CN116891457A

CN116891457A - Chimeric compound for androgen receptor protein targeted degradation, preparation method and medical application thereof

Info

Publication number: CN116891457A
Application number: CN202310373882.5A
Authority: CN
Inventors: 贾敏强; 陈刚; 刘志伟; 彭伟; 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: 2022-04-11
Filing date: 2023-04-10
Publication date: 2023-10-17

Abstract

The disclosure relates to a chimeric compound for androgen receptor protein targeted degradation, a preparation method thereof and application thereof in medicine. In particular, the present disclosure relates to heterocyclic compounds of general formula (I), methods for their preparation, pharmaceutical compositions containing them and their use as therapeutic agents, in particular as androgen receptor degrading agents and in the manufacture of medicaments for the treatment and/or prophylaxis of androgen receptor mediated or dependent diseases or conditions.

Description

Chimeric compound for androgen receptor protein targeted degradation, preparation method and medical application thereof

Technical Field

The present disclosure relates to a novel protein degradation targeting chimeric (PROTAC) compound, a preparation method thereof, and an application thereof in medicine. In particular, the present disclosure relates to heterocyclic compounds of general formula (I), methods for their preparation, pharmaceutical compositions containing them and their use as therapeutic agents, in particular as androgen receptor degrading agents and in the manufacture of medicaments for the treatment and/or prophylaxis of androgen receptor mediated or dependent diseases or conditions.

Background

PROTAC (PROteolysis TArgeting Chimera) is a hybrid bifunctional small molecule compound. The structure of the kit contains two different ligands, namely ubiquitin ligase E3 ligand and ligand combined with target protein, wherein the two ligands are connected through a connecting unit. PROTAC specifically degrades a target protein by bringing the target protein and intracellular ubiquitin ligase E3 into proximity to form a target protein-PROTAC-E3 ternary complex, then labeling the target protein with E3 ubiquitin ligase, and then starting an intracellular powerful ubiquitination-proteasome system, thereby achieving the effect of inhibiting the corresponding protein signaling pathway (Cell Biochem Funct.2019,37,21-30). Compared with the traditional small molecule inhibitor, the PROTAC has the unique advantages that 1, the PROTAC does not need to be combined with target proteins for a long time and high strength, and the target proteins can be circularly combined and degraded by the process of degrading the target proteins similar to catalytic reaction. Thereby reducing the systemic exposure of the medicine and reducing the occurrence of toxic and side effects. 2. The target protein needs to be synthesized again after being degraded to restore the function, so that the degradation of the target protein shows more efficient and durable anti-tumor effect than the inhibition of the activity of the target protein, and the drug resistance caused by the mutation of the target protein can not occur. 3. PROTAC also has therapeutic potential for targets currently considered non-patentable, such as transcription factors, scaffold proteins, regulatory proteins, and the like.

The discovery process for E3 ligase ligands of the CRBN type is relevant for studying the mechanism of action of thalidomide. In 2010, scientists have found that cerebelli (cereblon) is a binding protein for thalidomide (Science 2010,327,1345) during the study of thalidomide toxicity. Cerebellar proteins are part of the E3 ubiquitin ligase protein complex, which acts selectively as substrate receptors for ubiquitinated proteins. This study showed that thalidomide-cerebellar protein binding in vivo may be responsible for thalidomide teratogenicity. Subsequent researches find that the compound and related structures can be used as anti-inflammatory agents, anti-angiogenesis agents and anti-cancer agents, and lenalidomide and pomalidomide obtained by further modifying the structure of thalidomide are greatly improved in safety, teratogenic effect is obviously reduced, and lenalidomide is approved to be marketed by the FDA in 2006. Two open papers published in 2014 on Science that the nadimide functions by degrading two specific B cell transcription factors, ikaros family zinc finger structural proteins 1 and 3 (IKZF 1 and IKZF 3), further revealing that the thalidomide structure may further function in degrading target proteins by binding to the E3 ubiquitin ligase protein complex of cerebellum proteins (Science, 2014,343,301; science,2014,343, 305).

Androgen receptor (Androgen Receptor, AR) is a ligand-dependent trans-transcriptional regulator, a member of the nuclear receptor superfamily, which is found predominantly in the nucleus. The AR not bound to the ligand binds to heat shock proteins (Heat Shock Protein, HSP); while, after binding of AR to ligand, conformational changes occur, dissociation from HSP and increased affinity to DNA (activation of AR). Activated AR binds to a specific DNA sequence in the nucleus, the androgen response element (Androgen Response Element, ARE), in dimeric form and interacts with other transcription factors, thereby regulating the expression of the relevant genes, producing a biological effect. Studies have shown that abnormalities in the AR signaling pathway are closely related to the occurrence and development of diseases such as prostate cancer, benign prostatic hyperplasia, kennedy's Disease, male infertility, androgen insensitivity, and male breast cancer.

Prostate cancer is one of the most common malignant tumors. The statistics of nearly 130 thousands of new cases and 35.9 dead cases in 2018 worldwide account for 13.5% of the incidence rate of male malignant tumors, and are the second most frequent; accounting for 6.7% of mortality rate of male malignant tumor, it is the fifth most frequent. A number of AR antagonists have been approved for the market, successfully applied to castration-resistant prostate cancer treatment, and have become the primary treatment modality for prostate cancer. However, most patients develop drug resistance after 0.5-2 years of treatment, resulting in progression of the condition. For a fraction of drug resistant patients, the growth of cancer cells remains dependent on the AR signaling pathway.

There is a need to develop more effective treatments for prostate cancer. Unlike AR antagonists, PROTAC can degrade AR, can inhibit the AR signaling pathway more effectively, and is likely to be a potential treatment for prostate cancer. Published patent applications for the targeted degradation of PROTAC compounds by AR proteins include WO2015160845A2, WO2016197032A1, US2015291562A1, WO2018071606A1, WO2019023553A1, WO2016118666A1, WO2018144649A1, WO2020142228A1, WO2020198711A1, WO2021061644A1 and WO2021055756A1.

Disclosure of Invention

The object of the present disclosure is to provide a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof,

wherein:

ring a is selected from aryl, heteroaryl, cycloalkyl and heterocyclyl;

ring B is selected from the group consisting of bond, aryl, heteroaryl, cycloalkyl, and heterocyclyl;

each R is ⁶ Each R is ⁷ Identical OR different and are each independently selected from oxo, halogen, alkyl, alkenyl, alkynyl, cyano, nitro, -OR ¹¹ 、-(CH ₂ ) _u NR ¹² R ¹³ 、-C(O)R ¹¹ 、-C(O)OR ¹¹ 、-C(O)NR ¹² R ¹³ 、-S(O) _s R ¹¹ 、-S(O) _s NR ¹² R ¹³ Cycloalkyl, heterocyclyl, aryl and heteroaryl, each of which is independently optionally substituted with one or more substituents selected from oxo, halo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, haloalkoxy, hydroxy, cyano, nitro, amino, cycloalkyl and heterocyclyl;

When ring B is a bond, (R) ⁷ ) _q Absence of;

x is N or CR ^A ；

R ¹ 、R ^A 、R ^A1 And R is ^A2 The same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxyalkyl, haloalkoxy, cyano, amino, hydroxy, and nitro;

R ² and R is ³ The same or different, and are each independently a hydrogen atom or an alkyl group;

or R is ² And R is ³ Together with the attached carbon atom, form a cycloalkyl or heterocyclyl group, each of which is independently optionally substituted with one or more substituents selected from oxo, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cyano, nitro, hydroxy and amino;

each R is ⁴ The same or different and are each independently selected from the group consisting of halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cyano, nitro, hydroxy, and amino;

R ⁵ selected from the group consisting of a hydrogen atom, an alkyl group, and a cycloalkyl group;

Z ¹ and Z ² Identical or different and are each independently N or CR ^Z ；

R ^Z Selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, hydroxy, cyano, haloalkyl, and hydroxyalkyl;

l is-J ¹ -J ² -J ³ -J ⁴ -; wherein J ¹ Is connected with ring B, J ⁴ And Z is ² Are connected;

J ¹ selected from bonds, -O-, -S-, -NR ^8a -、-C(O)-、-S(O) ₂ -、-(CR ^9a R ^10a ) _m1 -, alkenyl, and alkynyl;

J ² Is cycloalkyl or heterocyclyl, each of which is independently optionally substituted with a member selected from oxo, halogen, alkyl, alkoxy, haloalkyl, hydroxyalkyl, haloalkoxy, cyano, nitro, hydroxy and- (CH) ₂ ) _v1 NR ^a R ^b Is substituted by one or more substituents;

J ³ selected from bonds, -O-, -S-, -NR ^8b -、-C(O)-、-S(O) ₂ -、-(CR ^9b R ^10b ) _m2 -, alkenyl, alkynyl, cycloalkyl and heterocyclyl, each of said cycloalkyl and heterocyclyl being independently optionally substituted with a member selected from oxo, halo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, haloalkoxyCyano, nitro, hydroxy and- (CH) ₂ ) _v2 NR ^c R ^d Is substituted by one or more substituents;

J ⁴ selected from bonds, -C (O) NR ^8c -、-NR ^8c C(O)-、-O-、-S-、-NR ^8c -、-C(O)-、-S(O) ₂ -、-(CR ^9c R ^10c ) _m3 -, alkenyl, alkynyl, cycloalkyl and heterocyclyl, each of said cycloalkyl and heterocyclyl being independently optionally substituted with a member selected from oxo, halo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, haloalkoxy, cyano, nitro, hydroxy and- (CH) ₂ ) _v3 NR ^e R ^f Is substituted by one or more substituents;

R ^8a 、R ^8b and R is ^8c The same or different and are each independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, and heterocyclylalkyl;

R ^9a 、R ^10a 、R ^9b 、R ^10b 、R ^9c and R is ^10c Identical or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, hydroxy, - (CH) ₂ ) _x NR ^g R ^h Cyano, haloalkyl, haloalkoxy and hydroxyalkyl;

R ¹¹ and are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, and heterocyclyl, each independently optionally substituted with one or more substituents selected from oxo, halogen, alkyl, alkoxy, haloalkyl, hydroxyalkyl, haloalkoxy, hydroxy, cyano, nitro, amino, cycloalkyl, and heterocyclyl;

R ¹² and R is ¹³ And are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, and heterocyclyl, each independently optionally substituted with one or more substituents selected from oxo, halogen, alkyl, alkoxy, haloalkyl, hydroxyalkyl, haloSubstituted with one or more substituents selected from the group consisting of alkoxy, hydroxy, cyano, nitro, amino, cycloalkyl and heterocyclyl;

alternatively, R ¹² And R is ¹³ Together with the nitrogen atom to which they are attached, form a heterocyclic group, which is optionally substituted with one or more substituents selected from oxo, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, cyano and hydroxyalkyl;

R ^a 、R ^b 、R ^c 、R ^d 、R ^e 、R ^f 、R ^g And R is ^h 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, and a cycloalkyl group;

s is 0, 1 or 2;

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

p and q are each independently 0, 1, 2, 3 or 4;

m1, m2 and m3 are each independently 1, 2 or 3;

u, v1, v2, v3 and x are each independently 0, 1, 2, 3 or 4.

In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R ^8a Is a hydrogen atom or C _1-6 An alkyl group; preferably, R ^8a Is a hydrogen atom.

In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein J ¹ Selected from the group consisting of-C (O) -, -O-; -S-and NH; preferably J ¹ is-C (O) -.

In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein J ² Is a 3 to 12 membered cycloalkyl or a 3 to 12 membered heterocyclyl, each of said 3 to 12 membered cycloalkyl and 3 to 12 membered heterocyclyl being independently optionally substituted with a member selected from oxo, halogen, C _1-6 Alkyl, C _1-6 Alkoxy and C _1-6 One or more substituents in the haloalkyl group; preferably J ² Is a 3 to 12 membered heterocyclyl; more preferably, J ² Is a 3 to 8 membered heterocyclyl; further preferably, J ² Selected from the group consisting of piperidinyl, piperazinyl, and azetidinyl.

In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein J ² Is a 6 membered heterocyclic group; preferably J ² Is piperidinyl.

In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein J ² Selected from the following structures:

preferably +.>Wherein the bond is of the type J ³ Is connected with each other.

In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R ^9b And R is ^10b Identical or different and are each independently selected from the group consisting of hydrogen, halogen and C _1-6 An alkyl group; preferably, R ^9b And R is ^10b Each independently is a hydrogen atom.

In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein J ³ Is a bond or- (CH) ₂ ) _m2 -, m2 is 1, 2 or 3; preferably J ³ Is a bond or-CH ₂ -; more preferably, J ³ is-CH ₂ -。

In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein J ⁴ Is a bond or a 3 to 12 membered heterocyclyl; preferably J ⁴ Is a key.

In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein L is-J ¹ -J ² -J ³ -J ⁴ -; wherein J ¹ Is connected with ring B, J ⁴ And Z is ² Are connected; j (J) ¹ Selected from the group consisting of-C (O) -, -O-; -S-and NH; j (J) ² Is a 3 to 12 membered cycloalkyl or a 3 to 12 membered heterocyclyl, each of said 3 to 12 membered cycloalkyl and 3 to 12 membered heterocyclyl being independently optionally substituted with a member selected from oxo, halogen, C _1-6 Alkyl, C _1-6 Alkoxy and C _1-6 One or more substituents in the haloalkyl group; j (J) ³ Is a bond or- (CH) ₂ ) _m2 -, m2 is 1, 2 or 3; j (J) ⁴ Is a bond or a 3 to 12 membered heterocyclyl; preferably J ¹ is-C (O) -; j (J) ² Is a 3 to 12 membered heterocyclyl; j (J) ³ Is a bond or-CH ₂ -；J ⁴ Is a bond; more preferably, J ¹ is-C (O) -; j (J) ² Is a 6 membered heterocyclic group; j (J) ³ is-CH ₂ -；J ⁴ Is a key.

In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein L, i.e., -J ¹ -J ² -J ³ -J ⁴ -selected from the following structures:

preferably isWherein is a bond with Z ² Is connected with each other.

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 C is a 3 to 12 membered heterocyclic group containing at least one nitrogen atom;

each R is ¹⁴ Identical or different and are each independently selected from oxo, halogen, alkyl, alkoxy, haloalkyl, hydroxyalkyl, haloalkoxy, cyano, nitro, hydroxy and- (CH) ₂ ) _v1 NR ^a R ^b ；

t is 0, 1, 2 or 3;

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

Ring a, ring B, J ⁴ 、Z ¹ 、Z ² 、X、R ^A1 、R ^A2 、R ¹ To R ⁷ 、R ^a 、R ^b V1, p, q and n are as defined in formula (I).

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:

t is 0, 1, 2 or 3;

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

In some embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III), or a pharmaceutically acceptable salt thereof, wherein R ¹ Selected from halogen, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy and cyano; preferably, R ¹ Is halogen or C _1-6 A haloalkyl group; more preferably, R ¹ Is a chlorine atom or trifluoromethyl.

General formula (I), general formula (II), general formula (III) described in the present disclosureThe compounds shown, or pharmaceutically acceptable salts thereof, in some embodiments, R ¹ Is halogen; in some embodiments, R ¹ Is C _1-6 A haloalkyl group; in some embodiments, R ¹ Is a chlorine atom; in some embodiments, R ¹ Is trifluoromethyl.

In some embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III), or a pharmaceutically acceptable salt thereof, wherein R ^A1 And R is ^A2 Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy and cyano; preferably, R ^A1 And R is ^A2 Identical or different and are each independently selected from the group consisting of hydrogen, halogen and C _1-6 An alkyl group; more preferably, R ^A1 And R is ^A2 Each independently is a hydrogen atom.

In some embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III), or a pharmaceutically acceptable salt thereof, wherein R ¹ Selected from halogen, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy and cyano; and/or R ^A1 And R is ^A2 Each independently is a hydrogen atom; preferably, R ¹ Is halogen or C _1-6 A haloalkyl group; and/or R ^A1 And R is ^A2 Is a hydrogen atom.

In some embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III), or a pharmaceutically acceptable salt thereof, wherein R ^A Selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy and cyano; preferably, R ^A Is a hydrogen atom.

In some embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III), or a pharmaceutically acceptable salt thereof, wherein X is N or CH; preferably, X is CH.

In some embodiments of the present disclosure, the general formula (I), general formula (II)A compound of formula (III) or a pharmaceutically acceptable salt thereof, whereinSelected from->

Preferably, the method comprises the steps of,is->

The compounds of formula (I), formula (II), formula (III) or pharmaceutically acceptable salts thereof described in this disclosure, in some embodiments,is->In some embodiments, the->Is that

In some embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III), or a pharmaceutically acceptable salt thereof, wherein R ² And R is ³ Identical or different and are each independently C _1-6 An alkyl group; or R is ² And R is ³ Together with the attached carbon atoms, form a 3 to 8 membered cycloalkyl or 3 to 8 membered heterocyclyl.

In some embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III), or a pharmaceutically acceptable salt thereof, wherein R ² And R is ³ Identical or different and are each independently C _1-6 An alkyl group; preferably, R ² And R is ³ All are armorA base.

In some embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III), or a pharmaceutically acceptable salt thereof, wherein each R ⁴ Identical or different and are each independently selected from halogen, C _1-6 Alkyl, C _1-6 Haloalkyl and cyano.

In some embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III), or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1; preferably, n is 0.

In some embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III), or a pharmaceutically acceptable salt thereof, wherein R ⁵ Is 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 (II), or a pharmaceutically acceptable salt thereof, whereinIs->Preferably, the +>Is that

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

In some embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III), or a pharmaceutically acceptable salt thereof, wherein R ¹¹ Is the same or different at each occurrence and is each independently selected from a hydrogen atom, C _1-6 Alkyl and C _1-6 A haloalkyl group.

In some embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III), or a pharmaceutically acceptable salt thereof, wherein each R ⁶ Identical or different and are each independently selected from oxo, halogen, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, cyano and C _1-6 A hydroxyalkyl group; preferably, each R ⁶ Identical or different and are each independently selected from halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group.

The compounds of general formula (I), general formula (II), general formula (III) or pharmaceutically acceptable salts thereof described in this disclosure, in some embodiments, R ⁶ Is halogen; in some embodiments, R ⁶ F.

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

The compounds of formula (I), formula (II), formula (III), or pharmaceutically acceptable salts thereof described in this disclosure, in some embodiments, p is 1.

In some embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III), or a pharmaceutically acceptable salt thereof, wherein each R ⁷ Identical or different and are each independently selected from oxo, halogen, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, cyano and C _1-6 A hydroxyalkyl group; preferably, each R ⁷ Identical or different and are each independently selected from halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group.

General formula (I), general formula (II), general formula (III) described in the present disclosure) The compounds shown, or pharmaceutically acceptable salts thereof, in some embodiments, R ⁷ Is halogen; in some embodiments, R ⁷ F.

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

The compounds of formula (I), formula (II), formula (III), or pharmaceutically acceptable salts thereof described in this disclosure, in some embodiments q is 1.

In some embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III), or a pharmaceutically acceptable salt thereof, wherein R ^Z Selected from hydrogen atom, hydroxy, halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl and C _1-6 A hydroxyalkyl group; preferably, R ^Z Is a hydrogen atom.

In some embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III), or a pharmaceutically acceptable salt thereof, wherein Z ¹ And Z ² Identical or different and are each independently N or CH; preferably Z ¹ And Z ² Are all N.

In some embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III), 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 a 6 to 10 membered aryl; more preferably, ring a is phenyl or naphthyl.

A compound of formula (I), formula (II), formula (III), or a pharmaceutically acceptable salt thereof, as described in the present disclosure, in some embodiments, ring a is phenyl; in some embodiments, ring a is naphthyl.

In some embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III), or a pharmaceutically acceptable salt thereof, whereinIs->The ribbon is connected to the right side structure.

The compounds of formula (I), formula (II), formula (III) or pharmaceutically acceptable salts thereof described in this disclosure, in some embodiments,is->R ⁶ And p is as defined in formula (I); in some embodiments, the->Selected from-> In some embodiments, the->Is->R ⁶ And p is as defined in formula (I); in some embodiments, the->Selected from->And->In some embodiments, the->Is- >The ribbon is connected to the right side structure.

In some embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III), or a pharmaceutically acceptable salt thereof, wherein ring B is selected from the group consisting of a bond, a 6 to 10 membered aryl, a 5 to 10 membered heteroaryl, a 3 to 8 membered cycloalkyl, and a 3 to 8 membered heterocyclyl; preferably, ring B is selected from the group consisting of a bond, a 6 to 10 membered aryl group, and a 3 to 8 membered heterocyclyl group; more preferably, ring B is selected from the group consisting of bond, phenyl and azetidinyl.

A compound of formula (I), formula (II), formula (III), or a pharmaceutically acceptable salt thereof, as described in the present disclosure, in some embodiments, ring B is a bond; in some embodiments, ring B is a 6 to 10 membered aryl; in some embodiments, ring B is phenyl; in some embodiments, ring B is a 3 to 8 membered heterocyclyl; in some embodiments, ring B is a 4 to 6 membered heterocyclyl; in some embodiments, ring B is azetidinyl; in some embodiments, ring B is selected from the group consisting of a bond, phenyl, and a 4 to 6 membered heterocyclyl.

In some embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III), or a pharmaceutically acceptable salt thereof, whereinSelected from the group consisting of bond, (-) and (I)>The ribbon is connected to the right side structure.

The compounds of formula (I), formula (II), formula (III) or pharmaceutically acceptable salts thereof described in this disclosure, in some embodiments,selected from the group consisting of bond, (-) and (I)>R ⁷ And q is as defined in formula (I); in some embodiments, the->Selected from the group consisting of bond, (-) and (I)> In some embodiments, the->Is a bond; in some embodiments, the->Selected from the group consisting ofIn some embodiments, the->Is->The ribbon is connected to the right side structure.

In some embodiments of the present disclosure, the compound of formula (II), formula (III), or a pharmaceutically acceptable salt thereof, wherein ring C is a 3-to 8-membered heterocyclyl containing at least one nitrogen atom; preferably, ring C is selected from piperidinyl, piperazinyl and azetidinyl; more preferably, ring C is piperidinyl.

In some embodiments of the present disclosure, the compound of formula (II), formula (III), or a pharmaceutically acceptable salt thereof, wherein ring C is a 6 membered heterocyclyl containing at least one nitrogen atom.

In some embodiments of the present disclosure, the compound of formula (II), formula (III), or a pharmaceutically acceptable salt thereof, whereinSelected from->Preferably, the +>Is->The ribbon is connected to the right side structure.

In some embodiments of the present disclosure,the compound shown in the general formula (II), the general formula (III) or pharmaceutically acceptable salts thereof, wherein J ⁴ Is a key.

In some embodiments of the present disclosure, the compound of formula (II), formula (III), or a pharmaceutically acceptable salt thereof, wherein r is 0 or 1; preferably, r is 1.

In some embodiments of the present disclosure, the compound of formula (II), formula (III), or a pharmaceutically acceptable salt thereof, wherein each R ¹⁴ Identical or different and are each independently selected from oxo, halogen, C _1-6 Alkyl, C _1-6 Alkoxy and C _1-6 A haloalkyl group; preferably, each R ¹⁴ Identical or different and are each independently selected from halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group.

In some embodiments of the present disclosure, the compound of formula (II), formula (III), or a pharmaceutically acceptable salt thereof, wherein t is 0 or 1; preferably, t is 0.

In some embodiments of the present disclosure, the compound of formula (II), formula (III), or a pharmaceutically acceptable salt thereof, whereinSelected from->And->Preferably +.>Wherein is a bond with Z ² Is connected with each other.

In some embodiments of the present disclosure, the compound of formula (II), formula (III), or a pharmaceutically acceptable salt thereof, whereinIs->R ² And R is ³ Identical or different and are each independently C _1-6 An alkyl group; or R is ² And R is ³ Together with the attached carbon atoms, form a 3 to 8 membered cycloalkyl or 3 to 8 membered heterocyclyl; each R is ⁴ Identical or different and are each independently selected from halogen, C _1-6 Alkyl, C _1-6 Haloalkyl and cyano; n is 0 or 1; r is R ⁵ Is a hydrogen atom; ring a is a 6 to 10 membered aryl or a 5 to 10 membered heteroaryl; each R is ⁶ Identical or different and are each independently selected from halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; p is 0 or 1; ring B is selected from the group consisting of a bond, a 6 to 10 membered aryl, a 5 to 10 membered heteroaryl, a 3 to 8 membered cycloalkyl, and a 3 to 8 membered heterocyclyl; when ring B is a bond, (R) ⁷ ) _q Absence of; each R is ⁷ Identical or different and are each independently selected from halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; q is 0 or 1; r is 0 or 1; ring C is a 3 to 12 membered heterocyclic group containing at least one nitrogen atom; t is 0; j (J) ⁴ Is a bond; and Z is ¹ And Z ² Identical or different and are each independently N or CH.

In some embodiments of the present disclosure, the compound of formula (II), formula (III), or a pharmaceutically acceptable salt thereof, whereinIs->R ² And R is ³ Identical or different and are each independently C _1-6 An alkyl group; each R is ⁴ Identical or different and are each independently selected from halogen, C _1-6 Alkyl, C _1-6 Haloalkyl and cyano; n is 0 or 1; r is R ⁵ Is a hydrogen atom; ring a is a 6 to 10 membered aryl or a 5 to 10 membered heteroaryl; each R is ⁶ Identical or different and are each independently selected from halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; p is 0 or 1; ring B is selected from the group consisting of a bond, a 6 to 10 membered aryl group, and a 3 to 8 membered heterocyclyl group; when ring B is a bond, (R) ⁷ ) _q Absence of; each R is ⁷ Identical or different and are each independently selected from halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; q is 0 or 1; />Is->Wherein is a bond with Z ² Is connected with each other; and Z is ¹ And Z ² Identical or different and are each independently N or CH.

In some embodiments of the present disclosure, the compound of formula (II), formula (III), or a pharmaceutically acceptable salt thereof, whereinIs->R ² And R is ³ Identical or different and are each independently C _1-6 An alkyl group; n is 0; r is R ⁵ Is a hydrogen atom; ring A is phenyl or naphthyl; r is R ⁶ Is halogen; p is 0 or 1; ring B is selected from the group consisting of bond, phenyl, and 4-to 6-membered heterocyclyl; when ring B is a bond, (R) ⁷ ) _q Absence of; r is R ⁷ Is halogen; q is 0 or 1; />Is thatWherein is a bond with Z ² Is connected with each other; and Z is ¹ And Z ² Are all N.

In some embodiments of the present disclosure, the compound of formula (III) or a pharmaceutically acceptable salt thereof, whereinIs-> Is->R ² And R is ³ Is methyl; ring A is phenyl or naphthyl; r is R ⁶ Is halogen; p is 0 or 1; ring B is selected from the group consisting of bond, phenyl and azetidinyl; when ring B is a bond, (R) ⁷ ) _q Absence of; r is R ⁷ Is halogen; q is 0 or 1; Is->Wherein is a bond with Z ² Is connected with each other; and Z is ¹ And Z ² Are all N.

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

/>

further, the present disclosure provides a compound represented by the general formula (IIA):

/>

wherein:

ring a, ring B, X, R ^A1 、R ^A2 、R ¹ 、R ² 、R ³ 、R ⁶ 、R ⁷ P and q are as defined in formula (II); provided that, when ring B is a bond,is not selected from-> The bond is attached to ring B.

Further, the present disclosure provides a compound represented by the general formula (IIB):

wherein:

J ⁴ is a bond;

r is 1;

ring C, Z ¹ 、Z ² 、R ⁴ 、R ⁵ 、R ¹⁴ N and t are as defined in formula (II).

The compound shown in the general formula (IIB) or salt thereof is notOr a salt thereof.

Further, the present disclosure provides a compound represented by the general formula (IIIB):

wherein:

ring C, Z ¹ 、Z ² 、J ⁴ 、R ⁴ 、R ⁵ 、R ¹⁴ R, n and t are as defined in formula (III).

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 (II) or a pharmaceutically acceptable salt thereof, comprising:

the compound shown in the general formula (IIA) or salt thereof and the compound shown in the general formula (IIB) or salt thereof undergo condensation reaction to obtain the compound shown in the general formula (II) or pharmaceutically acceptable salt thereof;

Wherein:

ring a, ring B, ring C, J ⁴ 、Z ¹ 、Z ² 、X、R ^A1 、R ^A2 、R ¹ To R ⁷ 、R ¹⁴ P, q, r, t and n are as defined in formula (II).

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 (IIA) or salt thereof and the compound shown in the general formula (IIIB) or salt thereof undergo condensation reaction to obtain the compound shown in the general formula (III) or pharmaceutically acceptable salt thereof;

wherein:

ring a, ring B, ring C, J ⁴ 、Z ¹ 、Z ² 、X、R ^A1 、R ^A2 、R ¹ To R ⁷ 、R ¹⁴ P, q, r, t and n are as defined in formula (III).

Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of the above general formula (I), general formula (II), general formula (III) or table a or a pharmaceutically acceptable salt thereof of the present disclosure, and one or more pharmaceutically acceptable carriers, diluents or excipients.

The present disclosure further relates to the use of a compound of formula (I), formula (II), formula (III) or table a above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for modulating ubiquitination and degradation of Androgen Receptor (AR) proteins in a subject.

The present disclosure further relates to the use of a compound of the above general formula (I), general formula (II), general formula (III) or 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 an androgen receptor mediated or dependent disease or disorder, preferably selected from the group consisting of tumors, male sexual dysfunction and kennedy's disease; more preferably selected from the group consisting of prostate cancer, prostatic hyperplasia, hirsutism, alopecia, anorexia nervosa, breast cancer, acne, male sexual dysfunction, kennedy's disease and aids, most preferably prostate cancer, most preferably hormone-sensitive prostate cancer or hormone refractory prostate cancer.

The present disclosure also relates to a method of modulating ubiquitination and degradation of an Androgen Receptor (AR) protein in a subject comprising administering to a patient in need thereof a therapeutically effective amount of a compound represented by formula (I), formula (II), formula (III), or 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 an androgen receptor mediated or dependent disease or condition, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (II), formula (III) or table a above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, wherein the androgen receptor mediated or dependent disease or condition is preferably selected from the group consisting of tumors, male sexual dysfunction and kennedy's disease; more preferably selected from the group consisting of prostate cancer, prostatic hyperplasia, hirsutism, alopecia, anorexia nervosa, breast cancer, acne, male sexual dysfunction, kennedy's disease and aids, most preferably prostate cancer, most preferably hormone-sensitive prostate cancer or hormone refractory prostate cancer.

The present disclosure further relates to a compound represented by the above general formula (I), general formula (II), general formula (III) or 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 a compound of the above formula (I), formula (II), formula (III) or table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament for modulating ubiquitination and degradation of Androgen Receptor (AR) proteins in a subject.

The present disclosure further relates to a compound represented by the above general formula (I), general formula (II), general formula (III) or table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament for the treatment and/or prevention of androgen receptor mediated or dependent diseases or conditions; wherein the androgen receptor mediated or dependent disease or condition is preferably selected from the group consisting of tumors, male sexual dysfunction and kennedy's disease; more preferably selected from the group consisting of prostate cancer, prostatic hyperplasia, hirsutism, alopecia, anorexia nervosa, breast cancer, acne, male sexual dysfunction, kennedy's disease and aids, most preferably prostate cancer, most preferably hormone-sensitive prostate cancer or hormone refractory prostate cancer.

The disclosure further relates to compounds of the above general formula (I), general formula (II), general formula (III) or table a, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for modulating ubiquitination and degradation of Androgen Receptor (AR) proteins in a subject.

The present disclosure further relates to compounds of the above general formula (I), general formula (II), general formula (III) or table a, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in the treatment and/or prevention of diseases or conditions mediated by or dependent on the androgen receptor; wherein the androgen receptor mediated or dependent disease or condition is preferably selected from the group consisting of tumors, male sexual dysfunction and kennedy's disease; more preferably selected from the group consisting of prostate cancer, prostatic hyperplasia, hirsutism, alopecia, anorexia nervosa, breast cancer, acne, male sexual dysfunction, kennedy's disease and aids, most preferably prostate cancer, most preferably hormone-sensitive prostate cancer or hormone refractory prostate cancer.

In certain embodiments, the disease or disorder is asthma, multiple sclerosis, cancer, kennedy's disease, ciliated disease, cleft palate, diabetes, heart disease, hypertension, inflammatory bowel disease, mental retardation, mood disorders, obesity, ametropia, infertility, angelman syndrome, caner's disease, celiosis, chard-mar-tourette's disease, cystic fibrosis, duchenne muscular dystrophy, hemochromatosis, hemophilia, grignard syndrome, neurofibromas, phenylketonuria, polycystic kidney disease, (PKD 1) or 4 (PKD 2) pan-wei-syndrome, sickle cell disease, tenascus disease, terna syndrome. Wherein the cancer is squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, renal cell carcinoma, bladder carcinoma, bowel cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, neck cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, leukemia, benign and malignant lymphomas (particularly burkitt's lymphoma and non-hodgkin's lymphoma), benign and malignant melanoma, myeloproliferative disorders, sarcomas (including ewing's sarcoma, angiosarcoma, kaposi's sarcoma, liposarcoma, myosarcoma, peripheral nerve epithelium tumor, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioma, neuroblastoma, meningioma, neurofibroma and schwannoma), endometrial carcinoma, testicular cancer, thyroid cancer, sarcoma, hodgkin's disease, wei Erm s tumor, or fetoma. In certain embodiments, the disease to be treated is cancer (e.g., prostate cancer) or kennedy's disease.

The active compounds may be formulated in a form suitable for administration by any suitable route, preferably in unit dosage form, or in a form whereby the patient may 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.

As a general guideline, suitable unit doses may be from 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.

Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral administration, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the group consisting of: sweeteners, flavoring agents, coloring agents and preservatives to provide a pleasing and palatable pharmaceutical preparation. 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 or 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, 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 injectable solution or microemulsion may be injected into the blood stream of a patient by topical bolus 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 suspension may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. 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.

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-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, 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, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkenyl" refers to an alkyl group 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, isopropenyl, butenyl, and the like. Alkenyl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atoms, alkoxy groups, halogen, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups.

The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, where 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 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 they may be substituted at any available point of attachment, the substituents preferably being selected from the group consisting of D atoms, alkoxy groups, halogen, haloalkyl groups, haloalkoxy groupsOne or more of a group, 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 include: methoxy, ethoxy, propoxy, butoxy, and the like. The alkoxy 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, 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, full-carbocyclic (i.e., monocyclic cycloalkyl) or polycyclic (i.e., polycyclic cycloalkyl) system 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) ring atoms (i.e., 3 to 20 membered cycloalkyl). The cycloalkyl group is preferably a cycloalkyl group having 3 to 12 ring atoms (i.e., a 3 to 12 membered cycloalkyl group), more preferably a cycloalkyl group having 3 to 8 ring atoms (i.e., a 3 to 8 membered cycloalkyl group), and most preferably a cycloalkyl group having 3 to 6 ring atoms (i.e., a 3 to 6 membered cycloalkyl group).

Non-limiting examples of such monocyclic cycloalkyl groups include: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl and the like.

The polycyclic cycloalkyl group includes: spirocycloalkyl, fused ring alkyl, and bridged cycloalkyl.

The term "spirocycloalkyl" refers to a polycyclic ring system having one or more carbon atoms (referred to as spiro atoms) shared between the rings, which may contain one or more double bonds within the ring, or which may contain one or more heteroatoms selected from nitrogen, oxygen and sulfur within the ring (the nitrogen may optionally be oxidized, i.e., to form a nitroxide; the sulfur may optionally be oxo, i.e., to form a sulfoxide or sulfone, but excluding-O-, -O-S-, or-S-S-), provided that at least one full carbocyclic ring is contained and the point of attachment is on the full carbocyclic ring, which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20 membered spirocycloalkyl). The spirocycloalkyl group is preferably a spirocycloalkyl group having 6 to 14 ring atoms (i.e., a 6 to 14 membered spirocycloalkyl group), more preferably a spirocycloalkyl group having 7 to 10 ring atoms (i.e., a 7 to 10 membered spirocycloalkyl group). The spirocycloalkyl group includes a mono-spirocycloalkyl group and a multi-spirocycloalkyl group (e.g., a double spirocycloalkyl group, etc.), preferably a mono-spirocycloalkyl group or a double spirocycloalkyl 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/5-membered, 5-membered/6-membered, 5-membered/7-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered/6-membered single spirocycloalkyl group. Non-limiting examples include:

The connection point can be at any position;

etc.

The term "fused ring alkyl" refers to a polycyclic ring system having two adjacent carbon atoms shared between the rings, which is a monocyclic cycloalkyl fused to one or more monocyclic cycloalkyl groups, or a monocyclic cycloalkyl fused to one or more of a heterocyclyl, aryl, or heteroaryl group, wherein the point of attachment is on the monocyclic cycloalkyl group, which may contain one or more double bonds within the ring, and which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20 membered fused ring alkyl groups). The condensed ring alkyl group is preferably a condensed ring alkyl group having 6 to 14 ring atoms (i.e., a 6 to 14 membered condensed ring alkyl group), more preferably a condensed ring alkyl group having 7 to 10 ring atoms (i.e., a 7 to 10 membered condensed ring alkyl group). The condensed ring alkyl group includes a bicyclic condensed ring alkyl group and a polycyclic condensed ring alkyl group (e.g., a tricyclic condensed ring alkyl group, a tetracyclic condensed ring alkyl group, etc.), preferably a bicyclic condensed ring alkyl group or a tricyclic condensed ring alkyl group, more preferably 3/4-, 3/5-, 3/6-, 4/4-, 4/5-, 4/6-, 5/3-, 5/4-, 5/5-, 5/6-, 5/7-, 6/3-, 6/4-, 6/5-, 6-or 6-membered6-, 7-, 5-, or 7-membered bicyclic fused ring alkyl. Non-limiting examples include: ，

The connection point can be at any position;

etc.

The term "bridged cycloalkyl" refers to an all-carbon polycyclic ring system having two carbon atoms in common between the rings that are not directly attached, which may contain one or more double bonds within the ring, and which has from 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., a 5 to 20 membered bridged cycloalkyl). The bridged cycloalkyl group is preferably a bridged cycloalkyl group having 6 to 14 carbon atoms (i.e., a 6 to 14 membered bridged cycloalkyl group), more preferably a bridged cycloalkyl group having 7 to 10 carbon atoms (i.e., a 7 to 10 membered bridged cycloalkyl group). The bridged cycloalkyl group includes a bicyclic bridged cycloalkyl group and a polycyclic bridged cycloalkyl group (e.g., a tricyclic bridged cycloalkyl group, a tetracyclic bridged cycloalkyl group, etc.), preferably a bicyclic bridged cycloalkyl group or a tricyclic bridged cycloalkyl group. Non-limiting examples include:

the connection point can be at any position.

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

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic heterocycle (i.e., monocyclic heterocyclyl) or polycyclic heterocyclic ring system (i.e., polycyclic heterocyclyl) having at least one (e.g., 1,2,3, or 4) heteroatom (S) selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized, i.e., forming a nitroxide; the sulfur may optionally be oxo, i.e., forming a sulfoxide or sulfone, but excluding-O-, -O-S-, or-S-), and 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 (i.e., 3 to 20 membered heterocyclyl) within the ring. The heterocyclic group is preferably a heterocyclic group having 3 to 12 ring atoms (i.e., a 3 to 12 membered heterocyclic group); further preferred are heterocyclyl groups having 3 to 8 ring atoms (i.e., 3 to 8 membered heterocyclyl groups); more preferably a heterocyclic group having 3 to 6 ring atoms (i.e., a 3 to 6 membered heterocyclic group); more preferably, a heterocyclic group having 4 to 6 ring atoms (i.e., a 4 to 6 membered heterocyclic group) is most preferably a heterocyclic group having 5 or 6 ring atoms (i.e., a 5 or 6 membered heterocyclic group).

Non-limiting examples of such monocyclic heterocyclic groups include: pyrrolidinyl, tetrahydropyranyl, 1,2,3, 6-tetrahydropyridinyl, piperidinyl, piperazinyl, azetidinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like.

The polycyclic heterocyclic group includes spiro heterocyclic group, condensed heterocyclic group and bridged heterocyclic group.

The term "spiroheterocyclyl" refers to a polycyclic heterocyclic ring system having one or more double bonds shared between the rings, which may contain one or more double bonds within the ring, and which contains at least one (e.g., 1, 2, 3 or 4) heteroatom (S) selected from nitrogen, oxygen and sulfur (which may optionally be oxidized, i.e., form nitrogen oxides; which may optionally be oxo, i.e., form sulfoxides or sulfones, but excluding-O-, -O-S-or-S-) with the proviso that at least one monocyclic heterocyclic ring is contained and the point of attachment is on the monocyclic heterocyclic ring, which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 5 to 20 membered spiroheterocyclic groups). The spiroheterocyclyl group is preferably a spiroheterocyclyl group having 6 to 14 ring atoms (i.e., a 6 to 14 membered spiroheterocyclyl group), more preferably a spiroheterocyclyl group having 7 to 11 ring atoms (i.e., a 7 to 11 membered spiroheterocyclyl group). The spiroheterocyclyl group includes a mono-spiroheterocyclyl group and a multi-spiroheterocyclyl group (e.g., a double-spiroheterocyclyl group, etc.), preferably a mono-or double-spiroheterocyclyl group, more preferably a 3/4-, 3/5-, 3/6-, 4/4-, 4/5-, 4/6-, 5/3-, 5/4-, 5/5-, 5/6-, 5/7-, 6/3-, 6/4-, 6/5-, 6/6-, 6/7-, 7/5-or 7-membered mono-spiroheterocyclyl group. Non-limiting examples include:

Etc.

The term "fused heterocyclyl" refers to a polycyclic heterocyclic ring system having two adjacent atoms shared between the rings, which may contain one or more double bonds within the ring, and which contains at least one (e.g., 1, 2, 3 or 4) heteroatom (S) selected from nitrogen, oxygen and sulfur within the ring (which may optionally be oxidized, i.e., form nitrogen oxides; which may optionally be oxo, i.e., form sulfoxides or sulfones, but excluding-O-, -O-S-or-S-), which is a monocyclic heterocyclic group fused to one or more monocyclic heterocyclic groups, or a monocyclic heterocyclic group fused to one or more of cycloalkyl, aryl or heteroaryl groups, wherein the point of attachment is on a monocyclic heterocyclic group and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 5 to 20 membered fused heterocyclic groups). The fused heterocyclic group is preferably a fused heterocyclic group having 6 to 14 ring atoms (i.e., a 6 to 14-membered fused heterocyclic group), more preferably a fused heterocyclic group having 7 to 10 ring atoms (i.e., a 7 to 10-membered fused heterocyclic group). The fused heterocyclic group includes a bicyclic and polycyclic fused heterocyclic group (e.g., a tricyclic fused heterocyclic group, a tetracyclic fused heterocyclic group, etc.), preferably a bicyclic fused heterocyclic group or a 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 include:

Etc.

The term "bridged heterocyclyl" refers to a polycyclic heterocyclic ring system having two atoms not directly connected between the rings, which may contain one or more double bonds within the ring, and which contains at least one (e.g., 1, 2, 3 or 4) heteroatom (S) selected from nitrogen, oxygen and sulfur within the ring (the nitrogen may optionally be oxidized, i.e., form a nitrogen oxide; the sulfur may optionally be oxo, i.e., form a sulfoxide or sulfone, but excluding-O-, -O-S-or-S-), which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 5 to 20 membered bridged heterocyclyl). The bridged heterocyclic group is preferably a bridged heterocyclic group having 6 to 14 ring atoms (i.e., a 6 to 14 membered bridged heterocyclic group), more preferably a bridged heterocyclic group having 7 to 10 ring atoms (i.e., a 7 to 10 membered bridged heterocyclic group). The number of constituent rings may be classified into a bicyclic bridged heterocyclic group and a polycyclic bridged heterocyclic group (e.g., a tricyclic bridged heterocyclic group, a tetracyclic bridged heterocyclic group, etc.), with a bicyclic bridged heterocyclic group or a tricyclic bridged heterocyclic group being preferred. Non-limiting examples 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 D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "aryl" refers to a monocyclic all-carbon aromatic ring (i.e., monocyclic aryl) or a polycyclic aromatic ring system (i.e., polycyclic aryl) having from 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., 6 to 14 membered aryl) having a conjugated pi electron system. The aryl group is preferably an aryl group having 6 to 10 ring atoms (i.e., a 6 to 10 membered aryl group). The monocyclic aryl group is, for example, phenyl. Non-limiting examples of such polycyclic aryl groups include: naphthyl, anthryl, phenanthryl, and the like. The polycyclic aryl group also includes a phenyl group fused to one or more of a heterocyclic group or a cycloalkyl group, or a naphthyl group fused to one or more of a heterocyclic group or a cycloalkyl group, wherein the point of attachment is on the phenyl or naphthyl group, and in such cases the number of ring atoms continues to represent the number of ring atoms in the polycyclic aromatic ring system, non-limiting examples include:

etc. />

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

The term "heteroaryl" refers to a monocyclic heteroaryl ring having a conjugated pi electron system (i.e., a monocyclic heteroaryl group) or a polycyclic heteroaryl ring system (i.e., a polycyclic heteroaryl group) containing at least one (e.g., 1, 2, 3, or 4) heteroatom (S) selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized, i.e., form a nitrogen oxide; the sulfur may optionally be oxo, i.e., form a sulfoxide or sulfone, but excluding-O-, -O-S-, or-S-) within the ring having 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., a 5 to 14 membered heteroaryl group). The heteroaryl group is preferably a heteroaryl group having 5 to 10 ring atoms (i.e., a 5 to 10 membered heteroaryl group), more preferably a heteroaryl group having 5 or 6 ring atoms (i.e., a 5 or 6 membered heteroaryl group).

Non-limiting examples of such monocyclic heteroaryl groups include: furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furazanyl, pyrrolyl, N-alkylpyrrolyl, pyridyl, pyrimidinyl, pyridonyl, N-alkylpyridones (e.g.)Etc.), pyrazinyl, pyridazinyl, etc.

Non-limiting examples of such polycyclic heteroaryl groups include: indolyl, indazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothienyl, quinazolinyl, benzothiazolyl, carbazolyl, and the like. The polycyclic heteroaryl group also includes a monocyclic heteroaryl group fused to one or more aryl groups, wherein the point of attachment is on the aromatic ring, and in which case the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaryl ring system. The polycyclic heteroaryl group also includes a monocyclic heteroaryl group fused to one or more of a cycloalkyl or heterocyclic group, where the point of attachment is on the monocyclic heteroaryl ring, and in such a case the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaryl ring system. Non-limiting examples include:

Etc.

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

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

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

The term "alkoxyalkyl" refers to an alkyl group substituted with one or more alkoxy groups, wherein alkoxy and alkyl are 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 "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 "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 "ubiquitin ligase" refers to a family of proteins that promote the transfer of ubiquitin to a specific substrate protein, targeting the substrate protein for degradation. For example, cerebellum proteins are E3 ubiquitin ligase proteins that, alone or in combination with E2 ubiquitin binding enzymes, result in the attachment of ubiquitin to a target protein and subsequent targeting of specific protein substrates for degradation by proteasome. Thus, E3 ubiquitin ligase alone or in combination with E2 ubiquitin binding enzyme is responsible for ubiquitin transfer to target proteins. Generally, ubiquitin ligases are involved in polyubiquitination, such that a second ubiquitin is linked to a first ubiquitin, a third ubiquitin is linked to a second ubiquitin, and so on. Polyubiquitin-tagged proteins are useful for degradation by proteasome. However, there are some ubiquitination events that are limited to monoubiquitination, where only a single ubiquitin is added to the substrate molecule by ubiquitin ligase. Monoubiquitinated proteins are not targeted to the proteasome for degradation, but may instead be altered in their cellular location or function, for example, by binding to other proteins having domains capable of binding ubiquitin. To complicate matters, different lysines on ubiquitin can be targeted by E3 to make chains. The most common lysine is Lys48 on the ubiquitin chain. This is the lysine used to prepare polyubiquitin, which is recognized by the proteasome.

The term "target protein" refers to proteins and peptides having any biological function or activity, including structure, regulation, hormone, enzymatic, genetic, immune, contractile, storage, transport, and signal transduction. In some embodiments, the target protein comprises a structural protein, a receptor, an enzyme, a cell surface protein, a protein associated with an integrated function of a cell, including proteins involved in: catalytic activity, aromatase activity, motor activity, helicase activity, metabolic processes (anabolism and catabolism), antioxidant activity, proteolysis, biosynthesis, proteins with kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme regulator activity, signal transduction factor activity, structural molecule activity, binding activity (protein, lipid carbohydrate), receptor activity, cell motility, membrane fusion, cell communication, regulation of biological processes, development, cell differentiation, stimulatory reactions, behavioral proteins, cell adhesion proteins, proteins involved in cell death, proteins involved in transport (including protein transport activity, nuclear transport, ion transport activity, channel transport activity, carrier activity), permease activity, secretion activity, electron transport activity, pathogenic agents, concomitant protein regulator activity, nucleic acid binding activity, transcriptional regulator activity, extracellular architecture and biological origin activity, translation regulator activity. The proteins include proteins from eukaryotes and prokaryotes including microorganisms, viruses, fungi and parasites and numerous others including humans, microorganisms, viruses, fungi and parasites targeted for pharmacotherapy, other animals including domestic animals), microorganisms and other antimicrobial agents of the subject gram and plants and even viruses for the determination of antibiotics and numerous others.

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 the unspecified configuration, i.e.the bond +.>Can be +.>Or->Or at the same time contain->And->Two configurations. For all carbon-carbon double bonds, Z and E are included even if only one configuration is named.

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 may comprise atropisomers. The term "atropisomer" is a conformational stereoisomer that results from a blocked or greatly slowed rotation about a single bond in a molecule (as a result of steric interactions with other parts of the molecule and the substituents being asymmetric at both ends of the single bond), whose interconversion is slow enough to allow separation and isolation under predetermined conditions. For example, certain compounds of the present disclosure may exist as a mixture of atropisomers (e.g., an equal proportion of a mixture, a mixture enriched for one atropisomer, etc.) or as a purified one atropisomer.

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 is specifically designated as deuterium D, that position is understood to be deuterium having an abundance that is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%), i.e. at least 15% deuterium incorporation. The natural abundance of the compounds in the examples may be at least 1000 times greater than the abundance of deuterium (i.e., at least 15% deuterium incorporation), at least 2000 times greater than the abundance of deuterium (i.e., at least 30% deuterium incorporation), at least 3000 times greater than the abundance of deuterium (i.e., at least 45% deuterium incorporation), at least 3340 times greater than the abundance of deuterium (i.e., at least 50.1% deuterium incorporation), at least 3500 times greater than the abundance of deuterium (i.e., at least 52.5% deuterium incorporation), at least 4000 times greater than the abundance of deuterium (i.e., at least 60% deuterium incorporation), at least 4500 times greater than the abundance of deuterium (i.e., at least 67.5% deuterium incorporation), at least 5000 times greater than the abundance of deuterium (i.e., at least 75% deuterium incorporation), at least 5500 times greater than the abundance of deuterium (i.e., at least 82.5% deuterium incorporation), at least 6000 times greater than the abundance of deuterium (i.e., at least 90% deuterium incorporation), at least 6333.3 times greater than the abundance of deuterium (i.e., at least 95% deuterium incorporation), at least 6466.7 times greater than the abundance of deuterium (i.e., at least 6600 times greater than the abundance of deuterium (i.99% of deuterium incorporation), or at least 6600 times greater than the abundance of deuterium (i.5% of deuterium incorporation).

"optional" or "optionally" means that the subsequently described event or circumstance may but is notIt must occur, including both cases where the event or circumstance occurs or not. For example "C optionally substituted by halogen or cyano _1-6 Alkyl "includes the case where alkyl is substituted with halogen or cyano and the case where alkyl is not substituted with halogen or cyano.

"substituted" or "substituted" means that one or more hydrogen atoms, preferably 1 to 6, more preferably 1 to 3, 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 bonds (e.g., alkenes).

"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. May be prepared separately during the final isolation and purification of the compound, 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

A process for the preparation of a compound of formula (II) or a pharmaceutically acceptable salt thereof, according to the present disclosure, comprising the steps of:

the compound shown in the general formula (IIA) or salt thereof and the compound shown in the general formula (IIB) or salt thereof are subjected to condensation reaction under the action of a condensing agent and an alkaline reagent to obtain a compound shown in the general formula (II) or pharmaceutically acceptable salt thereof;

wherein:

Scheme II

A process for the preparation of a compound of formula (III) or a pharmaceutically acceptable salt thereof, according to the present disclosure, comprising the steps of:

the compound shown in the general formula (IIA) or salt thereof and the compound shown in the general formula (IIIB) or salt thereof are subjected to condensation reaction under the action of a condensing agent and an alkaline reagent to obtain a compound shown in the general formula (III) or pharmaceutically acceptable salt thereof;

wherein:

In the above synthetic schemes, the condensing agent includes, but is not limited to, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N, N '-dicyclohexylcarbodiimide, N, N' -diisopropylcarbodiimide, O-benzotriazol-N, N, N ', N' -tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazol, O-benzotriazol-N, N, N ', N' -tetramethyluronium hexafluorophosphate, N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) hexafluorophosphate urea (HATU), 2- (7-oxybenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate, benzotriazol-1-yl-oxy-tripyrrolidinyl phosphate; preferably, the condensing agent is urea N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) Hexafluorophosphate (HATU).

In the above synthesis scheme, the alkaline reagent comprises organic alkali and inorganic alkali; the organic base includes but is not limited to triethylamine, N-dimethylethylamine, N-diisopropylethylamine, N-butyllithium, lithium diisopropylamide, potassium acetate, sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide; the inorganic base includes, but is not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide monohydrate, lithium hydroxide, and potassium hydroxide; preferably, the basic reagent is N, N-dimethylethylamine or N, N-diisopropylethylamine.

The above synthetic schemes are preferably carried out in solvents 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.

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 is Tetramethylsilane (TMS).

MS was determined 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 (manufacturers: waters, MS model: waters ACQuity Qda Detector/waters SQ Detector)

Thermo Ultimate 3000-Q exact (manufacturer: thermo, MS model: thermo Qexact)

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 1260DAD 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 uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.

The silica gel column chromatography generally uses 200-300 mesh silica gel of yellow sea of the tobacco stand 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, shaog chemical technology (Accela ChemBio Inc), 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 reaction temperature is room temperature and is 20-30 deg.c without specific explanation in the examples.

The progress of the reaction in the examples was monitored by Thin Layer Chromatography (TLC), the developing reagent used for the reaction, the eluent system for column chromatography used for purifying the compound and the developing reagent system for thin layer chromatography included: a: dichloromethane/methanol system, B: in the n-hexane/ethyl acetate system, the volume ratio of the solvent is regulated according to the polarity of the compound, and small amounts of alkaline or acidic reagents such as triethylamine, acetic acid and the like can be added for regulation.

Example 1

(±) -2-chloro-4- (3- (6- (4- ((4- (3- ((2, 6-dioxopiperidin-3-yl) amino) phenyl) piperazin-1-yl) methyl) piperidine)

-1-carbonyl) naphthalen-2-yl) -4, 4-dimethyl-5-oxo-2-thiouronylimidazolidin-1-yl-benzonitrile 1

First step (. + -.) -4- ((4- (3- ((2, 6-dioxopiperidin-3-yl) amino) phenyl) piperazin-1-yl) methyl) piperidine-1-carboxylic acid tert-butyl ester 1c

To a 25mL three-necked flask was added 3mL of a mixed solution of dichloromethane and methanol (V/V=2/1), (. + -.) -3- ((3- (piperazin-1-yl) phenyl) amino) piperidine-2, 6-dione hydrochloride 1a (90 mg,0.25mmol, prepared by the method disclosed in Compound 86 at page 266 of the specification in patent application "WO 2018237026 A1"), anhydrous sodium acetate (102 mg,1.24 mmol), and reacted for 15 minutes, 4-formylpiperidine-1-carboxylic acid tert-butyl ester 1b (85 mg,0.40mmol, medical) was added, and sodium triacetoxyborohydride (106 mg,0.50 mmol) was slowly added and reacted for 30 minutes. The reaction was quenched by adding 10mL of saturated sodium bicarbonate solution under ice-bath cooling, extracted with dichloromethane (20 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride solution (20 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title compound 1c (110 mg, yield: 90%).

MS m/z(ESI):486.6[M+1]。

Second step

(±) -3- ((3- (4- (piperidin-4-ylmethyl) piperazin-1-yl) phenyl) amino) piperidine-2, 6-dione dihydrochloride 1d

Compound 1c (105 mg,0.22 mmol) was dissolved in 3mL of dichloromethane, and a 4M solution of 1, 4-dioxane (0.53 mL) in hydrogen chloride was slowly added under ice-bath and reacted for 4 hours. The reaction solution was concentrated and dried in vacuo to give the title compound 1d (99 mg, yield: 98%) as a crude product, which was used in the next reaction without purification.

MS m/z(ESI):386.5[M+1]。

Third step

2- ((6- (methoxycarbonyl) naphthalen-2-yl) amino) -2-methylpropanoic acid 1g

Methyl 6-bromo-2-naphthoate 1e (500 mg,1.89mmol, shanghai Bi. Medical), 2-amino-2-methylpropanoic acid 1f (29 mg,2.82mmol, shanghai Bi. Medical) was dissolved in N, N-dimethylformamide (20 mL), water (0.8 mL), triethylamine (0.05 mL), cuprous iodide (54 mg,0.28 mmol), anhydrous potassium carbonate (678 mg,4.91 mmol), acetylacetone (151 mg,1.51 mmol), nitrogen were added, the temperature was raised to 140℃for 1 hour, the reaction was 120℃for 12 hours, cooled to room temperature, 25mL of water was added, the pH of the reaction solution was adjusted to about 4 with 2M diluted hydrochloric acid, ethyl acetate was used for extraction (25 mL. Times.5), the organic phases were combined, dried with anhydrous sodium sulfate, filtration, the filtrate was concentrated under reduced pressure to remove the solvent, and the obtained residue was purified by silica gel column chromatography as eluent system B to give the title compound 1g (500 mg, yield: 92%).

MS m/z(ESI):288.6[M+1]。

Fourth step

6- (3- (3-chloro-4-cyanophenyl) -5, 5-dimethyl-4-oxo-2-thioideneimidazolidin-1-yl) -2-naphthoic acid methyl ester 1i

1g (200 mg,0.70 mmol) of the compound was dissolved in 10mL of a mixed solvent of toluene and methylene chloride (V/V=4:1), triethylamine (71 mg,0.70 mmol) was added, the reaction was warmed to 35℃and stirred until the solution became clear, 2mL of a toluene solution of 2-chloro-4-isothiocyanatobenzonitrile (203 mg,1.04mmol, shanghai Bi. Ed. Medical) was added, the reaction was warmed to 70℃and stirred for 16 hours, the reaction solution was concentrated, and the obtained residue was purified by silica gel column chromatography with eluent system B to give the title compound 1i (300 mg, yield: 93%).

MS m/z(ESI):464.1[M+1]。

Fifth step

6- (3- (3-chloro-4-cyanophenyl) -5, 5-dimethyl-4-oxo-2-thioylidenemidazolidin-1-yl) -2-naphthoic acid 1j

Compound 1i (150 mg,0.32 mmol) was dissolved in methanol (2 mL), 1M sodium hydroxide solution (1.3 mL) was added dropwise, and the mixture was reacted at 35℃for 17 hours after completion of the dropwise addition. Water (15 mL) was added, the pH of the reaction mixture was adjusted to about 4 with 1M diluted hydrochloric acid, extracted with ethyl acetate (25 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure to give the title compound 1j (120 mg, yield: 82%) as a crude product, which was used in the next reaction without purification.

MS m/z(ESI):450.0[M+1]。

Sixth step (±) -2-chloro-4- (3- (6- (4- ((4- (3- ((2, 6-dioxopiperidin-3-yl) amino) phenyl) piperazin-1-yl) methyl) piperidine)

Compound 1j (45 mg,0.081 mmol), compound 1d (43 mg,0.081 mmol) was dissolved in N, N-dimethylformamide (2 mL), N, N-dimethylethylamine (62 mg,0.48 mmol), N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) hexafluorophosphoric acid urea (49 mg,0.13 mmol) was added, and the reaction mixture was purified by high performance liquid chromatography (Waters 2767-SQ detector 2, elution system: 10mM ammonium bicarbonate aqueous solution and acetonitrile, gradient of acetonitrile: 45% -65%, flow rate: 30 mL/min) to give the title compound 1 (racemate, ratio 1:1, 35mg, yield: 54%).

MS m/z(ESI):817.2[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )δ10.75(s,1H),8.20(d,1H),8.18(d,1H),8.12(d,1H),8.06(d,2H),8.03(s,1H),7.77(d,1H),7.59-7.55(m,2H),6.90(t,1H),6.25(s,1H),6.18(d,1H),6.13(d,1H),5.62(d,1H),4.54(s 1H),4.34-4.26(m,1H),3.64(s,1H),3.18-2.99(m,5H),2.90-2.79(m,1H),2.78-2.68(m,1H),2.62-2.53(m,1H),2.49-2.40(m,4H),2.26-2.17(m,2H),2.13-2.05(m,1H),2.03-1.80(m,3H),1.72-1.64(m,1H),1.57(s,6H),1.20-1.09(m,2H)。

Example 2

(±) -4- (3- (4- ((4- (3- ((2, 6-dioxopiperidin-3-yl) amino) phenyl) piperazin-1-yl) methyl) piperidine-1-carbonyl) azetidin-1-yl) phenyl) -4, 4-dimethyl-5-oxo-2-thioideneamidazolidin-1-yl) -2- (trifluoromethyl) phenyl)

Benzonitrile 2

First step

1- (4- ((2-Cyanoprop-2-yl) amino) phenyl) azetidine-3-carboxylic acid methyl ester 2b

Methyl 1- (4-aminophenyl) azetidine-3-carboxylate 2a (600 mg,2.91mmol, prepared as disclosed in patent application "WO 2012067965A 1, page 881, example 1246B") was dissolved in acetone (25 mL), cooled to 0 ℃, and trimethylsilane cyanide (579 mg,5.84 mmol), elemental iodine (75 mg,0.30 mmol) was added dropwise and reacted for 12 hours. The reaction solution was concentrated, ethyl acetate (100 mL) and a saturated sodium thiosulfate solution (30 mL) were added to the concentrated solution, an organic phase was separated, the organic phase was washed with a saturated sodium chloride solution (25 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent, and the obtained residue was purified by silica gel column chromatography with eluent system A to give the title compound 2b (260 mg, yield: 33%).

MS m/z(ESI):274.2[M+1]。

Second step

1- (4- (3- (4-cyano-3- (trifluoromethyl) phenyl) -4-aminosubunit-5, 5-dimethyl-2-thioxofenam-1-yl) phenyl) azetidine-3-carboxylic acid methyl ester 2d

Compound 2b (260 mg,0.95 mmol), 4-isothiocyanato-2- (trifluoromethyl) benzonitrile 2c (260 mg,1.14mmol, shanghai Bifide. Medicine) was dissolved in toluene (20 mL), 4-dimethylaminopyridine (176 mg,1.43 mmol) was added, the reaction was warmed to 100℃for 12 hours, the reaction solution was concentrated, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title compound 2d (80 mg, yield: 17%).

MS m/z(ESI):502.1[M+1]。

Third step

1- (4- (3- (4-cyano-3- (trifluoromethyl) phenyl) -5, 5-dimethyl-4-oxo-2-thioxoyimidazolidin-1-yl) phenyl) azetidine-3-carboxylic acid 2e

Compound 2d (80 mg,0.16 mmol) was dissolved in methanol (15 mL), 3M hydrochloric acid (0.05 mL) was added, the reaction was warmed to 70℃for 2 hours, the reaction solution was concentrated, and dried in vacuo to give the crude title compound 2e (80 mg, 99%) which was used in the next reaction without purification.

MS m/z(ESI):489.1[M+1]。

Fourth step (±) -4- (3- (4- ((4- (3- ((2, 6-dioxopiperidin-3-yl) amino) phenyl) piperazin-1-yl) methyl) piperidin-1-carbonyl) azetidin-1-yl) phenyl) -4, 4-dimethyl-5-oxo-2-thioideneamidazoidin-1-yl) -2- (trifluoromethyl)

Benzonitrile 2

Compound 2e (90 mg,0.18 mmol) and compound 1d (85 mg,0.18 mmol) were dissolved in N, N-dimethylformamide (4 mL), and urea N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) hexafluorophosphate (106 mg,0.28 mmol), N, N-dimethylethylamine (96 mg,0.73 mmol) were added to the solution, and the reaction mixture was purified by high performance liquid chromatography (Waters 2767-SQ detector 2, elution system: 10mM ammonium bicarbonate aqueous solution and acetonitrile, gradient of acetonitrile: 45% -65%, flow rate: 30 mL/min) to give the title compound 2 (racemate, ratio 1:1, 10mg, yield: 6%).

MS m/z(ESI):856.3[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )δ10.76(s,1H),8.38(d,1H),8.28(s,1H),8.07(d,1H)，7.14(d,2H),6.91(t,1H),6.56(d,2H),6.26(s,1H),6.18(d,1H),6.14(d,1H),5.62(d,1H),4.40-4.34(m,1H),4.33-4.27(m,1H),4.15-4.05(m,2H),3.98-3.91(m,2H),3.89-3.83(m,1H),3.66-3.61(m,1H),3.10-2.96(m,5H),2.78-2.68(m,1H),2.65-2.54(m,4H),2.38-2.34(m,1H),2.20-2.14(m,2H),2.12-2.07(m,1H),1.88-1.70(m,5H),1.47(s,6H),1.06-0.93(m,2H)。

Example 3

(±) -4- (3- (4 '- (4- ((4- (3- ((2, 6-dioxopiperidin-3-yl) amino) phenyl) piperazin-1-yl) methyl) piperidine-1-carbonyl) - [1,1' -diphenyl ] -4-yl) -4, 4-dimethyl-5-oxo-2-thioideneamidazolidin-1-yl) -2- (trifluoromethyl) benzonitrile trifluoroacetate 3

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First step

2- ((4-bromophenyl) amino) -2-methylpropanenitrile 3b

4-Bromoaniline 3a (5.0 g,29.06mmol, shanghai Bi-medicine) was dissolved in acetone (50 mL), cooled to 0℃and trimethylcyanogen (5.8 g,58.46 mmol), elemental iodine (100 mg,0.39 mmol) was added dropwise and reacted for 12 hours. The reaction solution was concentrated, ethyl acetate (100 mL) and a saturated sodium thiosulfate solution (30 mL) were added to the concentrated solution, and the organic phase was separated, washed successively with a saturated sodium chloride solution (25 mL. Times.2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove the solvent, and the obtained residue was purified by silica gel column chromatography with eluent system A to give the title compound 3b (6.8 g, yield: 98%).

MS m/z(ESI):239.0[M+1]。

Second step

4- (3- (4-bromophenyl) -5-aminosubunit-4, 4-dimethyl-2-thiourosubunit imidazolidin-1-yl) -2- (trifluoromethyl) benzonitrile 3c

Compound 3b (3 g,12.55 mmol), compound 2c (2.9 g,12.71 mmol) was dissolved in toluene (50 mL), 4-dimethylaminopyridine (2.4 g,19.48 mmol) was added, the reaction was warmed to 100℃for 12 hours, the reaction solution was concentrated, and the resulting residue was purified by silica gel column chromatography using eluent system A to give the title compound 3c (2.1 g, yield: 36%).

MS m/z(ESI):464.9[M-1]。

Third step

4- (3- (4-bromophenyl) -4, 4-dimethyl-5-oxo-2-thioxoyimidazolidin-1-yl) -2- (trifluoromethyl) benzonitrile 3d

Compound 3c (2.1 g,4.49 mmol) was dissolved in methanol (30 mL), 3M hydrochloric acid (4 mL) was added, the reaction was warmed to 70℃for 2 hours, the reaction solution was concentrated, and dried in vacuo to give the title compound 3d (2.1 g, yield: 99%) as a crude product, which was used in the next reaction without purification.

MS m/z(ESI):468.0[M+1]

Fourth step

4'- (3- (4-cyano-3- (trifluoromethyl) phenyl) -5, 5-dimethyl-4-oxo-2-thioxoyiidene imidazolidin-1-yl) - [1,1' -diphenyl ] -4-carboxylic acid 3f

Compound 3d (100 mg,0.21 mmol), 4-carboxyphenylboronic acid pinacol ester 3e (53 mg,0.21mmol, shanghai Bi-A. RTM.) was dissolved in 6mL of a mixed solvent of 1, 4-dioxane and water (V/V=5:1), 1-bis (diphenylphosphine) ferrocene palladium dichloride (16 mg,0.021mmol, shanghai Bi. RTM.), potassium carbonate (59 mg,0.43 mmol), nitrogen was added and the reaction was carried out three times with nitrogen substitution, warmed to 100℃for 16 hours, the reaction solution was filtered with celite, the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title compound 3f (50 mg, yield: 46%).

MS m/z(ESI):508.0[M-1]。

Fifth step (±) -4- (3- (4 '- (4- ((4- (3- ((2, 6-dioxopiperidin-3-yl) amino) phenyl) piperazin-1-yl) methyl) piperidine-1-carbonyl) - [1,1' -diphenyl ] -4-yl) -4, 4-dimethyl-5-oxo-2-thioideneamidazolidin-1-yl) -2- (trifluoromethyl) benzonitrile trifluoroacetate 3

Compound 3f (50 mg,0.098 mmol) and compound 1d (50 mg,0.11 mmol) were dissolved in N, N-dimethylformamide (4 mL), and urea N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) hexafluorophosphate (75 mg,0.20 mmol), N, N-dimethylethylamine (38 mg,0.29 mmol) were added to conduct a reaction for 2 hours, and the reaction solution was purified by high performance liquid chromatography (Waters 2767-SQ detector 2, elution system: 0.1% aqueous trifluoroacetic acid and acetonitrile, gradient of acetonitrile: 40% -60%, flow rate: 30 mL/min) to give the title compound 3 (racemate, ratio: 1,8mg, yield: 9%).

MS m/z(ESI):877.2[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )δ10.80(s,1H),9.17(s,1H),8.41(d,1H),8.32(s,1H),8.11(d,1H)，7.92(d,2H),7.84(d,2H),7.57-7.47(m,4H),6.98(t,2H),6.32(s,1H),6.28-6.17(m,2H),4.36-4.28(m,1H),3.81-3.68(m,2H),3.65-3.54(m,2H),3.23-3.09(m,4H),3.05-2.95(m,2H),2.93-2.86(m,2H),2.76-2.68(m,2H),2.66-2.56(m,3H),2.23-2.04(m,2H),1.94-1.82(m,2H),1.56(s,6H),1.27-1.18(m,2H)。

Example 4

(±) -2-chloro-4- (3- (4' - (4- ((4- (3- ((2, 6-dioxopiperidin-3-yl) amino) phenyl) piperazin-1-yl) methyl) piperidine)

-1-carbonyl) - [1,1' -biphenyl ] -4-yl) -4, 4-dimethyl-5-oxo-2-thioideneamidazolidin-1-yl-benzonitrile 4

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First step

4- (3- (4-bromophenyl) -5-aminosubunit-4, 4-dimethyl-2-thiosubunit imidazolidin-1-yl) -2-chlorobenzonitrile 4a

Compound 1h (1.0 g,5.14 mmol), compound 3b (1.3 g,5.44 mmol) was dissolved in toluene (50 mL), 4-dimethylaminopyridine (942 mg,7.71 mmol) was added, the reaction was warmed to 100℃for 12 hours, the reaction solution was concentrated, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title compound 4a (760 mg, yield: 34%).

MS m/z(ESI):432.9[M+1]。

Second step

4- (3- (4-bromophenyl) -4, 4-dimethyl-5-oxo-2-thioideneamidazolin-1-yl) -2-chlorobenzonitrile 4b

Compound 4a (750 mg,1.73 mmol) was dissolved in methanol (15 mL), 3M diluted hydrochloric acid (2 mL) was added, the reaction was warmed to 70℃for 2 hours, the reaction solution was concentrated, and dried in vacuo to give the title compound 4b (760 mg, yield: 100%) as a crude product, which was used in the next reaction without purification.

MS m/z(ESI):434.0[M+1]。

Third step

4'- (3- (3-chloro-4-cyanophenyl) -5, 5-dimethyl-4-oxo-2-thioxoyiidene imidazolidin-1-yl) - [1,1' -biphenyl ] -4-carboxylic acid methyl ester 4d

Compound 4b (650 mg,1.50 mmol) and (4-methoxycarbonylphenyl) boronic acid 4c (270 mg,1.50mmol, shanghai Bifide) were dissolved in 25mL of a mixed solvent of 1, 4-dioxane and water (V/V=5/1), and 1,1' -bis (diphenylphosphine) ferrocene palladium dichloride (111 mg,0.15 mmol) and cesium carbonate (731 mg,2.24 mmol) were added. The nitrogen is replaced three times, and the temperature is raised to 100 ℃ for reaction for 16 hours. The reaction solution was filtered through celite, and the filtrate was concentrated, and the obtained residue was purified by silica gel column chromatography with eluent system A to give the title compound 4d (490 mg, yield: 67%).

MS m/z(ESI):490.0[M+1]。

Fourth step

4'- (3- (3-chloro-4-cyanophenyl) -5, 5-dimethyl-4-oxo-2-thioxoideneimidazolidin-1-yl) - [1,1' -biphenyl ] -4-carboxylic acid 4e

Compound 4d (490 mg,1.00 mmol) was dissolved in 40mL of a mixed solvent of tetrahydrofuran and water (V/V=1/1), and lithium hydroxide monohydrate (126 mg,3.00 mmol) was added to react for 2 hours. The reaction mixture was adjusted to pH 6-7 by the addition of 1M hydrochloric acid solution, extracted with ethyl acetate (20 mL. Times.3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried in vacuo to give the title compound 4e (450 mg, yield: 95%) as a crude product, which was used in the next reaction without purification.

MS m/z(ESI):476.0[M+1]。

Fifth step (±) -2-chloro-4- (3- (4' - (4- ((4- (3- ((2, 6-dioxopiperidin-3-yl) amino) phenyl) piperazin-1-yl) methyl) piperidine)

Compound 4e (100 mg,0.21 mmol) and compound 1d (89 mg,0.20 mmol) were dissolved in N, N-dimethylformamide (4 mL), and urea N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) hexafluorophosphate (120 mg,0.32 mmol), N, N-diisopropylethylamine (110 mg,0.85 mmol) was added to react for 2 hours. The reaction solution was purified by high performance liquid chromatography (Waters 2767-SQ detector 2, elution system: 10mM ammonium bicarbonate aqueous solution and acetonitrile, gradient of acetonitrile: 40% -70%, flow rate: 30 mL/min) to give the title compound 4 (racemate, ratio 1:1, 26mg, yield: 15%).

MS m/z(ESI):843.7[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )δ10.75(s,1H),8.19(d,1H),8.05(s,1H),7.90(d,2H),7.81(d,2H),7.75(d,1H),7.53-7.46(m,4H),6.90(t,1H),6.25(s,1H),6.18(d,1H),6.13(d,1H),5.61(d,1H),4.53-4.43(m,1H),4.33-4.26(m,1H),3.71-3.57(m,1H),3.09-3.00(m,4H),2.85-2.54(m,5H),2.24-2.18(m,2H),2.12-2.05(m,1H),2.03-1.95(m,1H),1.89-1.79(m,4H),1.74-1.66(m,1H),1.54(s,6H),1.16-1.06(m,3H)。

Example 5

(±) -2-chloro-4- (3- (4 ' - (4- ((4- (3- ((2, 6-dioxopiperidin-3-yl) amino) phenyl) piperazin-1-yl) methyl) piperidine-1-carbonyl) -2' -fluoro- [1,1' -biphenyl ] -4-yl) -4, 4-dimethyl-5-oxo-2-thioideneamidazolidin-1-yl) benzonitrile 5

First step

3-fluoro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzoic acid methyl ester 5b

Methyl 4-bromo-3-fluorobenzoate 5a (5.0 g,21.46mmol, shanghai Bi. Medical) pinacol biborate (6.5 g,25.60 mmol), 1' -bis (diphenylphosphine) ferrocene palladium dichloride (785 mg,1.07 mmol), potassium acetate (6.5 g,66.23 mmol) were weighed into a 250mL single-necked flask, 50mL dimethyl sulfoxide was added, nitrogen was replaced three times, and the temperature was raised to 100℃for 16 hours. After the reaction was cooled to room temperature, water (50 mL) was added, extracted with ethyl acetate (50 ml×3), and the organic phases were combined, washed with water (50 mL), washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title compound 5B (2.8 g, yield: 47%).

¹ H NMR(500MHz,CDCl ₃ )δ7.79-7.59(m,3H),3.91(s,3H),1.24(s,12H)。

Second step

4'- (3- (3-chloro-4-cyanophenyl) -5, 5-dimethyl-4-oxo-2-thioxoyien-1-yl) -2-fluoro- [1,1' -biphenyl ] -4-carboxylic acid methyl ester 5c

Compound 4b (150 mg,0.35 mmol) and compound 5b (108 mg,0.39 mmol) were dissolved in a mixed solvent of 6mL of 1, 4-dioxane and water (V/V=5/1), 1' -bis (diphenylphosphine) ferrocene palladium dichloride (28 mg,0.038 mmol), cesium carbonate (228 mg,0.70 mmol) were added, nitrogen was substituted three times, the reaction was carried out at 110℃for 1 hour with celite, the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title compound 5c (90 mg, yield: 51%).

MS m/z(ESI):508.1[M+1]。

Third step

4'- (3- (3-chloro-4-cyanophenyl) -5, 5-dimethyl-4-oxo-2-thioxoyien-1-yl) -2-fluoro- [1,1' -biphenyl ] -4-carboxylic acid 5d

Compound 5c (90 mg,0.18 mmol) was dissolved in a mixed solvent of 10mL of tetrahydrofuran and water (V/v=1/1), and lithium hydroxide monohydrate (25 mg,0.6 mmol) was added to react for 2 hours. The reaction mixture was adjusted to pH 6-7 by the addition of 1M diluted hydrochloric acid, extracted with ethyl acetate (10 mL. Times.3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried in vacuo to give the title compound 5d (68 mg, yield: 78%) as a crude product, which was used in the next reaction without purification.

MS m/z(ESI):494.6[M+1]。

Fourth step (±) -2-chloro-4- (3- (4 ' - (4- ((4- (3- ((2, 6-dioxopiperidin-3-yl) amino) phenyl) piperazin-1-yl) methyl) piperidine-1-carbonyl) -2' -fluoro- [1,1' -biphenyl ] -4-yl) -4, 4-dimethyl-5-oxo-2-thioideneimidazolidin-1-yl) benzonitrile 5

Compound 5d (80 mg,0.16 mmol) and compound 1d (70 mg,0.15 mmol) were dissolved in N, N-dimethylformamide (4 mL), and urea N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) hexafluorophosphate (93 mg,0.24 mmol), N, N-diisopropylethylamine (85 mg,0.66 mmol) was added to react for 2 hours. The reaction solution was purified by high performance liquid chromatography (Waters 2767-SQ detector 2, elution system: 10mM ammonium bicarbonate aqueous solution and acetonitrile, gradient of acetonitrile: 50% -70%, flow rate: 30 mL/min) to give the title compound 5 (racemate, ratio 1:1, 16mg, yield: 11%).

MS m/z(ESI):861.2[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )δ10.75(s,1H),8.19(d,1H),8.05(s,1H),7.79(d,2H),7.75(d,1H),7.69(t,1H),7.52(d,2H),7.39(d,1H),7.33(d,1H),6.90(t,1H),6.25(s,1H),6.18(d,1H),6.13(d,1H),5.61(d,1H),4.53-4.43(m,1H),4.33-4.26(m,1H),3.67-3.57(m,1H),3.08-3.00(m,4H),2.87-2.69(m,3H),2.64-2.54(m,2H),2.25-2.17(m,2H),2.13-2.05(m,2H),1.91-1.79(m,4H),1.74-1.66(m,1H),1.54(s,6H),1.18-1.08(m,3H)。

Example 6

(±) -2-chloro-4- (3- (4 ' - (4- ((4- (3- ((2, 6-dioxopiperidin-3-yl) amino) phenyl) piperazin-1-yl) methyl) piperidine-1-carbonyl) -3' -fluoro- [1,1' -biphenyl ] -4-yl) -4, 4-dimethyl-5-oxo-2-thioideneamidazolidin-1-yl) benzonitrile 6

First step

4'- (3- (3-chloro-4-cyanophenyl) -5, 5-dimethyl-4-oxo-2-thioxoyiidene imidazolidin-1-yl) -3-fluoro- [1,1' -biphenyl ] -4-carboxylic acid methyl ester 6b

Compound 4b (300 mg,0.69 mmol), (3-fluoro-4- (methoxycarbonyl) phenyl) boronic acid 6a (151 mg,0.76mmol, shanghai Bifide) was dissolved in 18mL of a mixed solvent of 1, 4-dioxane and water (V/V=5/1), 1' -bis (diphenylphosphine) ferrocene palladium dichloride (51 mg,0.069 mmol), cesium carbonate (560 mg,1.73 mmol) was added, nitrogen was replaced three times, and the temperature was raised to 100℃for reaction for 5 hours. The reaction solution was filtered through celite, and the filtrate was concentrated, and the obtained residue was purified by silica gel column chromatography with eluent system A to give the title compound 6b (210 mg, yield: 60%).

MS m/z(ESI):508.1[M+1]。

Second step

4'- (3- (3-chloro-4-cyanophenyl) -5, 5-dimethyl-4-oxo-2-thioxoyiidene imidazolidin-1-yl) -3-fluoro- [1,1' -biphenyl ] -4-carboxylic acid 6c

Compound 6b (50 mg,0.098 mmol) was dissolved in a mixed solvent of 6mL of tetrahydrofuran and water (V/v=1/1), and lithium hydroxide monohydrate (13 mg,0.31 mmol) was added to react for 2 hours. The reaction mixture was adjusted to pH 6-7 by the addition of 1M hydrochloric acid solution, extracted with ethyl acetate (10 mL. Times.3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried in vacuo to give the title compound 6c (50 mg, yield: 100%) as a crude product, which was used in the next reaction without purification.

MS m/z(ESI):494.1[M+1]。

Third step (±) -2-chloro-4- (3- (4 ' - (4- ((4- (3- ((2, 6-dioxopiperidin-3-yl) amino) phenyl) piperazin-1-yl) methyl) piperidine-1-carbonyl) -3' -fluoro- [1,1' -biphenyl ] -4-yl) -4, 4-dimethyl-5-oxo-2-thioideneimidazolidin-1-yl) benzonitrile 6

Compound 6c (50 mg,0.10 mmol) and compound 1d (45 mg,0.10 mmol) were dissolved in N, N-dimethylformamide (4 mL), and urea N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) hexafluorophosphate (93 mg,0.24 mmol), N, N-diisopropylethylamine (66 mg,0.51 mmol) was added to react for 2 hours. The reaction solution was purified by high performance liquid chromatography (Waters 2767-SQ detector 2, elution system: 10mM ammonium bicarbonate aqueous solution and acetonitrile, gradient of acetonitrile: 40% -70%, flow rate: 30 mL/min) to give the title compound 6 (racemate, ratio 1:1, 20mg, yield: 23%).

MS m/z(ESI):861.2[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )δ10.75(s,1H),8.20(d,1H),8.05(d,1H),7.94(d,2H),7.74(t,2H),7.68(d,1H),7.55-7.45(m,3H),6.90(t,1H),6.25(s,1H),6.18(d,1H),6.13(d,1H),5.61(d,1H),4.55-4.49(m,1H),4.33-4.27(m,1H),3.50-3.24(m,2H),3.12-3.02(m,4H),2.83(t,2H),2.78-2.69(m,2H),2.65-2.58(m,2H),2.23-2.16(m,2H),2.12-2.06(m 1H),1.89-1.80(m,3H),1.74-1.68(m,1H),1.54(s,6H),1.13-1.01(m,3H)。

Example 7 (. + -.) -2-chloro-4- (3- (4 '- (4- ((4- (3- ((2, 6-dioxopiperidin-3-yl) amino) phenyl) piperazin-1-yl) methyl) piperidine-1-carbonyl) -3-fluoro- [1,1' -biphenyl ] -4-yl) -4, 4-dimethyl-5-oxo-2-thioideneamidazolin-1-yl) benzonitrile 7

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First step

2- ((4-bromo-2-fluorophenyl) amino) -2-methylpropanenitrile 7b

4-bromo-2-fluoroaniline 7a (5.0 g,26.31mmol, shanghai Bizhi) was dissolved in acetone (50 mL), cooled to 0℃and trimethylcyanogen (5.2 g,52.72 mmol), elemental iodine (91 mg,0.36 mmol) was added dropwise and reacted for 12 hours. The reaction solution was concentrated, ethyl acetate (100 mL) and a saturated sodium thiosulfate solution (30 mL) were added to the concentrated solution, and an organic phase was separated, washed with a saturated sodium chloride solution (25 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system A to give the title compound 7b (3.0 g, yield: 44%).

Second step

4- (3- (4-bromo-2-fluorophenyl) -5-aminosubunit-4, 4-dimethyl-2-thiosubunit imidazolidin-1-yl) -2-chlorobenzonitrile 7c

Compound 7b (1 g,5.14 mmol) and compound 1h (1.3 g,5.14 mmol) were dissolved in toluene (100 mL), 4-dimethylaminopyridine (314 mg,2.57 mmol) was added, the reaction was warmed to 100℃for 5 hours, the reaction solution was concentrated, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title compound 7c (100 mg, yield: 4%).

MS m/z(ESI):451.0[M+1]。

Third step

4' - (3- (3-chloro-4-cyanophenyl) -4-aminosubunit-5, 5-dimethyl-2-thiourosubunit imidazolidin-1-yl) -3' -fluoro- [1,1' -biphenyl ] -4-carboxylic acid methyl ester 7d

Compound 7c (100 mg,0.22 mmol) and compound 4c (44 mg,0.24 mmol) were dissolved in 3mL of a mixed solvent of 1, 4-dioxane and water (V/V=5/1), and 1,1' -bis (diphenylphosphine) ferrocene palladium dichloride (16 mg,0.02 mmol), cesium carbonate (146 mg,0.44 mmol), nitrogen gas was added to the mixture to react three times, and the temperature was raised to 100℃for 5 hours. The reaction solution was filtered through celite, and the filtrate was concentrated, and the obtained residue was purified by silica gel column chromatography with eluent system A to give the title compound 7d (50 mg, yield: 45%).

MS m/z(ESI):507.2[M+1]。

Fourth step

4' - (3- (3-chloro-4-cyanophenyl) -5, 5-dimethyl-4-oxo-2-thioxoyiidene imidazolidin-1-yl) -3' -fluoro- [1,1' -biphenyl ] -4-carboxylic acid methyl ester 7e

Compound 7d (50 mg,0.1 mmol) was dissolved in methanol (5 mL), 3M hydrochloric acid (0.2 mL) was added, and the temperature was raised to 70℃for 2 hours. The reaction solution was concentrated and dried in vacuo to give the title compound 7e (50 mg, yield: 99%) as a crude product, which was used in the next reaction without purification.

MS m/z(ESI):508.1[M+1]

Fifth step

4' - (3- (3-chloro-4-cyanophenyl) -5, 5-dimethyl-4-oxo-2-thioxoyiidene imidazolidin-1-yl) -3' -fluoro- [1,1' -biphenyl ] -4-carboxylic acid 7f

Compound 7e (50 mg,0.1 mmol) was dissolved in a mixed solvent of 6mL of tetrahydrofuran and water (V/v=1/1), and lithium hydroxide monohydrate (42 mg,1.0 mmol) was added to react for 2 hours. The pH of the reaction solution was adjusted to between 6 and 7 by adding 1M hydrochloric acid solution, extraction was performed with ethyl acetate (5 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and dried in vacuo to give the title compound 7f (47 mg, yield: 97%) as a crude product, which was used in the next reaction without purification.

MS m/z(ESI):494.2[M+1]

Sixth step (±) -2-chloro-4- (3- (4 '- (4- ((4- (3- ((2, 6-dioxopiperidin-3-yl) amino) phenyl) piperazin-1-yl) methyl) piperidine-1-carbonyl) -3-fluoro- [1,1' -biphenyl ] -4-yl) -4, 4-dimethyl-5-oxo-2-thioideneimidazolidin-1-yl) benzonitrile 7

Compound 7f (47 mg,0.095 mmol), compound 1d (41 mg,0.089 mmol) was dissolved in N, N-dimethylformamide (3 mL), and urea N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) hexafluorophosphate (55 mg,0.14 mmol), N, N-dimethylethylamine (62 mg,0.48 mmol) was added to react for 2 hours. The reaction solution was purified by high performance liquid chromatography (Waters 2767-SQ detector 2, elution system: 10mM ammonium bicarbonate aqueous solution and acetonitrile, gradient of acetonitrile: 40% -60%, flow rate: 30 mL/min) to give the title compound 7 (racemate, ratio 1:1, 11mg, yield: 13%).

MS m/z(ESI):861.2[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )δ10.75(s,1H),8.20(d,1H),8.08(s,1H),7.89-7.83(m,3H)，7.77(t,2H),7.57(t,1H),7.50(d,2H),6.90(t,1H),6.25(s,1H),6.18(d,1H),6.13(d,1H),5.61(d,1H),4.54-4.43(m,1H),4.33-4.27(m,1H),3.68-3.56(m,1H),3.13-2.99(m,4H),2.85-2.69(m,3H),2.65-2.54(m,2H),2.26-2.17(m,2H),2.15-1.95(m,3H),1.91-1.77(m,4H),1.61(s,3H),1.49(s,3H),1.17-1.06(m,3H)。

Example 8

(±) -2-chloro-4- (3- (4 '- (4- ((4- (3- ((2, 6-dioxopiperidin-3-yl) amino) phenyl) piperazin-1-yl) methyl) piperidine-1-carbonyl) -2-fluoro- [1,1' -biphenyl ] -4-yl) -4, 4-dimethyl-5-oxo-2-thioideneamidazolidin-1-yl) benzonitrile 8

First step

2- ((4-bromo-3-fluorophenyl) amino) -2-methylpropanenitrile 8b

4-bromo-3-fluoroaniline 8a (5.0 g,26.31mmol, shanghai Bizhi) was dissolved in acetone (50 mL), cooled to 0℃and trimethylcyanogen (5.2 g,52.72 mmol), elemental iodine (91 mg,0.36 mmol) was added dropwise and reacted for 12 hours. The reaction solution was concentrated, ethyl acetate (100 mL) and a saturated sodium thiosulfate solution (30 mL) were added to the concentrated solution, and the organic phase was separated, washed with a saturated sodium chloride solution (25 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system A to give the title compound 8b (3.1 g, yield: 46%).

Second step

4- (3- (4-bromo-3-fluorophenyl) -5-aminosubunit-4, 4-dimethyl-2-thiosubunit imidazolidin-1-yl) -2-chlorobenzonitrile

8c

Compound 8b (1.0 g,5.14 mmol), compound 1h (1.3 g,5.14 mmol) was dissolved in toluene (100 mL), 4-dimethylaminopyridine (314 mg,2.57 mmol) was added, the reaction was warmed to 100℃for 5 hours, the reaction solution was concentrated, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title compound 8c (500 mg, yield: 22%).

MS m/z(ESI):451.0[M+1]。

Third step

4' - (3- (3-chloro-4-cyanophenyl) -4-aminosubunit-5, 5-dimethyl-2-thiourosubunit imidazolidin-1-yl) -2' -fluoro- [1,1' -biphenyl ] -4-carboxylic acid methyl ester 8d

Compound 8c (50 mg,0.11 mmol), compound 4c (22 mg,0.12 mmol) was dissolved in 3mL of a mixed solvent of 1, 4-dioxane and water (V/V=5/1), 1' -bis (diphenylphosphine) ferrocene palladium dichloride (9 mg,0.01 mmol), cesium carbonate (73 mg,0.22 mmol) were added, nitrogen was replaced three times, the reaction was warmed to 100℃for 5 hours, the reaction solution was filtered with celite, and the filtrate was concentrated, and the obtained residue was purified by silica gel column chromatography with eluent system A to give the title compound 8d (46 mg, yield: 82%).

MS m/z(ESI):507.2[M+1]。

Fourth step

4' - (3- (3-chloro-4-cyanophenyl) -5, 5-dimethyl-4-oxo-2-thioxoyiidene imidazolidin-1-yl) -2' -fluoro- [1,1' -biphenyl ] -4-carboxylic acid methyl ester 8e

Compound 8d (46 mg,0.09 mmol) was dissolved in methanol (3 mL), 3M hydrochloric acid (0.2 mL) was added, the reaction was warmed to 70℃for 2 hours, the reaction solution was concentrated, and dried in vacuo to give the title compound 8e (46 mg, yield: 99%) as a crude product, which was used in the next reaction without purification.

MS m/z(ESI):508.1[M+1]

Fifth step

4' - (3- (3-chloro-4-cyanophenyl) -5, 5-dimethyl-4-oxo-2-thioxoyiidene imidazolidin-1-yl) -2' -fluoro- [1,1' -biphenyl ] -4-carboxylic acid 8f

Compound 8e (50 mg,0.09 mmol) was dissolved in a mixed solvent of 6mL of tetrahydrofuran and water (V/v=1/1), and lithium hydroxide monohydrate (20 mg,0.48 mmol) was added to react for 2 hours. The pH of the reaction solution was adjusted to between 6 and 7 by adding 1M hydrochloric acid solution, extraction was performed with ethyl acetate (5 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and dried in vacuo to give the title compound 8f (43 mg, yield: 96%) as a crude product, which was used in the next reaction without purification.

MS m/z(ESI):494.2[M+1]

Sixth step (±) -2-chloro-4- (3- (4 '- (4- ((4- (3- ((2, 6-dioxopiperidin-3-yl) amino) phenyl) piperazin-1-yl) methyl) piperidine-1-carbonyl) -2-fluoro- [1,1' -biphenyl ] -4-yl) -4, 4-dimethyl-5-oxo-2-thioideneimidazolidin-1-yl) benzonitrile 8

Compound 8f (43 mg,0.087 mmol) and compound 1d (37 mg,0.081 mmol) were dissolved in N, N-dimethylformamide (3 mL), and urea N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) hexafluorophosphate (50 mg,0.13 mmol), N, N-dimethylethylamine (57 mg,0.44 mmol) was added and reacted for 2 hours. The reaction solution was purified by high performance liquid chromatography (Waters 2767-SQ detector 2, elution system: 10mM ammonium bicarbonate aqueous solution and acetonitrile, gradient of acetonitrile: 45% -65%, flow rate: 30 mL/min) to give the title compound 8 (racemate, ratio 1:1, 10mg, yield: 13%).

MS m/z(ESI):861.2[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )δ10.76(s,1H),8.20(d,1H),8.04(s,1H),7.79(t,1H),7.74(d,1H),7.70(d,2H),7.52(d,2H),7.48(d,1H),7.37(d,1H),6.90(t,1H),6.25(s,1H),6.18(d,1H),6.13(d,1H),5.62(d,1H),4.54-4.43(m,1H),4.34-4.26(m,1H),3.76-3.54(m,1H),3.15-2.97(m,4H),2.84-2.69(m,3H),2.66-2.54(m,2H),2.24-2.18(m,2H),2.12-2.06(m,1H),2.03-1.95(m,2H),1.92-1.68(m,4H),1.56(s,6H),1.17-1.06(m,3H)。

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, degradation Activity of compounds of the present disclosure on androgen receptor in LNCaP cells assay

The in vitro cell assays described below can determine the degradation activity of test compounds on androgen receptor (Androgen receptor, AR) in human prostate cancer cell lines, which activity can be used as DCs ₅₀ Values are expressed. On the first day of the experiment, LNCaP cells (ATCC, CRL-1740) were seeded in 96-well plates at 20000 cells/well with 200. Mu.L of cell suspension per well using phenol red free RPMI 1640 medium (Gibco, 11835-030) containing 5% activated charcoal treated fetal bovine serum (S-FBS-AU-045, shanghai Bosch Biotech Co., ltd.) at 37℃with 5% CO ₂ The cell culture was incubated in an incubator for three days. On the fourth day, 22. Mu.L of a test compound diluted in a gradient with a plating medium containing 1nM R1881 (Alatine, M305037) was added to each well, the final concentration of R1881 was 0.1nM, the final concentration of the compound was 7 concentration points at 6-fold gradient dilution starting from 2.5. Mu.M, a blank cell well containing 0.5% DMSO was set, and the well plate was placed at 37℃with 5% CO ₂ Is cultured for 24 hours. On the fifth day, 96-well cell culture plates were removed, cell culture supernatants in well plates were removed by pipetting and washing the cells once with 300. Mu.L of ice PBS, then 50. Mu.L of ddH was added ₂ O-diluted 1 Xlysate (Cell Signaling Technology, # 9803S) containing 1mM PMSF was shaken for 1 minute with a micro-oscillator, and then the cell plates were put on ice for 15 to 20 minutes, and after being blown and mixed with a row gun, centrifuged at 4000rpm at 4℃for 10 minutes. Protein levels of AR were detected using the AR ELISA kit (Cell Signaling Technology, # 12850) according to the instructions. 96 mu L of sample diluent and 4 mu L of sample lysate or blank lysate are added into a 96-well ELISA plate, the plates are sealed and mixed by shaking, and then the plates are placed in a 37 ℃ incubator for 2 hours. The wells were discarded, and after five washes of 300. Mu.L of wash solution were added to each well, 100. Mu.L of detection antibody working solution was added, the plates were sealed and incubated in a 37℃incubator for 1 hour. The wells were discarded, and after five washes of 300. Mu.L of wash solution were added to each well, 100. Mu.L of enzyme conjugate working solution was added, and the wells were sealed and incubated in a 37℃incubator for 30 minutes. Removing liquid in the wells, adding 300 μl of washing solution into each well, washing the plate five times, adding 100 μl of color development solution, sealing, and placingIncubate for 5 min at normal temperature in the dark, add 100. Mu.L stop solution per well. Immediately after mixing, the mixture was placed in an microplate reader (BMG Labtech, PHERAstar FS) to read OD450 and OD540 values. The absorbance value of OD450 in all wells was subtracted from the absorbance value of OD540 in the corresponding well to give a corrected absorbance value of OD450 (OD 450-correction). The degradation rate of each concentration of the compound was calculated by the following formula, wherein the maximum value (Max) is the maximum degradation rate of the compound to degrade AR. Curve fitting was performed using GraphPad Prism based on the logarithmic concentration of the compound and degradation efficiency and DC was calculated ₅₀ Values.

Degradation rate (%) = (OD 450-correction) _{Blank control} -OD450-correction _{Compounds of formula (I)} )/(OD450-correction _{Blank control} -OD450-correction _{Lysate control} )×100％

The biological activity of the compounds of the present disclosure was obtained from the above analysis, calculated DC ₅₀ And Max values are as follows:

TABLE 1 degradation Activity of the compounds of the present disclosure on androgen receptors in LNCaP cells

Examples numbering	LNCaP DC ₅₀ (nM)	Max(％)
			1	12.9	91
2	20.0	91
			3	10.1	94
4	5.3	95
			5	7.5	97
6	8.4	96
			7	6.8	98
8	6.1	97

Conclusion: the compounds of the present disclosure have significant degradative activity on the androgen receptor in LNCaP cells.

Test example 2 proliferation inhibition assay of LNCaP by the compounds of the present disclosure

The proliferation inhibitory activity of the test compounds on human prostate cancer cell lines can be determined by the in vitro cell assay described below, and the activity can be determined using IC ₅₀ Values are expressed. On the first day of the experiment, LNCaP cells (ATCC, CRL-1740) were seeded in 96-well plates at a density of 7500 cells/well with 200. Mu.L of cell suspension per well using phenol red free RPMI 1640 medium (Gibco, 11835-030) containing 5% activated charcoal treated fetal bovine serum (S-FBS-AU-045, shanghai Bosch Biotech Co., ltd.) at 37℃with 5% CO ₂ The cell culture was incubated in an incubator for three days. On day four, 22. Mu.L of gradient dilution with 1nM R1881 (Allatin, M305037) in plating medium was added to each wellThe final concentration of released test compound, R1881, was 0.1nM, the final concentration of the compound was 9 concentration points from 10. Mu.M on a 4-fold gradient dilution, a blank control cell well containing 0.5% DMSO and a cell-free vehicle control well were set, the well plate was placed at 37℃and 5% CO ₂ Is cultured in a cell culture incubator for six days. On the tenth day, 96-well cell culture plates were removed, 110. Mu.L of cell culture supernatant was aspirated from each well, discarded, and 50. Mu.L was then addedLuminescent Cell Viability Assay (Promega, G7573), after 10 minutes at room temperature, the luminescence signal value (RLU) was read using a multifunctional microplate reader (PerkinElmer, VICTOR 3). The inhibition ratio of each concentration of the compound was calculated by the following formula, wherein the maximum value (Max) is the maximum inhibition ratio of the compound to inhibit proliferation. Curve fitting was performed using GraphPad Prism based on log concentration of compound and inhibition rate and IC was calculated ₅₀ Values.

Inhibition (%) = (RLU) _{Blank control} -RLU _{Compounds of formula (I)} )/(RLU _{Blank control} -RLU _{Vehicle control} )×100％

The biological activity of the compound of the present disclosure is obtained by the above analysis, and the calculated IC ₅₀ The values are given in table 2 below.

TABLE 2 proliferation inhibitory Activity of the compounds of the present disclosure on LNCaP cells

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Conclusion: the compounds of the present disclosure have good proliferation inhibitory activity on LNCaP cells.

Test example 3 in vivo pharmacokinetic evaluation in mice

TPGS: d-alpha-vitamin E polyethylene glycol succinate

HPMC: hydroxypropyl methylcellulose

PEG400: polyethylene glycol 400

Comparative example 1 (see patent WO2020132014A1, synthesis of compound 10) has the following structure:

1. Summary

The drug concentration in plasma was determined at various times following the administration of the compounds of the present disclosure using LC/MS method in mice as test animals. Pharmacokinetic behavior of the compounds of the present disclosure in mice was studied and their pharmacokinetic profile was assessed.

2. Test protocol

2.1 test drug

The compound of example 4;

comparative example 1.

2.2 test animals

SCID-Beige mice, 18 males, were equally divided into 2 groups, supplied by Venlhua laboratory animal Co. Gastric administration was performed after overnight fast.

2.3 pharmaceutical formulation

A certain amount of the compound to be tested is weighed, and 20% PEG400+75% (10% TPGS) +5% (1% HPMC K100 LV) is added to prepare a solution of 0.5 mg/mL.

2.4 administration of drugs

The administration dosage is 10.0mg/kg, and the administration volume is 20mL/kg.

3. Operation of

Blood was collected for 0.1mL at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, 24.0 hours before and after administration, and the blood was placed in EDTA-K2 anticoagulant tubes and centrifuged at 10000rpm for 1 minute (4 ℃) to separate plasma within 1 hour, and stored at-20 ℃. The blood collection to centrifugation process was operated under ice bath conditions.

Determination of the content of test compounds in the plasma of mice following administration of different concentrations of drug: plasma samples were taken at each time after dosing at 20. Mu.L, 200. Mu.L acetonitrile (compound 4 containing internal standard verapamil 100ng/mL; comparative example 1 containing internal standard camptothecin 100 ng/mL) was added to precipitate the protein, vortexed for 5min, and centrifuged at 4000rmp for 10 min, and the supernatant (compound 4 loading volume 4. Mu.L; comparative example 1 loading volume 1. Mu.L) was taken for LC/MS/MS analysis (compound 4 was analyzed with an AB SCIEX4000 triple quadrupole tandem mass spectrometer) and comparative example 1 was analyzed with a Waters Xevo TQ-XS triple quadrupole tandem mass spectrometer).

4. Pharmacokinetic parameter results

TABLE 3 pharmacokinetic parameters of the compounds of the present disclosure in mice

Conclusion: compared with comparative example 1, the public compound has higher exposure in mice, better drug-substituted absorption activity and obvious pharmacokinetic advantage.

Claims

1. A compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof,

wherein:

ring a is selected from aryl, heteroaryl, cycloalkyl and heterocyclyl;

each R is ⁶ Each R is ⁷ Identical OR different and are each independently selected from oxo, halogen, alkyl, alkenyl, alkynyl, cyano, nitro, -OR ¹¹ 、-(CH ₂ ) _u NR ¹² R ¹³ 、-C(O)R ¹¹ 、-C(O)OR ¹¹ 、-C(O)NR ¹² R ¹³ 、-S(O) _s R ¹¹ 、-S(O) _s NR ¹² R ¹³ Cycloalkyl, heterocyclyl, aryl and heteroaryl, each of which is independently optionally substituted with one or more members selected from oxo, halo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, haloalkoxy, hydroxy, cyano, nitro, amino, cycloalkyl and heterocyclylSubstituted by substituents;

when ring B is a bond, (R) ⁷ ) _q Absence of;

x is N or CR ^A ；

Z ¹ and Z ² Identical or different and are each independently N or CR ^Z ；

J ² is cycloalkyl or heterocyclyl, each of which is independently optionally substituted with a member selected from oxo, halogen, alkyl, alkoxy, haloalkyl, hydroxyalkyl, haloalkoxy, cyanoNitro, hydroxy and- (CH) ₂ ) _v1 NR ^a R ^b Is substituted by one or more substituents;

J ³ Selected from bonds, -O-, -S-, -NR ^8b -、-C(O)-、-S(O) ₂ -、-(CR ^9b R ^10b ) _m2 -, alkenyl, alkynyl, cycloalkyl and heterocyclyl, each of said cycloalkyl and heterocyclyl being independently optionally substituted with a member selected from oxo, halo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, haloalkoxy, cyano, nitro, hydroxy and- (CH) ₂ ) _v2 NR ^c R ^d Is substituted by one or more substituents;

R ¹¹ and are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, and heterocyclyl, each independently optionally substituted with one or more substituents selected from oxo, halogen, alkyl, alkoxy, haloalkyl, hydroxyalkyl, halo Substituted with one or more substituents selected from the group consisting of alkoxy, hydroxy, cyano, nitro, amino, cycloalkyl and heterocyclyl;

R ¹² and R is ¹³ And are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, and heterocyclyl, each independently optionally substituted with one or more substituents selected from oxo, halogen, alkyl, alkoxy, haloalkyl, hydroxyalkyl, haloalkoxy, hydroxy, cyano, nitro, amino, cycloalkyl, and heterocyclyl;

s is 0, 1 or 2;

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

p and q are each independently 0, 1, 2, 3 or 4;

m1, m2 and m3 are each independently 1, 2 or 3;

u, v1, v2, v3 and x are each independently 0, 1, 2, 3 or 4.

2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein L is-J ¹ -J ² -J ³ -J ⁴ -; wherein J ¹ Is connected with ring B, J ⁴ And Z is ² Are connected; j (J) ¹ Selected from the group consisting of-C (O) -, -O-; -S-and NH; j (J) ² Is a 3 to 12 membered cycloalkyl or a 3 to 12 membered heterocyclyl, each of said 3 to 12 membered cycloalkyl and 3 to 12 membered heterocyclyl being independently optionally substituted with a member selected from oxo, halogen, C _1-6 Alkyl, C _1-6 Alkoxy and C _1-6 One or more substituents in the haloalkyl group; j (J) ³ Is a bond or- (CH) ₂ ) _m2 -, m2 is 1, 2 or 3; j (J) ⁴ Is a bond or a 3 to 12 membered heterocyclic group.

3. 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 (II):

wherein:

t is 0, 1, 2 or 3;

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

Ring a, ring B, J ⁴ 、Z ¹ 、Z ² 、X、R ^A1 、R ^A2 、R ¹ To R ⁷ 、R ^a 、R ^b V1, p, q and n are as defined in claim 1.

4. A compound of the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R ¹ Selected from halogen, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy and cyano; and/or R ^A1 And R is ^A2 Each independently is a hydrogen atom; preferably, R ¹ Is halogen or C _1-6 A haloalkyl group; and/or R ^A1 And R is ^A2 Is a hydrogen atom.

5. A compound of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein X is N or CH; preferably, X is CH.

6. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein R ² And R is ³ Identical or different and are each independently C _1-6 An alkyl group; or R is ² And R is ³ Together with the attached carbon atoms, form a 3 to 8 membered cycloalkyl or 3 to 8 membered heterocyclyl; preferably, R ² And R is ³ Identical or different and are each independently C _1-6 An alkyl group.

7. A compound of general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein each R ⁴ Identical or different and are each independently selected from halogen, C _1-6 Alkyl, C _1-6 Haloalkyl and cyano.

8. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R ⁵ Is a hydrogen atom.

9. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein each R ⁶ Identical or different and are each independently selected from halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; preferably, R ⁶ Is halogen.

10. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein each R ⁷ Identical or different and are each independently selected from halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; preferably, R ⁷ Is halogen.

11. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein Z ¹ And Z ² Identical toOr different and each is independently N or CH; preferably Z ¹ And Z ² Are all N.

12. A compound of general formula (I) according to any one of claims 1 to 11, 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 or naphthyl.

13. A compound of general formula (I) according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein ring B is selected from a bond, a 6 to 10 membered aryl group and a 3 to 8 membered heterocyclyl group; preferably, ring B is selected from the group consisting of bond, phenyl and azetidinyl.

14. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein J ⁴ Is a key.

15. A compound of formula (I) according to any one of claims 3 to 14, or a pharmaceutically acceptable salt thereof, wherein t is 0.

16. 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:

17. a compound represented by the general formula (IIA) or a salt thereof:

wherein:

ring a, ring B, X, R ^A1 、R ^A2 、R ¹ 、R ² 、R ³ 、R ⁶ 、R ⁷ P and q are as defined in claim 3; provided that, when ring B is a bond,is not selected from-> The bond is attached to ring B.

18. A compound represented by the general formula (IIB):

wherein:

J ⁴ is a bond;

r is 1;

ring C, Z ¹ 、Z ² 、R ⁴ 、R ⁵ 、R ¹⁴ N and t are as defined in claim 3.

19. A compound selected from the following compounds:

20. a process for preparing a compound of formula (II) or a pharmaceutically acceptable salt thereof according to claim 3, which comprises:

wherein:

ring a, ring B, ring C, J ⁴ 、Z ¹ 、Z ² 、X、R ^A1 、R ^A2 、R ¹ To R ⁷ 、R ¹⁴ P, q, r, t and n are as defined in claim 3.

21. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

22. Use of a compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 21, in the manufacture of a medicament for modulating ubiquitination and degradation of Androgen Receptor (AR) proteins.

23. Use of a compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 21, in the manufacture of a medicament for the treatment and/or prophylaxis of a disease or condition mediated or dependent by an androgen receptor; wherein the androgen receptor mediated or dependent disease or condition is preferably selected from the group consisting of a tumor, male sexual dysfunction and kennedy's disease.

24. The use according to claim 23, wherein the androgen receptor mediated or dependent disease or condition is selected from prostate cancer, prostatic hyperplasia, hirsutism, alopecia, anorexia nervosa, breast cancer, acne, male sexual dysfunction, kennedy's disease and aids, preferably prostate cancer, more preferably hormone sensitive prostate cancer or hormone refractory prostate cancer.