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CN113387879B - Amine derivative, preparation method thereof and application thereof in medicine - Google Patents

Amine derivative, preparation method thereof and application thereof in medicine Download PDF

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CN113387879B
CN113387879B CN202110263122.XA CN202110263122A CN113387879B CN 113387879 B CN113387879 B CN 113387879B CN 202110263122 A CN202110263122 A CN 202110263122A CN 113387879 B CN113387879 B CN 113387879B
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alkyl
alkoxy
alkenyl
alkynyl
carbocyclyl
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CN113387879A (en
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李进
窦登峰
刘川
康静文
陈秋霞
蔡龙英
刘港
张丽芳
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Hitgen Inc
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Abstract

The invention relates to a compound shown in a formula (I), or a stereoisomer, a pharmaceutically acceptable salt and application thereof in medicine. The compounds of formula (I) are capable of binding to BRD4 and are useful as inhibitors of BRD4 in the treatment of various diseases associated with BRD 4.

Description

Amine derivative, preparation method thereof and application thereof in medicine
Technical Field
The invention relates to the technical field of pharmaceutical chemistry, in particular to a compound shown in a formula (I), or a stereoisomer, a pharmaceutically acceptable salt and application thereof in medicines.
Background
BRD4 (bromodomain protein 4, bromodomain protein-containing protein) belongs to the BET family of members. The BET bromodomain comprises four proteins, BRD2, BRD3, BRD4 and BRDT (Mass-spectrum-based draft of the human protein nature 2014,509,582-587). Studies have shown that deregulation of BRD4 expression is associated with the development of various cancer diseases such as leukemia, breast cancer, colon cancer, and the like.
BRD3 and BRD4 fuse with nucleoprotein (Nuclear Protein in Testis, NUT) in the testes in error, leading to the occurrence of adenocarcinoma in NUT. BRD4 protein can be combined with RNA polymerase II (Pol II) and the forward transcription elongation factor to participate in the transcription process of oncogenes MYC, BCL2, BCL6 and the like (Mechanistic analysis of the roleof bromodomain-containing protein 4 (BRD 4) in BRD4-NUT oncoprotein-induced transcriptional activation.J Biol Chem 2015,290,2744-2758). One study in the langanite medical center of new york university in 2014 shows that BRD4 protein occupies the gene position of super enhancer, can keep cancer cells in relatively immature stem cell-like state, and drives cancer to a certain extent.
Studies have shown that many diseases in humans are closely related to BRD4 proteins, such as tumors, autoimmune or inflammatory diseases, viral infections. Among them, the BRD4 protein-associated tumors include breast cancer, brain cancer, cervical cancer, colorectal cancer, intestinal gastric cancer, esophageal cancer, liver cancer, lung cancer, pancreatic cancer, endometrial cancer, nasopharyngeal cancer, ovarian cancer, prostate cancer, and hematopoietic system tumors.
At present, although a plurality of drug compounds taking BRD4 as targets enter a clinical research stage, more novel and efficient BRD4 inhibitors still need to be searched for, and new choices are provided for treating diseases such as tumors.
Disclosure of Invention
The invention provides a novel compound shown in a formula (I), or a stereoisomer, a pharmaceutically acceptable salt and a composition, a preparation method and medical application thereof. The compound can be effectively combined with BRD4, has good BRD4 inhibition effect, and has good inhibition effect on various tumors.
The invention provides a compound shown in a formula (I), or a stereoisomer and pharmaceutically acceptable salt thereof:
Figure BDA0002971200020000021
R 1 、R 2 、R 3 、R 4 each independently selected from H, halogen, OH, CN, -NR m R n 、C 1 ～C 6 Alkyl, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl, C 1 ～C 6 Alkoxy, C 3 ～C 8 Carbocyclyl or C 5 ～C 8 Heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl or heterocyclyl being further substituted with 0 to 4 halogen, OH, CF 3 、CN、NH 2 、C 1 ～C 6 Alkyl, C 1 ～C 6 Alkoxy, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl, C 3 ～C 8 Carbocyclyl or C 3 ～C 8 A heterocyclic group substituted with 1 to 3 heteroatoms selected from N, O or S;
x, Y are each independently selected from O, S, CR 5 R 6 Or NR (NR) 5 ；
R 5 、R 6 Each is independently selected from H, halogen, OH, CN, NH 2 、-C(O)NR m R n 、-NR m C(O)R n 、-C(O)R m 、-C(O)OR m 、-O-R m 、-S-R m 、C 1 ～C 6 Alkyl, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl, C 1 ～C 6 Alkoxy, C 3 ～C 8 Carbocyclyl or C 3 ～C 8 Heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl or heterocyclyl being further substituted with 0 to 4 halogen, OH, CF 3 、CN、NH 2 、C 1 ～C 6 Alkyl, C 1 ～C 6 Alkoxy, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl, C 3 ～C 8 Carbocyclyl or C 3 ～C 8 A heterocyclic group substituted with 1 to 3 heteroatoms selected from N, O or S;
R m 、R n each is independently selected from H, halogen, OH, CN, NH 2 、-C(O)NR m R n 、-NR m C(O)R n 、-C(O)R m 、-C(O)OR m 、-O-R m 、-S-R m 、C 1 ～C 6 Alkyl, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl, C 1 ～C 6 Alkoxy, C 3 ～C 8 Carbocyclyl or C 3 ～C 8 Heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl or heterocyclyl being further substituted with 0 to 4 halogen, OH, CF 3 、CN、NH 2 、C 1 ～C 6 Alkyl, C 1 ～C 6 Alkoxy, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl, C 3 ～C 8 Carbocyclyl or C 3 ～C 8 A heterocyclic group substituted with 1 to 3 heteroatoms selected from N, O or S;
w, Q are each independently selected from C 5 ～C 12 Carbocyclyl or C 5 ～C 12 Heterocyclic groups, the carbocyclic or heterocyclic groups being monocyclic, spiro or fused rings, the monocyclic, spiro or fused rings being further substituted with 0-4 halogen, OH, CF3, CN, NH2, C 1 ～C 6 Alkyl, C 1 ～C 6 Alkoxy, C substituted by 0-4 halogen atoms 1 ～C 6 Alkoxy, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl, C 3 ～C 8 Carbocyclyl or C 3 ～C 8 A heterocyclic group substituted with a substituent, said heterocyclic group containing 1 to 3 heteroatoms selected from N, O or S.
In certain embodiments, the compounds of formula (I) provided herein have a structure represented by the compounds of formula (II):
Figure BDA0002971200020000031
W 1 selected from CR W1 Or N; w (W) 2 Selected from CR W2 Or N; w (W) 3 Selected from CR W3 Or N; w (W) 4 Selected from CR W4 Or N;
Q 1 selected from CR Q1 Or NR (NR) Q1 ；Q 2 Selected from CR Q2 Or NR (NR) Q2 ；Q 3 Selected from CR Q3 Or NR (NR) Q3 ；Q 4 Selected from CR Q4 Or NR (NR) Q4 ；
R W1 、R W2 、R W3 、R W4 、R Q1 、R Q2 、R Q3 、R Q4 Each is independently selected from H, halogen, OH, CN, NH 2 、-C(O)NR m R n 、-NR m C(O)R n 、-C(O)R m 、-C(O)OR m 、-O-R m 、-S-R m 、C 1 ～C 6 Alkyl, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl, C 1 ～C 6 Alkoxy, C substituted by 0-4 halogen atoms 1 ～C 6 Alkoxy, C 3 ～C 8 Carbocyclyl or C 3 ～C 8 Heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl or heterocyclyl being further substituted with 0 to 4 halogen, OH, CF 3 、CN、NH 2 、C 1 ～C 6 Alkyl, C 1 ～C 6 Alkoxy, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl, C 3 ～C 8 Carbocyclyl or C 3 ～C 8 A heterocyclic group substituted with 1 to 3 heteroatoms selected from N, O or S;
R 1 、R 2 、R 3 、R 4 each independently selected from H, halogen, OH, CN, -NR m R n 、C 1 ～C 6 Alkyl, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl, C 1 ～C 6 Alkoxy, C 3 ～C 8 Carbocyclyl or C 5 ～C 8 Heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl or heterocyclyl being further substituted with 0 to 4 halogen, OH, CF 3 、CN、NH 2 、C 1 ～C 6 Alkyl, C 1 ～C 6 Alkoxy, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl, C 3 ～C 8 Carbocyclyl or C 3 ～C 8 A heterocyclic group substituted with 1 to 3 heteroatoms selected from N, O or S;
x, Y are each independently selected from O, S, CR 5 R 6 Or NR (NR) 5 ；
R 5 、R 6 Each is independently selected from H, halogen, OH, CN, NH 2 、-C(O)NR m R n 、-NR m C(O)R n 、-C(O)R m 、-C(O)OR m 、-O-R m 、-S-R m 、C 1 ～C 6 Alkyl, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl, C 1 ～C 6 Alkoxy, C 3 ～C 8 Carbocyclyl or C 3 ～C 8 Heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl or heterocyclyl being further substituted with 0 to 4 halogen, OH, CF 3 、CN、NH 2 、C 1 ～C 6 Alkyl, C 1 ～C 6 Alkoxy, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl, C 3 ～C 8 Carbocyclyl or C 3 ～C 8 A heterocyclic group substituted with 1 to 3 heteroatoms selected from N, O or S;
R m 、R n each is independently selected from H, halogen, OH, CN, NH 2 、-C(O)NR m R n 、-NR m C(O)R n 、-C(O)R m 、-C(O)OR m 、-O-R m 、-S-R m 、C 1 ～C 6 Alkyl, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl, C 1 ～C 6 Alkoxy, C 3 ～C 8 Carbocyclyl or C 3 ～C 8 Heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl or heterocyclyl being further substituted with 0 to 4 halogen, OH, CF 3 、CN、NH 2 、C 1 ～C 6 Alkyl, C 1 ～C 6 Alkoxy, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl, C 3 ～C 8 Carbocyclyl or C 3 ～C 8 A heterocyclic group substituted with a substituent, said heterocyclic group containing 1 to 3 heteroatoms selected from N, O or S.
Further, the method comprises the steps of,
R 1 、R 2 、R 3 、R 4 each independently selected from H, halogen, C 1 ～C 6 Alkyl, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl, C 1 ～C 6 Alkoxy, said alkyl, alkenyl, alkynyl or alkoxy being further substituted with 0 to 4 halogen, C 1 ～C 6 Alkyl, C 1 ～C 6 Alkoxy, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl substituent is substituted;
x, Y are each independently selected from O or S;
W 1 selected from CR W1 ；W 2 Selected from CR W2 ；W 3 Selected from CR W3 Or N; w (W) 4 Selected from CR W4 ；
Q 1 Selected from CR Q1 ；Q 2 Selected from CR Q2 ；Q 3 Selected from CR Q3 ；
Q 4 Selected from NR Q4 ；
R W1 、R W2 、R W3 、R W4 、R Q1 、R Q2 、R Q3 、R Q4 Each independently selected from H, halogen, C 1 ～C 6 Alkyl, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl, C 1 ～C 6 Alkoxy, C substituted by 0-3F atoms 1 ～C 6 Alkoxy, said alkyl, alkenyl, alkynyl or alkoxy being further substituted with 0 to 4 halogen, C 1 ～C 6 Alkyl, C 1 ～C 6 Alkoxy, C 2 ～C 6 Alkenyl or C 2 ～C 6 The substituent of alkynyl is substituted.
Further, the method comprises the steps of,
R 1 、R 2 、R 3 、R 4 each independently selected from H, methyl, ethyl, isopropyl, or methoxy;
x, Y are each independently selected from O;
W 3 selected from CR W3 ；
R W1 、R W2 、R W3 、R W4 Each independently selected from H, methyl, ethyl, methoxy,
Figure BDA0002971200020000041
R Q1 、R Q2 、R Q3 Each independently selected from H, methyl, ethyl, isopropyl, or methoxy;
Q 4 selected from NR Q4 ；
R Q4 Each independently selected from H, methyl, ethyl, isopropyl, or methoxy.
Further, the method comprises the steps of,
R 1 、R 2 、R 3 、R 4 each independently selected from H, methyl, ethyl, isopropyl, or methoxy;
x, Y are each independently selected from O;
W 3 selected from N;
R W1 、R W2 、R W4 each independently selected from H, methyl, ethyl, methoxy,
Figure BDA0002971200020000051
R Q1 、R Q2 、R Q3 Each independently selected from H, methyl, ethyl, isopropyl, or methoxy;
Q 4 selected from NR Q4 ；
R Q4 Each independently selected from H, methyl, ethyl, isopropyl, or methoxy.
In certain embodiments, the compounds of formula (I) provided herein have the structure shown by the compounds of formula (II-1):
Figure BDA0002971200020000052
W 3 selected from CR W3 Or N;
R W1 、R W3 、R W4 、R Q2 、R Q4 each is independently selected from H, halogen, OH, CN, NH 2 、-C(O)NR m R n 、-NR m C(O)R n 、-C(O)R m 、-C(O)OR m 、-O-R m 、-S-R m 、C 1 ～C 6 Alkyl, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl, C 1 ～C 6 Alkoxy, C substituted by 0-4 halogen atoms 1 ～C 6 Alkoxy, C 3 ～C 8 Carbocyclyl or C 3 ～C 8 Heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl or heterocyclyl being further substituted with 0 to 4 halogen, OH, CF 3 、CN、NH 2 、C 1 ～C 6 Alkyl, C 1 ～C 6 Alkoxy, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl, C 3 ～C 8 Carbocyclyl or C 3 ～C 8 A heterocyclic group substituted with 1 to 3 heteroatoms selected from N, O or S;
R 1 、R 2 、R 3 、R 4 each independently selected from H, halogen, OH, CN, -NR m R n 、C 1 ～C 6 Alkyl, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl, C 1 ～C 6 Alkoxy, C 3 ～C 8 Carbocyclyl or C 5 ～C 8 Heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl or heterocyclyl being further substituted with 0 to 4 halogen, OH, CF 3 、CN、NH 2 、C 1 ～C 6 Alkyl, C 1 ～C 6 Alkoxy, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl, C 3 ～C 8 Carbocyclyl or C 3 ～C 8 A heterocyclic group substituted with a substituent, said heterocyclic group containing 1 to 3 heteroatoms selected from N, O or S.
Further, the method comprises the steps of,
R 1 、R 2 、R 3 、R 4 each independently selected from H, methyl, ethyl, isopropyl, or methoxy;
x, Y are each independently selected from O;
W 3 selected from CR W3 ；
R W1 、R W3 、R W4 Each independently selected from H, methyl, ethyl, methoxy,
Figure BDA0002971200020000061
R Q2 Selected from H, methyl, ethyl, isopropyl or methoxy;
R Q4 selected from H, methyl, ethyl, isopropyl or methoxy.
Further, the method comprises the steps of,
R 1 、R 2 、R 3 、R 4 each independently selected from H, methyl, ethyl, isopropyl, or methoxy;
x, Y are each independently selected from O;
W 3 selected from N;
R W1 、R W3 、R W4 each independently selected from H, methyl, ethyl, methoxy,
Figure BDA0002971200020000062
R Q2 Each independently selected from H, methyl, ethyl, isopropyl, or methoxy;
R Q4 each independently selected from H, methyl, ethyl, isopropyl, or methoxy.
In certain embodiments, the compounds of formula (I) provided herein have a structure represented by the compounds of formula (III):
Figure BDA0002971200020000063
W 1 selected from CR W1 Or N; w (W) 2 Selected from CR W2 Or N; w (W) 3 Selected from CR W3 Or N; w (W) 4 Selected from CR W4 Or N;
Q 5 selected from CR Q5 Or N; q (Q) 6 Selected from CR Q6 Or N; q (Q) 7 Selected from CR Q7 Or N;
R W1 、R W2 、R W3 、R W4 、R Q5 、R Q6 、R Q7 each is independently selected from H, halogen, OH, CN, NH 2 、-C(O)NR m R n 、-NR m C(O)R n 、-C(O)R m 、-C(O)OR m 、-O-R m 、-S-R m 、C 1 ～C 6 Alkyl, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl, C 1 ～C 6 Alkoxy, C 3 ～C 8 Carbocyclyl or C 3 ～C 8 Heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl or heterocycloalkyl being further substituted with 0 to 4 halogen, OH, CF 3 、CN、NH 2 、C 1 ～C 6 Alkyl, C 1 ～C 6 Alkoxy, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl, C 3 ～C 8 Carbocyclyl or C 3 ～C 8 A heterocyclic group substituted with 1 to 3 heteroatoms selected from N, O or S;
p is selected from C 5 ～C 12 Carbocyclyl or C 5 ～C 12 Heterocyclyl, said carbocyclyl or heterocyclyl being further substituted with 0-4 halogen, OH, CF3, CN, NH2, C 1 ～C 6 Alkyl, C 1 ～C 6 Alkoxy, = O, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl, C 3 ～C 8 Carbocyclyl or C 3 ～C 8 A heterocyclic group substituted with 1 to 3 heteroatoms selected from N, O or S;
R 1 、R 2 、R 3 、R 4 each independently selected from H, halogen, OH, CN, -NR m R n 、C 1 ～C 6 Alkyl, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl, C 1 ～C 6 Alkoxy, C 3 ～C 8 Carbocyclyl or C 5 ～C 8 Heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl or heterocyclyl being further substituted with 0 to 4 halogen, OH, CF 3 、CN、NH 2 、C 1 ～C 6 Alkyl group,C 1 ～C 6 Alkoxy, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl, C 3 ～C 8 Carbocyclyl or C 3 ～C 8 A heterocyclic group substituted with 1 to 3 heteroatoms selected from N, O or S;
x, Y are each independently selected from O, S, CR 5 R 6 Or NR (NR) 5 ；
R 5 、R 6 Each is independently selected from H, halogen, OH, CN, NH 2 、-C(O)NR m R n 、-NR m C(O)R n 、-C(O)R m 、-C(O)OR m 、-O-R m 、-S-R m 、C 1 ～C 6 Alkyl, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl, C 1 ～C 6 Alkoxy, C 3 ～C 8 Carbocyclyl or C 3 ～C 8 Heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl or heterocyclyl being further substituted with 0 to 4 halogen, OH, CF 3 、CN、NH 2 、C 1 ～C 6 Alkyl, C 1 ～C 6 Alkoxy, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl, C 3 ～C 8 Carbocyclyl or C 3 ～C 8 A heterocyclic group substituted with 1 to 3 heteroatoms selected from N, O or S;
R m 、R n each is independently selected from H, halogen, OH, CN, NH 2 、-C(O)NR m R n 、-NR m C(O)R n 、-C(O)R m 、-C(O)OR m 、-O-R m 、-S-R m 、C 1 ～C 6 Alkyl, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl, C 1 ～C 6 Alkoxy, C 3 ～C 8 Carbocyclyl or C 3 ～C 8 Heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl or heterocyclyl being further substituted with 0 to 4 halogen, OH, CF 3 、CN、NH 2 、C 1 ～C 6 Alkyl, C 1 ～C 6 Alkoxy, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl, C 3 ～C 8 Carbocyclyl or C 3 ～C 8 A heterocyclic group substituted with a substituent, said heterocyclic group containing 1 to 3 heteroatoms selected from N, O or S.
Further, the method comprises the steps of,
the ring P is selected from
Figure BDA0002971200020000071
R P1 、R P2 、R P3 Each is independently selected from H, halogen, OH, CN, NH 2 、-C(O)NR m R n 、-NR m C(O)R n 、-C(O)R m 、-C(O)OR m 、-O-R m 、-S-R m 、C 1 ～C 6 Alkyl, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl, C 1 ～C 6 Alkoxy, C 3 ～C 8 Carbocyclyl or C 3 ～C 8 Heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl or heterocyclyl being further substituted with 0 to 4 halogen, OH, CF 3 、CN、NH 2 、C 1 ～C 6 Alkyl, C 1 ～C 6 Alkoxy, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl, C 3 ～C 8 Carbocyclyl or C 3 ～C 8 A heterocyclic group substituted with a substituent, said heterocyclic group containing 1 to 3 heteroatoms selected from N, O or S.
Further, the method comprises the steps of,
R 1 、R 2 、R 3 、R 4 each independently selected from H, halogen, C 1 ～C 6 Alkyl, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl, C 1 ～C 6 Alkoxy, said alkyl, alkenyl, alkynyl or alkoxy being further substituted with 0 to 4 halogen, C 1 ～C 6 Alkyl, C 1 ～C 6 Alkoxy, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl substituent is substituted;
x, Y are each independently selected from O or S;
W 1 selected from CR W1 ；W 2 Selected from CR W2 ；W 3 Selected from CR W3 ；W 4 Selected from CR W4 ；
Q5 is selected from CR Q5 ；Q 6 Selected from CR Q6 ；Q 7 Selected from CR Q7 ；
R W1 、R W2 、R W3 、R W4 、R Q5 、R Q6 、R Q7 Each independently selected from H, halogen, C 1 ～C 6 Alkyl, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl or C 1 ～C 6 Alkoxy, said alkyl, alkenyl, alkynyl or alkoxy being further substituted with 0 to 4 halogen, C 1 ～C 6 Alkyl, C 1 ～C 6 Alkoxy, C 2 ～C 6 Alkenyl or C 2 ～C 6 The substituent of alkynyl is substituted.
The ring P is selected from
Figure BDA0002971200020000081
R P1 Each independently selected from H, halogen, C 1 ～C 6 Alkyl, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl or C 1 ～C 6 Alkoxy, said alkyl, alkenyl, alkynyl or alkoxy being further substituted with 0 to 4 halogen, C 1 ～C 6 Alkyl, C 1 ～C 6 Alkoxy, C 2 ～C 6 Alkenyl or C 2 ～C 6 The substituent of alkynyl is substituted.
Further, the method comprises the steps of,
R 1 、R 2 、R 3 、R 4 each independently selected from H, methyl, ethyl, isopropyl, or methoxy;
x, Y are each independently selected from O;
R W1 、R W2 、R W3 、R W4 each independently selected from H, methyl, ethyl, methoxy,
Figure BDA0002971200020000082
R Q5 、R Q6 、R Q7 Each independently selected from H, methyl, ethyl, isopropyl, or methoxy;
R P1 selected from H, methyl, ethyl, isopropyl or methoxy.
In certain embodiments, the compounds of formula (I) provided herein have the structure shown by the compounds of formula (III-1):
Figure BDA0002971200020000091
R W1 each is independently selected from H, halogen, OH, CN, NH 2 、-C(O)NR m R n 、-NR m C(O)R n 、-C(O)R m 、-C(O)OR m 、-O-R m 、-S-R m 、C 1 ～C 6 Alkyl, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl, C 1 ～C 6 Alkoxy, C 3 ～C 8 Carbocyclyl or C 3 ～C 8 Heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl or heterocycloalkyl being further substituted with 0 to 4 halogen, OH, CF 3 、CN、NH 2 、C 1 ～C 6 Alkyl, C 1 ～C 6 Alkoxy, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl, C 3 ～C 8 Carbocyclyl or C 3 ～C 8 A heterocyclic group substituted with 1 to 3 heteroatoms selected from N, O or S;
R P1 、R P2 、R P3 each is independently selected from H, halogen, OH, CN, NH 2 、-C(O)NR m R n 、-NR m C(O)R n 、-C(O)R m 、-C(O)OR m 、-O-R m 、-S-R m 、C 1 ～C 6 Alkyl, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl, C 1 ～C 6 Alkoxy, C 3 ～C 8 Carbocyclyl or C 3 ～C 8 Heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl or heterocyclyl being further substituted with 0 to 4 halogen, OH, CF 3 、CN、NH 2 、C 1 ～C 6 Alkyl, C 1 ～C 6 Alkoxy, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl, C 3 ～C 8 Carbocyclyl or C 3 ～C 8 A heterocyclic group substituted with 1 to 3 heteroatoms selected from N, O or S;
R 1 、R 2 、R 3 、R 4 each independently selected from H, halogen, OH, CN, -NR m R n 、C 1 ～C 6 Alkyl, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl, C 1 ～C 6 Alkoxy, C 3 ～C 8 Carbocyclyl or C 5 ～C 8 Heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl or heterocyclyl being further substituted with 0 to 4 halogen, OH, CF 3 、CN、NH 2 、C 1 ～C 6 Alkyl, C 1 ～C 6 Alkoxy, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl, C 3 ～C 8 Carbocyclyl or C 3 ～C 8 A heterocyclic group substituted with a substituent, said heterocyclic group containing 1 to 3 heteroatoms selected from N, O or S.
Further, the method comprises the steps of,
R W1 each independently selected from H, halogen, C 1 ～C 6 Alkyl, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl or C 1 ～C 6 Alkoxy, said alkyl, alkenyl, alkynyl or alkoxy being further substituted with 0 to 4 halogen, C 1 ～C 6 Alkyl, C 1 ～C 6 Alkoxy, C 2 ～C 6 Alkenyl or C 2 ～C 6 The substituent of alkynyl is substituted.
R P1 、R P2 、R P3 Each independently selected from H, halogen, C 1 ～C 6 Alkyl, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl or C 1 ～C 6 Alkoxy, said alkyl, alkenyl, alkynyl or alkoxy being further substituted with 0 to 4 halogen, C 1 ～C 6 Alkyl, C 1 ～C 6 Alkoxy, C 2 ～C 6 Alkenyl or C 2 ～C 6 The substituent of alkynyl is substituted.
R 1 、R 2 、R 3 、R 4 Each independently selected from H, halogen, C 1 ～C 6 Alkyl, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl, C 1 ～C 6 Alkoxy, said alkyl, alkenyl, alkynyl or alkoxy being further substituted with 0 to 4 halogen, C 1 ～C 6 Alkyl, C 1 ～C 6 Alkoxy, C 2 ～C 6 Alkenyl, C 2 ～C 6 The substituent of alkynyl is substituted.
Further, the method comprises the steps of,
R 1 、R 2 、R 3 、R 4 each independently selected from H, methyl, ethyl, isopropyl, or methoxy;
R W1 、R W2 、R W3 、R W4 each independently selected from H, methyl, ethyl, methoxy,
Figure BDA0002971200020000101
R P1 Selected from H, methyl, ethyl, isopropyl or methoxy.
In certain embodiments, the compounds of formula (I) provided herein have a structure represented by the compounds of formula (IV):
Figure BDA0002971200020000102
W 5 selected from CR W5 Or N; w (W) 6 Selected from CR W6 Or N;
Q 1 selected from CR Q1 Or NR (NR) Q1 ；Q 2 Selected from CR Q2 Or NR (NR) Q2 ；Q 3 Selected from CR Q3 Or NR (NR) Q3 ；Q 4 Selected from CR Q4 Or NR (NR) Q4 ；
R W5 、R W6 、R Q1 、R Q2 、R Q3 、R Q4 Each is independently selected from H, halogen, OH, CN, NH 2 、-C(O)NR m R n 、-NR m C(O)R n 、-C(O)R m 、-C(O)OR m 、-O-R m 、-S-R m 、C 1 ～C 6 Alkyl, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl, C 1 ～C 6 Alkoxy, C 3 ～C 8 Carbocyclyl or C 3 ～C 8 Heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl or heterocyclyl being further substituted with 0 to 4 halogen, OH, CF 3 、CN、NH 2 、C 1 ～C 6 Alkyl, C 1 ～C 6 Alkoxy, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl, C 3 ～C 8 Carbocyclyl or C 3 ～C 8 A heterocyclic group substituted with 1 to 3 heteroatoms selected from N, O or S;
ring Z is selected from
Figure BDA0002971200020000103
T is selected from O or S;
R Z1 selected from H, halogen, OH, CN, NH 2 、-C(O)NR m R n 、-NR m C(O)R n 、-C(O)R m 、-C(O)OR m 、-O-R m 、-S-R m 、C 1 ～C 6 Alkyl, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl, C 1 ～C 6 Alkoxy, C 3 ～C 8 Carbocyclyl or C 3 ～C 8 Heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl or heterocyclyl being further substituted with 0 to 4 halogen, OH, CF 3 、CN、NH 2 、C 1 ～C 6 Alkyl, C 1 ～C 6 Alkoxy, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl, C 3 ～C 8 Carbocyclyl or C 3 ～C 8 A heterocyclic group substituted with 1 to 3 heteroatoms selected from N, O or S;
R 1 、R 2 、R 3 、R 4 each independently selected from H, halogen, OH, CN, -NR m R n 、C 1 ～C 6 Alkyl, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl, C 1 ～C 6 Alkoxy, C 3 ～C 8 Carbocyclyl or C 5 ～C 8 Heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl or heterocyclyl being further substituted with 0 to 4 halogen, OH, CF 3 、CN、NH 2 、C 1 ～C 6 Alkyl, C 1 ～C 6 Alkoxy, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl, C 3 ～C 8 Carbocyclyl or C 3 ～C 8 A heterocyclic group substituted with 1 to 3 heteroatoms selected from N, O or S;
x, Y are each independently selected from O, S, CR 5 R 6 Or NR (NR) 5 ；
R 5 、R 6 Each is independently selected from H, halogen, OH, CN, NH 2 、-C(O)NR m R n 、-NR m C(O)R n 、-C(O)R m 、-C(O)OR m 、-O-R m 、-S-R m 、C 1 ～C 6 Alkyl, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl, C 1 ～C 6 Alkoxy, C 3 ～C 8 Carbocyclyl or C 3 ～C 8 Heterocyclyl radicals, said alkyl radicals, alkeneThe radicals, alkynyl, alkoxy, carbocyclyl or heterocyclyl being further substituted by 0-4 halogen, OH, CF 3 、CN、NH 2 、C 1 ～C 6 Alkyl, C 1 ～C 6 Alkoxy, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl, C 3 ～C 8 Carbocyclyl or C 3 ～C 8 A heterocyclic group substituted with 1 to 3 heteroatoms selected from N, O or S;
R m 、R n each is independently selected from H, halogen, OH, CN, NH 2 、-C(O)NR m R n 、-NR m C(O)R n 、-C(O)R m 、-C(O)OR m 、-O-R m 、-S-R m 、C 1 ～C 6 Alkyl, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl, C 1 ～C 6 Alkoxy, C 3 ～C 8 Carbocyclyl or C 3 ～C 8 Heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl or heterocyclyl being further substituted with 0 to 4 halogen, OH, CF 3 、CN、NH 2 、C 1 ～C 6 Alkyl, C 1 ～C 6 Alkoxy, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl, C 3 ～C 8 Carbocyclyl or C 3 ～C 8 A heterocyclic group substituted with 1 to 3 heteroatoms selected from N, O or S;
further, the method comprises the steps of,
R 1 、R 2 、R 3 、R 4 each independently selected from H, halogen, C 1 ～C 6 Alkyl, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl, C 1 ～C 6 Alkoxy, said alkyl, alkenyl, alkynyl or alkoxy being further substituted with 0 to 4 halogen, C 1 ～C 6 Alkyl, C 1 ～C 6 Alkoxy, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl substituent is substituted;
x, Y are each independently selected from O or S;
W 5 selected from CR W5 ；W 6 Selected from CR W6 ；
Q 1 Selected from CR Q1 ；Q 3 Selected from CR Q3 ；Q 4 Selected from CR Q4 ；
Q 2 Selected from NR Q2 ；
R W5 、R W6 、R Q1 、R Q2 、R Q3 、R Q4 Each independently selected from H, halogen, C 1 ～C 6 Alkyl, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl or C 1 ～C 6 Alkoxy, said alkyl, alkenyl, alkynyl or alkoxy being further substituted with 0 to 4 halogen, C 1 ～C 6 Alkyl, C 1 ～C 6 Alkoxy, C 2 ～C 6 Alkenyl or C 2 ～C 6 The substituent of alkynyl is substituted.
Ring Z is selected from
Figure BDA0002971200020000121
R Z1 Independently selected from H, halogen, C 1 ～C 6 Alkyl, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl or C 1 ～C 6 Alkoxy, said alkyl, alkenyl, alkynyl or alkoxy being further substituted with 0 to 4 halogen, C 1 ～C 6 Alkyl, C 1 ～C 6 Alkoxy, C 2 ～C 6 Alkenyl or C 2 ～C 6 The substituent of alkynyl is substituted.
Further, the method comprises the steps of,
R 1 、R 2 、R 3 、R 4 each independently selected from H, methyl, ethyl, isopropyl, or methoxy;
x, Y are each independently selected from O;
R W5 、R W6 each independently selected from H, methyl, ethyl, methoxy,
Figure BDA0002971200020000122
R Q1 、R Q2 、R Q3 、R Q4 Each independently selected from H, methyl, ethyl, isopropyl, or methoxy;
R Z1 selected from H, methyl, ethyl, isopropyl or methoxy.
In certain embodiments, the compounds of formula (I) provided herein have the structure shown by the compounds of formula (IV-1):
Figure BDA0002971200020000123
R W5 、R Q2 、R Q4 each is independently selected from H, halogen, OH, CN, NH 2 、-C(O)NR m R n 、-NR m C(O)R n 、-C(O)R m 、-C(O)OR m 、-O-R m 、-S-R m 、C 1 ～C 6 Alkyl, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl, C 1 ～C 6 Alkoxy, C 3 ～C 8 Carbocyclyl or C 3 ～C 8 Heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl or heterocyclyl being further substituted with 0 to 4 halogen, OH, CF 3 、CN、NH 2 、C 1 ～C 6 Alkyl, C 1 ～C 6 Alkoxy, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl, C 3 ～C 8 Carbocyclyl or C 3 ～C 8 A heterocyclic group substituted with 1 to 3 heteroatoms selected from N, O or S;
t is selected from O or S;
R Z1 selected from H, halogen, OH, CN, NH 2 、-C(O)NR m R n 、-NR m C(O)R n 、-C(O)R m 、-C(O)OR m 、-O-R m 、-S-R m 、C 1 ～C 6 Alkyl, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl, C 1 ～C 6 Alkoxy, C 3 ～C 8 Carbocyclyl or C 3 ～C 8 Heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl or heterocyclyl being further substituted with 0 to 4 halogen, OH, CF 3 、CN、NH 2 、C 1 ～C 6 Alkyl, C 1 ～C 6 Alkoxy, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl, C 3 ～C 8 Carbocyclyl or C 3 ～C 8 A heterocyclic group substituted with 1 to 3 heteroatoms selected from N, O or S;
R 1 、R 2 、R 3 、R 4 each independently selected from H, halogen, OH, CN, -NR m R n 、C 1 ～C 6 Alkyl, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl, C 1 ～C 6 Alkoxy, C 3 ～C 8 Carbocyclyl or C 5 ～C 8 Heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl or heterocyclyl being further substituted with 0 to 4 halogen, OH, CF 3 、CN、NH 2 、C 1 ～C 6 Alkyl, C 1 ～C 6 Alkoxy, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl, C 3 ～C 8 Carbocyclyl or C 3 ～C 8 A heterocyclic group substituted with a substituent, said heterocyclic group containing 1 to 3 heteroatoms selected from N, O or S.
Further, the method comprises the steps of,
R 1 、R 2 、R 3 、R 4 each independently selected from H, halogen, C 1 ～C 6 Alkyl, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl, C 1 ～C 6 Alkoxy, said alkyl, alkenyl, alkynyl or alkoxy being further substituted with 0 to 4 halogen, C 1 ～C 6 Alkyl, C 1 ～C 6 Alkoxy, C 2 ～C 6 Alkenyl, C 2 ～C 6 Substituted by substituents of alkynyl groups；
T is selected from O;
R W5 、R Q2 、R Q4 each independently selected from H, halogen, C 1 ～C 6 Alkyl, C 2 ～C 6 Alkenyl, C 2 ～C 6 Alkynyl or C 1 ～C 6 Alkoxy, said alkyl, alkenyl, alkynyl or alkoxy being further substituted with 0 to 4 halogen, C 1 ～C 6 Alkyl, C 1 ～C 6 Alkoxy, C 2 ～C 6 Alkenyl or C 2 ～C 6 The substituent of alkynyl is substituted.
Further, the method comprises the steps of,
R 1 、R 2 、R 3 、R 4 each independently selected from H, methyl, ethyl, isopropyl, or methoxy;
R W5 、R W6 each independently selected from H, methyl, ethyl, methoxy,
Figure BDA0002971200020000131
R Q1 、R Q2 、R Q3 、R Q4 Each independently selected from H, methyl, ethyl, isopropyl, or methoxy;
R Z1 selected from H, methyl, ethyl, isopropyl or methoxy.
In a particular embodiment of the invention, the compound of formula (I) is specifically selected from:
Figure BDA0002971200020000141
the invention also provides a pharmaceutical composition comprising the above compound or a stereoisomer, pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers and/or excipients.
The invention also provides application of the compound, or stereoisomers, pharmaceutically acceptable salts and compositions thereof in preparing medicines for treating diseases related to BRD4 activity.
The invention also provides application of the compound, or stereoisomers, pharmaceutically acceptable salts and compositions thereof in preparing medicines for treating inflammatory diseases, autoimmune diseases, infectious diseases, cancers or precancerous syndromes.
The invention also provides a medicine which is a preparation prepared by taking the compound, or the stereoisomer, the pharmaceutically acceptable salt and the composition thereof as active ingredients and adding pharmaceutically acceptable auxiliary materials.
A disease associated with BRD4 activity as defined herein is one in which BRD4 plays an important role in the pathogenesis of the disease.
Diseases associated with BRD4 activity include inflammatory, allergic and autoimmune diseases, infectious diseases, cancer, pre-cancerous syndromes.
Definition of terms used in connection with the present invention:
unless otherwise indicated, the initial definitions provided for groups or terms herein apply to the groups or terms throughout the specification; for terms not specifically defined herein, the meanings that one skilled in the art can impart based on the disclosure and the context.
The minimum and maximum values of the carbon atom content in the hydrocarbon group are represented by prefixes, for example, prefixes (C a～b ) Alkyl indicates any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, (C) 1～4 ) Alkyl refers to alkyl groups containing 1 to 4 carbon atoms.
"substituted" means that a hydrogen atom in a molecule is replaced by a different atom or molecule.
"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. Such as: "alkyl optionally substituted with Cl" refers to an alkyl group that may be, but is not necessarily, substituted with Cl, and is intended to include both the case where the alkyl group is substituted with Cl and the case where the alkyl group is not substituted with Cl.
Halo or halogen is preferably fluoro, chloro, bromo or iodo, most preferably fluoro, chloro or bromo;if halogen is mentioned in the description of another group, for example halogenated C 1 ～C 7 Alkyl, halogenated C 1 ～C 7 -alkoxy, halo C 1 ～C 7 Alkanoyl or halo-aryl, then, if not explicitly stated, can mean that one or more (e.g., up to 3) halogen atoms are present; for example, particularly for halogenated C 1 ～C 7 The alkyl group may be trifluoromethyl, 2-difluoroethyl or 2, 2-trifluoroethyl.
The term "alkyl" refers to a straight or branched saturated hydrocarbon group having 1 to 20 carbon atoms. Where appropriate, the alkyl groups may have the indicated number of carbon atoms, e.g. C 1-6 Alkyl includes alkyl groups having 1,2, 3, 4,5, or 6 carbon atoms in a straight or branched configuration. Examples of suitable alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, 4-methylbutyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 5-methylpentyl, 2-ethylbutyl, 3-ethylbutyl, heptyl, octyl, nonyl and decyl.
The term "alkenyl" refers to a straight or branched hydrocarbon group having one or more double bonds between carbon atoms and having 2 to 20 carbon atoms. Where appropriate, alkenyl groups may have the indicated number of carbon atoms. For example, as "C 2 -C 6 C in alkenyl 2 -C 6 Including groups having 2, 3, 4,5 or 6 carbon atoms in a straight or branched configuration. Examples of suitable alkenyl groups include, but are not limited to, ethenyl, propenyl, isopropenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, hexadienyl, heptenyl, octenyl, nonenyl, and decenyl.
The term "alkynyl" refers to a straight or branched hydrocarbon group having one or more triple bonds and having 2 to 20 carbon atoms. Where appropriate, alkynyl groups may have the indicated number of carbon atoms. For example, as "C 2 -C 6 C in alkynyl 2 -C 6 Including groups having 2, 3, 4,5 or 6 carbon atoms in a straight or branched configuration. Is suitable forExamples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.
The term "alkylene" refers to a divalent saturated hydrocarbon chain having 1 to 20 carbon atoms. Where appropriate, the alkylene groups may have the indicated number of carbon atoms, e.g. C 1-6 Alkylene groups include alkylene groups having 1,2, 3, 4,5 or 6 carbon atoms in a linear configuration. Examples of suitable alkylene groups include, but are not limited to, -CH 2 -、-CH 2 CH 2 -、-CH 2 CH 2 CH 2 -、-CH 2 CH 2 CH 2 CH 2 -、-CH 2 CH 2 CH 2 CH 2 CH 2 -and-CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -。
The term "alkenylene" refers to a divalent unsaturated hydrocarbon chain having 2 to 20 carbon atoms and at least one double bond. Where appropriate, alkenylene groups may have the indicated number of carbon atoms, e.g. C 2-6 Alkenylene includes alkenylene groups having 2, 3, 4,5, or 6 carbon atoms in a straight chain configuration. The double bond may be in the E or Z configuration. Examples of suitable alkenylenes include, but are not limited to, -ch=ch-, -ch=chch 2 -、-CH 2 CH＝CH-、-CH＝CHCH 2 CH 2 -、-CH 2 CH＝CHCH 2 -、-CH 2 CH 2 CH＝CH-、-CH＝CH-CH＝CH-、-CH＝CHCH 2 CH 2 CH 2 -、-CH＝CH-CH＝CH 2 CH 2 -、-CH＝CH 2 CH 2 CH＝CH-。
The term "alkynylene" refers to a divalent unsaturated hydrocarbon chain having 2 to 20 carbon atoms and at least one triple bond. Where appropriate, alkynylene groups may have the indicated number of carbon atoms, e.g., C 2-6 Alkynylene includes alkynylene groups having 2, 3, 4,5, or 6 carbon atoms in a linear configuration. Examples of suitable alkynylene groups include, but are not limited to, -C.ident.C-, -C.ident.CCH 2 -、-CH 2 C≡C-、-C≡CCH 2 CH 2 -、-CH 2 C≡CCH 2 -、-CH 2 CH 2 C≡C-、-C≡C-C≡C-、-C≡CCH 2 CH 2 CH 2 -、-CH 2 C≡CCH 2 CH 2 -、-CH 2 CH 2 C≡CCH 2 -、-C≡C-C≡C-CH 2 -、-CH 2 C≡C-C≡C-CH 2 -、-C≡CCH 2 CH 2 CH 2 CH 2 -、-CH 2 C≡CCH 2 CH 2 CH 2 -、-CH 2 CH 2 C≡CCH 2 CH 2 -、-CH 2 CH 2 CH 2 C≡CCH 2 -and-CH 2 CH 2 CH 2 CH 2 C≡C-。
The term "alkoxy" refers to a monovalent radical of an O-alkyl group, wherein alkyl is as defined herein, and alkoxy examples include, but are not limited to, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-1-propoxy, 2-butoxy, 2-methyl-2-propoxy, 1-pentoxy, 2-pentoxy, 3-pentoxy, 2-methyl-2-butoxy, 3-methyl-1-butoxy, 2-methyl-1-butoxy, and the like.
The term "carbocycle" or "carbocyclyl" refers to a saturated, partially saturated or unsaturated monocyclic or bicyclic carbocycle containing 3 to 12 ring atoms, wherein one or more-CH 2 The groups may optionally be replaced by a corresponding number of-C (O) -groups. Illustrative examples of "carbocyclyl" include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, indanyl, naphthyl, oxo-cyclopentyl, 1-oxo-indanyl, phenyl, and tetrahydronaphthyl.
The term "heterocyclyl" refers to a saturated, partially saturated or unsaturated monocyclic or bicyclic ring containing 4 to 12 ring atoms, at least one of which is selected from nitrogen, sulfur and oxygen, and which may be attached through carbon or nitrogen, unless otherwise specified, and in which-CH 2 The group may optionally be replaced by a-C (O) -group. The episulfide atoms can optionally be oxidized to form S-oxides. The ring nitrogen atoms may optionally be oxidized to form an N-oxide. Illustrative examples of the term "heterocyclyl" include, but are not limited to, 1, 3-benzodioxolyl, 3, 5-dioxopiperidinyl, imidazolyl, indolyl, isoquinolyl, isothiazolylIsoxazolyl, morpholino, 2-oxa-5-azabicyclo [2.2.1]Hept-5-yloxy pyrrolidinyl, 2-oxo-1, 3-thiazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolyl, pyridinyl, pyrrolyl, pyrrolidinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, 4-pyridonyl, quinolinyl, tetrahydropyranyl, thiazolyl, thiadiazolyl, thiazolidinyl, thiomorpholino, thienyl, pyridinyl-N-oxide and quinolinyl-N-oxide.
Heteroatoms are atoms other than carbon and hydrogen, preferably nitrogen (N), oxygen (O) or sulfur (S), especially nitrogen or oxygen.
The term "heterocycle" or "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms in which one or more ring atoms are selected from nitrogen, oxygen or S (O) m (wherein m is an integer from 0 to 2), but does not include a ring moiety of-O-O-, -O-S-, or-S-S-, and the remaining ring atoms are carbon. Preferably containing 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably 3 to 10 ring atoms, wherein 1-4 are heteroatoms; more preferably from 5 to 6 ring atoms; wherein 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 heterocyclyl groups include spiro, fused and bridged heterocyclic groups.
Each alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkynylene, alkoxy, carbocyclyl, and heterocyclyl, whether individual or as part of a larger entity, may be optionally substituted with one or more optional substituents selected from the group consisting of: c (C) 1-6 Alkyl, C 2-6 Alkenyl, C 3-6 Carbocyclyl, oxo (=o), -OH, -SH, C 1-6 Alkyl O-, C 2-6 Alkenyl O-, C 3-6 Carbocyclyl O-, C 1-6 Alkyl S-, C 2-6 Alkenyl S-, C 3-6 Carbocyclyl S-, -CO 2 H、-CO 2 C 1-6 Alkyl, -NH 2 、-NH(C 1-6 Alkyl), -N (C) 1-6 Alkyl group 2 -NH (phenyl), -N (phenyl) 2 Oxo, -CN, -NO 2 -halogen, -CF 3 、-OCF 3 、-SCF 3 、-CHF 2 、-OCHF 2 、-SCHF 2 -phenyl, carbocyclyl, -heterocyclyl, -heteroaryl, -O-heterocyclyl, -O-phenyl, -O-carbocyclyl, -C (=o) phenyl, -C (=o) C 1-6 An alkyl group. Examples of suitable substituents include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, vinyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, methylthio, ethylthio, propylthio, isopropylthio, butylthio, hydroxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, fluoro, chloro, bromo, iodo, cyano, nitro, -CO 2 H、-CO 2 CH 3 Trifluoromethyl, trifluoromethoxy, trifluoromethylthio, difluoromethyl, difluoromethoxy, difluoromethylthio, morpholino, amino, methylamino, dimethylamino, phenyl, phenoxy, phenylcarbonyl, benzyl and acetyl.
"cancer" or "malignancy" refers to any of a variety of diseases characterized by uncontrolled cellular abnormal proliferation, the ability of affected cells to spread locally or through the blood stream and lymphatic system to other sites, the body (i.e., metastasis), and any of a number of characteristic structures and/or molecular features. "cancer cells" refers to cells that undergo early, mid, or late stages of multistep tumor progression. Cancers include sarcomas, breast cancer, lung cancer, brain cancer, bone cancer, liver cancer, kidney cancer, colon cancer, and prostate cancer. In some embodiments, the compounds of formula I are useful for treating cancers selected from colon cancer, brain cancer, breast cancer, fibrosarcoma, and squamous cell carcinoma. In some embodiments, the cancer is selected from melanoma, breast cancer, colon cancer, lung cancer, and ovarian cancer. In some embodiments, the cancer treated is a metastatic cancer.
Inflammatory diseases include a variety of conditions characterized by histopathological inflammation. Examples of inflammatory diseases include acne vulgaris, asthma, celiac disease, chronic prostatitis, glomerulonephritis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, rheumatoid arthritis, sarcoidosis, vasculitis, airway inflammation caused by house dust mites, and interstitial cystitis. There is a significant overlap between inflammatory and autoimmune diseases. Some embodiments of the invention relate to the treatment of inflammatory disease asthma. The immune system is generally involved in inflammatory diseases, which are manifested in both allergic reactions and in some myopathies, many of which lead to abnormal inflammation.
Detailed Description
The materials and equipment used in the embodiments of the present invention are all known products and are obtained by purchasing commercially available products.
The compounds and derivatives provided in the present invention may be named according to IUPAC (international union of pure and applied chemistry) or CAS (chemical abstract service, columbus, OH) naming system.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or (sum) Mass Spectrometry (MS). NMR shift (. Delta.) is given in units of 10-6 (ppm). NMR measurements were performed using a Bruker Avance III 400 and Bruker Avance 300 magnetonucleuses with deuterated dimethyl sulfoxide (DMSO-d 6), deuterated chloroform (CDCl 3), deuterated methanol (CD 3 OD) as an internal standard, and Tetramethylsilane (TMS). The LC-MS was measured using Shimadzu LC-MS 2020 (ESI). HPLC was performed using a Shimadzu high pressure liquid chromatograph (Shimadzu LC-20A). Reverse phase preparative chromatography a Gilson GX-281 reverse phase preparative chromatograph was used. The specification of the thin layer chromatography separation and purification product adopted by the smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate is 0.4 mm-0.5 mm. Column chromatography generally uses tobacco stand yellow sea silica gel 200-300 mesh silica gel as a carrier.
The known starting materials of the present invention may be synthesized using or according to methods known in the art, or may be purchased from An Naiji chemical, chengkoulochemical, shaoshan chemical technology, carbofuran technology, and the like.
The temperature of the reaction was room temperature, unless otherwise specified in the examples. The room temperature is the most suitable reaction temperature and is 20-30 ℃. The overnight period was 12.+ -. 3h. EtOH: ethanol. (BOC) 2 O: BOC anhydride. DMF: n, N-dimethylformamide. DMSO: dimethyl sulfoxide. DCM: dichloromethane.
Example 1, method for synthesizing compound A, B, C, D, E of the invention:
Figure BDA0002971200020000181
step 1, synthesis of Compound 3
To a 100mL reaction flask, compound 1 (2.00 g,10.57 mmol), DIPEA (4.10 g,31.71mmol,5.52 mL), HATU (4.42 g,0.66 mmol) and DMF (20 mL) were added sequentially, after the reaction system temperature had fallen to 0deg.C, compound 2 (1.06 g,15.70 mmol) was added, the reaction was quenched after stirring for 1 hour under ice bath conditions (LC-MS monitoring), saturated NaCl solution (20 mL) and ethyl acetate (3X 20 mL) were extracted, the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was evaporated, and purified by MPLC, and the solvent was removed by concentration under reduced pressure to give compound 3 (1.70 g,7.56mmol,71.57% yield).
Step 2, synthesis of Compound 4
To a 100mL reaction flask, compound 3 (1.01 g,5 mmol), diethylamine (5.01 mmol,12 mL) and methylene chloride (10 mL) were sequentially added, the reaction was quenched (monitored by LC-MS) after stirring at room temperature for 30 minutes, the pH of the system was adjusted to 6-7 with 1N hydrochloric acid solution, and the reaction mixture was concentrated to give compound 4 (600.00 mg, crude product).
Step 3, compound 6 (R 1 =o-OMe)
Into a 100mL reaction flask, compound 5 (R) 1 After the reaction system temperature was reduced to 0deg.C, compound 4 (102.13 mg,1.00 mmol) was added to DIPEA (387.72 mg,3.00mmol, 522.53. Mu.L), and DMF (20 mL), the reaction was stirred for 1 hour under ice bath conditions and quenched (LC-MS monitoring), the extraction was completed with saturated NaCl solution (20 mL) and ethyl acetate (3X 20 mL), the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was evaporated, and concentrated under reduced pressure to give Compound 6 (R) 1 o-OMe) (290.00 mg,720.67 μmol,72.07% yield).
Step 4, synthesis of Compound A
To a 50mL reaction flask under nitrogen protection, compound 6 (R 1 o-OMe) (289.73 mg,0.8 mmol), compound 7 (R 2 ＝CH 3 )(133.58mg,800.00μmol)，K 2 CO 3 (202.39 mg,2.00 mmol), 1, 4-dioxane and water (4 mL/1 mL) and Pd (dppf) Cl 2 (29.32 mg,0.25 mol%). The reaction was sealed and quenched after stirring at 80℃for 2 hours (LC-MS monitoring). The extraction was completed with saturated NaCl solution (20 mL) and ethyl acetate (3×20 mL), the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was evaporated, and the column chromatography was carried out using an eluent in a volume ratio of petroleum ether/ethyl acetate=1:100 to 1:5, and the solvent was removed by concentration under reduced pressure to give compound a (22.70 mg,62.62 μmol,7.83% yield). LC-MS: c (C) 19 H 24 N 3 O 4 ,[M+H] + 358.2. 1 H NMR(400MHz,CD3OD)δ8.00(d,J＝8.1Hz,1H),7.98(d,J＝2.4Hz,1H),7.83(d,J＝1.4Hz,1H),7.28(d,J＝1.4Hz,1H),7.25(dd,J＝8.2,1.6Hz,1H),4.57(q,J＝7.0Hz,1H),4.10(s,3H),3.66(s,3H),2.78(s,3H),2.20(s,3H),1.44(d,J＝7.0Hz,3H)。
According to the method from step 1 to step 4, different R are used 1 Compound 6, different R 2 The following compound was prepared starting from compound 7:
Figure BDA0002971200020000201
compound B (10.80 mg, 26.47. Mu. Mol,3.31% yield). LC-MS: c (C) 19 H 22 F 2 N 3 O 4 ,[M+H] + 394.1。 1 HNMR(400MHz,CD3OD)δ7.96(d,J＝2.3Hz,1H),7.90(dd,J＝8.6,2.3Hz,1H),7.75(d,J＝2.4Hz,1H),7.65(dd,J＝2.4,1.1Hz,1H),7.33(d,J＝8.6Hz,1H),6.92(t,J＝73.2Hz,1H),4.53(d,J＝7.2Hz,1H),3.65(s,3H),2.75(s,3H),2.18(s,3H),1.45(dd,J＝7.2,4.3Hz,3H)。
Compound C (44 mg, 114.04. Mu. Mol,43.86% yield). LC-MS: c (C) 21 H 27 N 3 O 4 ,[M+H] + 386.2。 1 H NMR(400MHz,CD3OD)δ8.11(d,J＝2.4Hz,1H),8.04(d,J＝8.2Hz,1H),7.93(dd,J＝9.4,2.6Hz,1H),7.29(d,J＝1.3Hz,1H),7.22(dd,J＝8.2,1.6Hz,1H),6.66(d,J＝9.4Hz,1H),5.11-4.96(m,1H),4.58(q,J＝6.9Hz,1H),3.67(s,3H),2.78(s,3H),1.49(dt,J＝8.7,4.4Hz,6H),1.45(d,J＝6.9Hz,3H)。
Compound D (38 mg, 102.10. Mu. Mol,39.27% yield). LC-MS: c (C) 20 H 26 N 3 O 4 ,[M+H] + 372.2。 1 H NMR(400MHz,CD3OD)δ8.06(d,J＝8.2Hz,1H),7.62-7.57(m,1H),7.55(s,1H),7.35(s,1H),7.31(dd,J＝8.2,1.5Hz,1H),7.21(d,J＝8.4Hz,1H),5.12-4.93(m,1H),4.59(d,J＝6.9Hz,1H),3.39(s,3H),3.09-2.88(m,2H),2.78(s,3H),2.65(d,J＝6.9Hz,2H),1.50(dd,J＝6.0,2.2Hz,6H),1.45(d,J＝6.9Hz,3H)。
Step 5, synthesis of Compound E
To a 50mL reaction flask under nitrogen protection, compound 6 (R 1 ＝o-OCH(CH 3 ) 2 ) (89.24 mg, 260.00. Mu. Mol), compound 8 (53.30 mg, 260.00. Mu. Mol), K 2 CO 3 (90.35 mg,0.65 mmol), 1, 4-dioxane and water (4 mL/1 mL) and Pd (dppf) Cl 2 (9.53 mg,0.25 mol%). The reaction was sealed and quenched after stirring at 80℃for 2 hours (LC-MS monitoring). The extraction was completed with saturated NaCl solution (20.0 mL) and ethyl acetate (3×20 mL), the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was evaporated, and the column chromatography was carried out using an eluent in a volume ratio of petroleum ether/ethyl acetate=1:100 to 1:5, followed by concentration under reduced pressure to remove the solvent, to give compound E (58.90 mg,138.94 μmol,53.44% yield). LC-MS: c (C) 24 H 29 N 3 O 4 ,[M+H] + 424.2。 1 H NMR(400MHz,CD3OD)δ8.03(d,J＝8.2Hz,1H),7.93(d,J＝2.2Hz,1H),7.77(d,J＝1.1Hz,1H),7.27(s,1H),7.20(dd,J＝8.2,1.5Hz,1H),5.01(dt,J＝12.1,6.0Hz,1H),4.58(q,J＝6.9Hz,1H),3.65(s,3H),2.78(s,3H),2.19(s,3H),1.49(d,J＝6.0Hz,6H),1.45(d,J＝6.9Hz,3H)。
Example 2, method for the synthesis of compound F of the invention:
Figure BDA0002971200020000211
step 1, synthesis of Compound 9
In a 100mL reaction flask was charged compound 9a (1.08 g,5 mmol), compound 9b (1.43 g,6.00 mmol), K 2 CO 3 (2.08 g,15.00 mmol) and MeCN (20 mL), the reaction was stirred at 70℃for 24 hours and then quenched with water (LC-MS monitoring). Saturated NaCl solution (25 mL) was extracted with ethyl acetate (3X 25 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent to give compound 9c (2.00 g, crude).
To a 100mL reaction flask, compound 9c (2.00 g, crude product), sodium hydroxide (2.14 g,53.59 mmol), ethanol (10 mL) and water (10 mL) were sequentially added, the reaction was quenched (LC-MS monitoring) after stirring at 70℃for 4 hours, the pH of the system was adjusted to 6-7 with 2N hydrochloric acid solution, and the mixture was purified by MPLC and concentrated under reduced pressure to remove the solvent to give compound 9 (700.00 mg,2.47mmol,46.09% yield).
Step 2 Synthesis of Compound 10
To a 100mL reaction flask, compound 9 (204.05 mg,0.8 mmol), DIPEA (310.18 mg,2.40mmol, 418.03. Mu.L), HATU (334.40 mg,0.88 mmol) and DMF (10 mL) were added in sequence, after the reaction system temperature had fallen to 0deg.C, compound 4 (81.71 mg,0.8 mmol) was added, the reaction was quenched after stirring for 1 hour under ice-bath conditions (LC-MS monitoring), saturated NaCl solution (20 mL) and ethyl acetate (3X 20 mL) were extracted, the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was evaporated, and purified by MPLC, and the solvent was removed by concentration under reduced pressure to give compound 10 (210.00 mg, 619.13. Mu. Mol,77.39% yield).
Step 3, synthesis of Compound F
To a 50mL reaction flask under nitrogen atmosphere was added compound 10 (271.35 mg,0.8 mmol), compound 7 (133.58 mg, 800.00. Mu. Mol), K sequentially 2 CO 3 (278.41 mg,2 mmol), 1, 4-dioxane and water (4 mL/1 mL) and Pd (dppf) Cl 2 (29.32 mg,0.25 mol%). The reaction was sealed and quenched after stirring at 80℃for 2 hours (LC-MS monitoring). Saturated NaCl solution (20 mL) and ethyl acetate (3X 20 mL) are extracted, organic phases are combined, the organic phases are dried by anhydrous sodium sulfate, the solvent is evaporated, the column chromatography is carried out, the volume ratio of eluent used is petroleum ether/ethyl acetate=1:100-1:5, and the compound is obtained after the solvent is removed by decompression concentrationF (7.30 mg, 18.93. Mu. Mol,2.37% yield). LC-MS: c (C) 21 H 24 N 3 O 4 ,[M+H] + 382.2。 1 H NMR(400MHz,CD3OD)δ7.82(d,J＝2.3Hz,1H),7.78(s,1H),7.66(d,J＝1.4Hz,1H),7.53(s,1H),7.44(d,J＝0.7Hz,1H),4.60(d,J＝7.1Hz,1H),3.66(s,3H),2.77(s,3H),2.63(s,3H),2.20(s,3H),1.50(d,J＝7.2Hz,3H)。
Example 3, method for the synthesis of compound G of the invention:
Figure BDA0002971200020000221
step 1, synthesis of Compound 12
To a 50mL reaction flask, compound 11 (279.03 mg,1.00 mmol), DIPEA (387.72 mg,3.00mmol, 522.53. Mu.L), HATU (418.00 mg,1.10 mmol) and DMF (10 mL) were sequentially added, after the reaction system temperature had fallen to 0 ℃, compound 4 (102.13 mg,0.99 mmol) was added, the reaction was quenched after stirring under ice bath conditions for 1 hour (LC-MS monitoring), saturated NaCl solution (20 mL) and ethyl acetate (3X 20 mL) were extracted, the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was evaporated, and then purified by MPLC, and the solvent was removed by concentration under reduced pressure to give compound 12 (289.72 mg, 797.73. Mu. Mol,79.73% yield).
Step 2, synthesis of Compound G
Into a 100mL reaction flask was charged compound 12 (217.36 mg,0.8 mmol), compound 7 (133.58 mg, 800.00. Mu. Mol), K under nitrogen 2 CO 3 (278.41 mg,2 mmol), 1, 4-dioxane and water (4 mL/1 mL) and Pd (dppf) Cl 2 (29.32mg mg,0.25mol%). The reaction was sealed and quenched after stirring at 80℃for 2 hours (LC-MS monitoring). The extraction was completed with saturated NaCl solution (20 mL) and ethyl acetate (3×20 mL), the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was evaporated, and the column chromatography was carried out using an eluent in a volume ratio of petroleum ether/ethyl acetate=1:100 to 1:5, and the solvent was removed by concentration under reduced pressure to give compound G (15.20 mg,39.27 μmol,4.91% yield). LC-MS: c (C) 18 H 23 N 4 O 4 ,[M+H] + 359.2。 1 H NMR(400MHz,CD3OD)δ7.91(d,J＝2.4Hz,1H),7.89(d,J＝7.6Hz,1H),7.74(d,J＝7.6Hz,1H),7.73-7.70(m,1H),4.57(d,J＝7.0Hz,1H),4.10(s,3H),3.64(s,3H),2.78(s,3H),2.19(d,J＝12.5Hz,3H),1.47(t,J＝7.1Hz,3H)。
In order to illustrate the beneficial effects of the present invention, the present invention provides the following test examples.
Test example 1, biological Activity test
The compound was preincubated with BRD4-GST recombinant protein in 20mM sodium phosphate, 0.08% bovine serum albumin, pH7.0 buffer for 15 min at room temperature, followed by addition of Cy-5 labeled probe binding to BRD4-GST and incubation for 30 min at room temperature. And adding the Eu-labeled anti-GST antibody, incubating for 1 hour at room temperature, selecting a time-resolved fluorescence mode on an enzyme-labeled instrument, reading the wavelength of excitation light=320 nm/emission light=665/620 nm, and calculating the blocking effect of the compound on the binding of BRD4-GST and the probe.
The BRD4 inhibitory activity of the compounds of the invention is as follows:
example Compounds IC 50 (μM) Example Compounds IC 50 (μM)
A 0.85 B 6.57
C 0.35 D 2.16
E 3.65 F 0.75
G 0.77
In conclusion, the compound of the invention shows good BRD4 inhibition activity, and provides a new medicinal possibility for clinically treating diseases related to BRD4 activity abnormality.

Claims (7)

1. A compound of formula (II), or a stereoisomer, pharmaceutically acceptable salt thereof:
Figure FDA0004140572040000011
R 1 、R 2 、R 3 、R 4 each independently selected from H, C 1 ～C 6 An alkyl group;
x, Y are each independently selected from O;
W 1 selected from CR W1 Or N; w (W) 2 Selected from CR W2 Or N; w (W) 3 Selected from CR W3 Or N; w (W) 4 Selected from CR W4 Or N;
Q 1 selected from CR Q1 ；Q 2 Selected from CR Q2 ；Q 3 Selected from CR Q3 ；Q 4 Selected from NR Q4 ；
R Q4 Selected from C 1 ～C 6 An alkyl group;
R W1 、R W2 、R W3 、R W4 、R Q1 、R Q2 、R Q3 each independently selected from H, C 1 ～C 6 Alkyl, C 1 ～C 6 Alkoxy, C substituted by 0-4 halogen atoms 1 ～C 6 An alkoxy group.
2. A compound according to claim 1, wherein,
R 1 、R 2 、R 3 、R 4 each independently selected from H, methyl, ethyl, isopropyl;
x, Y are each independently selected from O;
W 1 selected from CR W1 ；W 2 Selected from CR W2 ；W 3 Selected from CR W3 Or N; w (W) 4 Selected from CR W4 ；
Q 1 Selected from CR Q1 ；Q 2 Selected from CR Q2 ；Q 3 Selected from CR Q3 ；
Q 4 Selected from NR Q4 ；
R Q4 Selected from C 1 ～C 6 An alkyl group;
R W1 、R W2 、R W3 、R W4 、R Q1 、R Q2 、R Q3 each independently selected from H, C 1 ～C 6 Alkyl, C 1 ～C 6 Alkoxy, C substituted by 0-3F atoms 1 ～C 6 An alkoxy group.
3. A compound according to claim 1, wherein,
R 1 、R 2 、R 3 、R 4 each independently selected from H, methyl;
x, Y are each independently selected from O;
W 3 selected from CR W3 ；
R W1 、R W2 、R W3 、R W4 Each independently selected from H, methyl, ethyl, methoxy,
Figure FDA0004140572040000021
R Q1 、R Q2 、R Q3 Each independently selected from H, methyl;
Q 4 selected from NR Q4 ；
R Q4 Selected from methyl groups.
4. A compound according to claim 1, wherein,
R 1 、R 2 、R 3 、R 4 each independently selected from H, methyl;
x, Y are each independently selected from O;
W 3 selected from N;
R W1 、R W2 、R W4 each independently selected from H, methyl, ethyl, methoxy,
Figure FDA0004140572040000022
R Q1 、R Q2 、R Q3 Each independently selected from H, methyl;
Q 4 selected from NR Q4 ；
R Q4 Selected from methyl groups.
5. The compound according to claim 1, wherein said compound is specifically selected from the group consisting of:
Figure FDA0004140572040000023
6. a pharmaceutical composition comprising a compound of any one of claims 1-5, or a stereoisomer, pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.
7. Use of a compound according to any one of claims 1 to 5, or a stereoisomer, a pharmaceutically acceptable salt thereof, or a composition according to claim 6 in the manufacture of a medicament for the treatment of cancer.
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