CN114163444A

CN114163444A - Chimeric compound for targeted degradation of androgen receptor protein, preparation method thereof and application thereof in medicine

Info

Publication number: CN114163444A
Application number: CN202111059712.7A
Authority: CN
Inventors: 杨方龙; 郁楠; 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: 2020-09-11
Filing date: 2021-09-10
Publication date: 2022-03-11
Anticipated expiration: 2041-09-10
Also published as: CN114163444B

Abstract

The disclosure relates to a chimeric compound for targeted degradation of androgen receptor protein, a preparation method thereof and application thereof in medicine. Specifically, the disclosure relates to an AR protein targeted degradation chimera (PROTAC) compound containing a fused heterocyclic cereblon (cereblon) E3 ubiquitin ligase ligand shown in a general formula (IM), a preparation method thereof and application thereof in medicine.

Description

Chimeric compound for targeted degradation of androgen receptor protein, preparation method thereof and application thereof in medicine

Technical Field

The disclosure belongs to the field of medicine, and relates to a novel chimera (PROTAC) compound for targeted degradation of Androgen Receptor (AR) protein, a preparation method thereof, and an application thereof in medicine. Specifically, the disclosure relates to an AR protein targeted degradation chimera (PROTAC) compound containing a fused heterocyclic cereblon (cereblon) E3 ubiquitin ligase ligand shown in a general formula (IM), a preparation method thereof and application thereof in medicine. The use of the present disclosure in medicine demonstrates (but is not limited to) its use as an androgen receptor degrading agent in the treatment 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 protein contains two different ligands, one is ubiquitin ligase E3 ligand, the other is target protein binding ligand, and the two ligands are connected by a connecting unit. PROTAC forms a ternary complex of target protein-PROTAC-E3 by bringing the target protein and intracellular ubiquitin ligase E3 closer, then the E3 ubiquitin ligase labels ubiquitinated protein tags to the target protein, and then initiates a strong ubiquitination-protease system in cells to specifically degrade the target protein, 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 protein of interest for a long time and with high strength, and the target protein degradation process is similar to a catalytic reaction and can be combined and degraded circularly. Thereby reducing the systemic exposure of the medicine and reducing the occurrence of toxic and side effects. 2. The target protein is degraded and needs to be synthesized again to restore the function, so that the degraded 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. ProTACs also have therapeutic potential for targets that are currently considered to be non-druggable, such as transcription factors, scaffold proteins, and regulatory proteins.

The discovery process for the CRBN-type E3 ligase ligand is relevant to the study of the mechanism of action of thalidomide. In 2010, scientists discovered cerebellin (cereblon) to be a binding protein for thalidomide during studies on thalidomide toxicity (Science 2010,327,1345). Cereblon is part of the E3 ubiquitin ligase protein complex, which selects for ubiquitinated proteins as substrate receptors. This study suggests that thalidomide-cerebellin binding in vivo may be responsible for thalidomide teratogenicity. Subsequent researches find that the compound and related structures can be used as an anti-inflammatory agent, an anti-angiogenesis agent and an anti-cancer agent, the safety of lenalidomide and pomalidomide obtained by further modifying the structure of the thalidomide is greatly improved, the teratogenesis is obviously reduced, and the lenalidomide is approved by FDA to be on the market in 2006. Two pioneering papers published in Science 2014 that show that lenalidomide acts by degrading two specific B-cell transcription factors, ikros family zinc finger structure proteins 1 and 3(IKZF1 and IKZF3), further revealed that thalidomide structure may further act in degrading target proteins by binding to E3 ubiquitin ligase protein complex of cerebellin (Science,2014,343,301; Science,2014,343,305).

The Androgen Receptor (AR) is a ligand-dependent trans-transcriptional regulator protein that is a member of the nuclear Receptor superfamily and is found primarily in the nucleus. AR not bound to the ligand binds to Heat Shock Protein (HSP); after the binding of AR to the ligand, a conformational change occurs, which dissociates from HSP and increases the affinity for DNA (activation of AR). Activated AR binds in dimeric form to a specific DNA sequence in the nucleus, the Androgen Response Element (ARE), and interacts with other transcription factors to regulate 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 progression of prostate cancer, benign prostatic hyperplasia, Kennedy's Disease, male infertility, androgen insensitivity, and breast cancer in men.

Prostate cancer is one of the most common malignancies. According to statistics, nearly 130 million new cases and 35.9 million death cases exist in 2018 all over the world, account for 13.5 percent of the incidence rate of male malignant tumors, and are high in the second place; accounts for 6.7 percent of the mortality rate of male malignant tumors, and is higher than the fifth position. Several AR antagonists have been approved for marketing, successful application to castration-resistant prostate cancer therapy, and have become the primary treatment for prostate cancer. However, most patients develop drug resistance after 0.5-2 years of treatment, which leads to the progress of the disease. In some drug resistant patients, the growth of cancer cells is still dependent on the AR signaling pathway.

There is a need to develop more effective prostate cancer treatments. Unlike AR antagonists, PROTAC degrades AR, inhibits AR signaling pathways more effectively, and is likely to be a potential treatment for prostate cancer. Patent applications for the targeted degradation of procac compounds by AR proteins have been disclosed including WO2015160845a2, WO2016197032a1, US2015291562a1, WO2018071606a1, WO2019023553a1, WO2016118666a1 and WO2018144649a 1.

Disclosure of Invention

The object of the present disclosure is to provide a compound having the CLM-L-PTM structure, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: CLM is cereblon (cereblon) E3 ubiquitin ligase protein binding ligand compound fragment represented by general formula (IM);

ring a is aryl or heteroaryl;

G¹and G²Identical or different, each independently CH₂Or C (═ O), and G¹And G²At least one of which is C (═ O);

z is selected from NR^aAn O atom and an S atom;

R¹the same or different, and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, cyano, amino, carboxyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R^aselected from the group consisting of hydrogen atoms, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups;

l is a connecting unit for connecting the CLM and the PTM;

PTM is androgen receptor antagonist fragment selected from general formula (IN-1), general formula (IN-2) and general formula (IN-3);

Y¹、Y²、Y³and Y⁴Are the same or different and are each independently a C atom or a N atom;

R²the same or different, and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, cyano, amino, carboxyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R³the same or different, and each is independently selected from the group consisting of hydrogen atoms, halogens, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, carboxyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups, wherein the alkyl groups, alkoxy groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl groups, alkoxy groups, haloalkyl groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups;

n is 0, 1 or 2;

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

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

q is 0, 1,2,3,4 or 5.

In some embodiments of the present disclosure, there is provided a compound having the CLM-L-PTM structure, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein:

CLM is cereblon (cereblon) E3 ubiquitin ligase protein binding ligand compound fragment represented by general formula (IM);

ring a is aryl or heteroaryl;

z is selectedFrom NR^aAn O atom and an S atom;

l is a connecting unit for connecting the CLM and the PTM;

Y¹、Y²、Y³and Y⁴Are the same or different and are each independently a C atom or a N atom; provided that Y is¹、Y²、Y³And Y⁴At most two of which are N atoms;

n is 0, 1 or 2;

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

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

q is 0, 1,2,3,4 or 5.

In some embodiments of the present disclosure, there is provided a compound of the CLM-L-PTM structure, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, that is a compound of formula (I), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

l is a connecting unit for connecting the CLM and the PTM;

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

q is 0, 1,2,3,4 or 5; and is

G¹、G²Z, ring A, R¹N and m are as defined in formula (IM).

wherein:

l is a connecting unit for connecting the CLM and the PTM;

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

q is 0, 1,2,3,4 or 5; and is

G¹、G²Z, ring A, R¹N and m are as defined in formula (IM).

In some embodiments of the present disclosure, there is provided a compound having the CLM-L-PTM structure, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring a is a 6-to 10-membered aryl or 5-to 10-membered heteroaryl; preferably, ring a is phenyl.

In some embodiments of the present disclosure, there is provided a compound having CLM-L-PTM structure, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (II) or general formula (III), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

G¹、G²、Z、L、Y¹、Y²、Y³、Y⁴、R¹～R³n, m, p and q are as defined in formula (I).

In some embodiments of the present disclosure, there is provided a compound having the structure CLM-L-PTM, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L is selected from L¹、L²、L³、L⁴、L¹-L²-L⁴-L³And L¹-L²-L³-L⁴；

L¹And L³Identical or different and are each independently selected from the group consisting of a covalent bond, an O atom, an S atom, an NR^1L、CR^2LR^3L、C(O)、S(O)、S(O)₂、C(S)、C(O)O、C(O)NR^4LAnd NR^4LC(O)；

L²And L⁴Is the same as orDifferent and each independently selected from the group consisting of a covalent bond, alkylene, heteroalkylene, alkenylene, alkynylene, cycloalkyl, heterocyclyl, alkylene-heterocyclyl, heterocyclyl-alkylene, aryl, and heteroaryl, wherein said alkylene, heteroalkylene, alkenylene, alkynylene, cycloalkyl, heterocyclyl, alkylene-heterocyclyl, heterocyclyl-alkylene, aryl, and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, oxo, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R^1Lselected from the group consisting of hydrogen atoms, alkyl groups, haloalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups;

R^2Land R^3LThe same or different, and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, oxo, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R^4Lselected from the group consisting of hydrogen atoms, alkyl groups, haloalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups.

In some embodiments of the present disclosure, there is provided a compound having the structure CLM-L-PTM, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L is L¹-L²-L³-L⁴Or L¹-L²-L⁴-L³；L¹And L³Identical or different and are each independently selected from the group consisting of a covalent bond, an O atom, CH₂And NR^1L；R^1LSelected from hydrogen atoms, C_1-6Alkyl, halo C_1-6Alkyl, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl, 6-to 10-membered aryl, and 5-to 10-membered heteroaryl; l is²And L⁴Identical or different and are each independently selected from the group consisting of a covalent bond, C_1-12Alkylene, 1-to 12-membered heteroalkylene, C_2-12Alkenylene radical, C_2-12Alkynylene, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl, C_1-12Alkylene-3-to 8-membered heterocyclyl, 3-to 8-membered heterocyclyl-C_1-12Alkylene, 6-to 10-membered aryl and 5-to 10-membered heteroaryl, wherein said C_1-12Alkylene, 1-to 12-membered heteroalkylene, C_2-12Alkenylene radical, C_2-12Alkynylene, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl, C_1-12Alkylene-3-to 8-membered heterocyclyl, 3-to 8-membered heterocyclyl-C_1-12Alkylene, 6-to 10-membered aryl and 5-to 10-membered heteroaryl are each independently optionally selected from halogen, C_1-12Alkyl radical, C_1-12Alkoxy, halo C_1-12Alkyl, hydroxy C_1-12Alkyl, cyano, amino, oxo, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl, 6-to 10-membered aryl and 5-to 10-membered heteroaryl; preferably, L is L¹-L²-L³-L⁴；L¹Selected from the group consisting of a covalent bond, an O atom, and NH; l is²And L⁴Are the same or different and are each independently selected from C_1-12Alkylene, 1-to 12-membered heteroalkylene, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl, C_1-12Alkylene-3-to 8-membered heterocyclyl, 3-to 8-membered heterocyclyl-C_1-12An alkylene group; l is³Is CH₂(ii) a More preferably, L is L¹-L²-L³-L⁴；L¹Selected from the group consisting of a covalent bond, an O atom, and NH; l is²And L⁴Are the same or different and are each independently selected from C_1-12Alkylene, 1-to 12-membered heteroalkylene, 3-to 8-membered cycloalkyl, and 3-to 8-membered heterocyclyl; l is³Is CH₂。

In some embodiments of the present disclosure, there is provided a compound having a CLM-L-PTM structure, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (I-1), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

is a 4-to 8-membered heterocyclic group containing at least 1N atom;

L¹selected from covalent bonds, O atoms, S atoms, NR^1L、CR^2LR^3L、C(O)、S(O)、S(O)₂、C(S)、C(O)O、C(O)NR^4LAnd NR^4LC(O)；

L²A substituent selected from the group consisting of a covalent bond, alkylene, heteroalkylene, alkenylene, alkynylene, cycloalkyl, heterocyclyl, alkylene-heterocyclyl, heterocyclyl-alkylene, aryl, and heteroaryl, wherein said alkylene, heteroalkylene, alkenylene, alkynylene, cycloalkyl, heterocyclyl, alkylene-heterocyclyl, heterocyclyl-alkylene, aryl, and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, oxo, cycloalkyl, heterocyclyl, aryl, and heteroaryl; preferably, L²Selected from the group consisting of covalent bonds, alkylene, heteroalkylene, alkenylene, alkynylene, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkylene, heteroalkylene, alkenylene, alkynylene, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, oxo, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R^4Lselected from the group consisting of hydrogen atoms, alkyl groups, haloalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups;

G¹、G²ring ofA、Z、Y¹、Y²、Y³、Y⁴、R¹～R³N, m, p and q are as defined in formula (I).

In some embodiments of the present disclosure, there is provided a compound having a CLM-L-PTM structure, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (I-2), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

is a 4-to 8-membered heterocyclic group containing at least 1N atom;

L⁴A substituent selected from the group consisting of a covalent bond, alkylene, heteroalkylene, alkenylene, alkynylene, cycloalkyl, heterocyclyl, alkylene-heterocyclyl, heterocyclyl-alkylene, aryl, and heteroaryl, wherein said alkylene, heteroalkylene, alkenylene, alkynylene, cycloalkyl, heterocyclyl, alkylene-heterocyclyl, heterocyclyl-alkylene, aryl, and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, oxo, cycloalkyl, heterocyclyl, aryl, and heteroaryl; preferably, L⁴Selected from the group consisting of covalent bonds, alkylene, heteroalkylene, alkenylene, alkynylene, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkylene, heteroalkylene, alkenylene, alkynylene, cycloalkyl, heterocyclyl, aryl, and heteroarylEach aryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, oxo, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

G¹、G²ring A, Z, Y¹、Y²、Y³、Y⁴、R¹～R³N, m, p and q are as defined in formula (I).

In some embodiments of the present disclosure, there is provided a compound having CLM-L-PTM structure, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (II-1), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein: g¹、G²Z, ring B, Y¹、Y²、Y³、Y⁴、L¹、L²、R¹～R³N, m, p and q are as defined in the general formula (I-1).

In some embodiments of the present disclosure, there is provided a compound having CLM-L-PTM structure, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (II-2), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein: g¹、G²Z, ring C, Y¹、Y²、Y³、Y⁴、L¹、L⁴、R¹～R³N, m, p and q are as defined in the general formula (I-2).

In some embodiments of the present disclosure, there is provided a compound having CLM-L-PTM structure, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (III-1), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein: g¹、G²Z, ring B, Y¹、Y²、Y³、Y⁴、L¹、L²、R¹～R³N, m, p and q are as defined in the general formula (I-1). In some embodiments of the present disclosure, there is provided a compound having the structure CLM-L-PTM, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein G is¹Is CH₂(ii) a And G²Is C (═ O).

In some embodiments of the present disclosure, formula (I-1), formula (II-1), or formula (III-1) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L is¹Selected from the group consisting of covalent bonds, O atoms andNR^1L；R^1Lselected from hydrogen atoms, C_1-6Alkyl, halo C_1-6Alkyl, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl, 6-to 10-membered aryl, and 5-to 10-membered heteroaryl; l is²Selected from covalent bond, C_1-12Alkylene, 1-to 12-membered heteroalkylene, C_2-12Alkenylene radical, C_2-12Alkynylene, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl, C_1-12Alkylene-3-to 8-membered heterocyclyl, 3-to 8-membered heterocyclyl-C_1-12Alkylene, 6-to 10-membered aryl and 5-to 10-membered heteroaryl, wherein said C_1-12Alkylene, 1-to 12-membered heteroalkylene, C_2-12Alkenylene radical, C_2-12Alkynylene, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl, C_1-12Alkylene-3-to 8-membered heterocyclyl, 3-to 8-membered heterocyclyl-C_1-12Alkylene, 6-to 10-membered aryl and 5-to 10-membered heteroaryl are each independently optionally selected from halogen, C_1-12Alkyl radical, C_1-12Alkoxy, halo C_1-12Alkyl, hydroxy C_1-12Alkyl, cyano, amino, oxo, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl, 6-to 10-membered aryl and 5-to 10-membered heteroaryl; preferably, L¹Selected from the group consisting of a covalent bond, an O atom, and NH; l is²Is selected from C_1-12Alkylene, 1-to 12-membered heteroalkylene, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl, C_1-12Alkylene-3-to 8-membered heterocyclyl and 3-to 8-membered heterocyclyl-C_1-12An alkylene group.

In some embodiments of the present disclosure, formula (I-1), formula (II-1) or formula (III-1) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein

Selected from:

j is 0, 1,2,3,4, 5 or 6; and is

k is 0, 1,2,3,4, 5 or 6; preferably, j is 0 or 1; k is 0 or 1.

In some embodiments of the present disclosure, a compound of formula (I-2) or formula (II-2) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L¹Selected from the group consisting of covalent bonds, O atoms and NR^1L；R^1LSelected from hydrogen atoms, C_1-6Alkyl, halo C_1-6Alkyl, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl, 6-to 10-membered aryl, and 5-to 10-membered heteroaryl; l is⁴Selected from covalent bond, C_1-12Alkylene, 1-to 12-membered heteroalkylene, C_2-12Alkenylene radical, C_2-12Alkynylene, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl, C_1-12Alkylene-3-to 8-membered heterocyclyl, 3-to 8-membered heterocyclyl-C_1-12Alkylene, 6-to 10-membered aryl and 5-to 10-membered heteroaryl, wherein said C_1-12Alkylene, 1-to 12-membered heteroalkylene, C_2-12Alkenylene radical, C_2-12Alkynylene, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl, C_1-12Alkylene-3-to 8-membered heterocyclyl, 3-to 8-membered heterocyclyl-C_1-12Alkylene, 6-to 10-membered aryl and 5-to 10-membered heteroaryl are each independently optionally selected from halogen, C_1-12Alkyl radical, C_1-12Alkoxy, halo C_1-12Alkyl, hydroxy C_1-12Alkyl, cyano, amino, oxo, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl, 6-to 10-membered aryl and 5-to 10-membered heteroaryl; preferably, L¹Selected from the group consisting of a covalent bond, an O atom, and NH; l is⁴Is selected from C_1-12Alkylene, 1-to 12-membered heteroalkylene, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl, C_1-12Alkylene-3-to 8-membered heterocyclyl and 3-to 8-membered heterocyclyl-C_1-12An alkylene group.

In some embodiments of the present disclosure, a compound of formula (I-2) or formula (II-2) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein

Selected from:

j is 0, 1,2,3,4, 5 or 6; preferably, j is 0 or 1.

In some embodiments of the present disclosure, a compound of formula (I-1), formula (I-2), formula (II-1), formula (II-2), or formula (III-1) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L is¹Is a covalent bond or an O atom.

In some embodiments of the present disclosure, a compound of formula (I-1), formula (II-1), or formula (III-1) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L is²Selected from covalent bond, C_1-12Alkylene, 3-to 8-membered heterocyclyl and 3-to 8-membered heterocyclyl-C_1-12An alkylene group; preferably, L²Is selected from- (CH)₂)_k-、

j is 0, 1,2,3,4, 5 or 6; and k is 0, 1,2,3,4, 5 or 6; preferably, j is 0 or 1; k is 0 or 1.

In some embodiments of the present disclosure, a compound of formula (I-2) or formula (II-2) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L⁴Is 3-to 8-membered heterocyclyl or C_1-12Alkylene-3 to 8 membered heterocyclyl; preferably, L⁴Is composed of

j is 0, 1,2,3,4, 5 or 6; preferably, j is 0 or 1.

In some embodiments of the present disclosure, a compound of formula (I-1), formula (II-1), or formula (III-1) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein

Is selected from

In some embodiments of the present disclosure, a compound of formula (I-2) or formula (II-2) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L¹Is a covalent bond or an O atom; and L is⁴Is composed of

j is 0, 1,2,3,4, 5 or 6; preferably, j is 0 or 1.

In some embodiments of the present disclosure, there is provided a compound having the structure CLM-L-PTM, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Z is an NH or O atom.

In some embodiments of the present disclosure, there is provided a compound having the structure CLM-L-PTM, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein n is 1.

In some embodiments of the present disclosure, there is provided a compound having the structure CLM-L-PTMOr a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Y¹、Y²、Y³And Y⁴Are the same or different and are each independently a C atom or a N atom; provided that Y is¹、Y²、Y³And Y⁴Up to two of which are N atoms.

In some embodiments of the present disclosure, there is provided a compound having the CLM-L-PTM structure, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein

Is selected from

R²And p is as defined in formula (I).

In some embodiments of the present disclosure, there is provided a compound having the structure CLM-L-PTM, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is¹Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C_1-6An alkyl group.

In some embodiments of the present disclosure, there is provided a compound having the structure CLM-L-PTM, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is²Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C_1-6An alkyl group.

In some embodiments of the present disclosure, there is provided a compound having the structure CLM-L-PTM, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is³Are the same or different and eachIndependently selected from hydrogen atom, halogen, C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkyl, halo C_1-6Alkoxy, hydroxy C_1-6Alkyl, cyano and amino.

In some embodiments of the present disclosure, there is provided a compound having the structure CLM-L-PTM, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein CLM is selected from the group consisting of:

in some embodiments of the present disclosure, there is provided a compound having the structure CLM-L-PTM, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L is selected from the group consisting of:

j is 0, 1,2,3,4, 5 or 6; and is

k is 0, 1,2,3,4, 5 or 6; preferably, j is 0 or 1; k is 0 or 1.

j is 0, 1,2,3,4, 5 or 6; and is

k is 0, 1,2,3,4, 5 or 6; preferably, j is 0 or 1; k is 0 or 1.

j is 0, 1,2,3,4, 5 or 6; and is

k is 0, 1,2,3,4, 5 or 6.

In some embodiments of the present disclosure, there is provided a compound having the structure CLM-L-PTM, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein PTM is selected from the group consisting of:

in some embodiments of the present disclosure, there is provided a compound having the structure CLM-L-PTM, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2.

In some embodiments of the present disclosure, there is provided a compound having the structure CLM-L-PTM, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein q is 0, 1,2, or 3, preferably 2.

In some embodiments of the present disclosure, there is provided a compound having the structure CLM-L-PTM, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, or 2.

In some preferred embodiments of the present disclosure, the compound of formula (II) or formula (III), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein G¹Is CH₂(ii) a And G²Is C (═ O); z is NH or O atom; n is 1; y is¹、Y²、Y³And Y⁴Are the same or different and are each independently a C atom or a N atom; provided that Y is¹、Y²、Y³And Y⁴At most two of which are N atoms; r¹Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C_1-6An alkyl group; r²Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C_1-6An alkyl group; r³Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkyl, halo C_1-6Alkoxy, hydroxy C_1-6Alkyl, cyano and amino; p is 0, 1 or 2; m is 0, 1 or 2; q is 0, 1,2 or 3; l is selected from:

In some preferred embodiments of the present disclosure, a compound of formula (II-1), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein G¹Is CH₂(ii) a And G²Is C (═ O); z is NH or O atom; n is 1; y is¹、Y²、Y³And Y⁴Are the same or different and are each independently a C atom or a N atom; provided that Y is¹、Y²、Y³And Y⁴At most two of which are N atoms; r¹Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C_1-6An alkyl group; r²Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C_1-6An alkyl group; r³Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkyl, halo C_1-6Alkoxy, hydroxy C_1-6Alkyl, cyano and amino; p is 0, 1 or 2; m is 0, 1 or 2; q is 0, 1,2 or 3;

selected from:

j is 0, 1,2,3,4, 5 or 6; and k is 0, 1,2,3,4, 5 or 6.

In some preferred embodiments of the present disclosure, a compound of formula (II-2), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein G¹Is CH₂(ii) a And G²Is C (═ O); z is NH or O atom; n is 1; y is¹、Y²、Y³And Y⁴Are the same or different and are each independently a C atom or a N atom; provided that Y is¹、Y²、Y³And Y⁴At most two of which are N atoms; r¹Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C_1-6An alkyl group; r²Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C_1-6An alkyl group; r³Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C_1-6Alkyl, aryl, heteroaryl, and heteroaryl,C_1-6Alkoxy, halo C_1-6Alkyl, halo C_1-6Alkoxy, hydroxy C_1-6Alkyl, cyano and amino; p is 0, 1 or 2; m is 0, 1 or 2; q is 0, 1,2 or 3;

selected from:

j is 0, 1,2,3,4, 5 or 6.

In some preferred embodiments of the present disclosure, a compound of formula (III-1), or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, G¹Is CH₂(ii) a And G²Is C (═ O); z is NH or O atom; n is 1; y is¹、Y²、Y³And Y⁴Are the same or different and are each independently a C atom or a N atom; provided that Y is¹、Y²、Y³And Y⁴At most two of which are N atoms; r¹Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C_1-6An alkyl group; r²Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C_1-6An alkyl group; r³Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkyl, halo C_1-6Alkoxy, hydroxy C_1-6Alkyl, cyano and amino; p is 0, 1 or 2; m is 0, 1 or 2; q is 0, 1,2 or 3;

selected from:

j is 0, 1,2,3,4, 5 or 6; and k is 0, 1,2,3,4, 5 or 6.

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

or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

Another aspect of the present disclosure relates to a compound represented by the general formula (IC-1) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof,

wherein:

is a 4-to 8-membered heterocyclic group containing at least 1N atom;

G¹、G²z, ring A, R¹N and m are as defined in formula (IM).

Another aspect of the present disclosure relates to a compound represented by the general formula (IIC-1) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof,

wherein:

is a 4-to 8-membered heterocyclic group containing at least 1N atom;

G¹、G²、Z、R¹n and m are as defined in formula (IM).

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

wherein:

is a 4-to 8-membered heterocyclic group containing at least 1N atom;

G¹、G²、Z、R¹n and m are as defined in formula (IM).

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

or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a salt thereof.

Another aspect of the present disclosure relates to a compound represented by formula (IC-1), formula (IIC-1) or formula (IIIC-1) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof, wherein the salt is trifluoroacetate or hydrochloride.

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

subjecting the compound of the general formula (ID-1) and the compound of the general formula (IC-1) or a salt thereof to a reductive amination reaction to obtain a compound represented by the general formula (I-1);

G¹、G²z, Ring A, Ring B, L¹、L²、Y¹、Y²、Y³、Y⁴、R¹～R³N, m, p and q are as defined in the general formula (I-1).

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

subjecting the compounds of the general formula (ID-1) and the general formula (IIC-1) or salts thereof to reductive amination reaction to obtain a compound shown in the general formula (II-1);

G¹、G²z, ring B, L¹、L²、Y¹、Y²、Y³、Y⁴、R¹～R³N, m, p and q are as defined in the general formula (I-1).

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

carrying out reductive amination reaction on the compounds of the general formula (ID-1) and the general formula (IIIC-1) or salts thereof to obtain a compound shown in the general formula (III-1);

Another aspect of the present disclosure relates to a compound of formula (IC-2) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof,

wherein:

L⁴selected from the group consisting of covalent bonds, alkylene groups, heteroalkylene groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclic groups, alkylene groups(ii) yl-heterocyclyl, heterocyclyl-alkylene, aryl and heteroaryl, wherein said alkylene, heteroalkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, alkylene-heterocyclyl, heterocyclyl-alkylene, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, oxo, cycloalkyl, heterocyclyl, aryl and heteroaryl;

G¹、G²z, ring A, R¹N and m are as defined in formula (IM).

Another aspect of the present disclosure relates to a compound represented by the general formula (IIC-2) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof,

wherein:

L⁴selected from the group consisting of covalent bonds, alkylene, heteroalkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, alkylene-heterocyclyl, heterocyclyl-alkylene, aryl, and heteroaryl, wherein said alkylene, heteroalkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, alkylene-heterocyclyl, heterocyclyl-alkylene, aryl, and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, oxo, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

G¹、G²、Z、R¹n and m are as defined in formula (IM).

Table C typical 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 the general formula (I-2) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:

subjecting the compound of the general formula (ID-2) or a salt thereof and the compound of the general formula (IC-2) to a reductive amination reaction to obtain a compound represented by the general formula (I-2);

G¹、G²z, Ring A, Ring C, L¹、L⁴、Y¹、Y²、Y³、Y⁴、R¹～R³N, m, p and q are as defined in the general formula (I-2).

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

subjecting the compound of the general formula (ID-2) or a salt thereof and the compound of the general formula (IIC-2) to a reductive amination reaction to obtain a compound of the general formula (II-2);

G¹、G²z, ring C, L¹、L⁴、Y¹、Y²、Y³、Y⁴、R¹～R³N, m, p and q are as defined in the general formula (I-2).

In some embodiments of the present disclosure, a compound of formula (ID-1) or formula (ID-2) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L¹Is a covalent bond or an O atom.

In some embodiments of the present disclosure, a compound of formula (ID-1) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L²Selected from covalent bond, C_1-12Alkylene, 3-to 8-membered heterocyclyl and 3-to 8-membered heterocyclyl-C_1-12An alkylene group; preferably, L²Is selected from- (CH)₂)_k-、

In some embodiments of the present disclosure, a compound of formula (IC-2) or formula (IIC-2) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L is⁴Is 3-to 8-membered heterocyclyl or C_1-12Alkylene-3 to 8 membered heterocyclyl; preferably, L⁴Is composed of

j is 0, 1,2,3,4, 5 or 6; preferably, j is 0 or 1.

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

Is selected from

Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound represented by any one of the above general formulae having the CLM-L-PTM structure of the present disclosure or a compound represented by table a, or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

The disclosure further relates to a use of any one of the compounds having the general formula shown in CLM-L-PTM structure or the compound shown in table a, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for modulating ubiquitination and degradation of Androgen Receptor (AR) protein in a subject.

The present disclosure further relates to the use of a compound having the structural formula CLM-L-PTM as described above or a compound as shown in table a or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for the treatment and/or prevention of a condition mediated or dependent by androgen receptors, wherein the condition mediated or dependent by androgen receptors is preferably selected from the group consisting of tumors, male sexual dysfunction, and kennedy's disease; more preferably selected from prostate cancer, prostate 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 the use of any one of the compounds having the structural formula CLM-L-PTM or a compound shown in table a, or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the preparation of a medicament for the treatment or prevention of a condition that is treated by binding to a cereblon protein in a subject.

The present disclosure also relates to a method for modulating ubiquitination and degradation of Androgen Receptor (AR) protein in a subject comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds having the structural formula CLM-L-PTM or a compound of table a, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same

The present disclosure also relates to a method for treating or preventing a disorder treated by binding to a cereblon protein in a subject, comprising administering to a patient in need thereof a therapeutically effective amount of any one of the compounds having the general structural formula CLM-L-PTM or a compound shown in table a, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure further relates to a compound of any of the above-mentioned compounds having the general structural formula CLM-L-PTM or a compound of table a or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.

The present disclosure further relates to any one of the compounds having the structural formula of CLM-L-PTM or the compound shown in table a, or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for modulating ubiquitination and degradation of Androgen Receptor (AR) protein in a subject.

The present disclosure further relates to any one of the compounds having the structural formula CLM-L-PTM or a compound shown in table a, or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in treating or preventing a disorder that is treated by binding to a cereblon protein in a subject.

In certain embodiments, the disease or disorder is selected from asthma, multiple sclerosis, cancer, kennedy's disease, cilial disease, cleft palate, diabetes, heart disease, hypertension, inflammatory bowel disease, mental retardation, mood disorders, obesity, ametropia, infertility, Angelman's syndrome, canavan's disease, celiac disease, charcot-marie-tooth disease, cystic fibrosis, duchenne's muscular dystrophy, hemochromatosis, hemophilia, gleither's syndrome, neurofibromatosis, phenylketonuria, polycystic kidney disease, (PKD1) or 4(PKD2) pa-weidi syndrome, sickle cell disease, tay-saxophone disease, and tanner syndrome. Wherein the cancer is squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, renal cell carcinoma, bladder carcinoma, intestinal carcinoma, breast carcinoma, cervical carcinoma, colon carcinoma, esophageal carcinoma, head carcinoma, kidney carcinoma, liver carcinoma, lung carcinoma, neck carcinoma, ovarian carcinoma, pancreatic carcinoma, prostate carcinoma, gastric carcinoma, leukemia, benign and malignant lymphomas (particularly Burkitt's lymphoma and non-Hodgkin's lymphoma), benign and malignant melanoma, myeloproliferative diseases, sarcomas (including Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcoma, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioneuroma, medulloblastoma, pinealocytoma, meningioma, meningiosarcoma, meningioma, neuroblastoma, meningioma, neuroblastoma, meningioma, neuroblastoma, and melanoma, meningioma, and melanoma, Neurofibroma and schwann cell tumor), endometrial cancer, testicular cancer, thyroid cancer, carcinosarcoma, hodgkin's disease, wilms' tumor, or teratocarcinoma. In certain embodiments, the disease to be treated is cancer, e.g., prostate cancer or kennedy's disease.

In a preferred embodiment, the subject described above is a human. The active compound may be formulated so as to be suitable for administration by any suitable route, preferably in unit dose form, or in such a way that the patient may self-administer it in a single dose. The unit dose of a compound or composition of the present disclosure may be expressed in the form of a tablet, capsule, cachet, bottled liquid, powder, granule, lozenge, suppository, reconstituted powder, or liquid.

As a general guide, a suitable unit dose may be 0.1 to 1000 mg.

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

The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, 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: sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide a pleasant to the eye 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 which mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.

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

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

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

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent or one or more preservatives. Suitable dispersing or wetting agents and suspending agents are illustrative of the examples given above. Other excipients, for example sweetening, flavoring and coloring agents, may also be present. These compositions are preserved by the addition of an antioxidant such as ascorbic acid.

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

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

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

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

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

Description of the terms

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

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

The term "heteroalkyl" refers to one or more-CH's in an alkyl group₂-is substituted by a heteroatom selected from N, O and S; wherein said alkyl is as defined above; heteroalkyl groups may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachment, and the substituents are preferably independently optionally selected from one or more substituents of D atom, halogen, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

The term "alkylene" refers to a saturated straight or branched aliphatic hydrocarbon group, which is a residue derived from the parent alkane by removal of two hydrogen atoms from the same carbon atom or two different carbon atoms, and is a straight or branched group containing 1 to 20 carbon atoms, preferably an alkylene group containing 1 to 12 (e.g., 1,2,3,4, 5,6, 7, 8, 9, 10, 11, and 12) carbon atoms, more preferably 1 to 6 carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH)₂-), 1-ethylidene (-CH (CH)₃) -), 1, 2-ethylene (-CH)₂CH₂) -, 1-propylene (-CH (CH)₂CH₃) -), 1, 2-propylene (-CH)₂CH(CH₃) -), 1, 3-propylene (-CH)₂CH₂CH₂-) 1, 4-butylene (-CH₂CH₂CH₂CH₂-) and the like. The alkylene group may be substituted or unsubstituted and, when substituted, may be substituted at any available point of attachment, the substituents preferably being independently optionally selected from one or more substituents of alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo.

The term "heteroalkylene" refers to one or more (preferably 1,2,3,4, or 5) -CH groups in an alkylene group₂-is substituted by a heteroatom selected from N, O and S; wherein said alkylene is as defined above; the heteroalkylene group may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachment, with the substituents preferably being independently optionally substituted with one or more substituents selected from the group consisting of D atom, halogen, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

The term "alkenyl" refers to an alkyl compound containing at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more substituents independently selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkynyl" refers to an alkyl compound containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above. Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more substituents independently selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkenylene" refers to an alkylene compound having at least one carbon-carbon double bond in the molecule, wherein alkylene is as defined above. Alkenylene groups may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachment, and the substituents are preferably independently optionally one or more substituents selected from alkynyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, and oxo.

The term "alkynylene" refers to an alkylene compound having at least one carbon-carbon triple bond in the molecule, wherein alkylene is as defined above. Alkynylene may be substituted or unsubstituted and, when substituted, may be substituted at any available point of attachment, the substituents preferably being independently optionally selected from one or more substituents of alkenyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, preferably 3 to 8 carbon atoms (e.g., 3,4, 5,6, 7, and 8), more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.

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

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

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

the cycloalkyl ring includes cycloalkyl as described above (includingMonocyclic, spiro, fused, and bridged) are fused to an aryl, heteroaryl, or heterocycloalkyl ring, wherein the rings joined together with the parent structure are cycloalkyl, non-limiting examples of which include

Etc.; preference is given to

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

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

The term "heterocyclyl" refers to a saturated or partially unsaturated mono-or polycyclic cyclic substituent comprising 3 to 20 ring atoms, wherein one or more of the ring atoms is selected from nitrogen, oxygen, sulfur, S (O) or S (O)₂But does not include the ring moiety of-O-, -O-S-or-S-, the remaining ring atoms being carbon. Preferably 3 to 12 (e.g., 3,4, 5,6, 7, 8, 9, 10, 11 and 12) ring atoms, of which 1 to 4 (e.g., 1,2,3 and 4) are heteroatoms; more preferably 3 to 8 ring atoms (e.g. 3,4, 5,6, 7 and 8), wherein 1-3 is a heteroatomSub (e.g., 1,2, and 3); more preferably 3 to 6 ring atoms, of which 1-3 are heteroatoms; most preferably 5 or 6 ring atoms, of which 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3, 6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups.

The term "spiroheterocyclyl" refers to a 5-to 20-membered polycyclic heterocyclic group in which one atom (referred to as the spiro atom) is shared between monocyclic rings, and in which one or more ring atoms is selected from nitrogen, oxygen, sulfur, S (O) or S (O)₂The remaining ring atoms are carbon. It may contain one or more double bonds. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). The spiro heterocyclic group is classified into a mono-spiro heterocyclic group, a di-spiro heterocyclic group or a multi-spiro heterocyclic group, preferably a mono-spiro heterocyclic group and a di-spiro heterocyclic group, according to the number of spiro atoms shared between rings. More preferably 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered mono spiroheterocyclyl. Non-limiting examples of spiro heterocyclic groups include:

the term "fused heterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system, and one or more of the rings may contain one or more double bonds in which one or more of the ring atoms is selected from nitrogen, oxygen, sulfur, S (O) or S (O)₂The remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups according to the number of constituting rings, preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered and 6-membered/6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

the term "bridged heterocyclyl" refers to a 5 to 14 membered polycyclic heterocyclic group in which any two rings share two atoms which are not directly attached, which may contain one or more double bonds in which one or more ring atoms is selected from nitrogen, oxygen, sulfur, S (O) or S (O)₂The remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

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

and the like.

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

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

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

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

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

The above cycloalkyl, heterocyclyl, aryl and heteroaryl groups have a residue derived from the parent carbon atom by the removal of one hydrogen atom, or a residue derived from the parent carbon atom by the removal of two hydrogen atoms from the same carbon atom or from two different carbon atoms. For example, the pyrrolidinyl group mentioned above may be of 1 residue

Or may have two residues

The term "amino protecting group" is intended to protect an amino group with a group that can be easily removed in order to keep the amino group unchanged when the rest of the molecule is subjected to a reaction. Non-limiting examples include (trimethylsilane) ethoxymethyl, tetrahydropyranyl, t-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), acetyl, benzyl, allyl, and p-methoxybenzyl (PMB), and the like. These groups may be optionally substituted with 1 to 3 substituents selected from halogen, alkoxy or nitro.

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

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

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

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

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

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

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

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

The term "hydroxy" refers to-OH.

The term "mercapto" refers to-SH.

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

The term "cyano" refers to — CN.

The term "nitro" means-NO₂。

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

The term "carbonyl" refers to C ═ O.

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

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

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

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

Can be that

Or

Or at the same time contain

And

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

The configuration is not specified, i.e., either the Z configuration or the E configuration, or both configurations are contemplated.

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

The term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of ubiquitin to a specific substrate protein, targeting the substrate protein for degradation. For example, cereblon is an E3 ubiquitin ligase protein alone or in combination with E2 ubiquitin-binding enzyme resulting in the attachment of ubiquitin to lysine on the target protein and subsequent targeting of specific protein substrates for degradation by the proteasome. Thus, E3 ubiquitin ligase alone or complexed with E2 ubiquitin conjugating enzyme is responsible for ubiquitin transfer to the target protein. In general, ubiquitin ligases are involved in polyubiquitination, such that a second ubiquitin is joined to a first ubiquitin, a third ubiquitin is joined to a second ubiquitin, and so on. Polyubiquitinated marker proteins are used for degradation by the 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. Monoubiquinated proteins are not targeted to the proteasome for degradation, but may instead be altered in their cellular location or function, for example, via binding to other proteins with 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 lysine, which is used to make polyubiquitin, which is recognized by the proteasome.

The term "target protein" refers to proteins and peptides having any biological function or activity, including structural, regulatory, hormonal, enzymatic, genetic, immunological, contractile, storage, trafficking, and signal transduction. In some embodiments, the target protein includes 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, locomotor activity, helicase activity, metabolic processes (anabolic and catabolic), antioxidant activity, proteolysis, biosynthesis, proteins with kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme regulatory factor activity, signal transduction factor activity, structural molecule activity, binding activity (proteins, lipid carbohydrates), receptor activity, cell motility, membrane fusion, cell communication, biological process regulation, development, cell differentiation, stimulatory responses, behavioral proteins, cell adhesion proteins, white matter involved in cell death, proteins involved in transport (including protein transport activity, nuclear transport, ion transport activity, channel transport activity, carrier activity), permease activity, protein metabolism, protein metabolism protein, protein metabolism protein, protein metabolism protein, protein, Secretion activity, electron transport activity, pathogen, chaperone regulatory factor activity, nucleic acid binding activity, transcription regulatory factor activity, extracellular conformation and biogenic activity, translation regulatory factor activity. The proteins include proteins from eukaryotes and prokaryotes, including microorganisms, viruses, fungi, and parasites, as well as numerous others, including humans, microorganisms, viruses, fungi, and parasites as targets for drug therapy, other animals including domestic animals), microorganisms and other antimicrobials of the species tannophilus for the determination of antibiotics, and plants and even viruses, among many others.

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

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

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

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

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

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

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

Synthesis of the Compounds of the disclosure

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

scheme one

The invention discloses a method for synthesizing a compound shown as a general formula (I-1), or a tautomer, a racemate, an enantiomer, a diastereoisomer, a mixture form or a pharmaceutically acceptable salt form thereof, which comprises the following steps:

subjecting a compound of the general formula (ID-1) and a compound of the general formula (IC-1) or a salt thereof (preferably trifluoroacetate or hydrochloride) to a reductive amination reaction under alkaline conditions in the presence of a reducing agent to obtain a compound represented by the general formula (I-1);

Scheme two

The present disclosure relates to a method for synthesizing a compound represented by the general formula (II-1), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

subjecting the compounds of the general formula (ID-1) and the general formula (IIC-1) or salts thereof (preferably trifluoroacetate or hydrochloride) to reductive amination reaction under alkaline conditions in the presence of a reducing agent to obtain a compound shown in the general formula (II-1);

Scheme three

A method for synthesizing a compound represented by the general formula (III-1) of the present disclosure, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

carrying out reductive amination on the compounds of the general formula (ID-1) and the general formula (IIIC-1) or salts thereof (preferably trifluoroacetate or hydrochloride) under alkaline conditions in the presence of a reducing agent to obtain a compound shown in the general formula (III-1);

G¹、G²z, ring B, L¹、L²、Y¹、Y²、Y³、Y⁴、R¹～R³N, m, p and q are as defined in the general formula (III-1).

Scheme four

The present disclosure relates to a method for synthesizing a compound represented by general formula (I-2), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

subjecting the compound of the general formula (ID-2) or a salt thereof (preferably trifluoroacetate or hydrochloride) and the compound of the general formula (IC-2) to a reductive amination reaction under alkaline conditions in the presence of a reducing agent to obtain a compound represented by the general formula (I-2);

Scheme five

The invention discloses a method for synthesizing a compound shown as a general formula (II-2) or a tautomer, a racemate, an enantiomer, a diastereoisomer, a mixture form or a pharmaceutically acceptable salt form thereof, which comprises the following steps:

subjecting the compound of the general formula (ID-2) or a salt thereof (preferably trifluoroacetate or hydrochloride) and the compound of the general formula (IIC-2) to a reductive amination reaction under alkaline conditions in the presence of a reducing agent to obtain a compound represented by the general formula (II-2);

In the above synthesis scheme, the reducing agent includes, but is not limited to, sodium borohydride acetate, sodium triacetoxyborohydride, sodium borohydride, lithium borohydride, sodium cyanoborohydride, sodium acetylborohydride, and the like, and preferably sodium borohydride acetate or sodium triacetoxyborohydride.

In the above synthesis scheme, the reagent providing basic conditions comprises organic bases and inorganic bases, wherein the organic bases include but are not limited to triethylamine, N-diisopropylethylamine, N-butyllithium, lithium diisopropylamide, sodium acetate, potassium acetate, sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide, and the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide monohydrate, lithium hydroxide and potassium hydroxide; sodium acetate is preferred.

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 a mixture thereof.

Detailed Description

The present disclosure is further described below with reference to examples, but these examples do not 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^-6The units in (ppm) are given. NMR was measured using a Bruker AVANCE-400 nuclear magnetic instrument or Bruker AVANCE NEO 500M in deuterated dimethyl sulfoxide (DMSO-d)₆) Deuterated chloroform (CDCl)₃) Deuterated methanol (CD)₃OD), internal standard Tetramethylsilane (TMS).

MS was determined using an Agilent 1200/1290DAD-6110/6120Quadrupole MS LC MS (manufacturer: Agilent, MS model: 6110/6120Quadrupole MS).

waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS model: waters ACQuity Qda Detector/waters SQ Detector)

THERMO Ultimate 3000-Q active (manufacturer: THERMO, MS model: THERMO Q active)

High Performance Liquid Chromatography (HPLC) analysis used Agilent HPLC1200 DAD, Agilent HPLC1200VWD and Waters HPLC e 2695-2489.

Chiral HPLC assay using Agilent 1260DAD HPLC.

High performance liquid phase preparation Waters 2545-2767, Waters2767-SQ Detector 2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs were used.

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

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

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

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

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

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

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

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

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

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

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

The microwave reaction was carried out using a CEM Discover-S908860 type microwave reactor.

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

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

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

Abbreviations for groups appearing in the structures of the examples are as follows:

PMB is p-methoxybenzyl;

boc is tert-butyloxycarbonyl;

cbz is benzyloxycarbonyl.

Example 1

N- ((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -4- ((5- (4- (2- (2, 6-dioxopiperidin-3-yl) -3-oxo-1, 2,3, 4-tetrahydropyrrolo [3,4-b ] indol-6-yl) piperazin-1-yl) pentyl) oxy) benzamide 1

First step of

6-bromo-3-formyl-1H-indole-2-carboxylic acid ethyl ester 1b

Phosphorus oxychloride (17.2g,112mmol,10mL) was slowly added dropwise to N, N-dimethylformamide (16.36g,224mmol,17mL) under ice-bath cooling under argon, and reacted at 0 ℃ for 20 minutes. A solution of 6-bromo-1H-indole-2-carboxylic acid ethyl ester 1a (15g,56mmol, Shanghai Bigdi pharmaceutical science Co., Ltd.) in N, N-dimethylformamide (30mL) was added thereto, and the mixture was reacted at 60 ℃ for 4 hours. The reaction was cooled, poured into ice water (500mL), filtered, the filter cake washed with water (50 mL. times.3), the filter cake collected and dried in vacuo to give the title compound 1b (18.6g), which was used in the next reaction without purification.

MS m/z(ESI):295.9[M+1]。

Second step of

6-bromo-3-formyl-1- (4-methoxybenzyl) -1H-indole-2-carboxylic acid ethyl ester 1c

Compound 1b (8.6g,25.8mmol, hydrochloride salt) was dissolved in N, N-dimethylformamide (100mL), and cesium carbonate (16.85g,51.7mmol) and 4-methoxybenzyl chloride (8.1g,51.7mmol,7mL) were added. Reacting at 80 deg.C for 1 hr, filtering, and concentrating the filtrate under reduced pressure. The resulting residue was purified by silica gel column chromatography with developer system B to give the title compound 1c (10.76g), yield: 100 percent.

MS m/z(ESI):416.0[M+1]。

The third step

6- (4- (tert-Butoxycarbonyl) piperazin-1-yl) -3-formyl-1- (4-methoxybenzyl) -1H-indole-2-carboxylic acid ethyl ester 1d

Compound 1c (10.5g,25.2mmol), N-Boc-piperazine (4.7g,25.2mmol, Shanghai Biden pharmaceutical science Co., Ltd.), cesium carbonate (9.87g,30.3mmol), tris (dibenzylideneacetone) dipalladium (462mg,0.5mmol) and S- (-) -1,1 '-binaphthyl-2, 2' -bis-diphenylphosphine (629mg,1mmol) were added to 1, 4-dioxane (150 mL). The reaction was heated to 100 ℃ and stirred for 16 hours under argon atmosphere. Additional tris (dibenzylideneacetone) dipalladium (462mg,0.5mmol) and S- (-) -1,1 '-binaphthyl-2, 2' -bis-diphenylphosphine (629mg,1mmol) were added and the reaction stirred at 100 ℃ for an additional 3 hours. Filtering, and concentrating the filtrate under reduced pressure. The resulting residue was purified by silica gel column chromatography with developer system B to give the title compound 1d (1g), yield: 8 percent.

MS m/z(ESI):522.1[M+1]。

The fourth step

6- (4- (tert-Butoxycarbonyl) piperazin-1-yl) -3-formyl-1- (4-methoxybenzyl) -1H-indole-2-carboxylic acid 1e

Compound 1d (1.0g,1.9mmol) was added to a mixed solvent of 12mL tetrahydrofuran and water (V/V ═ 3/1), and lithium hydroxide monohydrate (322mg,7.7mmol) was added to react at 65 ℃ for 3 hours. The reaction solution was cooled and the solution was adjusted to weak acidity (pH 6) with dilute hydrochloric acid (1M). Saturated sodium chloride solution (25mL) was added, extracted with ethyl acetate (25 mL. times.3), the organic phases combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound, crude 1e (946mg), which was used in the next reaction without purification.

MS m/z(ESI):494.1[M+1]。

The fifth step

6- (4- (tert-Butoxycarbonyl) piperazin-1-yl) -3- (((2, 6-dioxopiperidin-3-yl) amino) methyl) -1- (4-methoxybenzyl) -1H-indole-2-carboxylic acid 1f

3-amino-piperidine-2, 6-dione hydrochloride (316mg,1.9mmol, Shanghai Bigdi pharmaceutical science Co., Ltd.) was dissolved in 27mL of a mixed solvent of dichloromethane and methanol (V/V. RTM. 2/1), and sodium acetate (629mg,7.6mmol) was added to stir the reaction for 10 minutes. Compound 1e (946mg,1.9mmol) was added and the reaction stirred for an additional 16 hours, followed by addition of sodium cyanoborohydride (241mg,3.8mmol) and stirring for 1 hour. Saturated sodium chloride solution (100mL) was added, extracted with ethyl acetate (50 mL. times.3), the organic phases combined, dried over anhydrous sodium chloride, filtered, and concentrated under reduced pressure to give the title compound, 1f, as crude product (1.16g), which was used in the next reaction without purification. MS M/z (ESI) 604.4[ M-1 ].

The sixth step

4- (2- (2, 6-dioxopiperidin-3-yl) -4- (4-methoxybenzyl) -3-oxo-1, 2,3, 4-tetrahydropyrrolo [3,4-b ] indol-6-yl) piperazine-1-carboxylic acid tert-butyl ester 1g

Compound 1f (1.16g,1.9mmol) was dissolved in N, N-dimethylformamide (10mL), and 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (788mg,2.1mmol) and triethylamine (572mg,5.6mmol) were added. The reaction was stirred for 1 hour. Ethyl acetate (50mL) was added, the mixture was washed with saturated sodium chloride solution (50 mL. times.3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with developer system B to give the title compound 1g (830mg), yield: 75 percent.

MS m/z(ESI):588.1[M+1]。

Seventh step

3- (3-oxo-6- (piperazin-1-yl) pyrrolo [3,4-b ] indole-2 (1H,3H,4H) -yl) piperidine-2, 6-dione trifluoroacetate salt for 1H

Compound 1g (830mg,1.4mmol) was added to trifluoroacetic acid (10mL) and reacted at 60 ℃ for 16 hours. The reaction was concentrated under reduced pressure to give the title compound as a crude product (1.1g) for 1h, which was used in the next reaction without purification.

MS m/z(ESI):368.1[M+1]。

Eighth step

4- (4- (1, 3-Dioxolan-2-yl) butoxy) benzoic acid methyl ester 1j

Methyl 4-hydroxybenzoate 1i (170mg,1.1mmol, national pharmaceutical group chemical Co., Ltd.) was dissolved in N, N-dimethylformamide (5mL), and 2- (4-bromobutyl) -1, 3-dioxolane (257mg,1.2mmol, Jiangsu Aikang biomedical research and development Co., Ltd.) and cesium carbonate (728mg,2.2344mmol) were added. The reaction was heated to 80 ℃ for 2 hours. Saturated sodium chloride solution (25mL) was added, extracted with ethyl acetate (10 mL. times.3), the organic phases combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound, 1j, as a crude product (313mg), which was used in the next reaction without purification.

The ninth step

4- (4- (1, 3-dioxolan-2-yl) butoxy) benzoic acid 1k

Compound 1j (313mg,1.1mmol) was dissolved in a mixed solvent of tetrahydrofuran (2mL), methanol (2mL) and water (2mL), sodium hydroxide (179mg,4.5mmol) was added, and the reaction was heated to 50 ℃ and stirred for 16 hours. The reaction solution was concentrated under reduced pressure, the solution was adjusted to weak acidity (pH 5) with dilute hydrochloric acid (1M), filtered, and the cake was collected and dried in vacuo to give the title compound 1k (280mg), yield: 94 percent.

The tenth step

4- (4- (1, 3-dioxolan-2-yl) butoxy) -N- ((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) benzamide 1m

Compound 1k (96mg,0.36mmol) and 4- ((1r,3r) -3-amino-2, 2,4, 4-tetramethylcyclobutoxy) -2-chlorobenzonitrile 1l (100mg,0.36mmol, prepared by the well-known method J.Med.chem.2011,54, 7693-7704) were dissolved in N, N-dimethylformamide (3mL), and 2- (7-oxybenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (164mg,0.43mmol) and triethylamine (109mg,1mmol) were added. The reaction was stirred for 16 hours. Ethyl acetate (50mL) was added, washed with saturated sodium chloride solution (10mL × 3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound 1m (170mg), yield: 90 percent.

MS m/z(ESI):527.2[M+1]。

The eleventh step

N- ((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -4- ((5-oxopentyl) oxy) benzamide 1N

Compound 1M (100mg,0.19mmol) was dissolved in tetrahydrofuran (10mL), sulfuric acid (2M,1mL) was added, and the reaction was heated to 70 ℃ and stirred for 2 hours. Saturated sodium bicarbonate solution was added, extracted with ethyl acetate (10mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 1n (91mg), which was used in the next reaction without purification.

MS m/z(ESI):483.0[M+1]。

The twelfth step

Compound 1h (30mg,0.08mmol) was dissolved in 3mL of a mixed solution of dichloromethane and methanol (V/V ═ 2/1), and sodium acetate (40mg,0.49mmol) was added to react for 10 minutes. Compound 1n (49mg,0.08mmol) was added and reacted for 15 minutes. Sodium borohydride acetate (35mg,0.16mmol) was added and the reaction was carried out for 1 hour. Dichloromethane (20mL) was added, washed with saturated sodium chloride solution (10mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was prepared by high performance liquid chromatography (Waters2767-SQ Detector 2, elution: trifluoroacetic acid: 0.1%, water: 60%, acetonitrile: 40%) to obtain the title compound 1(11mg), yield: 16 percent.

MS m/z(ESI):834.3[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ11.70(s,1H),10.95(s,1H),9.47(s,1H),7.92-7.90(m,1H),7.86-7.85(m,1H),7.68-7.66(m,1H),7.57-7.55(m,1H),7.22-7.19(m,2H),7.03-6.97(m,3H),6.92-6.90(m,1H),5.01-4.98(m,1H),4.42-4.25(m,3H),4.09-4.06(m,2H),3.87-3.84(m,2H),3.64-3.61(m,2H),3.21-3.19(m,3H),3.04-2.99(m,2H),2.93-2.87(m,1H),2.64-2.59(m,1H),2.40-2.37(m,3H),2.03-1.98(m,2H),1.83-1.77(m,3H),1.52-1.46(m,2H),1.23(s,6H),1.14(s,6H)。

Example 2

N- ((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -4- ((5- (4- (2- (2, 6-dioxopiperidin-3-yl) -3-oxo-1, 2,3, 4-tetrahydropyrrolo [3,4-b ] indol-7-yl) piperazin-1-yl) pentyl) oxy) benzamide 2

Referring to the synthesis of example 1, the first step starting material 1a was replaced with the compound ethyl 5-bromo-1-H-indole-2-carboxylate (shanghai bi medical science co., ltd.) to give the title compound 2(15 mg).

MS m/z(ESI):834.2[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ11.80(s,1H),11.02(s,1H),9.53(s,1H),7.92-7.90(m,1H),7.86-7.85(m,2H),7.68-7.66(m,1H),7.42-7.39(m,1H),7.25-7.22(m,1H)7.20-7.18(s,1H),7.03-6.97(m,3H),5.05-5.02(m,1H),4.40-4.38(m,1H),4.25-4.21(m,3H),4.07-4.03(m,3H),3.86-3.82(m,2H),3.21-3.18(m,4H),3.01-2.98(m,3H),2.63-2.60(m,1H),2.41-2.36(m,2H),2.05-2.02(m,1H),1.85-1.79(m,4H),1.49-1.46(m,2H),1.25(s,6H),1.16(s,6H)。

Example 3

N- ((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -4- (4- ((4- (2- (2, 6-dioxopiperidin-3-yl) -3-oxo-1, 2,3, 4-tetrahydropyrrolo [3,4-b ] indol-6-yl) piperazin-1-yl) methyl) piperidin-1-yl) benzamide 3

First step of

4- (Dimethoxymethyl) piperidine-1-carboxylic acid benzyl ester 3b

Benzyl 4-formylpiperidine-1-carboxylate 3a (10g,40.4mmol, Shanghai Biao pharmaceutical science Co., Ltd.) was dissolved in methanol (80mL), trimethyl orthoformate (40mL) and p-toluenesulfonic acid monohydrate (385mg,2.024mmol) were added, and the reaction was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure, and a saturated sodium bicarbonate solution (80mL) was added to the mixture, followed by extraction with ethyl acetate (80 mL. times.3). The combined organic phases were washed with saturated sodium chloride solution (80 mL. times.3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude title compound 3b (12g), which was used in the next reaction without purification.

Second step of

4- (Dimethoxymethyl) piperidine 3c

Compound 3b (12g,40.9mmol) was dissolved in methanol (100mL), palladium on carbon (1.3g, 10 wt%) was added, and the reaction was stirred under a hydrogen atmosphere for 3 hours. The reaction was filtered and the filtrate was concentrated under reduced pressure to give the crude title compound 3c (6g), which was used in the next reaction without purification.

The third step

4- (4- (Dimethoxymethyl) piperidin-1-yl) benzoic acid ethyl ester 3d

Compound 3c (710mg,4.5mmol) and methyl 4-fluorobenzoate (500mg,3mmol) were dissolved in acetonitrile (15mL), potassium carbonate (606mg,6mmol) was added, and the reaction was heated to 100 ℃ and stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with developer system B to give the title compound 3d (620mg), yield: 68 percent.

MS m/z(ESI):308.0[M+1]。

The fourth step

4- (4- (Dimethoxymethyl) piperidin-yl) benzoic acid 3e

Compound 3d (620mg,2mmol) was dissolved in a mixed solvent of tetrahydrofuran (2mL), methanol (2mL) and water (2mL), lithium hydroxide monohydrate (424mg,10mmol) was added, and the reaction was heated at 50 ℃ and stirred for 3 hours. The reaction solution was concentrated under reduced pressure, the solution was adjusted to weak acidity (pH 5) with dilute hydrochloric acid (1M), filtered, and the cake was collected and dried in vacuo to give the title compound 3e (550mg), yield: 98 percent.

MS m/z(ESI):280.1[M+1]。

The fifth step

N- ((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -4- (4- (dimethoxymethyl) piperidin-1-yl) benzamide 3f

Compound 3e (120mg,0.43mmol) and compound 1l (100mg,0.36mmol) were dissolved in N, N-dimethylformamide (3mL), and 2- (7-oxybenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (205mg,0.54mmol) and triethylamine (109mg,1mmol) were added. The reaction was stirred for 2 hours. Water was added, filtered, the filter cake collected and dried in vacuo to give the title compound, crude 3f (193mg), which was used in the next reaction without purification.

MS m/z(ESI):540.1[M+1]。

The sixth step

3g of N- ((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -4- (4-formylpiperidin-1-yl) benzamide

Compound 3f (193mg,0.36mmol) was dissolved in tetrahydrofuran (2mL), sulfuric acid (2M,2mL) was added, and the reaction was heated to 70 ℃ and stirred for 0.5 hour. Saturated sodium bicarbonate solution was added to adjust the reaction solution to neutral. Concentrated under reduced pressure, filtered, the filter cake washed with water (0.5 mL. times.3), the filter cake collected and dried in vacuo to give the title compound as 3g of crude product (150mg), which was used in the next reaction without purification.

MS m/z(ESI):494.1[M+1]。

Seventh step

Compound 3g (60mg,0.1mmol) was dissolved in 3mL of a mixed solution of dichloromethane and methanol (V/V ═ 2/1), and sodium acetate (40mg,0.49mmol) was added to the solution, followed by reaction for 10 minutes. The compound was added for 1h (50mg,0.1mmol) and reacted for 15 min. Sodium borohydride acetate (64mg,0.3mmol) was added and the reaction was carried out for 1 hour. Dichloromethane (20mL) was added, washed with saturated sodium chloride solution (10mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was prepared by high performance liquid chromatography (Waters2767-SQ Detector 2, elution: trifluoroacetic acid: 0.1%, water: 60%, acetonitrile: 40%) to obtain the title compound 3(20mg), yield: 23 percent. MS M/z (ESI) 845.5[ M +1 ].

¹H NMR(500MHz,DMSO-d₆)δ11.74(s,1H),10.93(s,1H),9.45(s,1H),7.93-7.90(m,1H),7.80-7.75(m,2H),7.63-7.60(m,1H),7.54-7.52(m,1H),7.22-7.19(m,1H),7.04-7.00(m,3H),6.92-6.90(m,1H),5.02-4.99(m,1H),4.40-4.26(m,3H),4.10-4.07(m,1H),3.80-3.76(m,2H),3.74-3.70(m,2H),3.68-3.65(m,2H),3.60-3.55(m,2H),3.25-3.20(m,2H),3.18-3.14(m,2H),2.90-2.83(m,3H),2.55-2.53(m,1H),2.35-2.33(m,1H),2.12-2.10(m,1H),2.03-2.01(m,1H),1.80-1.76(m,2H),1.30-1.25(m,2H),1.20(s,6H),1.13(s,6H)。

Example 4

N- ((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -4- ((5- (4- (2- (2, 6-dioxopiperidin-3-yl) -3-oxo-2, 3-dihydro-1H-benzofuro [2,3-c ] pyrrol-6-yl) piperazin-1-yl) pentyl) oxy) benzamide 4

First step of

6-bromo-3-methylbenzofuran-2-carboxylic acid ethyl ester 4b

1- (4-bromo-2-hydroxyphenyl) ethan-1-one 4a (17g,79mmol, Saen chemical technology (Shanghai) Co., Ltd.) was dissolved in N, N-dimethylformamide (150mL), and cesium carbonate (64.4g,198mmol) was added and the reaction was stirred for 0.5 hour. Ethyl 2-bromoacetate (15.9g,95.2mmol, Chemicals, Inc., national drug group) was slowly added dropwise thereto, and the reaction was stirred for 16 hours. The reaction mixture was filtered, and ethyl acetate (200mL) and water (200mL) were added to the filtrate to separate the layers. The organic phase was washed successively with water (100 mL. times.3) and a saturated sodium chloride solution (100 mL. times.3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with developer system B to give the title compound 4B (8.7g), yield: 39 percent.

Second step of

6-bromo-3- (bromomethyl) benzofuran-2-carboxylic acid ethyl ester 4c

Compound 4b (5.6g,19.8mmol), N-bromosuccinimide (3.9g,21.9mmol) and azobisisobutyronitrile (325mg,2mmol) were dissolved in carbon tetrachloride (40mL) and the reaction was heated to 80 ℃ and stirred for 3 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100mL) and washed with water (50 mL. times.3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the title compound 4c (6g), which was used in the next reaction without purification.

MS m/z(ESI):362.9[M+1]。

The third step

6-bromo-3-formylbenzofuran-2-carboxylic acid ethyl ester 4d

Compound 4c (2.6g,7.2mmol) was dissolved in tetrahydrofuran (50mL), N-methyl-N-oxomorpholine (4.2g,35.8mmol) was added, and the reaction was stirred for 3 hours. Ethyl acetate (100mL) and water (100mL) were added and the layers were separated. The organic phase was washed successively with water (50 mL. times.3) and saturated sodium chloride solution (50 mL. times.3). Dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with developer system B to give the title compound 4d (1.5g), yield: 70 percent.

MS m/z(ESI):297.0[M+1]。

The fourth step

6- (4- (tert-Butoxycarbonyl) piperazin-1-yl) -3-formylbenzofuran-2-carboxylic acid 4e

Compound 4d (800mg,2.7mmol) and N-Boc-piperazine (652mg,3.5mmol) were dissolved in N, N-dimethylformamide (15mL), and cesium carbonate (2.2g,6.8mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (RuPhos Pd G3,113mg,0.14mmol) were added. The reaction was stirred at 95 ℃ for 4 hours under an argon atmosphere. Ethyl acetate (50mL) and water (50mL) were added and the layers were separated. The organic phase was washed successively with water (10 mL. times.3) and saturated sodium chloride solution (10 mL. times.3). Dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with developer system B to give the title compound 4e (430mg), yield: and 43 percent. Simultaneously, the unhydrolyzed product, ethyl 6- (4- (tert-butoxycarbonyl) piperazin-1-yl) -3-formylbenzofuran-2-carboxylate (500mg) was isolated, yield: 46 percent.

MS m/z(ESI):373.0[M-1]。

The fifth step

6- (4- (tert-Butoxycarbonyl) piperazin-1-yl) -3- (((2, 6-dioxopiperidin-3-yl) amino) methyl) benzofuran-2-carboxylic acid 4f

3-amino-piperidine-2, 6-dione hydrochloride (45mg,0.27mmol) was dissolved in 3mL of a mixed solvent of dichloromethane and methanol (V/V ═ 2/1), and sodium acetate (90mg,1.1mmol) was added to react for 10 minutes. Compound 4e (80mg,0.21mmol) was added and reacted for 15 minutes. Sodium cyanoborohydride (30mg,0.48mmol) was added and reacted for 1 hour. The reaction solution was concentrated under reduced pressure, the solution was adjusted to weak acidity (pH 4) with dilute hydrochloric acid (1M), filtered, and the cake was collected and dried in vacuo to give the title compound 4f (35mg), yield: 34 percent.

MS m/z(ESI):487.1[M+1]。

The sixth step

4g of tert-butyl 4- (2- (2, 6-dioxopiperidin-3-yl) -3-oxo-2, 3-dihydro-1H-benzofuro [2,3-c ] pyrrol-6-yl) piperazine-1-carboxylate

Compound 4f (35mg,0.07mmol) was dissolved in N, N-dimethylformamide (2mL), and 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (40mg,0.1mmol) and triethylamine (30mg,0.23mmol) were added. The reaction was stirred for 1 hour. The reaction was concentrated under reduced pressure, ethyl acetate (2mL) was added, filtered, and the filter cake was collected and dried in vacuo to give the title compound 4g (33mg), yield: 98 percent.

MS m/z(ESI):469.1[M+1]。

Seventh step

3- (3-oxo-6- (piperazin-1-yl) -1H-benzofuro [2,3-c ] pyrrol-2 (3H) -yl) piperidine-2, 6-dione hydrochloride 4H

Compound 4g (33mg,0.07mmol) was added to a solution of 4M hydrogen chloride in 1, 4-dioxane (2 mL). The reaction was stirred for 2h and concentrated under reduced pressure to give the title compound as a 4h crude product (28mg), which was used in the next reaction without purification.

Eighth step

Compound 4h (28mg,0.07mmol) was dissolved in 3mL of a mixed solution of dichloromethane and methanol (V/V ═ 2/1), and sodium acetate (40mg,0.49mmol) was added to react for 10 minutes. Compound 1n (33mg,0.07mmol) was added and reacted for 15 minutes. Sodium borohydride acetate (30mg,0.14mmol) was added and the reaction was carried out for 1 hour. Dichloromethane (20mL) was added, washed with saturated sodium chloride solution (10mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was prepared by high performance liquid chromatography (Waters2767-SQ Detector 2, elution: trifluoroacetic acid: 0.1%, water: 60%, acetonitrile: 40%) to obtain the title compound 4(15mg), yield: 23 percent.

MS m/z(ESI):835.3[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ11.01(s,1H),9.67(s,1H),7.93-7.90(m,1H),7.86-7.85(m,2H),7.70-7.68(m,2H),7.41-7.40(m,1H),7.22-7.18(m,1H),7.03-6.00(m,3H),5.02-4.99(m,1H),4.51-4.47(m,1H),4.37-4.33(m,2H),4.09-4.06(m,3H),4.03-4.00(m,2H),3.64-3.62(m,2H),3.22-3.17(m,3H),3.15-3.08(m,3H),2.91-2.88(m,1H),2.64-2.59(m,1H),2.41-2.38(m,1H),2.05-2.02(m,1H),1.84-1.74(m,4H),1.52-1.48(m,2H),1.23(s,6H),1.13(s,6H)。

Example 5

N- ((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -4- (3- ((4- (2- (2, 6-dioxopiperidin-3-yl) -3-oxo-2, 3-dihydro-1H-benzofuro [2,3-c ] pyrrol-6-yl) piperazin-1-yl) methyl) azetidin-1-yl) benzamide 5

First step of

4- (3- (hydroxymethyl) azetidin-1-yl) benzoic acid methyl ester 5b

Methyl 4-iodobenzoate 5a (470mg,1.8mmol, Shanghai Biao pharmaceutical science and technology Co., Ltd.) was dissolved in dimethyl sulfoxide (5mL), potassium carbonate (1.1g,8mmol), azetidin-3-ylmethanol (200mg,1.6mmol, Shanghai Biao pharmaceutical science and technology Co., Ltd.) and cuprous iodide (62mg,0.33mmol) and L-proline (75mg,0.65mmol) were added, and the mixture was replaced with nitrogen and heated at 100 ℃ for 16 hours. The reaction solution was concentrated under reduced pressure to remove the solvent, and the obtained residue was purified by silica gel column chromatography with developer system B to give the title compound 5B (260mg), yield: 73 percent.

MS m/z(ESI):222.1[M+1]。

Second step of

4- (3- (hydroxymethyl) azetidin-1-yl) benzoic acid 5c

Compound 5b (60mg,0.27mmol) was added to 2.5mL of a mixed solvent of methanol and water (V/V ═ 4/1), and sodium hydroxide (33mg,0.83mmol) was added, followed by heating to 60 ℃ for reaction for 6 hours. The reaction solution was concentrated under reduced pressure, the pH of the solution was adjusted to 5 with dilute hydrochloric acid (1M), filtered, and the filter cake was collected and dried to obtain the title compound 5c (35mg), yield: 62 percent.

MS m/z(ESI):208.1[M+1]。

The third step

N- ((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -4- (3- (hydroxymethyl) azetidin-1-yl) benzamide 5d

The compound 1l hydrochloride (50mg,0.16mmol) and the compound 5c (35mg,0.17mmol) were dissolved in N, N-dimethylformamide (3mL), and 2- (7-oxybenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (80mg,0.21mmol) and N, N-diisopropylethylamine (70mg,0.54mmol) were added and reacted at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure to remove the solvent, and the obtained residue was purified by silica gel column chromatography with developer system B to give the title compound 5d (79mg), yield: 99 percent.

MS m/z(ESI):468.1[M+1]。

The fourth step

N- ((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -4- (3-formylazetidin-1-yl) benzamide 5e

Compound 5d (79mg,0.17mmol) was dissolved in dichloromethane (3mL), followed by addition of dess-Martin oxidant (140mg,0.33mmol) and reaction at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to remove the solvent, and the obtained residue was purified by silica gel column chromatography with developer system B to give the title compound 5e (78mg), yield: 99 percent. MS M/z (ESI) 466.1[ M +1 ].

The fifth step

Compound 4h (40mg,0.1mmol) was dissolved in 3mL of a mixed solution of dichloromethane and methanol (V/V ═ 2/1), and sodium acetate (60mg,0.73mmol) was added to react for 10 minutes. Compound 5e (70mg,0.15mmol) was added and reacted for 15 minutes. Sodium triacetoxyborohydride (42mg,0.2mmol) was added thereto, and the reaction was carried out for 1 hour. Dichloromethane (20mL) was added, washed with saturated sodium chloride solution (10mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The obtained residue was prepared by high performance liquid chromatography (Waters2767-SQ Detector 2, elution: trifluoroacetic acid: 0.1%, water: 60%, acetonitrile: 40%) to obtain the title compound 5(6mg), yield: 6.5 percent.

MS m/z(ESI):818.3[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ11.05(s,1H),7.91(d,1H),7.77(d,2H),7.69(d,1H),7.48(d,1H),7.40(s,1H),7.25-7.20(m,2H),7.04-7.01(m,1H),6.47(d,2H),5.03-5.00(m,1H),4.45,4.35(dd,2H),4.34-4.33(m,1H),4.20-4.17(m,2H),4.05-4.00(m,3H),3.71(t,2H),3.60-3.50(m,4H),3.15-3.09(m,5H),2.90-2.85(m,1H),2.60-2.57(m,1H),2.40-2.34(m,1H),2.05-2.00(m,1H),1.22(s,6H),1.13(s,6H)。

Example 6

N- ((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -4- (4- (2- (4- (2- (2, 6-dioxopiperidin-3-yl) -3-oxo-2, 3-dihydro-1H-benzofuro [2,3-c ] pyrrol-6-yl) piperazin-1-yl) ethyl) piperidin-1-yl) benzamide 6

First step of

4- (2-hydroxyethyl) piperidine-1-carboxylic acid benzyl ester 6b

2- (piperidin-4-yl) ethanol 6a (4g,31mmol, Shanghai Tantake Technique Co., Ltd.) and N, N-diisopropylethylamine (6g,46.4mmol) were dissolved in tetrahydrofuran (100mL), cooled in an ice bath, and benzyl chloroformate (5.44g,31.9mmol) was added dropwise and reacted at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, ethyl acetate (200mL) was added, and the mixture was washed with a saturated sodium chloride solution (100 mL. times.3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude title compound 6b (7g), which was used in the next reaction without purification.

Second step of

4- (2-oxoethyl) piperidine-1-carboxylic acid benzyl ester 6c

Compound 6b (9g,34.2mmol) was dissolved in dichloromethane (150mL), cooled in an ice bath, and reacted at room temperature for 3 hours with dess-martin oxidant (15.9g,37.6 mmol). The reaction was quenched by the addition of saturated sodium bicarbonate solution (50mL) and insoluble material was filtered off. The filtrate was diluted with dichloromethane (100mL) and washed with saturated sodium chloride solution (30 mL. times.3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The resulting residue was purified by silica gel column chromatography with developer system a to give the title compound 6c (4.5g), yield: 65 percent. MS M/z (ESI) 262.2[ M +1 ].

¹HNMR(500MHz,CDCl₃)δ9.79(s,1H),7.60-7.07(m,5H),5.04(s,2H),4.36-4.10(m,2H),2.90-2.75(m,2H),2.40-2.30(m,2H),2.09-1.91(m,1H),1.80-1.65(m,2H),1.30-1.20(m,2H)。

The third step

4- (2, 2-Dimethoxyethyl) piperidine-1-carboxylic acid benzyl ester 6d

Compound 6c (4.5g,17.2mmol) was dissolved in methanol (50mL), and trimethyl orthoformate (16.6mL) and p-toluenesulfonic acid monohydrate (327mg,1.7mmol) were added to react at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, ethyl acetate (100mL) was added, and the mixture was washed with a saturated sodium bicarbonate solution (50 mL. times.3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove the solvent to give the crude title compound 6d (5.23g), which was used in the next reaction without purification.

The fourth step

4- (2, 2-Dimethoxyethyl) piperidine 6e

Compound 6d (5.23g,17mmol) was dissolved in methanol (50mL), palladium on carbon (900mg,10 wt%) was added, and the mixture was replaced with hydrogen three times and reacted under a hydrogen atmosphere for 3 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to remove the solvent, to give the title compound 6e (2.71g), which was used in the next reaction without purification.

The fifth step

4- (4- (2, 2-Dimethoxyethyl) piperidin-1-yl) benzoic acid methyl ester 6f

Methyl p-fluorobenzoate (500mg,3.2mmol) was dissolved in N, N-dimethylformamide (5mL), and compound 6e (622mg,3.6mmol) and potassium carbonate (896mg,6.5mmol) were added and heated to 100 ℃ for reaction for 16 hours. The reaction solution was concentrated under reduced pressure to remove the solvent, and the obtained residue was purified by silica gel column chromatography with developer system a to give the title compound 6f (230mg), yield: 23 percent.

MS m/z(ESI):308.2[M+1]。

The sixth step

4- (4- (2, 2-Dimethoxyethyl) piperidin-1-yl) benzoic acid 6g

Compound 6f (230mg,0.8mmol) was dissolved in 3mL of a mixed solvent of methanol and water (V/V ═ 2/1), and sodium hydroxide (126mg,3.2mmol) was added, followed by heating to 50 ℃ for 4 hours. The reaction solution was concentrated under reduced pressure to remove the solvent, the pH of the solution was adjusted to 5 with dilute hydrochloric acid (1M), and the filtrate was filtered to collect a cake and dried to obtain 6g (186mg) of the title compound, yield: 85 percent.

Seventh step

N- ((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -4- (4- (2, 2-dimethoxyethyl) piperidin-1-yl) benzamide 6h

6g (186mg,0.6mmol) of the compound was dissolved in N, N-dimethylformamide (5mL), and 1l of the hydrochloride salt (200mg,0.63mmol), 2- (7-oxybenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (289mg,0.8mmol) and triethylamine (193mg,1.9mmol) were added. The reaction was carried out at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to remove the solvent, and the obtained residue was purified by silica gel column chromatography with developer system B to give the title compound 6h (310mg), yield: 88 percent.

MS m/z(ESI):554.1[M+1]

Eighth step

N- ((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -4- (4- (2-oxoethyl) piperidin-1-yl) benzamide 6i

Compound 6h (310mg,0.6mmol) was dissolved in tetrahydrofuran (6mL), and diluted sulfuric acid solution (2M,3mL) was added to react at room temperature for 40 minutes. The reaction solution was cooled in an ice bath, and a saturated sodium bicarbonate solution was added to adjust the pH of the solution to 7. Extraction with ethyl acetate (10 mL. times.3) and combined organic phases, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent gave the title compound 6i (280mg), which was used in the next reaction without purification.

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

The ninth step

Compound 4h hydrochloride (72mg,0.18mmol) was dissolved in 6mL of a mixed solution of dichloromethane and methanol (V/V ═ 2/1), and sodium acetate (89mg,1.08mmol) was added to react for 10 minutes. Compound 6i (90mg,0.17mmol) was added and reacted for 15 minutes. Sodium triacetoxyborohydride (76mg,0.36mmol) was added thereto, and the reaction was carried out for 1 hour. Dichloromethane (20mL) was added, washed with saturated sodium chloride solution (10mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The obtained residue was prepared by high performance liquid chromatography (Waters2767-SQ Detector 2, elution: trifluoroacetic acid: 0.1%, water: 60%, acetonitrile: 40%) to obtain the title compound 6(33mg), yield: 21 percent.

MS m/z(ESI):860.2[M+1]。

¹HNMR(500MHz,DMSO-d₆)δ11.00(s,1H),7.92(d,1H),7.76(d,2H),7.69(d,1H),7.50(d,1H),7.41(s,1H),7.22-7.19(m,2H),7.03-6.93(m,3H),5.02-5.00(m,1H),4.45,4.35(dd,2H),4.34-4.32(m,1H),4.07-4.01(m,3H),3.89-3.86(m,2H),3.65-3.62(m,2H),3.27-3.08(m,5H),2.94-2.87(m,1H),2.80(t,2H),2.65-2.60(m,1H),2.42-2.37(m,1H),2.05-1.98(m,2H),1.80-1.77(m,2H),1.69-1.66(m,2H),1.59-1.52(m,1H),1.48-1.45(m,2H),1.23(s,6H),1.14(s,6H)。

Example 7

N- ((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -4- (4- ((4- (2- (2, 6-dioxopiperidin-3-yl) -3-oxo-2, 3-dihydro-1H-benzofuro [2,3-c ] pyrrol-6-yl) piperazin-1-yl) methyl) piperidin-1-yl) benzamide 7

First step of

Compound 4h (37mg,0.06mmol) was dissolved in 3mL of a mixed solution of dichloromethane and methanol (V/V ═ 2/1), and sodium acetate (32mg,0.4mmol) was added to react for 10 minutes. 3g of the compound (32mg,0.6mmol) was added thereto, and the reaction was carried out for 15 minutes. Sodium triacetoxyborohydride (28mg,0.13mmol) was added and reacted for 1 hour. Dichloromethane (20mL) was added, washed with saturated sodium chloride solution (10mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The obtained residue was prepared by high performance liquid chromatography (Waters2767-SQ Detector 2, elution: trifluoroacetic acid: 0.1%, water: 60%, acetonitrile: 40%) to obtain the title compound 7(33mg), yield: 21 percent.

MS m/z(ESI):846.2[M+1]。

¹HNMR(500MHz,DMSO-d₆)δ11.00(s,1H),7.92(d,1H),7.77(d,2H),7.69(d,1H),7.51(d,1H),7.41(s,1H),7.22-7.19(m,2H),7.03-6.99(m,3H),5.02-4.98(m,1H),4.45,4.35(dd,2H),4.38-4.33(m,1H),4.07-3.98(m,3H),3.90-3.92(m,2H),3.63-3.60(m,2H),3.22-3.15(m,3H),2.93-2.82(m,1H),2.64-2.60(m,2H),2.41-2.36(m,2H),2.12-1.98(m,4H),1.87-1.85(m,3H),1.32-1.28(m,2H),1.31(s,6H),1.15(s,6H)。

Example 8

N- ((1R,3R) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -4- (((3R) -1- (2- (1- (2- (2, 6-dioxopiperidin-3-yl) -3-oxo-2, 3-dihydro-1H-benzofuro [2,3-c ] pyrrol-6-yl) piperidin-4-yl) ethyl) pyrrolidin-3-yl) oxy) benzamide 8

First step of

6- (4- (2, 2-Dimethoxyethyl) piperidin-1-yl) -3-formylbenzofuran-2-carboxylic acid ethyl ester 8a

Compound 4d (1g,3.4mmol) and compound 6e (700mg,3.5mmol) were dissolved in N, N-dimethylformamide (15mL), and cesium carbonate (1.1g,3.4mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (RuPhos Pd G3,284mg,0.34mmol) were added. The reaction was heated to 100 ℃ for 4 hours under an argon atmosphere. Ethyl acetate (50mL) and water (50mL) were added and the layers were separated. The organic phase was washed successively with water (10 mL. times.3) and saturated sodium chloride solution (10 mL. times.3). Dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The obtained residue was purified by silica gel column chromatography with the developing solvent system B to obtain the title compound 8a (290mg), yield: 22 percent.

MS m/z(ESI):390.2[M+1]。

Second step of

6- (4- (2, 2-Dimethoxyethyl) piperidin-1-yl) -3-formylbenzofuran-2-carboxylic acid 8b

Compound 8a (290mg,0.7mmol) was dissolved in 10mL of a mixed solvent of tetrahydrofuran and water (V/V ═ 1.5/1), and lithium hydroxide monohydrate (156mg,3.7mmol) was added. The reaction was carried out at room temperature for 2 hours, cooled in an ice bath, and the solution was adjusted to pH 5 with dilute hydrochloric acid (1M). Water (20mL) was added, and the mixture was extracted with ethyl acetate (10 mL. times.3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and the solvent was removed by concentration under reduced pressure to give the crude title compound 8b (269mg), which was used in the next reaction without purification.

MS m/z(ESI):362.2[M+1]。

The third step

6- (4- (2, 2-Dimethoxyethyl) piperidin-1-yl) -3- (((2, 6-dioxopiperidin-3-yl) amino) methyl) benzofuran-2-carboxylic acid 8c

3-amino-piperidine-2, 6-dione hydrochloride (122mg,0.74mmol, Shanghai Bigdi pharmaceutical science Co., Ltd.) was dissolved in 25mL of a mixed solvent of dichloromethane and methanol (V/V. RTM. 4/1), and sodium acetate (306mg,3.7mmol) was added to the solution to react for 10 minutes. Compound 8b (269mg,0.74mmol) was added and the reaction was carried out for 15 minutes. Sodium cyanoborohydride (90mg,1.5mmol) was added and the reaction was carried out for 1 hour. The reaction solution was concentrated under reduced pressure to remove the solvent. The obtained residue was purified by silica gel column chromatography with the developer system a to obtain the title compound 8c (320mg), yield: 91 percent.

MS m/z(ESI):474.2[M+1]。

The fourth step

3- (6- (4- (2, 2-Dimethoxyethyl) piperidin-1-yl) -3-oxo-1H-benzofuro [2,3-c ] pyrrol-2 (3H) -yl) piperidine-2, 6-dione 8d

Compound 8c (320mg,0.67mmol) was dissolved in N, N-dimethylformamide (10mL), and 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (299mg,0.79mmol) and triethylamine (206mg,2mmol) were added and reacted at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to remove the solvent, and the obtained residue was purified by silica gel column chromatography with developer system a to give the title compound 8d (140mg), yield: 45 percent. MS M/z (ESI) 456.2[ M +1 ].

The fifth step

2- (1- (2- (2, 6-dioxopiperidin-3-yl) -3-oxo-2, 3-dihydro-1H-benzofuro [2,3-c ] pyrrol-6-yl) piperidin-4-yl) acetaldehyde 8e

Compound 8d (140mg,0.31mmol) was added to tetrahydrofuran (3mL) and dilute sulfuric acid (2M,1.5mL) was added. The reaction was carried out at room temperature for 1 hour, cooled in an ice bath, and the solution was adjusted to pH 7 with saturated sodium bicarbonate. Extraction was performed with ethyl acetate (10 mL. times.3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and the solvent was removed by concentration under reduced pressure to give the crude title compound 8e (125mg), which was used in the next reaction without purification.

MS m/z(ESI):410.2[M+1]。

The sixth step

(R) -3- (4- (methoxycarbonyl) phenoxy) pyrrolidine-1-carboxylic acid tert-butyl ester 8g

Methyl 4-hydroxybenzoate 8f (3g,19.7mmol, national pharmaceutical group chemical Co., Ltd.) and tert-butyl (S) -3-hydroxypyrrolidine-1-carboxylate (3.7g,19.7mmol, Shaoshima scientific and technological (Shanghai) Co., Ltd.) were dissolved in tetrahydrofuran (40 mL). Triphenylphosphine (6.21g,23.7mmol, Chemicals, Inc., national drug group) was added. Diisopropyl azodicarboxylate (4.8g,23.7mmol, Shaoshi Tech Co., Ltd.) was added dropwise. The reaction was heated to 60 ℃ for 24 hours. Water (100mL) was added, and the mixture was extracted with ethyl acetate (50 mL. times.3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent, and the resulting residue was purified by silica gel column chromatography with developer system B to give the title compound 8g (5.7g), yield: 90 percent.

MS m/z(ESI):266.2[M-55]。

Seventh step

(R) -4- ((1- (tert-Butoxycarbonyl) pyrrolidin-3-yl) oxy) benzoic acid 8h

Compound 8g (5.7g,17.7mmol) was dissolved in 90mL of a mixed solvent of methanol and water (V/V ═ 5/4), and sodium hydroxide (3.5g,88.5mmol) was added to the solution, followed by reaction at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, the pH of the solution was adjusted to 5 with dilute hydrochloric acid (1M), and the solution was extracted with ethyl acetate (50mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove the solvent, and the resulting residue was purified by silica gel column chromatography with developer system a to give the title compound 8h (3g), yield: and 55 percent.

MS m/z(ESI):252.1[M-55]。

Eighth step

(R) -3- (4- (((1R,3R) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) carboxamido) phenoxy) pyrrolidine-1-carboxylic acid tert-butyl ester 8i

1l of the hydrochloride salt of the compound (347mg,1.1mmol) and the compound (8 h) (340mg,1.1mmol) were dissolved in N, N-dimethylformamide (5mL), and 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (520mg,1.4mmol) and N, N-diisopropylethylamine (295mg,2.3mmol) were added and reacted at room temperature for 16 hours. The reaction solution was diluted with water (50mL), extracted with ethyl acetate (50 mL. times.3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent to give the title compound 8i crude product (350mg), which was used in the next reaction without purification.

MS m/z(ESI):512.0[M-55]

The ninth step

N- ((1R,3R) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -4- ((R) -pyrrolidin-3-yloxy) benzamide trifluoroacetate 8j

Compound 8i (328mg,0.6mmol) was dissolved in dichloromethane (10mL), trifluoroacetic acid (1mL) was added dropwise, and the reaction was carried out at room temperature for 1 hour, followed by concentration under reduced pressure to give the title compound 8j as a crude product (538mg), which was used in the next reaction without purification.

MS m/z(ESI):468.1[M+1]

The tenth step

Compound 8j (113mg,0.12mmol) was dissolved in 15mL of a mixed solvent of dichloromethane and methanol (V/V ═ 2/1), and sodium acetate (101mg,1.2mmol) was added to react for 10 minutes. Compound 8e (50mg,0.12mmol) was added and reacted for 15 minutes. Sodium triacetoxyborohydride (78mg,0.36mmol) was added thereto, and the reaction was carried out for 2 hours. Dichloromethane (20mL) was added, washed with saturated sodium chloride solution (10mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The obtained residue was prepared by high performance liquid chromatography (Waters2767-SQ Detector 2, elution: trifluoroacetic acid: 0.1%, water: 60%, acetonitrile: 40%) to obtain the title compound 8(15mg), yield: 14 percent.

MS m/z(ESI):861.3[M+1]。

¹HNMR(500MHz,DMSO-d₆)δ10.99(s,1H),7.91-7.88(m,3H),7.72(d,1H),7.59(d,1H),7.25(s,1H),7.21(d,1H),7.12-7.10(m,1H),7.08-7.02(m,3H),5.30-5.25(m,1H),4.98-4.96(m,1H),4.45,4.35(dd,2H),4.32(s,1H),4.07-4.05(m,1H),3.84-3.81(m,2H),3.80-3.78(m,2H),3.30-3.25(m,3H),2.94-2.86(m,1H),2.82-2.76(m,2H),2.66-2.58(m,2H),2.42-2.36(m,2H),2.11-1.96(m,2H),1.80-1.76(m,2H),1.67-1.61(m,2H),1.58-1.51(m,1H),1.34-1.25(m,2H),1.23(s,6H),1.14(s,6H)。

Example 9

N- ((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -4- ((1- (2- (1- (2- (2, 6-dioxopiperidin-3-yl) -3-oxo-2, 3-dihydro-1H-benzofuro [2,3-c ] pyrrol-6-yl) piperidin-4-yl) ethyl) azetidin-3-yl) oxy) benzamide 9

Referring to the synthesis of example 8, the sixth step of starting tert-butyl (S) -3-hydroxypyrrolidine-1-carboxylate was replaced with tert-butyl 3-hydroxyazetidine-1-carboxylate (shaoyuan technologies, inc.) to give the title compound 9(30 mg).

MS m/z(ESI):847.3[M+1]。

¹HNMR(500MHz,DMSO-d₆)δ10.99(s,1H),7.91(d,1H),7.88(d,2H),7.75(d,1H),7.59(d,1H),7.25-7.19(m,2H),7.12-7.10(m,1H),7.02-6.95(m,3H),5.22-5.15(m,1H),5.00-4.98(m,1H),4.76-4.70(m,1H),4.45,4.35(dd,2H),4.33(s,1H),4.29-4.24(m,1H),4.19-4.14(m,1H),4.07(d,1H),3.86-3.83(m,2H),3.35-3.25(m,3H),2.94-2.86(m,1H),2.82-2.78(m,2H),2.66-2.58(m,1H),2.43-2.34(m,1H),2.06-1.99(m,1H),1.80-1.72(m,2H),1.56-1.43(m,3H),1.34-1.25(m,2H),1.23(s,6H),1.14(s,6H)。

Example 10

N- ((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -4- (4- ((4- (2- (2, 6-dioxopiperidin-3-yl) -3-oxo-2, 3-dihydro-1H-benzofuro [2,3-c ] pyrrol-6-yl) -5, 6-dihydropyridin-1 (2H) -yl) methyl) piperidin-1-yl) benzamide 10

First step of

6-bromo-3- (bromomethyl) benzofuran-2-carboxylic acid 10a

Compound 4c (7.3g,20.2mmol) was dissolved in 45mL of a mixed solvent of tetrahydrofuran and water (V/V ═ 1/2), and lithium hydroxide monohydrate (1.7g,40.5mmol) was added to react at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, the pH of the solution was adjusted to 5 with diluted hydrochloric acid (1M), filtered, and the filter cake was collected and dried to obtain the crude title compound 10a (6g), which was used in the next reaction without purification.

MS m/z(ESI):333.0[M-1]。

Second step of

6-bromo-3- (((2, 6-dioxopiperidin-3-yl) amino) methyl) benzofuran-2-carboxylic acid 10b

Compound 10a (1.8g,5.4mmol), 3-aminopiperidine-2, 6-dione hydrochloride (888mg,5.4mmol) and N, N-diisopropylethylamine (2.1g,16.3mmol) were added to N, N-dimethylformamide (50mL), and the mixture was heated to 60 ℃ for reaction for 16 hours. The solvent was removed by concentration under reduced pressure, and the obtained residue was purified by silica gel column chromatography with developer system a to give the title compound 10b (1.25g), yield: 61 percent.

MS m/z(ESI):382.8[M+1]。

The third step

3- (6-bromo-3-oxo-1H-benzofuro [2,3-c ] pyrrol-2 (3H) -yl) piperidine-2, 6-dione 10c

Compound 10b (1.25g,3.3mmol) was dissolved in N, N-dimethylformamide (15mL), and 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (1.5g,3.9mmol) and N, N-diisopropylethylamine (1g,8mmol) were added and reacted at room temperature for 1 hour. The solvent was removed by concentration under reduced pressure, and the obtained residue was purified by silica gel column chromatography with developer system a to give the title compound 10c (1.1g), yield: 92 percent.

MS m/z(ESI):362.8[M+1]。

The fourth step

4- (2- (2, 6-dioxopiperidin-3-yl) -3-oxo-2, 3-dihydro-1H-benzofuro [2,3-c ] pyrrol-6-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester 10d

Compound 10c (400mg,1.1mmol) and N-Boc-1,2,5, 6-tetrahydropyridine-4-boronic acid pinacol ester (511mg,1.65mmol, Shanghai Shao Yuan pharmaceutical science, Inc.) were added to N, N-dimethylformamide (10 mL). Water (3mL), palladium [1,1' -bis (diphenylphosphino) ferrocene ] dichloride (81mg,0.11mmol, Prodweiser technologies, Inc.) and N, N-diisopropylethylamine (450mg,3.5mmol) were added. Argon was bubbled for 5 minutes and the reaction was heated to 100 ℃ in a microwave reactor for 1 hour. The reaction solution was diluted with water (20mL), extracted with ethyl acetate (10 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent to give the title compound 10d as a crude product (400mg), which was used in the next reaction without purification.

MS m/z(ESI):466.1[M+1]。

The fifth step

3- (3-oxo-6- (1,2,3, 6-tetrahydropyridin-4-yl) -1H-benzofuro [2,3-c ] pyrrol-2 (3H) -yl) piperidine-2, 6-dione trifluoroacetate 10e

Compound 10d (300mg,0.64mmol) was dissolved in dichloromethane (10mL), cooled in an ice bath, and trifluoroacetic acid (2mL) was added dropwise. Slowly raising the temperature to room temperature, and reacting for 2 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, to give the crude title compound 10e (100mg), which was used in the next reaction without purification.

MS m/z(ESI):366.0[M+1]。

The sixth step

Compound 10e (30mg,0.082mmol) was dissolved in 6mL of a mixed solvent of dichloromethane and methanol (V/V ═ 2/1), and sodium acetate (60mg,0.73mmol) was added to react for 10 minutes. 3g of the compound (41mg,0.082mmol) was added thereto, and the reaction was carried out for 15 minutes. Sodium triacetoxyborohydride (42mg,0.2mmol) was added thereto, and the reaction was carried out for 1 hour. Dichloromethane (20mL) was added, washed with saturated sodium chloride solution (10mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The obtained residue was prepared by high performance liquid chromatography (Waters2767-SQ Detector 2, elution: trifluoroacetic acid: 0.1%, water: 60%, acetonitrile: 40%) to obtain the title compound 10(10mg), yield: 14 percent.

MS m/z(ESI):843.3[M+1]。

¹HNMR(500MHz,DMSO-d₆)δ11.00(s,1H),7.97(d,1H),7.90(d,1H),7.85(d,1H),7.77(d,2H),7.69(d,1H),7.48(d,1H),7.25-7.15(m,1H),7.04-6.97(m,3H),6.42(t,1H),5.03-4.96(m,1H),4.45,4.35(dd,2H),4.33(s,1H),4.18-4.16(m,1H),4.08(d,1H),3.82-3.75(m,3H),3.73-3.70(m,1H),3.25-3.20(m,2H),2.95-2.85(m,4H),2.66-2.57(m,1H),2.45-2.39(m,1H),2.25-2.20(m,1H),2.18-2.14(m,2H),1.98-1.92(m,2H),1.30-1.25(m,3H),1.22(s,6H),1.13(s,6H)。

Example 11

N- ((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -4- (1- ((1- (2- (2, 6-dioxopiperidin-3-yl) -3-oxo-2, 3-dihydro-1H-benzofuro [2,3-c ] pyrrol-6-yl) piperidin-4-yl) methyl) piperidin-4-yl) benzamide 11

First step of

6- (4- (Dimethoxymethyl) piperidin-1-yl) -3-formylbenzofuran-2-carboxylic acid ethyl ester 11a

Compound 4d (2.54g,8.5mmol) and compound 3c (2.3g,14.4mmol) were dissolved in N, N-dimethylformamide (30mL), and cesium carbonate (4.2g,13mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (RuPhos Pd G3,711mg,0.85mmol) were added. The reaction was heated to 100 ℃ for 16 hours under an argon atmosphere. Ethyl acetate (100mL) and water (50mL) were added and the layers were separated. The organic phase was washed successively with water (20 mL. times.3) and saturated sodium chloride solution (20 mL. times.3). Dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The obtained residue was purified by silica gel column chromatography with the developing solvent system B to obtain the title compound 11a (450mg), yield: 14 percent.

MS m/z(ESI):376.2[M+1]。

Second step of

6- (4- (Dimethoxymethyl) piperidin-1-yl) -3-formylbenzofuran-2-carboxylic acid 11b

Compound 11a (450mg,1.2mmol) was dissolved in 10mL of a mixed solvent of tetrahydrofuran and water (V/V ═ 4/1), and lithium hydroxide monohydrate (75mg,1.8mmol) was added. The reaction was carried out at room temperature for 1 hour, cooled in an ice bath, and the solution was adjusted to pH 7 with dilute hydrochloric acid (1M). Water (20mL) was added, and the mixture was extracted with ethyl acetate (10 mL. times.3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and the solvent was removed by concentration under reduced pressure to give the crude title compound 11b (416mg), which was used in the next reaction without purification.

MS m/z(ESI):348.2[M+1]。

The third step

6- (4- (Dimethoxymethyl) piperidin-1-yl) -3- (((2, 6-dioxopiperidin-3-yl) amino) methyl) benzofuran-2-carboxylic acid 11c

3-amino-piperidine-2, 6-dione hydrochloride (211mg,1.28mmol) was dissolved in 20mL of a mixed solvent of dichloromethane and methanol (V/V ═ 3/1), and sodium acetate (450mg,5.5mmol) was added to react for 10 minutes. Compound 11b (370mg,1.1mmol) was added and reacted for 15 minutes. Sodium cyanoborohydride (138mg,2.2mmol) was added and reacted for 1 hour. The reaction solution was concentrated under reduced pressure to remove the solvent. The resulting residue was purified by silica gel column chromatography with developer system a to give the title compound 11c (175mg), yield: 30 percent.

MS m/z(ESI):460.2[M+1]。

The fourth step

3- (6- (4- (dimethoxymethyl) piperidin-1-yl) -3-oxo-1H-benzofuro [2,3-c ] pyrrol-2 (3H) -yl) piperidine-2, 6-dione 11d

Compound 11c (115mg,0.25mmol) was dissolved in N, N-dimethylformamide (5mL), and 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (100mg,0.26mmol) and triethylamine (53mg,0.52mmol) were added and reacted at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to remove the solvent, and the obtained residue was purified by silica gel column chromatography with developer system a to give the title compound 11d (70mg), yield: and 63 percent. MS M/z (ESI) 442.2[ M +1 ].

The fifth step

1- (2- (2, 6-dioxopiperidin-3-yl) -3-oxo-2, 3-dihydro-1H-benzofuro [2,3-c ] pyrrol-6-yl) piperidine-4-carbaldehyde 11e

Compound 11d (100mg,0.22mmol) was added to tetrahydrofuran (3mL) and dilute sulfuric acid (2M,1.5mL) was added. The reaction was carried out at room temperature for 1 hour, cooled in an ice bath, and the solution was adjusted to pH 7 with saturated sodium bicarbonate. Extraction was performed with ethyl acetate (10 mL. times.3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and the solvent was removed by concentration under reduced pressure to give the crude title compound 11e (90mg), which was used in the next reaction without purification.

MS m/z(ESI):396.0[M+1]。

The sixth step

4- (4- (methoxycarbonyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester 11g

Methyl 4-iodobenzoate 11f (677mg,2.6mmol) and N-Boc-1,2,5, 6-tetrahydropyridine-4-boronic acid pinacol ester (800mg,2.6mmol) were dissolved in a mixed solvent of toluene (20mL), ethanol (6mL) and water (2 mL). 2-dicyclohexylphosphine-2 ',6' -dimethoxy-biphenyl (213mg,0.52mmol), palladium (II) acetate (58mg,0.26mmol) and potassium phosphate (1.65g,7.8mmol) were added, the mixture was replaced with nitrogen 3 times, and the mixture was heated at 90 ℃ for 5 hours under a nitrogen atmosphere. The reaction solution was concentrated under reduced pressure to remove the solvent, and the obtained residue was purified by silica gel column chromatography with developer system B to obtain the title compound 11g (660mg), yield: 80 percent.

MS m/z(ESI):262.0[M-55]

Seventh step

4- (4- (methoxycarbonyl) phenyl) piperidine-1-carboxylic acid tert-butyl ester 11h

Compound 11g (227mg,0.72mmol) was dissolved in methanol (5mL), and palladium on carbon (22mg, 10% wt) was added to react under a hydrogen atmosphere at room temperature for 16 hours. The solvent was removed by concentration under reduced pressure to give the title compound 11h as crude product (228mg), which was used in the next reaction without purification.

MS m/z(ESI):264.0[M-55]

Eighth step

4- (1- (tert-Butoxycarbonyl) piperidin-4-yl) benzoic acid 11i

Compound 11h (228mg,0.72mmol) was dissolved in 6mL of a mixed solvent of methanol and water (V/V ═ 5/1), and sodium hydroxide (130mg,3.3mmol) was added and the mixture was heated to 65 ℃ for reaction for 3 hours. The reaction solution was concentrated under reduced pressure, the pH of the solution was adjusted to 5 with dilute hydrochloric acid (1M), filtered, and the filter cake was collected and dried to obtain the title compound 11i (200mg), yield: 91 percent.

MS m/z(ESI):250.1[M-55]

The ninth step

4- (4- (((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) carboxamido) phenyl) piperidine-1-carboxylic acid tert-butyl ester 11j

Compound 1l hydrochloride (104mg,0.33mmol) and compound 11i (100mg,0.33mmol) were dissolved in N, N-dimethylformamide (3mL), and 2- (7-oxybenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (150mg,0.39mmol) and N, N-diisopropylethylamine (220mg,1.7mmol) were added and reacted at room temperature for 2 hours. The reaction solution was diluted with water (50mL), extracted with ethyl acetate (50mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent, and the resulting residue was purified by silica gel column chromatography with developer system B to give the title compound 11j (160mg), yield: 86 percent.

MS m/z(ESI):510.1[M-55]

The tenth step

N- ((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -4- (piperidin-4-yl) benzamide hydrochloride 11k

Compound 11j (160mg,0.28mmol) was dissolved in dichloromethane (2mL), and dioxane hydrochloride solution (4M,1mL,4mmol) was added to the solution to react at room temperature for 2 hours. The solvent was removed by concentration under reduced pressure to give the title compound 11k (130mg), yield: 98 percent.

MS m/z(ESI):466.1[M+1]

The eleventh step

Compound 11k (36mg,0.07mmol) was dissolved in 4mL of a mixed solvent of dichloromethane and methanol (V/V ═ 2/1), and sodium acetate (40mg,0.49mmol) was added to react for 10 minutes. Compound 11e (20mg,0.05mmol) was added and reacted for 15 minutes. Sodium triacetoxyborohydride (22mg,0.1mmol) was added thereto, and the reaction was carried out for 1 hour. Dichloromethane (20mL) was added, washed with saturated sodium chloride solution (10mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The obtained residue was prepared by high performance liquid chromatography (Waters2767-SQ Detector 2, elution: trifluoroacetic acid: 0.1%, water: 60%, acetonitrile: 40%) to obtain the title compound 11(9mg), yield: 18 percent.

MS m/z(ESI):845.2[M+1]

¹HNMR(500MHz,DMSO-d₆)δ10.99(s,1H),7.91(d,1H),7.86-7.78(m,3H),7.61(d,1H),7.37(d,1H),7.28-7.22(m,2H),7.15-7.13(m,1H),7.09-7.06(m,1H),7.05-7.01(m,1H),5.03-4.96(m,1H),4.45,4.35(dd,2H),4.33-4.28(m,1H),4.08(d,1H),3.90(d,2H),3.66(d,2H),3.14-3.03(m,4H),2.97-2.80(m,4H),2.66-2.59(m,1H),2.44-2.38(m,1H),2.15-1.95(m,6H),1.89(d,2H),1.42-1.31(m,2H),1.24(s,6H),1.15(s,6H)。

Example 12

N- ((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -4- ((1- ((1- (2- (2, 6-dioxopiperidin-3-yl) -3-oxo-2, 3-dihydro-1H-benzofuro [2,3-c ] pyrrol-6-yl) piperidin-4-yl) methyl) azetidin-3-yl) oxy) benzamide 12

Referring to the synthesis method of example 8, the sixth step of starting tert-butyl (S) -3-hydroxypyrrolidine-1-carboxylate was replaced with tert-butyl 3-hydroxyazetidine-1-carboxylate to give compound 12a (104mg)

Compound 12a (104mg,0.11mmol) was dissolved in 3mL of a mixed solution of dichloromethane and methanol (V/V ═ 2/1), and sodium acetate (63mg,0.76mmol) was added to the solution, followed by reaction for 10 minutes. Compound 11e (30mg,0.076mmol) was added and reacted for 15 minutes. Sodium triacetoxyborohydride (33mg,0.16mmol) was added thereto, and the reaction was carried out for 1 hour. Dichloromethane (20mL) was added, washed with saturated sodium chloride solution (10mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The obtained residue was prepared by high performance liquid chromatography (Waters2767-SQ Detector 2, elution: trifluoroacetic acid: 0.1%, water: 60%, acetonitrile: 40%) to obtain the title compound 12(10mg), yield: 14 percent.

MS m/z(ESI):833.1[M+1]。

¹HNMR(500MHz,DMSO-d₆)δ10.99(s,1H),7.91(d,1H),7.88(d,2H),7.75(d,1H),7.59(d,1H),7.25(d,1H),7.21(d,1H),7.14-7.11(m,1H),7.03-6.95(m,3H),5.22-5.10(m,1H),5.00-4.98(m,1H),4.83-4.75(m,1H),4.60-4.54(m,1H),4.45,4.35(dd,2H),4.33(s,1H),4.27-4.22(m,1H),4.07(d,1H),3.86-3.83(m,2H),3.31-3.21(m,3H),2.94-2.86(m,1H),2.79-2.76(m,2H),2.66-2.58(m,1H),2.43-2.34(m,1H),2.06-1.99(m,1H),1.88-1.75(m,3H),1.34-1.25(m,2H),1.23(s,6H),1.14(s,6H)。

Example 13

N- ((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -4- ((1- ((1- (2- (2, 6-dioxopiperidin-3-yl) -3-oxo-2, 3-dihydro-1H-benzofuro [2,3-c ] pyrrol-6-yl) piperidin-4-yl) methyl) piperidin-4-yl) oxy) benzamide 13

Referring to the synthesis method of example 8, tert-butyl (S) -3-hydroxypyrrolidine-1-carboxylate, a starting material in the sixth step, was replaced with tert-butyl 4-hydroxypiperidine-1-carboxylate (Shao Yuan technology (Shanghai)) to obtain compound 13a (64 mg).

Compound 13a (64mg,0.13mmol) was dissolved in 3mL of a mixed solution of dichloromethane and methanol (V/V ═ 2/1), and sodium acetate (73mg,0.89mmol) was added to the solution, followed by reaction for 10 minutes. Compound 11e (35mg,0.088mmol) was added and reacted for 15 minutes. Sodium triacetoxyborohydride (38mg,0.18mmol) was added thereto, and the reaction was carried out for 1 hour. Dichloromethane (20mL) was added, washed with saturated sodium chloride solution (10mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The obtained residue was prepared by high performance liquid chromatography (Waters2767-SQ Detector 2, elution: trifluoroacetic acid: 0.1%, water: 60%, acetonitrile: 40%) to obtain the title compound 13(30mg), yield: 39 percent.

MS m/z(ESI):861.4[M+1]

¹HNMR(500MHz,DMSO-d₆)δ10.99(s,1H),7.91-7.85(m,3H),7.78(d,1H),7.61-7.58(m,1H),7.37-7.32(m,1H),7.23-7.20(m,1H),7.15-7.10(m,3H),7.05-7.02(m,1H),5.03-4.96(m,1H),4.45,4.35(dd,2H),4.33(s,1H),4.08(d,1H),3.90-3.85(m,2H),3.66-3.60(m,1H),3.52-3.48(m,1H),3.14-3.05(m,4H),2.92-2.80(m,3H),2.66-2.57(m,1H),2.44-2.38(m,1H),2.27-2.23(m,1H),2.18-2.05(m,5H),1.89-1.85(m,3H),1.42-1.31(m,2H),1.24(s,6H),1.15(s,6H)。

Example 14

N- ((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -4- (4- (2- (1- (2- (2, 6-dioxopiperidin-3-yl) -3-oxo-2, 3-dihydro-1H-benzofuro [2,3-c ] pyrrol-6-yl) piperidin-4-yl) ethyl) piperazin-1-yl) benzamide 14

First step of

4- (4- (methoxycarbonyl) phenyl) piperazine-1-carboxylic acid tert-butyl ester 14b

Methyl 4-fluorobenzoate 14a (917mg,5.9mmol, Shaoyuan (Shanghai) Co., Ltd.), tert-butyl piperazine-1-carboxylate (1.66g,8.9mmol, Shaoyuan (Shanghai) Co., Ltd.) and potassium carbonate (1.65g,12mmol) were dissolved in N, N-dimethylformamide (15mmol), and the reaction was heated to 100 ℃ for 24 hours. The reaction mixture was diluted with ethyl acetate (100mL), and the organic phase was washed successively with water (20 mL. times.3) and saturated sodium chloride solution (20 mL. times.3). Dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The resulting residue was purified by silica gel column chromatography with developer system B to give the title compound 14B (370mg), yield: 19 percent.

MS m/z(ESI):265.2[M-55]。

Second step of

4- (4- (tert-Butoxycarbonyl) piperazin-1-yl) benzoic acid 14c

Compound 14b (370mg,1.2mmol) was dissolved in 6mL of a mixed solvent of methanol and water (V/V ═ 2/1), and sodium hydroxide (133mg,2mmol) was added, followed by heating to 50 ℃ for reaction for 5 hours. The reaction solution was concentrated under reduced pressure to remove the solvent, the solution was adjusted to pH 5 with dilute hydrochloric acid (1M), filtered, and the filter cake was collected and dried to give the crude title compound 14c (330mg), which was used in the next reaction without purification.

MS m/z(ESI):251.2[M-55]。

The third step

4- (4- (((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) carboxamido) phenyl) piperazine-1-carboxylic acid tert-butyl ester

The compound 1l hydrochloride (340mg,1.1mmol) and the compound 14c (330mg,1.1mmol) were dissolved in N, N-dimethylformamide (5mL), and 2- (7-oxybenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (491mg,1.3mmol) and N, N-diisopropylethylamine (327mg,3.2mmol) were added and reacted at room temperature for 2 hours. The reaction solution was diluted with water (50mL), extracted with ethyl acetate (20mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent, and the resulting residue was purified by silica gel column chromatography with developer system B to give the title compound 14d (540mg), yield: 88 percent.

MS m/z(ESI):511.3[M-55]。

The fourth step

N- ((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -4- (piperazin-1-yl) benzamide hydrochloride 14e

Compound 14d (540mg,0.95mmol) was dissolved in dichloromethane (5mL), and dioxane hydrochloride solution (4M,2mL,8mmol) was added to the solution to react at room temperature for 2 hours. The solvent was removed by concentration under reduced pressure to give the title compound 14e (475mg), yield: 99 percent.

MS m/z(ESI):467.1[M+1]

The fifth step

N- ((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -4- (4- (2- (1- (2- (2, 6-dioxopiperidin-3-yl) -3-oxo-2, 3-dihydro-1H-benzofuran [2,3-c ] pyrrol-6-yl) piperidin-4-yl) ethyl) piperazin-1-yl) benzamide 14

Compound 14e (60mg,0.12mmol) was dissolved in 6mL of a mixed solvent of dichloromethane and methanol (V/V ═ 2/1), and sodium acetate (57mg,0.7mmol) was added to react for 10 minutes. Compound 8e (48mg,0.12mmol) was added and reacted for 15 minutes. Sodium triacetoxyborohydride (50mg,0.24mmol) was added thereto, and the reaction was carried out for 1 hour. Dichloromethane (20mL) was added, washed with saturated sodium chloride solution (10mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The obtained residue was prepared by high performance liquid chromatography (Waters2767-SQ Detector 2, elution: trifluoroacetic acid: 0.1%, water: 60%, acetonitrile: 40%) to obtain the title compound 14(15mg), yield: 14 percent.

MS m/z(ESI):859.8[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ10.99(s,1H),7.92(d,1H),7.82(d,2H),7.61-7.58(m,2H),7.25(d,1H),7.22-7.18(m,1H),7.13-7.10(m,1H),7.08-7.05(m,2H),7.03-7.00(m,3H),5.02-4.99(m,1H),4.45,4.35(dd,2H),4.33(s,1H),4.08-4.04(m,2H),3.86(d,2H),3.63(d,2H),3.26-3.24(m,1H),3.20-3.13(m,2H),3.09-3.04(m,2H),2.94-2.87(m,1H),2.83-2.78(m,1H),2.65-2.63(m,1H),2.43-2.37(m,1H),2.05-1.97(m,2H),1.82(d,2H),1.70-1.66(m,2H),1.56-1.54(m,1H),1.48-1.45(m,2H),1.23(m,6H),1.14(s,6H)。

Example 15

N- ((1r,3r) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -4- (4- ((4- (2- (2, 6-dioxopiperidin-3-yl) -3-oxo-2, 3-dihydro-1H-benzofuro [2,3-c ] pyrrol-6-yl) piperidin-1-yl) methyl) piperidin-1-yl) benzamide 15

First step of

4- (2- (2, 6-dioxopiperidin-3-yl) -3-oxo-2, 3-dihydro-1H-benzofuro [2,3-c ] pyrrol-6-yl) piperidine-1-carboxylic acid tert-butyl ester 15a

Compound 10d (400mg,0.86mmol) was dissolved in a mixed solvent of ethyl acetate (15mL) and tetrahydrofuran (15mL), palladium on carbon (150mg, 10% wt) was added, hydrogen substitution was carried out three times, and reaction was carried out for 24 hours under a hydrogen atmosphere. The solvent was removed by concentration under reduced pressure to give the crude title compound 15a (350mg), which was used in the next reaction without purification.

MS m/z(ESI):468.1[M+1]。

Second step of

3- (3-oxo-6- (piperidin-4-yl) -1H-benzofuro [2,3-c ] pyrrol-2 (3H) -yl) piperidine-2, 6-dione trifluoroacetate 15b

Compound 15a (350mg,0.75mmol) was dissolved in dichloromethane (10mL), cooled in an ice bath, and trifluoroacetic acid (2mL) was added dropwise and allowed to slowly warm to room temperature for 2 hours. The solvent was removed by concentration under reduced pressure to give the crude title compound 15b (250mg), which was used in the next reaction without purification.

MS m/z(ESI):368.1[M+1]。

The third step

Compound 15b (100mg,0.21mmol) was dissolved in 6mL of a mixed solvent of dichloromethane and methanol (V/V ═ 2/1), and sodium acetate (85mg,1mmol) was added to react for 10 minutes. 3g of the compound (103mg,0.21mmol) was added thereto, and the reaction was carried out for 15 minutes. Sodium triacetoxyborohydride (88mg,0.42mmol) was added thereto, and the reaction was carried out for 1 hour. Dichloromethane (20mL) was added, washed with saturated sodium chloride solution (10mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The obtained residue was prepared by high performance liquid chromatography (Waters2767-SQ Detector 2, elution: trifluoroacetic acid: 0.1%, water: 60%, acetonitrile: 40%) to obtain the title compound 15(15mg), yield: 9 percent.

MS m/z(ESI):845.3[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ11.00(s,1H),7.91(d,1H),7.85-7.78(m,2H),7.75(s,1H),7.55(d,1H),7.40(d,1H),7.25-7.20(m,1H),7.10(s,1H),7.04-6.97(m,3H),5.03-4.96(m,1H),4.45,4.35(dd,2H),4.33(s,1H),4.08-4.05(d,2H),3.98-3.94(d,2H),3.71-3.65(m,4H),3.43-3.37(m,2H),3.20-3.08(m,2H),2.95-2.85(m,3H),2.45-2.38(m,2H),2.25-2.00(m,4H),1.87-1.80(m,2H),1.42-1.37(m,2H),1.22(s,6H),1.13(s,6H)。

Example 16

N- ((1r,3S) -3- (3-chloro-4-cyanophenoxy) -2,2,4, 4-tetramethylcyclobutyl) -4- (((3S) -1- ((1- (2- (2, 6-dioxopiperidin-3-yl) -3-oxo-2, 3-dihydro-1H-benzofuro [2,3-c ] pyrrol-6-yl) piperidin-4-yl) methyl) pyrrolidin-3-yl) oxy) benzamide 16

Referring to the synthesis method of example 8, tert-butyl (S) -3-hydroxypyrrolidine-1-carboxylate, which is a raw material in the sixth step, was replaced with tert-butyl (R) -3-hydroxypyrrolidine-1-carboxylate (shanghai, seiki), to obtain compound 16a (50 mg).

Compound 16a (50mg,0.11mmol) was dissolved in 3mL of a mixed solution of dichloromethane and methanol (V/V ═ 2/1), and sodium acetate (73mg,0.89mmol) was added to the solution, followed by reaction for 10 minutes. Compound 11e (35mg,0.088mmol) was added and reacted for 15 minutes. Sodium triacetoxyborohydride (38mg,0.18mmol) was added thereto, and the reaction was carried out for 1 hour. Dichloromethane (20mL) was added, washed with saturated sodium chloride solution (10mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The obtained residue was prepared by high performance liquid chromatography (Waters2767-SQ Detector 2, elution: trifluoroacetic acid: 0.1%, water: 60%, acetonitrile: 40%) to obtain the title compound 16(12mg), yield: 13 percent.

MS m/z(ESI):847.2[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ10.99(s,1H),7.91-7.85(m,3H),7.78-7.86(m,1H),7.61-7.56(m,1H),7.28-7.25(m,1H),7.20-7.15(m,1H),7.20-7.00(m,4H),5.28-5.20(m,1H),5.03-4.96(m,1H),4.45,4.35(dd,2H),4.33(s,1H),4.08(d,2H),3.90-3.75(m,2H),3.66-3.63(m,1H),3.30-3.26(m,1H),3.24-3.10(m,2H),2.97-2.80(m,2H),2.66-2.57(m,2H),2.44-2.25(m,3H),2.20-2.00(m,3H),1.89-1.85(m,2H),1.42-1.31(m,2H),1.24(s,6H),1.15(s,6H)。

Test example:

biological evaluation

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

Test example 1: inhibitory Activity of the disclosed Compounds on LNCaP cell proliferation

LNCaP cells (ATCC, CRL-1740) were cultured in complete medium, RPMI1640 medium (Hyclone, SH30809.01) containing 10% fetal bovine serum (Corning, 35-076-CV). The first day of the experiment, LNCaP cells were seeded at a density of 1000 cells/well in 96-well plates using complete medium, 135. mu.L of cell suspension per well, placed at 37 ℃, 5% CO₂The cell culture box was cultured overnight. The following day, 15. mu.L of test compound diluted in a gradient of complete medium at 9 concentration points with 4-fold gradient starting from 10. mu.M was added to each well, a blank containing 0.5% DMSO was set, and the well plate was placed at 37 ℃ and 5% CO₂The cell culture chamber of (2) was cultured for 120 hours. On the seventh day, 96 well cell culture plates were removed and 50. mu.L of each well was added

Luminescennt Cell Viability Assay (Promega, G7573) was allowed to stand at room temperature for 10 minutes, and then the luminescence signal value was read using a multi-functional microplate reader (PerkinElmer, VICTOR 3), and IC of the inhibitory activity of the compound was calculated using Graphpad Prism software₅₀The values are shown in Table 1.

TABLE 1 IC of inhibitory Activity of the presently disclosed Compounds on LNCaP cell proliferation₅₀The value is obtained.

And (4) conclusion: the disclosed compounds can obviously inhibit LNCaP cell proliferation.

Test example 2: degradation activity of the compounds of the present disclosure on Androgen Receptors (ARs) in LNCaP cells.

Prostate cancer cell line LNCaP cells (ATCC, CRL-1740) were cultured in RPMI1640 medium (HyClone, SH30809.01) containing 10% fetal bovine serum (Corning, 35-010-CV). On the first day of the experiment, cells were digested with trypsin (gibco,25200-⁵one/mL. Add 100. mu.L of cell suspension to each well of a 96-well plate (Corning, 3599) and place the cells at 37 ℃ with 5% CO₂The culture was carried out overnight in an incubator. The next day of the experiment, compounds were formulated at 1000, 100, 10, 1, 0.1, 0.01, 0.001 μ M using a Bravo autosegregation apparatus to perform gradient dilutions in DMSO. Then 5. mu.L of the compound was added to 95. mu.L of phenol red-free RP containing 5% activated carbon-treated fetal bovine serumMI1640 medium, and mixed well with a microplate shaker. Then 10. mu.L of the compound diluted with the medium was added to the cells in the 96-well plate. The final concentrations of the compounds were 5000, 500, 50, 5, 0.5, 0.05 and 0.005 nM. Cells were incubated with compounds in an incubator for 20 to 24 hours. On day three of the experiment, the human AR total protein detection kit (Cell Signaling Technology,12850C) was equilibrated to room temperature, the Cell culture supernatant was discarded, the cells were washed once with 150 μ L per well of pre-cooled PBS, and 120 μ L of Cell lysate was added to each well. The cell lysate was 10X cell lysate in the kit and diluted to 1X with distilled water, and PMSF (Bio-Rad., A100754-0005) was added to the diluted cell lysate to a final concentration of 1 mM. Cells were lysed on ice for 15 minutes. Then 100. mu.L of each well of cell lysate was added to the ELISA plate pre-coated in the kit and incubated in an incubator at 37 ℃ for 2 hours. The 20 × wash solution in the kit was diluted to 1 × with distilled water, and the well plate was washed 5 times with 200 μ L of wash solution per well. Dissolving AR detection antibody freeze-dried powder in the kit completely by using 1mL of detection antibody diluent, adding the solution into the rest detection antibody diluent, mixing uniformly, adding 100 mu L of detection antibody into each hole, and incubating for 1 hour in an incubator at 37 ℃. The well plate is washed for 5 times, HRP coupling antibody freeze-dried powder in the kit is completely dissolved by using 1mL of HRP diluent and added into the rest HRP diluent to be fully mixed, then 100 mu L of HRP coupling antibody is added into each well, and the well is incubated at 37 ℃ for 30 minutes. The well plate was washed five more times, 100. mu.L of TMB substrate was added to each well, incubated at room temperature until blue color appeared, and 100. mu.L of stop solution was added to each well. OD450 signal values were read using a PHERAStar FS multifunctional microplate reader. DCs for Compound degradation Activity were calculated using Graphpad Prism software₅₀The value is obtained. The degradation activity of the compounds on AR in LNCaP cells is shown in table 2.

TABLE 2 DCs of degradation activity of compounds of the present disclosure on AR in LNCaP cells₅₀The value is obtained.

Compound (I)	DC₅₀(nM)
		1	6.2
2	6.1
		3	9.3
4	5.6
		6	11.6
8	18.6
		9	13.7
11	11.2
		13	16.3
14	23.1
		15	17.6
16	29.4

And (4) conclusion: the compound disclosed by the invention has good degradation activity on Androgen Receptor (AR) in LNCaP cells.

Claims

1. A compound having the CLM-L-PTM structure, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein:

ring a is aryl or heteroaryl;

z is selected from NR^aAn O atom and an S atom;

l is a connecting unit for connecting the CLM and the PTM;

Y¹、Y²、Y³and Y⁴Are the same or different, andeach independently is a C atom or a N atom;

n is 0, 1 or 2;

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

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

q is 0, 1,2,3,4 or 5.

2. The CLM-L-PTM compound of claim 1, which is a compound represented by the general formula (I), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

G¹、G²z, ring A, L, Y¹、Y²、Y³、Y⁴、R¹～R³N, m, p and q are as defined in claim 1.

3. The compound of CLM-L-PTM structure according to claim 1 or2, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring a is 6-to 10-membered aryl or 5-to 10-membered heteroaryl; preferably, ring a is phenyl.

4. The compound of CLM-L-PTM structure according to any one of claims 1 to 3, which is a compound of formula (II) or formula (III), or a tautomer, racemate, enantiomer, diastereomer or mixture thereof or a pharmaceutically acceptable salt thereof,

wherein:

G¹、G²、Z、L、Y¹、Y²、Y³、Y⁴、R¹～R³n, m, p and q are as defined in claim 1.

5. The CLM-L-PTM compound of structure according to any one of claims 1 to 4, wherein L is selected from L, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof¹、L²、L³、L⁴、L¹-L²-L⁴-L³And L¹-L²-L³-L⁴；

L²And L⁴The same or different, and each is independently selected from the group consisting of a covalent bond, alkylene, heteroalkylene, alkenylene, alkynylene, cycloalkyl, heterocyclyl, alkylene-heterocyclyl, heterocyclyl-alkylene, aryl, and heteroaryl, wherein said alkylene, heteroalkylene, alkenylene, alkynylene, cycloalkyl, heterocyclyl, alkylene-heterocyclyl, heterocyclyl-alkylene, aryl, and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, oxo, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

6. The CLM-L-PTM compound of structure according to any one of claims 1 to 5, wherein L is L, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof¹-L²-L³-L⁴Or L¹-L²-L⁴-L³；L¹And L³Identical or different and are each independently selected from the group consisting of a covalent bond, an O atom, CH₂And NR^1L；R^1LSelected from hydrogen atoms, C_1-6Alkyl, halo C_1-6Alkyl, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl, 6-to 10-membered aryl, and 5-to 10-membered heteroaryl; l is²And L⁴Identical or different and are each independently selected from the group consisting of a covalent bond, C_1-12Alkylene, 1-to 12-membered heteroalkylene, C_2-12Alkenylene radical, C_2-12Alkynylene, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl, C_1-12Alkylene-3-to 8-membered heterocyclic group, 3-to 8-membered heterocyclic group-C_1-12Alkylene, 6-to 10-membered aryl and 5-to 10-membered heteroaryl, wherein said C_1-12Alkylene, 1-to 12-membered heteroalkylene, C_2-12Alkenylene radical, C_2-12Alkynylene, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl, C_1-12Alkylene-3-to 8-membered heterocyclyl, 3-to 8-membered heterocyclyl-C_1-12Alkylene, 6-to 10-membered aryl and 5-to 10-membered heteroaryl are each independently optionally selected from halogen, C_1-12Alkyl radical, C_1-12Alkoxy, halo C_1-12Alkyl, hydroxy C_1-12Alkyl, cyano, amino, oxo, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl, 6-to 10-membered aryl and 5-to 10-membered heteroaryl; preferably, L is L¹-L²-L³-L⁴；L¹Selected from the group consisting of a covalent bond, an O atom, and NH; l is²And L⁴Are the same or different and are each independently selected from C_1-12Alkylene, 1-to 12-membered heteroalkylene, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl, C_1-12Alkylene-3-to 8-membered heterocyclyl and 3-to 8-membered heterocyclyl-C_1-12An alkylene group; l is³Is CH₂。

7. The CLM-L-PTM compound of structure according to any one of claims 1 to 3 and 5, which is a compound represented by the general formula (I-1), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

is a 4-to 8-membered heterocyclic group containing at least 1N atom;

L²A substituent selected from the group consisting of a covalent bond, alkylene, heteroalkylene, alkenylene, alkynylene, cycloalkyl, heterocyclyl, alkylene-heterocyclyl, heterocyclyl-alkylene, aryl, and heteroaryl, wherein said alkylene, heteroalkylene, alkenylene, alkynylene, cycloalkyl, heterocyclyl, alkylene-heterocyclyl, heterocyclyl-alkylene, aryl, and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, oxo, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

G¹、G²ring A, Z, Y¹、Y²、Y³、Y⁴、R¹～R³N, m, p and q are as defined in claim 1.

8. The CLM-L-PTM compound of structure according to any one of claims 1 to 3 and 5, which is a compound represented by the general formula (I-2), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

is a 4-to 8-membered heterocyclic group containing at least 1N atom;

L⁴A substituent selected from the group consisting of a covalent bond, alkylene, heteroalkylene, alkenylene, alkynylene, cycloalkyl, heterocyclyl, alkylene-heterocyclyl, heterocyclyl-alkylene, aryl, and heteroaryl, wherein said alkylene, heteroalkylene, alkenylene, alkynylene, cycloalkyl, heterocyclyl, alkylene-heterocyclyl, heterocyclyl-alkylene, aryl, and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, oxo, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

9. The CLM-L-PTM structure of a compound according to any one of claims 1 to 8, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein G¹Is CH₂(ii) a And G²Is C (═ O).

10. The compound of CLM-L-PTM structure according to any one of claims 1 to 9, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Z is an NH or O atom.

11. The compound of CLM-L-PTM structure according to any one of claims 1 to 10, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein n is 1.

12. The CLM-L-PTM structure of a compound according to any one of claims 1 to 11, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein

Is selected from

R²And p is as defined in claim 1.

13. The CLM-L-PTM structure of a compound according to any one of claims 1 to 12, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R¹Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C_1-6An alkyl group.

14. The CLM-L-PTM structure of a compound according to any one of claims 1 to 13, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R²Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C_1-6An alkyl group.

15. The CLM-L-PTM structure of a compound according to any one of claims 1 to 14, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R³Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkyl, halo C_1-6Alkoxy, hydroxy C_1-6Alkyl, cyano and amino.

16. The CLM-L-PTM structure compound of any one of claims 1 to 15, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein CLM is selected from:

17. the compound of CLM-L-PTM structure according to any one of claims 1 to 16, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L is selected from:

j is 0, 1,2,3,4, 5 or 6; and is

k is 0, 1,2,3,4, 5 or 6.

18. The compound of CLM-L-PTM structure according to any one of claims 1 to 17, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein PTM is selected from:

19. -a compound of CLM-L-PTM structure according to any of claims 1 to 18, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, selected from any one of the following compounds:

20. a compound represented by the general formula (IC-1) or (IC-2) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof,

wherein:

is a 4-to 8-membered heterocyclic group containing at least 1N atom;

G¹、G²z, ring A, R¹N and m are as defined in claim 1.

21. A compound according to claim 20, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or salt thereof, selected from any one of the following compounds:

22. a process for producing a compound represented by the general formula (I-1) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which comprises:

G¹、G²z, Ring A, Ring B, L¹、L²、Y¹、Y²、Y³、Y⁴、R¹～R³N, m, p and q are as defined in claim 7As defined.

23. A method for producing a compound represented by the general formula (I-2) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which comprises:

G¹、G²z, Ring A, Ring C, L¹、L⁴、Y¹、Y²、Y³、Y⁴、R¹～R³N, m, p and q are as defined in claim 8.

24. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19, or a tautomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

25. Use of a compound according to any one of claims 1 to 19, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 24, in the manufacture of a medicament for modulating ubiquitination and degradation of Androgen Receptor (AR) protein in a subject.

26. Use of a compound according to any one of claims 1 to 19, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 24, for the manufacture of a medicament for the treatment and/or prevention of a condition mediated or dependent by the androgen receptor, wherein the condition mediated or dependent by the androgen receptor is preferably selected from the group consisting of tumors, male sexual dysfunction, and kennedy's disease.

27. Use according to claim 26, wherein the androgen receptor mediated or dependent condition is selected from prostate cancer, prostate 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.