CN116669736A

CN116669736A - Fused heterocyclyl-substituted cyclohexanediimide derivatives, preparation method and medical application thereof

Info

Publication number: CN116669736A
Application number: CN202280008923.4A
Authority: CN
Inventors: 贾敏强; 汤焕宇; 杨方龙; 贺峰; 陶维康
Original assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Current assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Priority date: 2021-01-05
Filing date: 2022-01-05
Publication date: 2023-08-29
Also published as: TW202241872A; WO2022148358A1

Abstract

The present disclosure relates to fused heterocyclyl-substituted cyclohexanediimide derivatives, methods for their preparation and their use in medicine. In particular, the present disclosure relates to a fused heterocyclyl-substituted cyclohexanediimide derivative represented by general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, and use thereof as a therapeutic agent, particularly as a Cereblon modulator in the field of treating multiple myeloma.

Description

Fused heterocyclyl-substituted cyclohexanediimide derivatives, preparation method and medical application thereof

Technical Field

The present disclosure relates to a fused heterocyclyl-substituted cyclohexanediimide derivative, a preparation method thereof and a medical application thereof, belonging to the field of medicine. In particular, the present disclosure relates to fused heterocyclyl-substituted cyclohexanediimide derivatives of general formula (I), methods for their preparation and pharmaceutical compositions containing them, and their use as Cereblon modulators in the field of treatment of multiple myeloma.

Background

Multiple Myeloma (MM) is a malignant tumor, the main symptoms of which include hypercalcemia, kidney damage, anemia and skeletal diseases. MM is the second most common hematological malignancy next to non-hodgkin lymphoma, with 4-6 people per 100,000 people worldwide, about 1.6 people per 100,000 people in china each year, and current therapies are mainly drug therapy and autologous stem cell transplantation therapy. At present, four general types of medicines which are respectively immune modulators, proteasome inhibitors, hormones and monoclonal antibodies of the domicile are widely used clinically; drugs in clinical study stage include diabodies, ADCs, CAR-T, etc. The mechanism of action of these drugs is different, and the combination often achieves better therapeutic effects, and clinical uses of dual, triple, and even quadruple combination are generally adopted, and immune modulators, proteasome inhibitors and hormones are generally combined, and antibodies are sometimes added. Of these, lenalidomide is the most commonly used immunomodulator, and is used for first-line therapy, maintenance therapy after stem cell transplantation, and second-third-line therapy after recurrence. The drug is sold in 2018/2019 for $ 97 billion. In addition, the whole MM market is considerable and increases rapidly, due to the continuous improvement and perfection of diagnosis and treatment of MM, the life time of patients is longer, and the administration time is correspondingly prolonged. It is expected that the MM market will reach a $ 330 million scale in 2022, with the largest percentage still representing immunomodulators represented by lenalidomide.

The action mechanism of the immunomodulators (IMiDs) for treating MM is mainly that after IMiDs drug binds to Cereblon (CRBN) protein, E3 ligase activity of CRBN can be activated, and then the CRBN can be selectively combined with transcription factors Ikaros (IKZF 1) and Aiolos (IKZF 3); leading to rapid ubiquitination and degradation of Ikaros and Aiolos. Down-regulation of Ikaros/Aiolos results in down-regulation of c-Myc, followed by IRF4 down-regulation, and finally results in inhibition and apoptosis of myeloma cell growth. In addition, IKZF3 can inhibit the transcription of IL2 and TNF cytokines in T/NK cells, and the inhibition can be released after the degradation of the IKZF3 so as to promote the release of the cytokines, thereby playing an immunoregulation role. Clinical trials also show that the clinical benefit of the IMiDs drugs is also related to the level of CRBN expression. Knocking down CRBN in lenalidomide-sensitive cell lines (OPM 2 and KMS 18) was found to have lost activity in inhibiting cell growth, resulting in drug resistance, the level of CRBN knockdown being correlated with the extent of drug resistance; in cell proliferation experiments, decreasing the level of CRBN expression in cells (U266-CRBN 60 and U266-CRBN 75) decreased the activity of both lenalidomide and pomalidomide in inhibiting cell growth.

Currently approved IMiDs drugs on the market are thalidomide, lenalidomide, and pomalidomide, all from Celgene corporation (currently incorporated by BMS corporation). The binding force between the three compounds and CRBN is sequentially enhanced, so that the clinical dosage is sequentially reduced. The main indications for these three compounds are MM, thalidomide and lenalidomide, and other indications, especially lenalidomide, can also be treated and used to treat myelodysplastic syndrome (MDS). Lenalidomide and pomalidomide behave similarly in terms of side effects, which are toxicity associated with the target, with significant myelosuppression; thalidomide has a number of other side effects such as sedation, constipation, neurological side effects, and the like.

All adipoimide moieties of the IMiDs bind to hydrophobic pockets defined by three tryptophan residues in CRBN (referred to as "thalidomide binding pockets"). In contrast, phthalimide/isoindolone rings are exposed to solvents and alter the molecular surface of CRBN, thereby modulating substrate recognition; different IMiDs result in significant modification of the CRBN molecule surface and the preference for substrate recognition is different. Thus, modifications to the IMiDs may lead to degradation of other transcription factors, causing unwanted toxic side effects. This mode of action of the IMiDs, also known as molecular glue (molecular glue), symbolically represents the binding of such small molecules to two protein substrates.

Because the median survival time of the current multiple myeloma is more than five years, the prolongation of the survival time leads a plurality of patients to have high proportion of drug resistance to the drugs such as lenalidomide and pomalidomide which are already on the market, so that the treatment effect of the drugs is seriously reduced. Therefore, the inventor envisages developing drug molecules with better activity to overcome the problem of drug resistance, and simultaneously reduces the toxic and side effects of the compounds as much as possible.

Published Cereblon modulators patent applications include WO2008115516A2, WO2011100380A1, WO2019226770A1, WO2019014100A1, WO2020064002A1 and the like.

Disclosure of Invention

The purpose of the present disclosure is to provide a compound represented by general formula (I):

wherein:

G ¹ 、G ² and G ³ Identical 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 is ^b The same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, and a haloalkyl group;

x is CH ₂ Or C (O);

y is an oxygen atom or NH;

ring a is aryl or heteroaryl;

R ¹ selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, and hydroxy;

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

R ³ And R is ⁴ The same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, and an alkyl group;

R ⁵ is the same OR different at each occurrence and is each independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, oxo, cyano, amino, nitro, hydroxy, hydroxyalkyl, -C (O) OR ⁹ 、-CONR ¹⁰ R ¹¹ Cycloalkyl and heterocyclyl groups, wherein said alkyl, alkoxy,cycloalkyl and heterocyclyl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

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

R ⁷ 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, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, cycloalkyl, and heterocyclyl;

R ⁹ is the same or different at each occurrence and is each independently selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclyl group;

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

n is 1, 2 or 3;

m is 0, 1, 2 or 3;

p is 0, 1, 2, 3 or 4; and is also provided with

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

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

wherein:

ring A, X, Y, Z, G ¹ 、G ² 、G ³ 、R ¹ To R ⁷ M, n, p and q are as defined in formula (I).

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

wherein:

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

wherein:

In some embodiments of the present disclosure, the compound of formula (I), formula (I-1-1), 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 of formula (I), formula (I-1-1), formula (I-1-2), or a pharmaceutically acceptable salt thereof, wherein R ³ And R is ⁴ Are all hydrogen atoms.

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

wherein:

ring 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 formula (I).

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

Wherein:

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

wherein:

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

wherein:

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

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

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

wherein:

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 in formula (I).

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

wherein:

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

wherein:

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

Wherein:

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

In some embodiments of the present disclosure, the compound of formula (I), formula (I-1-1), formula (I-1-2), formula (II-1-1), formula (II-1-2), formula (III),Compounds of the general formula (III-1), the general formula (III-1-2) or pharmaceutically acceptable salts thereof, wherein R ¹ Is a hydrogen atom.

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

In some embodiments of the present disclosure, the compound of formula (I), formula (I-1-1), formula (I-1-2), formula (II-1-1), formula (II-1-2), formula (III-1-1), 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 compound of formula (I), formula (I-1-1), formula (I-1-2), formula (II-1-1), formula (II-1-2), formula (III-1-1), formula (III-1-2) or a pharmaceutically acceptable salt thereof, wherein R ⁶ Identical or different at each occurrence and each independentlySelected from hydrogen atoms, halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl and C _1-6 Haloalkoxy groups; preferably, R ⁶ Is halogen; more preferably, R ⁶ Is a fluorine atom.

In some embodiments of the present disclosure, the compound of formula (I), formula (I-1-1), formula (I-1-2), formula (II-1-1), formula (II-1-2), formula (III-1-1), formula (III-1-2) or a pharmaceutically acceptable salt thereof, wherein R ⁷ Selected from cyano, -S (O) ₂ R ⁹ and-S (O) ₂ NR ¹⁰ R ¹¹ Wherein R is ⁹ Is C _1-6 Alkyl, R ¹⁰ And R is ¹¹ All are hydrogen atoms; preferably, R ⁷ Is cyano.

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

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

In some embodiments of the present disclosure, the compound of formula (I), formula (I-1), formula (II-1) or a pharmaceutically acceptable salt thereof, whereinIs that

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, whereinIs that

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, whereinIs that

In some embodiments of the present disclosure, the compound of formula (III), formula (III-1), or a pharmaceutically acceptable salt thereof, whereinIs that

In some embodiments of the present disclosure, the compound of formula (III-1-1) or a pharmaceutically acceptable salt thereof, whereinIs that

In some embodiments of the present disclosure, the compound of formula (III-1-2) or a pharmaceutically acceptable salt thereof, whereinIs that

In some embodiments of the present disclosure, the compound of formula (I), formula (I-1-1), formula (I-1-2), formula (II-1)) A compound represented by the general formula (II-1-1), the general formula (II-1-2), the general formula (III-1-1), the general formula (III-1-2) or a pharmaceutically acceptable salt thereof, whereinIs thatR ⁶ Is halogen; r is R ⁷ Is cyano; preferably, the method comprises the steps of,is that

In some embodiments of the present disclosure, the compound of formula (I), formula (I-1-1), 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 is ^b Identical and each independently is a hydrogen atom or a halogen; x is CH ₂ The method comprises the steps of carrying out a first treatment on the surface of the Y is an oxygen atom; ring a is a 6 to 10 membered aryl or a 5 to 10 membered heteroaryl; r is R ¹ Is a hydrogen atom; r is R ² Is a hydrogen atom; r is R ³ And R is ⁴ All are hydrogen atoms; r is R ⁵ And are identical or different at each occurrence and are each independently a hydrogen atom or C _1-6 An alkyl group; r is R ⁶ Is the same or different at each occurrence and is each independently selected from the group consisting of a hydrogen atom, a halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl and C _1-6 Haloalkoxy groups; r is R ⁷ Selected from cyano, -S (O) ₂ R ⁹ and-S (O) ₂ NR ¹⁰ R ¹¹ Wherein R is ⁹ Is C _1-6 Alkyl, R ¹⁰ And R is ¹¹ All 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 of formula (I), 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 is ^b Identical and each independently is a hydrogen atom or a halogen; x is CH ₂ The method comprises the steps of carrying out a first treatment on the surface of the Y is an oxygen atom; ring a is a 6 to 10 membered aryl or a 5 to 10 membered heteroaryl; r is R ¹ Is a hydrogen atom; r is R ² Is a hydrogen atom; r is R ³ And R is ⁴ All are hydrogen atoms; r is R ⁵ And are identical or different at each occurrence and are each independently a hydrogen atom or C _1-6 An alkyl group; r is R ⁶ Is the same or different at each occurrence and is each independently selected from the group consisting of a hydrogen atom, a halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl and C _1-6 Haloalkoxy groups; r is R ⁷ Selected from cyano, -S (O) ₂ R ⁹ and-S (O) ₂ NR ¹⁰ R ¹¹ Wherein R is ⁹ Is C _1-6 Alkyl, R ¹⁰ And R is ¹¹ All are 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 of formula (II), formula (II-1-1), 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 is ^b Identical and each independently is a hydrogen atom or a fluorine atom; x is CH ₂ The method comprises the steps of carrying out a first treatment on the surface of the Ring A is phenyl; r is R ¹ Is a hydrogen atom; r is R ² Is a hydrogen atom; r is R ⁵ And are identical or different at each occurrence and are each independently a hydrogen atom or C _1-6 An alkyl group; r is R ⁶ Is the same or different at each occurrence and is each independently selected from the group consisting of a hydrogen atom, a halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl and C _1-6 Haloalkoxy groups; r is 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 of formula (II), 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 is ^b Identical and each independently is a hydrogen atom or a fluorine atom; x is CH ₂ The method comprises the steps of carrying out a first treatment on the surface of the Ring A is phenyl; r is R ¹ Is a hydrogen atom; r is R ² Is a hydrogen atom; r is R ⁵ And are identical or different at each occurrence and are each independently a hydrogen atom or C _1-6 An alkyl group; r is R ⁶ Is the same or different at each occurrence and is each independently selected from the group consisting of a hydrogen atom, a halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl and C _1-6 Haloalkoxy groups; r is 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 of formula (III), formula (III-1-1), 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 phenyl; r is R ¹ Is a hydrogen atom; r is R ² Is a hydrogen atom; r is R ⁵ And are identical or different at each occurrence and are each independently a hydrogen atom or C _1-6 An alkyl group; r is R ⁶ Is the same or different at each occurrence and is each independently selected from the group consisting of a hydrogen atom, a halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl and C _1-6 Haloalkoxy groups; r is 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 of formula (III), 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 phenyl; r is R ¹ Is a hydrogen atom; r is R ² Is a hydrogen atom; r is R ⁵ And are identical or different at each occurrence and are each independently a hydrogen atom or C _1-6 An alkyl group; r is R ⁶ Is the same or different at each occurrence and is each independently selected from the group consisting of a hydrogen atom, a halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl and C _1-6 Haloalkoxy groups; r is 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 of formula (III), formula (III-1-1), 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 phenyl; r is R ¹ Is a hydrogen atom; r is R ⁵ And are identical or different at each occurrence and are each independently a hydrogen atom or C _1-6 An alkyl group; r is R ⁶ Is the same or different at each occurrence and is each independently selected from a hydrogen atom, a halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl and C _1-6 Haloalkoxy groups; r is 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 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 G ¹ 、G ² And G ³ Are all CR ⁸ ；R ⁸ Is a hydrogen atom;is thatR ¹ Is a hydrogen atom; r is R ⁶ Is halogen; r is R ⁷ Is cyano; p is 0; q is 1; n is 1 or 2; m is 0.

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

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

wherein:

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

ring 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 compounds of formula (I).

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

wherein:

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

ring 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 compounds of the 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,

wherein:

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

ring A, X, Y, Z, G ¹ 、G ² 、G ³ 、R ¹ To R ⁷ M, n, p andq is as defined for compounds of the 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,

wherein:

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

ring 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 compounds of the general formula (I-1-2).

Another aspect of the present disclosure relates to a compound represented by the general formula (IIA):

wherein:

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

ring 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 compounds of formula (II).

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

wherein:

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

ring 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 compounds of the general formula (II-1).

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

wherein:

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

ring 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 compounds of the general formula (II-1-1).

Another aspect of the present disclosure relates to a compound represented by the general formula (IIA-1-2):

wherein:

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

ring 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 compounds of the general formula (II-1-2).

Another aspect of the present disclosure relates to a compound represented by general formula (IIIA):

wherein:

R ^m is C _1-6 An alkyl group; 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 compounds of formula (III).

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

wherein:

R ^m is C _1-6 An alkyl group; 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 compounds of the 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:

wherein:

R ^m is C _1-6 An alkyl group; 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 compounds of the general formula (III-1-1).

Another aspect of the present disclosure relates to a compound represented by the general formula (IIIA-1-2):

wherein:

R ^m is C _1-6 An alkyl group; 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 compounds of the 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 shown in the general formula (IA) or salt thereof undergoes intramolecular ring closure reaction to obtain the compound shown in the general formula (I) or pharmaceutically acceptable salt thereof,

wherein:

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

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

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

wherein:

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

ring A, X, Y, Z, G ¹ 、G ² 、G ³ 、R ¹ To R ⁷ M, n, p and q are as defined in formula (I-1).

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

the compound shown in the general formula (IA-1-1) or salt thereof undergoes intramolecular ring closure reaction to obtain the compound shown in the general formula (I-1-1) or pharmaceutically acceptable salt thereof,

wherein:

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

ring A, X, Y, Z, G ¹ 、G ² 、G ³ 、R ¹ To R ⁷ M, n, p and q are as defined in formula (I-1-1).

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

the compound shown in the general formula (IA-1-2) or salt thereof undergoes intramolecular ring closure reaction to obtain the compound shown in the general formula (I-1-2) or pharmaceutically acceptable salt thereof,

wherein:

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

ring 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, comprising:

the compound shown in the general formula (IIA) or salt thereof undergoes intramolecular ring closure reaction to obtain the compound shown in the general formula (II) or pharmaceutically acceptable salt thereof,

wherein:

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

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

the compound shown in the general formula (IIA-1) or salt thereof undergoes intramolecular ring closure reaction to obtain the compound shown in the general formula (II-1) or pharmaceutically acceptable salt thereof,

wherein:

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

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

the compound shown in the general formula (IIA-1-1) or salt thereof undergoes intramolecular ring closure reaction to obtain the compound shown in the general formula (II-1-1) or pharmaceutically acceptable salt thereof,

Wherein:

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

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

the compound shown in the general formula (IIA-1-2) or salt thereof undergoes intramolecular ring closure reaction to obtain the compound shown in the general formula (II-1-2) or pharmaceutically acceptable salt thereof,

wherein:

R ^m is C _1-6 An alkyl group; 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):

the compound shown in the general formula (IIIA) or salt thereof undergoes intramolecular ring closure reaction to obtain the compound shown in the general formula (III) or pharmaceutically acceptable salt thereof,

wherein:

R ^m is C _1-6 An alkyl group; 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 shown in the general formula (IIIA-1) or salt thereof undergoes intramolecular ring closure reaction to obtain the compound shown in the general formula (III-1) or pharmaceutically acceptable salt thereof,

wherein:

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

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

the compound shown in the general formula (IIIA-1-1) or salt thereof undergoes intramolecular ring closure reaction to obtain the compound shown in the general formula (III-1-1) or pharmaceutically acceptable salt thereof,

wherein:

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

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

the compound shown in the general formula (IIIA-1-2) or salt thereof undergoes intramolecular ring closure reaction to obtain the compound shown in the general formula (III-1-2) or pharmaceutically acceptable salt thereof,

wherein:

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

Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of formula (I), formula (I-1-1), formula (I-1-2), formula (II-1-1), formula (II-1-2), formula (III-1-1), formula (III-1-2) and a compound of Table A or a pharmaceutically acceptable salt thereof, in accordance with the present disclosure, and one or more pharmaceutically acceptable carriers, diluents or excipients.

The disclosure further relates to the use of a compound represented by general formula (I), general formula (I-1-1), general formula (I-1-2), general formula (II-1-2), general formula (III-1-1), general formula (III-1-2), and a compound represented by Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for treating and/or preventing diseases related to CRBN protein.

The present disclosure further relates to the use of a compound of formula (I), formula (I-1-1), formula (I-1-2), formula (II-1-1), formula (II-1-2), formula (III-1-1), formula (III-1-2), and a compound shown in table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for the treatment and/or prevention of cancer, angiogenesis-related disorders, pain, macular degeneration or related syndrome, skin disorders, pulmonary diseases, asbestos-related diseases, parasitic diseases, immunodeficiency diseases, central Nervous System (CNS) diseases, CNS injuries, atherosclerosis or related disorders, sleep disorders or related disorders, infectious diseases, hemoglobinopathies or related disorders, or tnfα -related disorders; preferably, the use in the manufacture of a medicament for the treatment and/or prophylaxis of cancer or CNS injury.

The present disclosure also relates to a method of treating and/or preventing a disease associated with CRBN protein, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (I-1-1), formula (I-1-2), formula (II-1-1), formula (II-1-2), formula (III-1-1), formula (III-1-2), and a compound of table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure also relates to a method of treating and/or preventing cancer, angiogenesis-related disorders, pain, macular degeneration or related syndromes, skin disorders, pulmonary diseases, asbestos-related diseases, parasitic diseases, immunodeficiency diseases, CNS injuries, atherosclerosis or related disorders, sleep disorders or related disorders, infectious diseases, hemoglobinopathies or related disorders or tnfα related disorders, preferably a method of treating and/or preventing cancer or CNS injuries, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (I-1-1), formula (I-1-2), formula (II-1-1), formula (II-1-2), formula (III-1-1), formula (III-1-2), formula (I-1-2), and a compound or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure further relates to a compound represented by general formula (I), general formula (I-1-1), general formula (I-1-2), general formula (II-1-2), general formula (III-1-1), general formula (III-1-2), and a compound represented by Table A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same, for use as a medicament.

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

The present disclosure further relates to compounds of general formula (I), general formula (I-1-1), general formula (I-1-2), general formula (II-1-2), general formula (III-1-1), general formula (III-1-2), and compounds shown in Table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for the treatment and/or prophylaxis of cancer, angiogenesis-related disorders, pain, macular degeneration or related syndromes, skin diseases, pulmonary diseases, asbestos-related diseases, parasitic diseases, immunodeficiency diseases, CNS injuries, atherosclerosis or related disorders, sleep disorders or related disorders, infectious diseases, haemoglobinopathies or related disorders or tnfα -related disorders; preferably for the treatment and/or prophylaxis of cancer or CNS damage.

The CRBN protein-associated disease described in the present disclosure is selected from cancer, angiogenesis-related disorders, pain, macular degeneration or related syndromes, skin diseases, pulmonary diseases, asbestos-related diseases, parasitic diseases, immunodeficiency diseases, CNS injuries, atherosclerosis or related disorders, sleep disorders or related disorders, infectious diseases, hemoglobinopathies or related disorders, or tnfα -related disorders; preferably cancer or CNS injury.

Cancers described in this disclosure are selected from leukemia, myeloma, lymphoma, melanoma, skin cancer, liver cancer (e.g., hepatocellular carcinoma), kidney cancer, lung cancer (e.g., non-small cell lung cancer and small cell lung cancer), nasopharyngeal cancer, stomach cancer, esophageal cancer (also known as esophageal cancer), colorectal cancer (e.g., colon cancer and rectal cancer), gall bladder cancer, bile duct cancer, chorionic epithelial cancer, pancreatic cancer, polycythemia vera, pediatric tumors, cervical cancer, ovarian cancer, breast cancer, bladder cancer, urothelial cancer, ureteral tumors, prostate cancer, seminoma, testicular tumors, head and neck cancer, head and neck squamous cell carcinoma, endometrial cancer, thyroid cancer, sarcomas (e.g., osteosarcoma and soft tissue sarcoma), bone tumors, neuroblastomas (i.e., neuroblastomas), neuroendocrine cancer, brain tumors, CNS cancers, astrocytomas, and gliomas (e.g., glioblastomas); preferably, the myeloma is preferably Multiple Myeloma (MM) and myelodysplastic syndrome (MDS); more preferably, the multiple myeloma is relapsed, refractory or resistant; most preferably, the multiple myeloma is lenalidomide or pomalidomide refractory or resistant.

The leukemia is preferably chronic lymphocytic leukemia, acute Lymphoblastic Leukemia (ALL), acute Myeloid Leukemia (AML), chronic Myelogenous 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, those described in U.S. publication No. 2005/0143344, published 6.30.2005, 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 neurological immune disorders such as Tourette's syndrome (Tourette syndrome), delusions, or conscious disturbance occurring in a short period of time, and memory loss, or discrete memory impairment occurring when other central nervous system injuries are absent.

Examples of CNS injury and related syndromes include, but are not limited to, the diseases described in U.S. publication No. 2006/012628, published at 6/8 2006, the contents of which are incorporated herein by reference. Specific examples include, but are not limited to, CNS injury/damage and related syndromes including, but not limited to, primary brain injury, secondary brain injury, traumatic brain injury, focal brain injury, diffuse axonal injury, craniocerebral injury, concussion, post concussion syndrome, bruise, subdural hematoma, epidermoid hematoma, post traumatic epilepsy, chronic autonomic nerve status, complete Spinal Cord Injury (SCI), incomplete SCI, acute SCI, subacute SCI, chronic SCI, central spinal cord syndrome, myelohemi-cut syndrome, pre-spinal cord syndrome, spinal cone syndrome, caudal equina syndrome, neurogenic shock, spinal cord shock, altered levels of consciousness, headache, nausea, vomiting, hypomnesis, dizziness, presbyopia, blurred vision, mood swings, sleep disorders, irritability, inattention, neuroma, behavioral disorders, 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 neovascular diseases, and iris erythrosis (corner of the house neoangiogenesis). Preferably including but not limited to arthritis, endometriosis, crohn's disease, heart failure, severe heart failure, kidney injury, endotoxemia, toxic shock syndrome, osteoarthritis, retroviral replication, wasting disease, meningitis, silica-induced fibrosis, asbestos-induced fibrosis, veterinary disease, malignancy-associated hypercalcemia, stroke, circulatory shock, periodontitis, gingivitis, megaloblastic anemia, refractory anemia, and 5q deficiency syndrome.

The active compounds can be formulated in a form suitable for administration by any suitable route, using one or more pharmaceutically acceptable carriers by conventional methods to formulate the compositions of the present disclosure. Accordingly, the active compounds of the present disclosure may be formulated in a variety of dosage forms for oral administration, injection (e.g., intravenous, intramuscular, or subcutaneous) 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, injections, dispersible powders or granules, suppositories, troches or syrups.

As a general guideline, the active compounds are preferably administered in unit doses, or in a manner whereby the patient can self-administer a single dose. The unit dosage of a compound or composition of the present disclosure may be expressed in the form of a tablet, capsule, cachet, bottled lotion, powder, granule, lozenge, suppository, reconstituted powder or liquid formulation. Suitable unit doses may be in the range 0.1 to 1000mg.

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

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

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

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

The oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, or in a mineral oil. The oil suspension may contain a thickener. The above-described sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of antioxidants.

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

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

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

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

The compounds of the present disclosure may be administered by adding water to prepare water-suspended dispersible powders and granules. These pharmaceutical compositions may be prepared by mixing 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 amount of drug administered depends on a variety of factors, including, but not limited to, the following: the activity of the specific compound used, the age of the patient, the weight of the patient, the health of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, the severity of the disease, etc.; in addition, the optimal mode of treatment, such as the mode of treatment, the daily amount of the compound, or the type of pharmaceutically acceptable salt, can be verified according to conventional treatment protocols.

Description of the terms

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

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

The term "alkylene" refers to a divalent alkyl group, where alkyl is as defined above, having 1 to 20 (e.g., 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19 or 20) carbon atoms (i.e. C _1-20 An alkylene group). The alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (i.e., C _1-12 Alkylene), more preferably an alkylene group having 1 to 6 carbon atoms (i.e., C _1-6 An alkylene group). Non-limiting examples of alkylene groups include, but are not limited to: methylene (-CH) ₂ (-), 1-ethylene (-CH (CH) ₃ ) (-), 1, 2-ethylene (-CH) ₂ CH ₂ ) -, 1-propylene (-CH (CH) ₂ CH ₃ ) (-), 1, 2-propylene (-CH) ₂ CH(CH ₃ ) (-), 1, 3-propylene (-CH) ₂ CH ₂ CH ₂ (-), 1, 4-butylene (-CH) ₂ CH ₂ CH ₂ CH ₂ (-), etc. The alkylene group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents preferably being selected from one or more of alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, 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 having 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C _2-12 Alkenyl). The alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (i.e., C _2-6 Alkenyl). Non-limiting examples include: ethenyl, propenyl, butenyl, pentenyl, hexenyl, and the like. Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably selected from one or more of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

The term "alkynyl" refers to an alkyl compound having at least one carbon-carbon triple bond in the moleculeWherein alkyl is as defined above, which has an alkynyl group (i.e., C) of 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms _2-12 Alkynyl). The alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (i.e., C _2-6 Alkynyl). 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 one or more of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, 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. The alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably selected from one or more of a D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

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

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

the term "fused ring alkyl" refers to an all-carbon polycyclic group having a contiguous pair of carbon atoms shared between 5 to 20 membered rings, wherein one or more of the rings may contain one or more double bonds. Preferably 6 to 14 membered, more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered). The polycyclic condensed ring alkyl group such as a bicyclic ring, a tricyclic ring, a tetracyclic ring and the like may be divided according to the number of constituent rings, and is preferably a bicyclic or tricyclic condensed ring alkyl group, more preferably a 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered and 6-membered/6-membered bicyclic condensed ring alkyl group. Non-limiting examples of fused ring alkyl groups include:

The term "bridged cycloalkyl" refers to an all-carbon polycyclic group in which any two rings of 5 to 20 members share two carbon atoms that are not directly attached, which may contain one or more double bonds. Preferably 6 to 14 membered, more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered). Polycyclic bridged cycloalkyl groups such as bicyclic, tricyclic, tetracyclic and the like can be divided according to the number of constituent rings, and are preferably bicyclic, tricyclic or tetracyclic bridged cycloalkyl groups, more preferably bicyclic or tricyclic bridged cycloalkyl groups. Non-limiting examples of bridged cycloalkyl groups include:

the cycloalkyl ring includes cycloalkyl (including monocyclic, spiro, fused, and bridged rings) fused to an aryl, heteroaryl, or heterocycloalkyl ring as described above, wherein the ring attached to the parent structure is cycloalkyl, non-limiting examples includeEtc.; preferably

Cycloalkyl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, the substituents preferably being selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, 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 from 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, which may optionally be oxo (i.e., form sulfoxides or sulfones), but excluding ring moieties of-O-, -O-S-or-S-, the remaining ring atoms being carbon. Preferably 3 to 12 ring atoms, of which 1 to 4 (e.g., 1,2,3, and 4) are heteroatoms (i.e., 3 to 12 membered heterocyclyl); more preferably 3 to 8 ring atoms, wherein 1 to 3 are heteroatoms (e.g., 1,2, and 3) (i.e., 3 to 8 membered heterocyclyl); more preferably 3 to 6 ring atoms, of which 1 to 3 are heteroatoms (i.e., 3 to 6 membered heterocyclyl); most preferably contain 5 or 6 ring atoms, of which 1 to 3 are heteroatoms (i.e., 5 or 6 membered heterocyclyl). Non-limiting examples of monocyclic heterocyclyl groups include: pyrrolidinyl, tetrahydropyranyl, 1,2,3, 6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocyclic groups include spiro heterocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups.

The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group having a single ring of 5 to 20 members sharing one atom (referred to as the spiro atom) wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e., form sulfoxides or sulfones), the remaining ring atoms being carbon. Which may contain one or more double bonds. Preferably 6 to 14 membered, more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered). The spiroheterocyclyl groups are classified into single spiroheterocyclyl groups or multiple spiroheterocyclyl groups (e.g., double spiroheterocyclyl groups) according to the number of common spiro atoms between rings, with single and double spiroheterocyclyl groups being preferred. More preferably a 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 single spiro heterocyclic group. Non-limiting examples of spiroheterocyclyl groups include:

the term "fused heterocyclyl" refers to a polycyclic heterocyclic group having 5 to 20 membered rings sharing an adjacent pair of atoms, one or more of which may contain one or more double bonds, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which sulfur may optionally be oxo (i.e., form sulfoxides or sulfones), the remaining ring atoms being carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered). The number of constituent rings may be classified into a polycyclic fused heterocyclic group such as a bicyclic, tricyclic, tetracyclic and the like, preferably a bicyclic or tricyclic fused heterocyclic group, more preferably a 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/3-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 5-membered/7-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclyl groups include:

The term "bridged heterocyclyl" refers to a polycyclic heterocyclic group in which any two rings of 5 to 14 members share two atoms not directly connected, which may contain one or more double bonds, wherein one or more of the ring atoms is selected from nitrogen, oxygen, and sulfur, which may optionally be oxo (i.e., form sulfoxides or sulfones), the remaining ring atoms being carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered). Polycyclic bridged heterocyclic groups such as a bicyclic, tricyclic, tetracyclic and the like can be classified according to the number of constituent rings, and are 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 heterocyclyl (including monocyclic, spiro, fused and bridged heterocyclic rings) as described above fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is heterocyclyl, non-limiting examples of which include:

etc.

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

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

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

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

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

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

The term "amino protecting group" refers to an easily removable group introduced on an amino group in order to keep the amino group unchanged when the reaction is performed at other positions of the molecule. Non-limiting examples include: (trimethylsilyl) ethoxymethyl, tetrahydropyranyl, t-butoxycarbonyl (Boc), acetyl, p-toluenesulfonyl (Ts), benzyl, allyl, p-methoxybenzyl, and the like. These groups may be optionally substituted with 1 to 3 substituents selected from halogen, alkoxy or nitro.

The term "hydroxy protecting group" refers to an easily removable group introduced on a hydroxy group, typically used to block or protect the hydroxy group to react with other functional groups of the compound. Non-limiting examples include: triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl (TBS), t-butyldiphenylsilyl, t-butyl, C _1-6 Alkoxy substituted C _1-6 Alkyl-or phenyl-substituted C _1-6 Alkyl groups (e.g., methoxymethyl (MOM), ethoxyethyl, etc.) (C) _1-10 Alkyl or aryl) acyl (e.g.: formyl, acetyl, benzoyl, p-nitrobenzoyl and the like), (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 a cycloalkyl-O-group, wherein cycloalkyl is as defined above.

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

The term "alkylthio" refers to an 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 the alkoxy group is as defined above.

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

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

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

The term "hydroxy" refers to-OH.

The term "mercapto" refers to-SH.

The term "amino" refers to-NH ₂ 。

The term "cyano" refers to-CN.

The term "nitro" refers to-NO ₂ 。

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

In the chemical structure of the compounds of the present disclosure, the bondIndicating unspecified configuration, i.e. bonds if chiral isomers are present in the chemical structureMay beOr (b)Or at the same time containAndtwo configurations.

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

as reference to pyrazolyl, it is understood to include mixtures of either or both tautomers of either of the following structures:

all tautomeric forms are within the scope of the disclosure, and the naming of the 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 wherein 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 compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, iodine, and the like, e.g., respectively ² H (deuterium, D), 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., deuterium is preferred.

Compared with non-deuterated medicines, deuterated medicines have the advantages of reducing toxic and side effects, increasing medicine stability, enhancing curative effect, prolonging biological half-life of medicines and the like. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are intended to be encompassed within the scope of the present disclosure. Each available hydrogen atom attached to a carbon atom may be independently replaced by a deuterium atom, wherein replacement of deuterium may be partial or complete, with partial replacement of deuterium meaning that at least one hydrogen is replaced by at least one deuterium.

When a position of a compound of the present disclosure is specifically designated as "deuterium" or "D", that position is understood to mean that the abundance of deuterium is at least 1000-fold greater than the natural abundance of deuterium (which is 0.015%), i.e., 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 (i.e., 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 (i.e., 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 (i.e., 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 (i.e., 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 (i.e., 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 (i.e., at least 60% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 4500-fold greater than the natural abundance of deuterium (i.e., 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 (i.e., 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 (i.e., 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 (i.e., 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 (i.e., 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 (i.e., 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 (i.e., at least 99.5% deuterium incorporation).

The present disclosure relates to compounds of general formula (I), general formula (I-1-1), general formula (I-1-2), general formula (II-1-1), general formula (II-1-2), general formula (III-1-2), and compounds of Table A or pharmaceutically acceptable salts thereof, including tautomers, racemates, enantiomers, diastereomers, cis-trans-isomers, or mixtures thereof.

"optionally" or "optionally" is intended to mean that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example "C optionally (optionally) substituted by halogen or cyano _1-6 Alkyl "means that halogen or cyano may be, but need not be, present, and this description includes the case where alkyl is substituted with halogen or cyano and the case where alkyl is not substituted with halogen and cyano.

"substituted" or "substituted" means that one or more hydrogen atoms, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms in the group are independently substituted with a corresponding number of substituents. The person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable when bound to carbon atoms having unsaturated (e.g., olefinic) bonds.

"pharmaceutical composition" means a mixture comprising one or more of the compounds described herein, or pharmaceutically acceptable salts thereof, and other chemical components, such as pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.

"pharmaceutically acceptable salts" refers to salts of the compounds of the present disclosure, which may be selected from inorganic salts or organic salts. Such salts are safe and effective when used in mammals and have desirable biological activity. Salts may be prepared separately during the final isolation and purification of the compounds, or by reacting the appropriate groups with an appropriate base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic and organic acids.

The term "therapeutically effective amount" with respect to a drug or pharmacologically active agent refers to an amount of the drug or agent sufficient to achieve or at least partially achieve the desired effect. The determination of a therapeutically effective amount will vary from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, and the appropriate therapeutically effective amount in an individual case can be determined by one of skill in the art based on routine experimentation.

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

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

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

Methods of synthesizing compounds of the present disclosure

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

scheme one

the compound shown in the general formula (IA) or salt thereof generates intramolecular ring closure reaction under acidic condition to obtain the compound shown in the general formula (I) or pharmaceutically acceptable salt thereof,

Wherein:

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

Scheme II

the compound shown in the general formula (IA-1) or salt thereof undergoes intramolecular ring closure reaction under acidic condition to obtain the compound shown in the general formula (I-1) or pharmaceutically acceptable salt thereof,

wherein:

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

Scheme III

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 shown in the general formula (IIA) or salt thereof undergoes intramolecular ring closure reaction under acidic condition to obtain the compound shown in the general formula (II) or pharmaceutically acceptable salt thereof,

wherein:

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

Scheme IV

The compound shown in the general formula (IIA-1) or salt thereof undergoes intramolecular ring closure reaction under acidic condition to obtain the compound shown in the general formula (II-1) or pharmaceutically acceptable salt thereof,

wherein:

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

Scheme 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, comprising:

the compound shown in the general formula (IIIA) or salt thereof undergoes intramolecular ring closure reaction under acidic condition to obtain the compound shown in the general formula (III) or pharmaceutically acceptable salt thereof,

wherein:

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

Scheme six

the compound shown in the general formula (IIIA-1) or the salt thereof generates intramolecular ring closure reaction under the acidic condition to obtain the compound shown in the general formula (III-1) or the pharmaceutically acceptable salt thereof,

wherein:

R ^m is C _1-6 An alkyl group; preferably, the method comprises the steps of,R ^m is tert-butyl;

Scheme seven

the compound shown in the general formula (IA-1-1) or salt thereof undergoes intramolecular ring closure reaction under acidic condition to obtain the compound shown in the general formula (I-1-1) or pharmaceutically acceptable salt thereof,

wherein:

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

Scheme eight

the compound shown in the general formula (IA-1-2) or salt thereof undergoes intramolecular ring closure reaction under acidic condition to obtain the compound shown in the general formula (I-1-2) or pharmaceutically acceptable salt thereof,

wherein:

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

Scheme nine

The compound shown in the general formula (IIA-1-1) or salt thereof undergoes intramolecular ring closure reaction under acidic condition to obtain the compound shown in the general formula (II-1-1) or pharmaceutically acceptable salt thereof,

wherein:

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

Scheme ten

the compound shown in the general formula (IIA-1-2) or salt thereof undergoes intramolecular ring closure reaction under acidic condition to obtain the compound shown in the general formula (II-1-2) or pharmaceutically acceptable salt thereof,

wherein:

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

Scheme eleven

the compound shown in the general formula (IIIA-1-1) or salt thereof undergoes intramolecular ring closure reaction under acidic condition to obtain the compound shown in the general formula (III-1-1) or pharmaceutically acceptable salt thereof,

wherein:

R ^m Is C _1-6 An alkyl group; preferably, R ^m Is tert-butyl;

Scheme twelve

the compound shown in the general formula (IIIA-1-2) or salt thereof undergoes intramolecular ring closure reaction under acidic condition to obtain the compound shown in the general formula (III-1-2) or pharmaceutically acceptable salt thereof,

wherein:

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

Reagents that provide acidic conditions in the above synthetic schemes include, but are not limited to, p-toluene sulfonic acid monohydrate, benzenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, sulfuric acid, hydrochloric acid, nitric acid, and trifluoroacetic acid; benzenesulfonic acid is preferred.

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

Drawings

FIG. 1 shows the efficacy data of the compound of example 2-1 and CC-92480 on NCI-H929 transplants in CB-17SCID mice.

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

Detailed Description

The present disclosure is further described below in conjunction with the examples, which are not intended to limit the scope of the present disclosure.

Examples

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift (. Delta.) of 10 ^-6 Units of (ppm) are given. NMR was performed using Bruker AVANCE-400 nuclear magnetic resonance apparatus or Bruker AVANCE NEO M with deuterated dimethyl sulfoxide (DMSO-d) ₆ ) Deuterated chloroform (CDCl) ₃ ) Deuterated methanol (CD) ₃ OD), internal standard of fourMethylsilane (TMS).

MS was measured using an Agilent 1200/1290DAD-6110/6120 Quadrapol MS liquid chromatography-mass spectrometry (manufacturer: agilent, MS model: 6110/6120 Quadrapol MS), waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS model: waters ACQuity Qda Detector/waters SQ Detector), THERMO Ultimate 3000-Q actual (manufacturer: THERMO, MS model: THERMO Q Exactive).

High Performance Liquid Chromatography (HPLC) analysis used Agilent HPLC 1200DAD, agilent HPLC 1200VWD, and Waters HPLC e2695-2489 high performance liquid chromatography.

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

The high performance liquid phase was prepared by using a Waters 2545-2767, waters 2767-SQ Detector 2, shimadzu LC-20AP and Gilson GX-281 preparative chromatograph.

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

The CombiFlash flash rapid prep instrument used CombiFlash Rf200 (teldyne ISCO).

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

Silica gel column chromatography generally uses a fumigant yellow sea silica gel of 200 to 300 mesh as a carrier.

Average inhibition rate of kinase and IC ₅₀ The values were measured using a NovoStar microplate reader (BMG, germany).

Known starting materials of the present disclosure may be synthesized using or following methods known in the art, or may be purchased from ABCR GmbH & co.kg, acros Organics, aldrich Chemical Company, J & K, shaoshao chemical technology (Accela ChemBio Inc), shanghai pichia medicine, dary chemicals, and the like.

The reaction can be carried out under argon atmosphere or nitrogen atmosphere without any particular explanation in examples.

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

The hydrogen atmosphere is defined as the reaction flask being connected to a balloon of hydrogen gas of about 1L volume.

The pressure hydrogenation reaction uses a Parr 3916 model EKX hydrogenometer and a clear blue QL-500 type hydrogen generator or HC2-SS type hydrogenometer.

The hydrogenation reaction is usually vacuumized, filled with hydrogen and repeatedly operated for 3 times.

The microwave reaction used was a CEM Discover-S908860 type microwave reactor.

The examples are not specifically described, and the solution refers to an aqueous solution.

The temperature of the reaction was room temperature and was 20℃to 30℃unless otherwise specified in the examples.

The monitoring of the progress of the reaction in the examples employed Thin Layer Chromatography (TLC), the developing reagent used for the reaction, the system of eluent for column chromatography employed for purifying the compound and the developing reagent system of thin layer chromatography included: a: a methylene chloride/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 be adjusted by adding a small amount of alkaline or acidic reagents such as triethylamine, acetic acid and the like.

Example 1

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

First step

5-oxo-5, 6,7, 8-tetrahydronaphthalene-2-carboxylic acid methyl ester 1b

5-oxo-5, 6,7, 8-tetrahydronaphthalene-2-carboxylic acid 1a (1.0 g,5.26mmol, shanghai Bifide. Medical) was dissolved in 100mL of methanol, concentrated sulfuric acid (0.6 mL,11.0 mmol) was added dropwise under ice bath, and the reaction solution was heated to 60℃and stirred overnight. Most of the methanol was removed by concentration under reduced pressure, diluted with water (200 mL), then extracted with ethyl acetate (100 ml×3), and 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 dried by suction to give the crude title compound 1b (1.0 g, yield: 96%).

MS m/z(ESI):205.2[M+1]。

Second step

5-hydroxy-5, 6,7, 8-tetrahydronaphthalene-2-carboxylic acid methyl ester 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, and the reaction was allowed to warm to room temperature and stirred for 4 hours. The reaction solution was concentrated, diluted with water (100 mL), extracted with ethyl acetate (100 mL. Times.3), and 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

5-chloro-5, 6,7, 8-tetrahydronaphthalene-2-carboxylic acid methyl ester 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 ice bath, and the reaction was stirred under ice bath for an additional 2 hours. The reaction was quenched by dropwise addition of ice water (100 mL), then extracted with dichloromethane (100 mL. Times.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%).

Fourth step

5- (4- (4-cyano-2-fluorophenyl) piperazin-1-yl) -5,6,7, 8-tetrahydronaphthalene-2-carboxylic acid methyl ester 1e

Compound 1d (520 mg,2.31 mmol), 3-fluoro-4- (piperazin-1-yl) benzonitrile (720 mg,3.51mmol, shanghai Bi-medical) was dissolved in N, N-dimethylformamide (5 mL), N-diisopropylethylamine (2 mL,12.1 mmol), tetrabutylammonium bromide (746 mg,2.31 mmol) was added, and the reaction was warmed to 50℃and stirred for 48 hours. The reaction solution was cooled to room temperature, diluted with water (100 mL), extracted with ethyl acetate (50 ml×3), and 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]。

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 22mL 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 with water (50 mL), then extracted with ethyl acetate (50 mL. Times.2), and 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 1f (340 mg, yield: 73%).

MS m/z(ESI):366.2[M+1]。

Sixth step

4- (4- (6- (chloromethyl) -1,2,3, 4-tetrahydronaphthalen-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 under ice, the reaction was slowly warmed to room temperature, and stirred for 2 hours. The reaction was quenched by addition of ice water (20 mL) and extracted with dichloromethane (20 mL. Times.3). The combined organic phases were 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 1g (50 mg, yield: 95%).

MS m/z(ESI):384.2[M+1]。

Seventh step

(4S) -5-amino-4- (4- ((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

1g (50 mg,0.130 mmol) of (S) -5-amino-4- (4-hydroxy-1-oxoisoindolin-2-yl) -5-oxopentanoic acid tert-butyl ester (46 mg,0.137mmol, prepared as described in "Journal of Medicinal Chemistry,2020,63 (13), 6648-6676") was dissolved in N, N-dimethylformamide (2 mL), anhydrous potassium carbonate (72 mg,0.521 mmol) and tetrabutylammonium bromide (42 mg,0.130 mmol) were added, and the reaction was heated to 60℃and stirred for 4 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL. Times.3). The combined organic phases were 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 1i (85 mg, yield: 95%).

MS m/z(ESI):682.3[M+1]。

Eighth step

Compound 1i (90 mg,0.132 mmol) was dissolved in acetonitrile (12 mL), benzenesulfonic acid (63 mg, 0.390 mmol) was added, and the reaction was heated to 85℃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: 10mmol/L ammonium bicarbonate aqueous solution and acetonitrile, gradient of acetonitrile: 45% -55%, flow rate: 30 mL/min) to give the title compound 1 (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) methyl) -1,2,3, 4-tetrahydronaphthalen-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 subjected to chiral resolution (separation conditions: shimadzu LC-20AP, column chromatography: CHIRALPAK AY (20X 250 mM), mobile phase: n-hexane/10 mmol/L ammonia (NH) ₃ ) Ethanol solution=70/30 (v/v), flow rate 20 mL/min) to give 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 min (Agilent 1260DAD, column: CHIRALPAK AY (4.6x150 mM), 5 μm; mobile phase: n-hexane/ethanol (0.1% diethylamine) =70/30 (v/v)), flow rate 1 mL/min).

Compound 1f-1:

MS m/z(ESI):366.2[M+1]。

chiral HPLC analysis method: retention time 5.43 min (Agilent 1260DAD, column: CHIRALPAK AY (4.6x150 mM), 5 μm; mobile phase: n-hexane/ethanol (0.1% diethylamine) =70/30 (v/v)), flow rate 1 mL/min).

Second step

(S) -4- (4- (6- (chloromethyl) -1,2,3, 4-tetrahydronaphthalen-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 addition of ice water (20 mL) and extracted with dichloromethane (50 mL. Times.3). The combined organic phases were washed with saturated sodium chloride solution (30 ml×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) was dissolved in N, N-dimethylformamide (10 mL), anhydrous potassium carbonate (710 mg,5.72 mmol) was added, tetrabutylammonium bromide (620 mg,1.92 mmol) and the reaction was heated to 40℃and stirred for 6 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (50 mL. Times.3). The combined organic phases were 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]。

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℃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: 10mmol/L ammonium bicarbonate aqueous solution and acetonitrile, gradient of acetonitrile: 45% -55%, flow rate: 30 mL/min) to give the title compound 2-1 (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) methyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) piperazin-1-yl) -3-fluorobenzonitrile 2-2

Following the synthesis route of example 2-1, compound 1f-1 was replaced with compound 1f-2 (830 mg) to give 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) -2, 3-dihydro-1H-inden-1-yl) piperazin-1-yl) -3-fluorobenzonitrile 3

First step

1-oxo-2, 3-dihydro-1H-indene-5-carboxylic acid methyl ester 3b

Compound 1-oxo-2, 3-dihydro-1H-indene-5-carboxylic acid 3a (1.0 g,5.68mmol, shanghai Haohong biomedical technologies Co., ltd.) was dissolved in 100mL of methanol, concentrated sulfuric acid (0.7 mL,12.9mmol,98% by mass) was added dropwise under ice bath, and after the addition, the reaction was heated to 60℃and stirred overnight. The majority of methanol was removed by concentration under reduced pressure, diluted with water (200 mL), then extracted with ethyl acetate (100 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and dried in vacuo to give 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-carboxylic acid methyl ester 3c

Compound 3b (1.05 g,5.5 mmol) was dissolved in methanol (20 mL), and potassium borohydride (800 mg,14.3 mmol) was added in portions under ice bath, and the mixture was allowed to warm to room temperature and reacted for 4 hours. The reaction solution was concentrated, diluted with water (100 mL), then extracted with ethyl acetate (100 mL. Times.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, and 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-carboxylic acid methyl ester 3d

Compound 3c (2.0 g,10.4 mmol) was dissolved in methylene chloride (10 mL), and thionyl chloride (1.5 mL,20.7 mmol) was added dropwise thereto under ice bath, followed by reaction under ice bath for 2 hours. The reaction was quenched by dropwise addition of ice water (100 mL), then extracted with methylene chloride (100 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride solution (100 mL), then dried over anhydrous sodium sulfate, filtered, and the filtrate 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%).

Fourth step

1- (4- (4-cyano-2-fluorophenyl) piperazin-1-yl) -2, 3-dihydro-1H-indene-5-carboxylic acid methyl ester 3e

Compound 3d (1.0 g,4.7 mmol), 3-fluoro-4-piperazinylbenzonitrile (1.02 g,4.9 mmol) was dissolved in N, N-dimethylformamide (5 mL), N-diisopropylethylamine (4 mL,24.2 mmol), tetrabutylammonium bromide (155 mg,0.48 mmol) was added and the temperature was raised to 50℃for reaction for 3 hours. Cooled to room temperature, the reaction mixture was diluted with water (100 mL), extracted with ethyl acetate (50 mL. Times.3), and 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]。

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 11mL of a mixed solution of tetrahydrofuran and methanol (V/v=10/1), lithium borohydride (140 mg,6.4 mmol) was added under ice-bath, and the reaction was stirred at room temperature for 12 hours. The reaction mixture was quenched with water (50 mL) and then extracted with ethyl acetate (50 mL. Times.2). The organic phases were combined, washed with saturated sodium chloride solution (50 mL) and then dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate under reduced pressure, and purification of the residue by column chromatography with eluent system B gave the title compound 3f (210 mg, yield: 43%).

MS m/z(ESI):352.2[M+1]。

Sixth step

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

Compound 3f (80 mg,0.228 mmol) was dissolved in methylene chloride (2 mL), and thionyl chloride (0.1 mL,1.38 mmol) was added dropwise under ice-bath, and the mixture was allowed to slowly warm to room temperature and reacted for 2 hours. The reaction was quenched with ice water (20 mL) and then extracted with dichloromethane (20 mL. Times.2). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried, filtered, and 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]。

Seventh step

(4S) -5-amino-4- (4- ((1- (4- (4-cyano-2-fluorophenyl) piperazin-1-yl) -2, 3-dihydro-1H-inden-5-yl) methoxy) -1-oxoisoindolin-2-yl) -5-oxopentanoic acid tert-butyl ester for 3H

3g (76 mg,0.205 mmol) of compound, 1h (70 mg,0.209 mmol) was dissolved in N, N-dimethylformamide (1 mL), anhydrous potassium carbonate (57 mg,0.412 mmol) and tetrabutylammonium bromide (66 mg,0.205 mmol) were added and the mixture was heated to 60℃to react for 4 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL. Times.2). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried, filtered, and 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]。

Eighth step

Compound 3h (100 mg,0.150 mmol) was dissolved in acetonitrile (10 mL), benzenesulfonic acid (72 mg,0.455 mmol) was added and heated to 85℃for reaction 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: 10mmol/L ammonium bicarbonate aqueous solution and acetonitrile, gradient of acetonitrile: 45% -63%, flow rate: 30 mL/min) to give the title compound 3 (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)。

Examples 4-1,4-2

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

Splitting:

compound 3f (180 mg) was subjected to chiral resolution (separation conditions: shimadzu LC-20AP, column chromatography: CHIRALPAK OJ (20X 250 mM), mobile phase: n-hexane/10 mmol/L ammonia (NH) ₃ ) Ethanol solution=70/30 (v/v), flow rate 20 mL/min) to give 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 min (Agilent 1260DAD, column: CHIRALPAK OJ (4.6x150 mM), 5 μm; mobile phase: n-hexane/ethanol (0.1% diethylamine) =60/40 (v/v)), flow rate 1 mL/min).

Compound 3f-2:

MS m/z(ESI):352.2[M+1]。

chiral HPLC analysis method: retention time 4.68 min (Agilent 1260DAD, column: CHIRALPAK OJ (4.6x150 mM), 5 μm; mobile phase: n-hexane/ethanol (0.1% diethylamine) =60/40 (v/v)), flow rate 1 mL/min).

Following the synthetic route for compound 3, 3f was replaced with compound 3f-1 (70 mg) to give compound 4-1 (59 mg).

Following the synthetic route for compound 3, 3f was replaced with compound 3f-2 (80 mg) to give 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 (63 mg):

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 explained in further detail below in connection with test examples, which are not meant to limit the scope of the present disclosure.

Test example 1 biological evaluation of NCI-H929 proliferation assay

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

NCI-H929 cells (ATCC, CRL-9068) were cultured in complete medium (i.e., RPMI1640 medium (Hyclone, SH 30809.01) containing 10% fetal bovine serum (Corning, 35-076-CV) and 0.05mM 2-mercaptoethanol (Sigma, M3148). On the first day of the experiment, H929 cells were seeded in 96-well plates at a density of 6000 cells/well with 100 μl of cell suspension per well, while 10 μl of gradient diluted test compound formulated with complete medium was added per well, the compound was first dissolved in DMSO at an initial concentration of 10mM, 5-fold concentration gradient serial dilutions were performed for a total of 9 concentration points, and blank control was 100% DMSO. Then, 5. Mu.L of the compound dissolved in DMSO was added to 95. Mu.L of complete medium, i.e., the compound was diluted 20-fold with complete medium. Finally, 10. Mu.L of each well of the compound diluted in the complete medium was added to the cell suspension at 9 concentration points at which 5-fold gradient dilutions were performed starting from 50. Mu.M, a blank containing 0.5% DMSO was set, and the mixture was left at 37℃with 5% CO ₂ The cell incubator was incubated for 5 days. On day six, 96-well cell culture plates were removed and 50. Mu.L of each well was addedLuminescent cell activity detection reagent (Promega, G7573), after 10 minutes of standing at room temperature, the luminescent signal value was read by using a multifunctional microplate enzyme-labeled instrument (PerkinElmer, enVision 2015), and the IC of the compound inhibitory activity was calculated by using Graphpad Prism software ₅₀ The values are shown in Table 1.

Table 1 the compounds of the present disclosure inhibit the activity of NCI-H929 cell proliferation.

Compounds of formula (I)	IC ₅₀ (nM)
Example 1	0.3
Example 2-1	0.17
Example 2-2	1.48
Example 3	0.07
Example 4-1	0.02
Example 4-2	0.31

Conclusion: the compound disclosed by the invention has good activity of inhibiting proliferation of NCI-H929 cells.

Test example 2 pharmacodynamic test

1 purpose of experiment

The compound of example 2-1 and CC-92480 were evaluated for their effect in inhibiting the growth of human multiple myeloma cell NCI-H929 (lenalidomide resistant strain) engraftment on CB-17SCID mice.

2 experiment medicine

The compound of example 2-1;

CC-92480： (synthesized by the method of example 2 of WO2019014100A 1);

both were formulated with 5% dmso+20% peg400+70% (10% tpgs) +5% (1% hpmc k100 lv).

3 Experimental methods and Experimental materials

3.1 laboratory animals and feeding conditions

Experimental animals: CB-17SCID female mice were purchased from Peking Vitre Liwa laboratory animal Co., ltd (certificate number: 20170011006049, SCXK (Shanghai) 2017-0011) and had a weight of about 19g when purchased.

Feeding conditions: 5 animals/cage, light/dark period adjustment for 12/12 hours, constant temperature of 23+/-1 ℃ and humidity of 50-60%, and free feeding of water.

3.2 grouping of animals

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

note that: qd is administered 1 time a day; g is gastric administration.

3.3 experimental method:

NCI-H929 cells in logarithmic growth phase were 5X 10 ⁶ Cell/mouse/100. Mu.L (containing 50. Mu.L matrigel) was inoculated subcutaneously in right rib of female CB-17SCID mouse, and tumor volume of tumor-bearing mouse reached 130mm after 11 days ³ On the left and right, mice were randomly divided into 6 groups according to tumor volume and body weight: vehicle control group, CC-92480-0.1mpk, CC-92480-1mpk, examples 2-1-0.1mpk, examples 2-1-0.3mpk and examples 2-1-1mpk, 8 per group. The day of grouping was set to D0 and the administration of intragastric administration was started once daily for 14 days, and the 14 th day after administration was set to D14 (table 2). Tumor volumes and body weights were measured with a vernier caliper and data recorded twice a week for tumor-bearing mice. When the tumor volume reaches 2000mm ³ Or when most tumors are broken or weight is reduced by 20%, euthanasia of the tumor-bearing animals is taken as the experimental end point.

3.4 data statistics

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

The tumor volume (V) was calculated as: v=1/2×a×b ² Wherein a and b respectively represent length and width.

Relative tumor proliferation rate T/C (%) = (T-T) ₀ )/(C-C ₀ ) X 100 (%), where T, C is tumor volume of the treatment and control groups at the end of the experiment; t (T) ₀ 、C ₀ Is the tumor volume at the beginning of the experiment.

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

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

Results 4 results

The efficacy data of the compound of example 2-1 and CC-92480 on NCI-H929 transplants in CB-17 SCID mice are shown in Table 2 and FIG. 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 FIG. 2.

TABLE 2 therapeutic effects of the compounds of the present disclosure on NCI-H929 transplants in CB-17 SCID mice

Note that: qd is administered 1 time a day; d is the day; g is gastric lavage administration; SEM is standard error.

Conclusion 5

The compound of example 2-1 was administered once daily, starting 11 days after tumor cell transplantation, and after 14 days of administration, the tumor suppression rate was 74% in the low-dose 0.1mpk group, 91% in the medium-dose 0.3mpk group, and 5% in the high-dose 1mpk group, with no effect on the body weight of the mice. Under the same conditions, the tumor inhibition rate of the low-dose 0.1mpk group of CC-92480 is 37%, the tumor inhibition rate of the high-dose 1mpk group is 91%, and the tumor does not regress.

Test example 3 pharmacokinetic evaluation

1 overview

The concentration of the drug in plasma at various times after the administration of the compound of example 2-1 and CC-92480 to beagle dogs was determined by LC/MS/MS method using beagle dogs as the test animals. Pharmacokinetic behavior of the compounds of the present disclosure in beagle dogs was studied and their pharmacokinetic profile was assessed.

2 test protocol

2.1 test drug

Example 2-1 and CC-92480.

2.2 test animals

The compound of example 2-1 was divided into 2 groups on average with 4 beagle dogs and two halves on each male and two halves, and 3 beagle dogs for CC-92480, male, each of which was supplied by Shanghai Meidixi Biometrics Co.

2.3 pharmaceutical formulation

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

CC-92480 is weighed, dissolved by adding 5% DMSO, 30% PG and 30% PEG400, and then prepared by adding 35% physiological saline.

2.4 administration of drugs

The compound of example 2-1 and CC-92480 were administered by gavage overnight fast at a dose of 2mg/kg and at a volume of 5mL/kg.

3 operation

The compound of example 2-1 and CC-92480 were collected by stomach infusion for 1mL at 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 12h, 24h before and after administration, placed in EDTA-K2 anticoagulant tubes, centrifuged at 10000rpm for 5 min (4 ℃) and plasma was isolated in 1h for storage at-80 ℃. The feed was fed 3h after administration. The blood collection to centrifugation process was operated under ice bath conditions.

Determination of the content of test compounds in beagle plasma after drug administration at different concentrations: 20. Mu.L of beagle plasma at each time after administration was taken, and an internal standard solution (100 ng/mL of tolbutamide as the internal standard solution of the compound of example 2-1, 100ng/mL of camptothecin as the internal standard solution of CC-92480) and 400. Mu.L of methanol were added, and the mixture was vortexed and mixed for 1min, followed by centrifugation for 10min (18000 g). 200 μl of supernatant was transferred to 96-well plates. Plasma samples were taken 1 μl of supernatant for LC/MS analysis.

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 the compounds of the present disclosure

Conclusion: the compound of the embodiment 2-1 of the disclosure has better drug absorption than CC-92480 and has pharmacokinetic advantage.

Claims

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

wherein:

G ¹ 、G ² and G ³ Identical 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 is ^b The same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, and a haloalkyl group;

x is CH ₂ Or C (O);

y is an oxygen atom or NH;

ring a is aryl or heteroaryl;

R ¹ selected from the group consisting of hydrogen, 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 a hydrogen atom, a halogen, an alkaneA group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a hydroxyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein each of the alkyl group, the alkoxy group, the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group is independently optionally substituted with one or more substituents selected from the group consisting of a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, a nitro group, a hydroxyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

R ³ and R is ⁴ The same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, and an alkyl group;

R ⁵ is the same OR different at each occurrence and is each independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, oxo, cyano, amino, nitro, hydroxy, hydroxyalkyl, -C (O) OR ⁹ 、-CONR ¹⁰ R ¹¹ Cycloalkyl and heterocyclyl, wherein each of said alkyl, alkoxy, cycloalkyl and heterocyclyl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ⁶ And are each independently at each occurrence identical or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R ⁷ 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, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, cycloalkyl, and heterocyclyl;

R ⁹ is the same or different at each occurrence and is each independently selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclyl group;

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

n is 1, 2 or 3;

m is 0, 1, 2 or 3;

p is 0, 1, 2, 3 or 4; and is also provided with

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 a compound represented by the general formula (I-1), the general formula (I-1-1) or the general formula (I-1-2):

wherein:

ring 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 compound of the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein Y is an oxygen atom.
A compound of the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R ³ And R is ⁴ Are all 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 a compound represented by the general formula (II), the general formula (II-1-1) or the general formula (II-1-2), or a pharmaceutically acceptable salt thereof:

wherein:

ring 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.
A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein X is CH ₂ 。
A compound of 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 is ^b And are identical and are each independently a hydrogen atom or a halogen.
The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, which is a compound represented by the general formula (III), the general formula (III-1-1) or the general formula (III-1-2), or a pharmaceutically acceptable salt thereof:

wherein:

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 in claim 1.
A compound of 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.
A compound of general formula (I) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein ring a is a 6 to 10 membered aryl or a 5 to 10 membered heteroaryl; preferably, ring a is phenyl.
A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein R ¹ Is a hydrogen atom.
A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein R ² Is a hydrogen atom.
A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein R ⁵ And are identical or different at each occurrence and are each independently a hydrogen atom or C _1-6 An alkyl group; preferably, R ⁵ Is a hydrogen atom.
A compound of 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 is each independently selected from the group consisting of a hydrogen atom, a halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl and C _1-6 Haloalkoxy groups; preferably, R ⁶ Is halogen; more preferably, R ⁶ Is a fluorine atom.
A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, wherein R ⁷ Selected from cyano, -S (O) ₂ R ⁹ and-S (O) ₂ NR ¹⁰ R ¹¹ Wherein R is ⁹ Is C _1-6 Alkyl, R ¹⁰ And R is ¹¹ All are hydrogen atoms; preferably, R ⁷ Is cyano.
A compound of general formula (I) according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, selected from the following compounds:
a compound represented by the general formula (IA) or a salt thereof,

wherein:

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

ring A, X, Y, Z, G ¹ 、G ² 、G ³ 、R ¹ To R ⁷ M, n, p andq is as defined in claim 1.
The compound of claim 17, or a salt thereof, selected from the following compounds:
a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, which comprises:

The compound shown in the general formula (IA) or salt thereof undergoes intramolecular ring closure reaction to obtain the compound shown in the general formula (I) or pharmaceutically acceptable salt thereof,

wherein:

R ^m is C _1-6 An alkyl group; preferably t-butyl;

ring 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 a compound of general formula (I) according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers, diluents or excipients.
Use of a compound of general formula (I) according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 20 for the manufacture of a medicament for the treatment and/or prophylaxis of cancer, angiogenesis-related disorders, pain, macular degeneration or related syndromes, skin disorders, pulmonary diseases, asbestos-related diseases, parasitic diseases, immunodeficiency diseases, central nervous system injuries, atherosclerosis or related disorders, sleep disorders or related disorders, infectious diseases, haemoglobinopathies or related disorders, or tnfα related disorders; preferably, the use in the manufacture of a medicament for the treatment and/or prophylaxis of cancer or central nervous system injury.
The use of claim 21, wherein the cancer is selected from leukemia, myeloma, lymphoma, melanoma, skin cancer, liver cancer, kidney cancer, lung cancer, nasopharyngeal cancer, stomach cancer, esophageal cancer, colorectal cancer, gall bladder cancer, bile duct cancer, chorioallantoic cancer, pancreatic cancer, polycythemia vera, pediatric tumor, 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, bone tumor, neuroblastoma, neuroendocrine cancer, brain tumor, central nervous system cancer, astrocytoma, and glioma; preferably, wherein said myeloma is multiple myeloma and myelodysplastic syndrome; more preferably, the multiple myeloma is relapsed, refractory or resistant; most preferably, wherein the multiple myeloma is lenalidomide or pomalidomide refractory or resistant.