure. Each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom, wherein the replacement of deuterium can be partial or complete, and a partial replacement of deuterium means that at least one hydrogen is replaced by at least one deuterium.

In the compounds of the present disclosure, when a position is specifically designated as "deuterium" or "D", that position is understood to be at least 1000 times more abundant (i.e., deuterium) than the natural abundance of deuterium, which is 0.015%. at least 15% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 1000 times greater than the natural abundance of deuterium (ie, at least 15% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 2000 times greater than the natural abundance of deuterium (ie, at least 30% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 3000 times greater than the natural abundance of deuterium (ie, at least 45% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 3340 times greater than the natural abundance of deuterium (ie, at least 50.1% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 3500 times greater than the natural abundance of deuterium (ie, at least 52.5% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 4000 times greater than the natural abundance of deuterium (ie, at least 60% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 4500 times greater than the natural abundance of deuterium (ie, at least 67.5% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 5000 times greater than the natural abundance of deuterium (ie, at least 75% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 5500 times greater than the natural abundance of deuterium (ie, at least 82.5% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6000 times greater than the natural abundance of deuterium (ie, at least 90% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6333.3 times greater than the natural abundance of deuterium (i.e., at least 95% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6466.7 times greater than the natural abundance of deuterium (ie, at least 97% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6600 times greater than the natural abundance of deuterium (ie, at least 99% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6633.3 times greater than the natural abundance of deuterium (ie, at least 99.5% deuterium incorporation).

General formula (I), general formula (I-1), general formula (I-1-1), general formula (I-1-2), general formula (II), general formula (II-1), General formula (II-1-1), general formula (II-1-2), general formula (III), general formula (III-1), general formula (III-1-1), general formula (III-1 The compounds shown in -2) and the compounds shown in Table A or their pharmaceutically acceptable salts, including their tautomers, racemates, enantiomers, diastereomers, cis-trans isomers form or a mixture thereof.

"Optionally" or "optionally" means that the subsequently described event or circumstance can, but need not, occur, and that the description includes instances where the event or circumstance occurs or instances where it does not. For example, "C _1-6 alkyl optionally (optionally) substituted by halogen or cyano" means that halogen or cyano may, but need not, be present, and the description includes the case where the alkyl is substituted by halogen or cyano and the alkane The case where the group is not substituted by halogen and cyano.

"Substituted" or "substituted" means that one or more hydrogen atoms in a group, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms, independently of one another, are substituted by the corresponding number of substituents. A person skilled in the art can determine possible or impossible substitutions (either experimentally or theoretically) without undue effort. For example, amino or hydroxyl groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (eg, olefinic) bonds.

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

"Pharmaceutically acceptable salt" refers to a salt of a compound of the present disclosure, which may be selected from inorganic or organic salts. Such salts are safe and effective when used in mammals, and have due biological activity. The salts can be prepared separately during the final isolation and purification of the compounds, or by reacting a suitable group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.

With respect to a drug or pharmacologically active agent, the term "therapeutically effective amount" refers to an amount of the drug or agent sufficient to achieve, or at least partially achieve, the desired effect. The determination of the therapeutically effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the specific active substance, and the appropriate therapeutically effective amount in each case can be determined by those skilled in the art based on routine experiments.

The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with patient tissue without undue toxicity, irritation, allergic response or Other problems or complications with a reasonable benefit/risk ratio and are 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 parameters such as pH, concentration, temperature, etc., it is indicated that the parameter may vary by ±10%, and sometimes more preferably within ±5%. As those skilled in the art will understand, when parameters are not critical, numbers are generally given for illustrative purposes only, and not limitations.

Synthetic methods of compounds of the present disclosure

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

Option One

The compound represented by the general formula (IA) or a salt thereof undergoes an intramolecular ring-closure reaction under acidic conditions to obtain the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof,

in:

R ^m is C _1-6 alkyl; preferably, R ^m is tert-butyl;

Option II

The compound represented by the general formula (IA-1) or a salt thereof undergoes an intramolecular ring-closure reaction under acidic conditions to obtain the compound represented by the general formula (I-1) or a pharmaceutically acceptable salt thereof,

in:

R ^m is C _1-6 alkyl; preferably, R ^m is tert-butyl;

third solution

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

The compound represented by the general formula (IIA) or a salt thereof undergoes an intramolecular ring-closing reaction under acidic conditions to obtain the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof,

in:

R ^m is C _1-6 alkyl; preferably, R ^m is tert-butyl;

Option 4

The compound represented by the general formula (IIA-1) or a salt thereof undergoes an intramolecular ring-closing reaction under acidic conditions to obtain the compound represented by the general formula (II-1) or a pharmaceutically acceptable salt thereof,

in:

R ^m is C _1-6 alkyl; preferably, R ^m is tert-butyl;

Option five

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III), or a pharmaceutically acceptable salt thereof, the method comprising:

The compound represented by the general formula (IIIA) or a salt thereof undergoes an intramolecular ring-closure reaction under acidic conditions to obtain the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof,

in:

R ^m is C _1-6 alkyl; preferably, R ^m is tert-butyl;

Option 6

The compound represented by the general formula (IIIA-1) or a salt thereof undergoes an intramolecular ring-closure reaction under acidic conditions to obtain the compound represented by the general formula (III-1) or a pharmaceutically acceptable salt thereof,

in:

R ^m is C _1-6 alkyl; preferably, R ^m is tert-butyl;

Option 7

The compound represented by the general formula (IA-1-1) or a salt thereof undergoes an intramolecular ring-closure reaction under acidic conditions to obtain the compound represented by the general formula (I-1-1) or a pharmaceutically acceptable salt thereof,

in:

R ^m is C _1-6 alkyl; preferably, R ^m is tert-butyl;

Option 8

The compound represented by the general formula (IA-1-2) or a salt thereof undergoes an intramolecular ring-closure reaction under acidic conditions to obtain the compound represented by the general formula (I-1-2) or a pharmaceutically acceptable salt thereof,

in:

R ^m is C _1-6 alkyl; preferably, R ^m is tert-butyl;

Option Nine

The compound represented by the general formula (IIA-1-1) or a salt thereof undergoes an intramolecular ring-closure reaction under acidic conditions to obtain the compound represented by the general formula (II-1-1) or a pharmaceutically acceptable salt thereof ,

in:

R ^m is C _1-6 alkyl; preferably, R ^m is tert-butyl;

Option ten

The compound represented by the general formula (IIA-1-2) or a salt thereof undergoes an intramolecular ring-closure reaction under acidic conditions to obtain the compound represented by the general formula (II-1-2) or a pharmaceutically acceptable salt thereof ,

in:

R ^m is C _1-6 alkyl; preferably, R ^m is tert-butyl;

Plan Eleven

The compound represented by the general formula (IIIA-1-1) or a salt thereof undergoes an intramolecular ring-closure reaction under acidic conditions to obtain the compound represented by the general formula (III-1-1) or a pharmaceutically acceptable salt thereof ,

in:

R ^m is C _1-6 alkyl; preferably, R ^m is tert-butyl;

Plan 12

The compound represented by the general formula (IIIA-1-2) or a salt thereof undergoes an intramolecular ring-closure reaction under acidic conditions to obtain the compound represented by the general formula (III-1-2) or a pharmaceutically acceptable salt thereof ,

in:

R ^m is C _1-6 alkyl; preferably, R ^m is tert-butyl;

Reagents providing acidic conditions in the above synthetic scheme include but are not limited to p-toluenesulfonic acid, p-toluenesulfonic acid monohydrate, benzenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, sulfuric acid, hydrochloric acid, nitric acid and trifluoroacetic acid; Preferred is benzenesulfonic acid.

The above reaction is preferably carried out in a solvent, and the solvent used includes but is not limited to: ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane Alkane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide and mixtures thereof.

Description of drawings

Figure 1 shows the efficacy data of the compound of Example 2-1 and CC-92480 on NCI-H929 xenografts in CB-17SCID mice.

Figure 2 shows the effect of the compound of Example 2-1 and CC-92480 on the body weight of CB-17SCID mice.

Detailed ways

The following examples are used to further describe the present disclosure, but these examples do not limit the scope of the present disclosure.

Example

The structures of the compounds were determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts ([delta]) are given in units of 10<" ⁶ > (ppm). NMR was measured by Bruker AVANCE-400 nuclear magnetic instrument or Bruker AVANCE NEO 500M, and the solvent was deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD) , the internal standard is tetramethylsilane (TMS).

Agilent 1200/1290DAD-6110/6120 Quadrupole MS LC/MS was used for MS determination (manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS), waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS model : waters ACQuity Qda Detector/waters SQ Detector), THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

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

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

HPLC preparations used Waters 2545-2767, Waters 2767-SQ Detector2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.

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

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

The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm to 0.2mm, and the specification used for TLC separation and purification products is 0.4mm to 0.5mm.

Silica gel column chromatography generally uses Yantai Huanghai silica gel 200 to 300 mesh silica gel as the carrier.

The average inhibition rate and IC ₅₀ value of kinases were measured with NovoStar microplate reader (BMG, Germany).

The known starting materials of the present disclosure can be synthesized using or according to methods known in the art, or can be purchased from ABCR GmbH & Co.KG, Acros Organics, Aldrich Chemical Company, J&K, Shaoyuan Chemical Technology (Accela ChemBio Inc. ), Shanghai Bide Pharmaceuticals, Darui Chemicals and other companies.

There is no special description in the examples, and the reaction can be carried out in an argon atmosphere or a nitrogen atmosphere.

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

Hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1 L.

The pressure hydrogenation reaction uses Parr 3916EKX hydrogenation apparatus and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenation apparatus.

The hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.

The microwave reaction used a CEM Discover-S 908860 microwave reactor.

There is no special description in the examples, and the solution refers to an aqueous solution.

There is no special description in the examples, and the reaction temperature is room temperature, ranging from 20°C to 30°C.

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

Example 1

4-(4-(6-(((2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl yl)-1,2,3,4-tetrahydronaphthalen-1-yl)piperazin-1-yl)-3-fluorobenzonitrile 1

first step

Methyl 5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate 1b

5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid 1a (1.0 g, 5.26 mmol, Shanghai Bide Pharmaceutical) was dissolved in 100 mL of methanol, and concentrated sulfuric acid (0.6 mL, 11.0 mmol), after the addition was completed, the reaction solution was heated to 60 °C and stirred overnight. Concentrate under reduced pressure to remove most of the methanol, add water (200 mL) to dilute, then extract with ethyl acetate (100 mL×3), combine the organic phases, wash with saturated sodium chloride solution (100 mL), dry over anhydrous sodium sulfate, and filter. The filtrate was concentrated under reduced pressure and suctioned to dryness to give the crude title compound 1b (1.0 g, yield: 96%).

MS m/z(ESI): 205.2[M+1].

second step

Methyl 5-hydroxy-5,6,7,8-tetrahydronaphthalene-2-carboxylate 1c

Compound 1b (1.0 g, 4.90 mmol) was dissolved in absolute ethanol (20 mL), potassium borohydride (530 mg, 9.82 mmol) was added in portions under ice bath, the reaction was naturally warmed to room temperature and stirred for 4 hours. The reaction solution was concentrated, diluted with water (100 mL), and then extracted with ethyl acetate (100 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography with eluent system B to give the title compound 1c (1.0 g, yield: 99%).

MS m/z(ESI): 207.2[M+1].

third step

Methyl 5-chloro-5,6,7,8-tetrahydronaphthalene-2-carboxylate 1d

Compound 1c (1.0 g, 4.85 mmol) was dissolved in dichloromethane (10 mL), thionyl chloride (0.6 mL, 8.27 mmol) was added dropwise under an ice bath, and the reaction was further stirred under an ice bath for 2 hours. Ice water (100 mL) was added dropwise to quench the reaction, then extracted with dichloromethane (100 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (100 mL), 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 B to give the title compound 1d (540 mg, yield: 50%).

the fourth step

Methyl 5-(4-(4-cyano-2-fluorophenyl)piperazin-1-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylate 1e

Compound 1d (520 mg, 2.31 mmol), 3-fluoro-4-(piperazin-1-yl) benzonitrile (720 mg, 3.51 mmol, Shanghai Biopharmaceuticals) was dissolved in N,N-dimethylformamide (5 mL) ), N,N-diisopropylethylamine (2 mL, 12.1 mmol) and tetrabutylammonium bromide (746 mg, 2.31 mmol) were added, and the reaction was heated to 50° C. and stirred for 48 hours. The reaction solution was cooled to room temperature, diluted with water (100 mL), and then extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (100 mL), 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 B to give the title compound 1e (820 mg, yield: 90%).

MS m/z (ESI): 394.2 [M+1].

the fifth step

3-Fluoro-4-(4-(6-(hydroxymethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)piperazin-1-yl)benzonitrile 1f

Compound 1e (500 mg, 1.27 mmol) was dissolved in 22 mL of a mixed solution of tetrahydrofuran and methanol (V/V=10:1), lithium borohydride (275 mg, 12.62 mmol) was added under ice bath, and the reaction was warmed to room temperature and stirred overnight. The reaction solution was quenched by adding water (50 mL), and then extracted with ethyl acetate (50 mL×2). The organic phases were combined, washed with saturated sodium chloride solution (50 mL), 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 B to give the title compound If (340 mg, yield: 73%).

MS m/z(ESI): 366.2[M+1].

Step 6

4-(4-(6-(chloromethyl)-1,2,3,4-tetrahydronaphthalene-1-yl)piperazin-1-yl)-3-fluorobenzonitrile 1g

Compound 1f (50 mg, 0.137 mmol) was dissolved in dichloromethane (2 mL), thionyl chloride (0.1 mL, 1.38 mmol) was added dropwise in an ice bath, the reaction was slowly warmed to room temperature and stirred for 2 hours. The reaction was quenched by adding ice water (20 mL) and extracted with dichloromethane (20 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried 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 1 g (50 mg, yield: 95%).

MS m/z (ESI): 384.2 [M+1].

Step 7

(4S)-5-Amino-4-(4-((5-(4-(4-cyano-2-fluorophenyl)piperazin-1-yl)-5,6,7,8-tetrahydro Naphthalen-2-yl)methoxy)-1-oxoisoindolin-2-yl)-5-oxopentanoic acid tert-butyl ester 1i

Compound 1g (50mg, 0.130mmol), (S)-5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoic acid tert-butyl ester 1h ( 46mg, 0.137mmol, prepared by the method disclosed in "Journal of Medicinal Chemistry, 2020, 63(13), 6648-6676") was dissolved in N,N-dimethylformamide (2mL), and anhydrous potassium carbonate was added (72 mg, 0.521 mmol), tetrabutylammonium bromide (42 mg, 0.130 mmol), the reaction was heated to 60°C and stirred for 4 hours. The reaction solution was diluted with water (20 mL), and extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), 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 li (85 mg, yield: 95%).

MS m/z(ESI): 682.3[M+1].

Step 8

Compound 1i (90 mg, 0.132 mmol) was dissolved in acetonitrile (12 mL), benzenesulfonic acid (63 mg, 0.396 mmol) was added, and the reaction was heated to 85°C and stirred overnight. The reaction solution was concentrated under reduced pressure, and the obtained residue was prepared by high performance liquid phase (Gilson GX-281, mobile phase: 10 mmol/L aqueous solution of ammonium bicarbonate and acetonitrile, gradient of acetonitrile: 45%-55%, flow rate: 30 mL/min) The title compound 1 was obtained (45 mg, yield: 56%).

MS m/z(ESI): 608.2[M+1].

¹ H NMR (500MHz, DMSO-d ₆ )δ11.0(s,1H), 7.70(dd,1H), 7.86(d,1H), 7.58(dd,1H), 7.50(t,1H), 7.39- 7.31(m, 2H), 7.28(d, 1H), 7.19(s, 1H), 7.13(t, 1H), 5.18(s, 2H), 5.12(dd, 1H), 4.41(d, 1H), 4.25 (d,1H), 3.93-3.80(m,1H), 3.38-3.10(m,4H), 2.99-2.85(m,1H), 2.81-2.54(m,7H), 2.48-2.40(m,1H) , 2.03-1.87 (m, 3H), 1.74-1.57 (m, 2H).

Example 2-1

4-(4-((S)-6-(((2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy yl)methyl)-1,2,3,4-tetrahydronaphthalene-1-yl)piperazin-1-yl)-3-fluorobenzonitrile 2-1

first step

(S)-3-Fluoro-4-(4-(6-(hydroxymethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)piperazin-1-yl)benzonitrile 1f-1

(R)-3-Fluoro-4-(4-(6-(hydroxymethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)piperazin-1-yl)benzonitrile 1f-2

Compound 1f (2.0 g) was resolved by chirality (separation conditions: Shimadzu LC-20AP, chromatographic column: CHIRALPAK AY (20×250 mM), mobile phase: n-hexane/10 mmol/L ammonia (NH ₃ ) ethanol solution=70 /30 (v/v)), flow rate 20 mL/min) to obtain the title compounds 1f-1 (730 mg) and 1f-2 (830 mg).

Compound 1f-2:

MS m/z(ESI): 366.2[M+1].

Chiral HPLC analysis method: retention time 4.27 minutes (Agilent1260DAD, chromatographic column: CHIRALPAK AY (4.6×150mM), 5μm; mobile phase: n-hexane/ethanol (containing 0.1% diethylamine)=70/30 (v/v) ), flow rate 1mL/min).

Compound 1f-1:

MS m/z(ESI): 366.2[M+1].

Chiral HPLC analysis method: retention time 5.43 minutes (Agilent1260DAD, chromatographic column: CHIRALPAK AY (4.6×150mM), 5μm; mobile phase: n-hexane/ethanol (containing 0.1% diethylamine)=70/30 (v/v) ), flow rate 1mL/min).

second step

(S)-4-(4-(6-(chloromethyl)-1,2,3,4-tetrahydronaphthalene-1-yl)piperazin-1-yl)-3-fluorobenzonitrile 1g-1

Compound 1f-1 (730 mg, 2.0 mmol) was dissolved in dichloromethane (10 mL), thionyl chloride (1.31 g, 11.03 mmol) was added dropwise under ice bath, the reaction was slowly warmed to room temperature and stirred for 4 hours. The reaction was quenched by adding ice water (20 mL) and extracted with dichloromethane (50 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL x 2), dried 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 1g-1 (760 mg, yield: 99%).

MS m/z (ESI): 384.2 [M+1].

third step

(S)-5-Amino-4-(4-(((S)-5-(4-(4-cyano-2-fluorophenyl)piperazin-1-yl)-5,6,7, 8-Tetrahydronaphthalen-2-yl)methoxy)-1-oxoisoindolin-2-yl)-5-oxopentanoic acid tert-butyl ester 1i-1

Compound 1g-1 (730 mg, 1.90 mmol), compound 1h (640 mg, 1.91 mmol) were dissolved in N,N-dimethylformamide (10 mL), anhydrous potassium carbonate (790 mg, 5.72 mmol) was added, tetrabutyl Ammonium bromide (620 mg, 1.92 mmol), the reaction was heated to 40°C and stirred for 6 hours. The reaction solution was diluted with water (20 mL), and extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL×2), 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 1i-1 (930 mg, yield: 72%).

MS m/z(ESI): 682.3[M+1].

the fourth step

Compound 1i-1 (930 mg, 1.36 mmol) was dissolved in acetonitrile (15 mL), benzenesulfonic acid (650 mg, 4.11 mmol) was added, and the reaction was heated to 85°C and stirred overnight. The reaction solution was concentrated under reduced pressure, and the obtained residue was prepared by high performance liquid phase (Gilson GX-281, mobile phase: 10 mmol/L aqueous solution of ammonium bicarbonate and acetonitrile, gradient of acetonitrile: 45%-55%, flow rate: 30 mL/min) The title compound 2-1 was obtained (510 mg, yield: 62%).

MS m/z(ESI): 608.2[M+1].

¹ H NMR (500MHz, DMSO-d ₆ )δ10.98(s,1H), 7.69(dd,1H), 7.66(d,1H), 7.57(dd,1H), 7.50(t,1H), 7.39- 7.31(m, 2H), 7.29(d, 1H), 7.20(s, 1H), 7.14(t, 1H), 5.18(s, 2H), 5.12(dd, 1H), 4.42(d, 1H), 4.26 (d,1H), 3.93-3.80(m,1H), 3.28-3.12(m,4H), 2.99-2.85(m,1H), 2.82-2.54(m,7H), 2.48-2.40(m,1H) , 2.05-1.87 (m, 3H), 1.78-1.58 (m, 2H).

Example 2-2

4-(4-((R)-6-(((2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy yl)methyl)-1,2,3,4-tetrahydronaphthalen-1-yl)piperazin-1-yl)-3-fluorobenzonitrile 2-2

Following the synthetic route of Example 2-1, compound 1f-1 was replaced with compound 1f-2 (830 mg) to obtain the title compound 2-2 (640 mg).

MS m/z(ESI): 608.2[M+1].

¹ H NMR (500MHz, DMSO-d ₆ )δ10.98(s,1H), 7.69(dd,1H), 7.66(d,1H), 7.57(dd,1H), 7.50(t,1H), 7.39- 7.31(m, 2H), 7.28(d, 1H), 7.19(s, 1H), 7.14(t, 1H), 5.18(s, 2H), 5.12(dd, 1H), 4.42(d, 1H), 4.26 (d,1H), 3.93-3.80(m,1H), 3.28-3.12(m,4H), 2.99-2.85(m,1H), 2.81-2.54(m,7H), 2.48-2.40(m,1H) , 2.05-1.87 (m, 3H), 1.75-1.57 (m, 2H).

Example 3

4-(4-(5-(((2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl yl)-2,3-dihydro-1H-inden-1-yl)piperazin-1-yl)-3-fluorobenzonitrile 3

first step

Methyl 1-oxo-2,3-dihydro-1H-indene-5-carboxylate 3b

Compound 1-oxo-2,3-dihydro-1H-indene-5-carboxylic acid 3a (1.0 g, 5.68 mmol, Shanghai Haohong Biomedical Technology Co., Ltd.) was dissolved in 100 mL of methanol, and added dropwise under ice bath Concentrated sulfuric acid (0.7 mL, 12.9 mmol, 98% by mass) was added, and the reaction was heated to 60°C and stirred overnight. It was concentrated under reduced pressure to remove most of the methanol, diluted with water (200 mL), and then extracted with ethyl acetate (100 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was Concentration under reduced pressure and drying in vacuo gave the crude title compound 3b (1.05 g, yield: 97%).

MS m/z (ESI): 191.1 [M+1].

second step

1-Hydroxy-2,3-dihydro-1H-indene-5-carboxylate methyl ester 3c

Compound 3b (1.05 g, 5.5 mmol) was dissolved in methanol (20 mL), potassium borohydride (800 mg, 14.3 mmol) was added in portions under ice bath, and the mixture was naturally warmed to room temperature and reacted for 4 hours. The reaction solution was concentrated, diluted with water (100 mL), and then extracted with ethyl acetate (100 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with eluent system B to give the title compound 3c (1.0 g, yield: 99%).

MS m/z (ESI): 193.1 [M+1].

third step

1-Chloro-2,3-dihydro-1H-indene-5-carboxylate methyl ester 3d

Compound 3c (2.0 g, 10.4 mmol) was dissolved in dichloromethane (10 mL), thionyl chloride (1.5 mL, 20.7 mmol) was added dropwise in an ice bath, and the reaction was carried out under an ice bath for 2 hours. The reaction was quenched by adding ice water (100 mL) dropwise, then extracted with dichloromethane (100 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (100 mL), then dried with anhydrous sodium sulfate, filtered, and the filtrate was It was concentrated under reduced pressure and the residue was purified by column chromatography with eluent system B to give the title compound 3d (1.0 g, yield: 46%).

the fourth step

Methyl 1-(4-(4-cyano-2-fluorophenyl)piperazin-1-yl)-2,3-dihydro-1H-indene-5-carboxylate 3e

Compound 3d (1.0 g, 4.7 mmol), 3-fluoro-4-piperazinyl benzonitrile (1.02 g, 4.9 mmol) was dissolved in N,N-dimethylformamide (5 mL), and N,N-bismuth was added. Isopropylethylamine (4 mL, 24.2 mmol), tetrabutylammonium bromide (155 mg, 0.48 mmol), warmed to 50°C and reacted for 3 hours. Cooled to room temperature, the reaction solution was diluted with water (100 mL), and then extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (100 mL), 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 B to give the title compound 3e (500 mg, yield: 28%).

MS m/z (ESI): 380.1 [M+1].

the fifth step

3-Fluoro-4-(4-(5-(hydroxymethyl)-2,3-dihydro-1H-inden-1-yl)piperazin-1-yl)benzonitrile 3f

Compound 3e (500 mg, 1.32 mmol) was dissolved in 11 mL of a mixed solution of tetrahydrofuran and methanol (V/V=10/1), lithium borohydride (140 mg, 6.4 mmol) was added under ice bath, the reaction was warmed to room temperature and stirred for 12 hours . The reaction solution was quenched by adding water (50 mL), and then extracted with ethyl acetate (50 mL×2). The organic phases were combined, washed with saturated sodium chloride solution (50 mL), and then dried over anhydrous sodium sulfate. Filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography with eluent system B to give the title compound 3f (210 mg, yield: 43%).

MS m/z(ESI): 352.2[M+1].

Step 6

4-(4-(5-(chloromethyl)-2,3-dihydro-1H-inden-1-yl)piperazin-1-yl)-3-fluorobenzonitrile 3g

Compound 3f (80 mg, 0.228 mmol) was dissolved in dichloromethane (2 mL), thionyl chloride (0.1 mL, 1.38 mmol) was added dropwise under an ice bath, and the mixture was slowly warmed to room temperature and reacted for 2 hours. The reaction solution was quenched with ice water (20 mL), and then extracted with dichloromethane (20 mL×2). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), 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 3g (76 mg, yield: 90%) .

MS m/z (ESI): 370.1 [M+1].

Step 7

(4S)-5-Amino-4-(4-((1-(4-(4-cyano-2-fluorophenyl)piperazin-1-yl)-2,3-dihydro-1H-indene -5-yl)methoxy)-1-oxoisoindolin-2-yl)-5-oxopentanoic acid tert-butyl ester 3h

Compound 3g (76mg, 0.205mmol), compound 1h (70mg, 0.209mmol) were dissolved in N,N-dimethylformamide (1mL), anhydrous potassium carbonate (57mg, 0.412mmol) was added, tetrabutyl bromide Ammonium (66 mg, 0.205 mmol) was heated to 60°C for 4 hours. The reaction solution was diluted with water (20 mL), and extracted with ethyl acetate (20 mL×2). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), 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 3h (102 mg, yield: 74%) .

MS m/z(ESI): 668.3[M+1].

Step 8

Compound 3h (100 mg, 0.150 mmol) was dissolved in acetonitrile (10 mL), benzenesulfonic acid (72 mg, 0.455 mmol) was added, and the reaction was heated to 85°C overnight. The reaction solution was concentrated under reduced pressure, and the obtained residue was prepared by high performance liquid phase (Gilson GX-281, mobile phase: 10 mmol/L ammonium bicarbonate aqueous solution and acetonitrile, gradient of acetonitrile: 45%-63%, flow rate: 30 mL/min) The title compound 3 was obtained (67 mg, yield: 75%).

MS m/z (ESI): 594.2 [M+1].

¹ H NMR (500MHz, DMSO-d ₆ )δ10.99(s,1H), 7.69(dd,1H), 7.57(dd,1H), 7.50(t,1H), 7.39-7.30(m,5H), 7.12(t, 1H), 5.23(s, 2H), 5.12(dd, 1H), 4.42(d, 1H), 4.35(t, 1H), 4.26(d, 1H), 3.25-3.10(m, 4H) , 3.00-2.86(m, 2H), 2.84-2.73(m, 1H), 2.70-2.53(m, 4H), 2.48-2.38(m, 1H), 2.15-1.92(m, 4H).

Example 4-1, 4-2

4-(4-((S)-5-(((2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy yl)methyl)-2,3-dihydro-1H-inden-1-yl)piperazin-1-yl)-3-fluorobenzonitrile 4-1

4-(4-((R)-5-(((2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy yl)methyl)-2,3-dihydro-1H-inden-1-yl)piperazin-1-yl)-3-fluorobenzonitrile 4-2

Split:

Compound 3f (180 mg) was resolved by chirality (separation conditions: Shimadzu LC-20AP, chromatographic column: CHIRALPAK OJ (20×250 mM), mobile phase: n-hexane/10 mmol/L ammonia (NH ₃ ) ethanol solution=70/ 30 (v/v)), flow rate 20 mL/min) to obtain compound 3f-1 (70 mg) and compound 3f-2 (80 mg).

Compound 3f-1:

MS m/z(ESI): 352.2[M+1].

Chiral HPLC analysis method: retention time 3.90 minutes (Agilent1260DAD, chromatographic column: CHIRALPAK OJ (4.6×150mM), 5μm; mobile phase: n-hexane/ethanol (containing 0.1% diethylamine)=60/40 (v/v) ), flow rate 1mL/min).

Compound 3f-2:

MS m/z(ESI): 352.2[M+1].

Chiral HPLC analysis method: retention time 4.68 minutes (Agilent1260DAD, chromatographic column: CHIRALPAK OJ (4.6×150mM), 5μm; mobile phase: n-hexane/ethanol (containing 0.1% diethylamine)=60/40 (v/v) ), flow rate 1mL/min).

Subsequently, according to the synthetic route of compound 3, 3f was replaced with compound 3f-1 (70 mg) to obtain compound 4-1 (59 mg).

Subsequently, according to the synthetic route of compound 3, 3f was replaced with compound 3f-2 (80 mg) to obtain compound 4-2 (63 mg).

Compound 4-1 (59 mg):

MS m/z (ESI): 594.2 [M+1].

¹ H NMR (500MHz, DMSO-d ₆ )δ10.99(s,1H), 7.69(dd,1H), 7.57(dd,1H), 7.50(t,1H), 7.42-7.27(m,5H), 7.12(t, 1H), 5.23(s, 2H), 5.12(dd, 1H), 4.42(d, 1H), 4.35(t, 1H), 4.26(d, 1H), 3.25-3.10(m, 4H) , 3.00-2.85(m, 2H), 2.84-2.75(m, 1H), 2.72-2.53(m, 4H), 2.48-2.38(m, 1H), 2.15-1.90(m, 4H).

Compound 4-2 (63mg):

MS m/z (ESI): 594.2 [M+1].

¹ H NMR (500MHz, DMSO-d ₆ )δ10.98(s,1H), 7.69(dd,1H), 7.57(dd,1H), 7.50(t,1H), 7.40-7.30(m,5H), 7.12(t, 1H), 5.23(s, 2H), 5.12(dd, 1H), 4.42(d, 1H), 4.35(t, 1H), 4.26(d, 1H), 3.25-3.10(m, 4H) , 2.98-2.86(m, 2H), 2.84-2.73(m, 1H), 2.70-2.53(m, 4H), 2.48-2.38(m, 1H), 2.13-1.92(m, 4H).

Biological evaluation

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

Test Example 1 NCI-H929 Proliferation Experimental Biological Evaluation

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

NCI-H929 cells (ATCC, CRL-9068) were treated with complete medium (i.e. RPMI1640 medium containing 10% fetal bovine serum (Corning, 35-076-CV) and 0.05 mM 2-mercaptoethanol (Sigma, M3148) ( Hyclone, SH30809.01)) were cultured. On the first day of the experiment, H929 cells were seeded in a 96-well plate at a density of 6,000 cells/well using complete medium, with 100 μL of cell suspension per well, and 10 μL of the compound to be tested in gradient dilution prepared in complete medium was added to each well. , the compound was first dissolved in DMSO with an initial concentration of 10 mM, and serially diluted by 5-fold concentration gradient, with a total of 9 concentration points, and the blank control was 100% DMSO. Then 5 μL of the compound dissolved in DMSO was added to 95 μL of complete medium, that is, the compound was diluted 20 times with complete medium. Finally, 10 μL of each well of the compound diluted in complete medium was added to the cell suspension, that is, the final concentration of the compound was 9 concentration points for 5-fold serial dilution starting from 50 μM, and a blank control containing 0.5% DMSO was set. Place in a 37 °C, 5% CO ₂ cell incubator for 5 days. On the sixth day, remove the 96-well cell culture plate and add 50 μL to each well

The luminescent cell activity detection reagent (Promega, G7573) was placed at room temperature for 10 minutes, and the luminescent signal value was read using a multi-function microplate reader (PerkinElmer, EnVision2015). The _IC50 value of the inhibitory activity of the compound was calculated by Graphpad Prism software. Table 1.

Table 1 Activity of compounds of the present disclosure to inhibit proliferation of NCI-H929 cells.

化合物compound	IC ₅₀(nM) _IC50 (nM)
实施例1Example 1	0.30.3
实施例2-1Example 2-1	0.170.17
实施例2-2Example 2-2	1.481.48
实施例3Example 3	0.070.07
实施例4-1Example 4-1	0.020.02
实施例4-2Example 4-2	0.310.31

CONCLUSION: The compounds of the present disclosure have a good activity of inhibiting the proliferation of NCI-H929 cells.

Test Example 2 Drug Efficacy Test

1 The purpose of the experiment

The compound of Example 2-1 and CC-92480 were evaluated to inhibit the growth of human multiple myeloma cell NCI-H929 (lenalidomide-resistant strain) xenograft tumor in CB-17SCID mice.

2 Experimental drugs

The compound of Example 2-1;

CC-92480:

(Synthesized with reference to the method of Example 2 of WO2019014100A1);

Both were formulated with 5% DMSO + 20% PEG400 + 70% (10% TPGS) + 5% (1% HPMC K100LV).

3 Experimental methods and experimental materials

3.1 Experimental animals and rearing conditions

Experimental animal: CB-17SCID female mice, purchased from Beijing Weitong Lihua Laboratory Animal Co., Ltd. (certificate number: 20170011006049, SCXK (Shanghai) 2017-0011), with a weight of about 19 g at the time of purchase.

Breeding conditions: 5 animals/cage, 12/12 hours light/dark cycle adjustment, constant temperature of 23±1°C, humidity of 50 to 60%, free food and water.

3.2 Animal grouping

After CB-17 SCID mice were adaptively reared, they were grouped as follows:

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

3.3 Experimental method:

The NCI-H929 cells in logarithmic growth phase were inoculated subcutaneously in the right flank of female CB-17SCID mice at 5×10 ⁶ cells/mouse/100 μL (containing 50 μL of Matrigel). After 11 days, the tumor volume of the tumor-bearing mice was When it reached about 130mm ³ , the mice were randomly divided into 6 groups according to tumor volume and body weight: vehicle control group, CC-92480-0.1mpk, CC-92480-1mpk, Example 2-1-0.1mpk, Example 2- 1-0.3mpk and Example 2-1-1mpk, 8 per group. The day of grouping was set as D0, and the oral administration was started once a day for a total of 14 days, and the 14th day after administration was set as D14 (Table 2). Tumor volume in tumor-bearing mice was measured with a caliper and body weight with a balance twice a week and the data were recorded. Tumor-bearing animals were euthanized as experimental endpoints when tumor volume reached 2000 mm ³ or when most tumors ruptured or lost 20% of body weight.

3.4 Statistics

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

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

Relative tumor proliferation rate T/C(%)=(TT ₀ )/(CC ₀ )×100(%), where T and C are the tumor volumes of the treatment group and control group at the end of the experiment; T ₀ and C ₀ are the experimental Tumor volume at the start.

Tumor inhibition rate TGI (%) = 1-T/C (%), when TGI (%) exceeds 100%, no specific value will be displayed, only >100%.

Tumor regression (%)=[(T ₀ -T)/T ₀ ]×100(%).

4 results

The efficacy data of the compound of Example 2-1 and CC-92480 on NCI-H929 xenograft tumor in CB-17 SCID mice are shown in Table 2 and Figure 1.

The effect of the compound of Example 2-1 and CC-92480 on the body weight of CB-17 SCID mice is shown in Figure 2.

Table 2 Efficacy of compounds of the present disclosure on NCI-H929 xenograft tumor in CB-17 SCID mice

Note: qd means administration once a day; d means day; i.g means intragastric administration; SEM means standard error.

5 Conclusion

The compound of Example 2-1 was administered 11 days after tumor cell transplantation, once a day. After 14 days of administration, the tumor inhibition rate of the low-dose 0.1mpk group was 74%, and the tumor-inhibitory rate of the middle-dose 0.3mpk group was 91%. The tumor volume in the 1mpk group regressed with a regression rate of 5%, and the administration had no effect on the body weight of the mice. Under the same conditions, the tumor inhibition rate of CC-92480 was 37% in the low-dose 0.1mpk group and 91% in the high-dose 1mpk group, and the tumor did not regress.

Test Example 3 Pharmacokinetic evaluation

1 Overview

Using beagle dogs as test animals, the LC/MS/MS method was used to determine the drug concentrations in plasma at different times after the beagle dogs were given the compound of Example 2-1 and CC-92480 by gavage. To study the pharmacokinetic behavior of the disclosed compounds in beagle dogs, and to evaluate their pharmacokinetic characteristics.

2 Test plan

2.1 Test drug

Example 2-1 Compound and CC-92480.

2.2 Experimental animals

The compound of Example 2-1 used 4 beagle dogs, half male and half, and were divided into 2 groups on average, and 3 beagle dogs were used for CC-92480, male, all provided by Shanghai Medicilon Biomedical Co., Ltd.

2.3 Drug preparation

The compound of Example 2-1 was weighed and dissolved by adding 5% DMSO, 30% PG and 30% PEG400, and then adding 35% physiological saline to prepare.

Weigh CC-92480, add 5% DMSO, 30% PG and 30% PEG400 to dissolve it, and then add 35% normal saline to prepare.

2.4 Administration

After an overnight fast, the mice were administered by gavage. The doses of the compound of Example 2-1 and CC-92480 were both 2 mg/kg, and the administration volumes were both 5 mL/kg.

3 operations

The compound of Example 2-1 and CC-92480 were administered by gavage, and 1 mL of blood was collected before administration and 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 12h, and 24h after administration, and EDTA-K2 antibody was placed. In a coagulation test tube, centrifuge at 10,000 rpm for 5 minutes (4°C), separate the plasma within 1 hour, and store at -80°C. Food was taken 3 hours after administration. The blood was collected until the centrifugation process was operated under ice bath conditions.

Determination of the content of the test compound in the beagle dog plasma after drug administration of different concentrations: take 20 μL of beagle dog plasma at each time after administration, add the internal standard solution (the internal standard solution of the compound of Example 2-1 is toluenesulfonic acid) Butylurea 100ng/mL, the internal standard solution of CC-92480 is camptothecin 100ng/mL) and methanol 400μL, vortex mixed for 1min, and centrifuged for 10min (18000g). Transfer 200 μL of supernatant to a 96-well plate. 1 μL of the supernatant of the plasma samples was taken for LC/MS/MS analysis.

4 Results of pharmacokinetic parameters

The pharmacokinetic parameters of the compounds of the present disclosure are shown in Table 3 below.

Table 3 Pharmacokinetic parameters of compounds of the present disclosure

Conclusion: The compound of Example 2-1 of the present disclosure has better pharmacokinetic absorption than CC-92480, and has a pharmacokinetic advantage.

Claims

A compound of general formula (I) or a pharmaceutically acceptable salt thereof:

in:

G 1 , G 2 and G 3 are the same or different, and are each independently CR 8 or a nitrogen atom;

Z is CR a R b or an oxygen atom;

R a and R b are the same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, and a haloalkyl group;

X is CH or C(O);

Y is oxygen atom or NH;

Ring A is aryl or heteroaryl;

R 1 is selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino and hydroxy;

R 2 is the same or different at each occurrence and is each independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, Cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, One or more substituents of alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl replaced;

R 3 and R 4 are the same or different, and are each independently selected from hydrogen atoms, halogens, and alkyl groups;

R 5 is the same or different at each occurrence and is each independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, oxo, cyano, amino, nitro, hydroxy, Hydroxyalkyl, -C(O)OR 9 , -CONR 10 R 11 , cycloalkyl and heterocyclyl, wherein said alkyl, alkoxy, cycloalkyl and heterocyclyl are each independently optionally One selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl or replaced by multiple substituents;

R 6 is the same or different at each occurrence and is each independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, Cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, One or more substituents of alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl replaced;

R 7 is selected from cyano, -S(O) 2 R 9 and -S(O) 2 NR 10 R 11 ;

R 8 is the same or different at each occurrence and is each independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, Cycloalkyl and heterocyclyl;

R9 is the same or different at each occurrence and is each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclyl group;

R 10 and R 11 are the same or different at each occurrence and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclyl group;

n is 1, 2 or 3;

m is 0, 1, 2 or 3;

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

q is 0, 1, 2, 3 or 4.
The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, which is the general formula (I-1), the general formula (I-1-1) or the general formula (I-1) -2) The compound shown or a pharmaceutically acceptable salt thereof:

in:

Rings A, X, Y, Z, G 1 , G 2 , G 3 , R 1 to R 7 , m, n, p and q are as defined in claim 1 .
The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein Y is an oxygen atom.
The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein both R 3 and R 4 are hydrogen atoms.
The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, which is the general formula (II), the general formula (II-1), the general formula (II) -1-1) or a compound represented by the general formula (II-1-2) or a pharmaceutically acceptable salt thereof:

in:

Rings A, X, Z, G 1 , G 2 , G 3 , R 1 , R 2 , R 5 to R 7 , m, n, p and q are as defined in claim 1 .
The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein X is CH 2 .
The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein Z is CR a R b ; R a and R b are the same, and are each independently hydrogen atom or halogen.
The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, which is general formula (III), general formula (III-1), general formula (III) -1-1) or a compound represented by the general formula (III-1-2) or a pharmaceutically acceptable salt thereof:

in:

Rings A, G 1 , G 2 , G 3 , R 1 , R 2 , R 5 to R 7 , m, n, p and q are as defined in claim 1 .
The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein G 1 , G 2 and G 3 are all CR 8 ; R 8 is a hydrogen atom.
The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein ring A is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group; preferably Typically, Ring A is phenyl.
The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein R 1 is a hydrogen atom.
The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein R 2 is a hydrogen atom.
The compound of general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein R 5 is the same or different at each occurrence, and is each independently a hydrogen atom or C 1-6 alkyl; preferably, R 5 is a hydrogen atom.
The compound of general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein R 6 is the same or different at each occurrence, and each is independently selected from hydrogen atoms , halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 haloalkoxy; preferably, R 6 is halogen; more preferably, R 6 is a fluorine atom .
The compound of general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, wherein R 7 is selected from cyano, -S(O) 2 R 9 and -S( O) 2 NR 10 R 11 , wherein R 9 is a C 1-6 alkyl group, and both R 10 and R 11 are hydrogen atoms; preferably, R 7 is a cyano group.
The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 15, which is selected from the following compounds:
A compound of general formula (IA) or its salt,

in:

R m is C 1-6 alkyl; preferably, R m is tert-butyl;

Rings A, X, Y, Z, G 1 , G 2 , G 3 , R 1 to R 7 , m, n, p and q are as defined in claim 1 .
The compound or salt thereof according to claim 17, which is selected from the group consisting of:
A method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

The compound represented by the general formula (IA) or a salt thereof undergoes an intramolecular ring closure reaction to obtain the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof,

in:

R m is C 1-6 alkyl; preferably tert-butyl;

Rings A, X, Y, Z, G 1 , G 2 , G 3 , R 1 to R 7 , m, n, p and q are as defined in claim 1 .
A pharmaceutical composition comprising the compound represented by the general formula (I) according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable salts thereof. acceptable carrier, diluent or excipient.
The compound represented by the general formula (I) according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 20 is prepared for the treatment and/or prevention of cancer , Angiogenesis-related disorders, pain, macular degeneration or related syndromes, skin diseases, lung diseases, asbestos-related diseases, parasitic diseases, immunodeficiency diseases, central nervous system diseases, central nervous system damage, atherosclerosis or related disorders, sleep disorders or related disorders, infectious diseases, hemoglobinopathies or related disorders, or TNFα-related disorders in the medicament; preferably, in the preparation of a medicament for the treatment and/or prevention of cancer or central nervous system damage use in.
The use according to claim 21, 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, polycythemia vera, pediatric cancer, cervical cancer, ovarian cancer, breast cancer, bladder cancer, urothelial cancer, ureteral cancer, prostate cancer, seminoma, Testicular tumors, head and neck cancer, head and neck squamous cell carcinoma, endometrial cancer, thyroid cancer, sarcoma, osteoma, neuroblastoma, neuroendocrine cancer, brain tumor, central nervous system cancer, astrocytoma and glioma ; preferably, wherein said myeloma is multiple myeloma and myelodysplastic syndrome; more preferably, said multiple myeloma is relapsed, refractory or resistant; most preferably , wherein the multiple myeloma is lenalidomide or pomalidomide refractory or resistant.