WO2020200209A1 - 芳香胺类化合物及其在制备ar和brd4双重抑制剂和调控剂中的用途 - Google Patents
芳香胺类化合物及其在制备ar和brd4双重抑制剂和调控剂中的用途 Download PDFInfo
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- WO2020200209A1 WO2020200209A1 PCT/CN2020/082513 CN2020082513W WO2020200209A1 WO 2020200209 A1 WO2020200209 A1 WO 2020200209A1 CN 2020082513 W CN2020082513 W CN 2020082513W WO 2020200209 A1 WO2020200209 A1 WO 2020200209A1
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- 0 C*CCC(N)=**=C(*)*=* Chemical compound C*CCC(N)=**=C(*)*=* 0.000 description 3
- KROHNJAXRAQACN-UHFFFAOYSA-N CCN(c(cc1)ccc1-[n]1nncc1)c1cc(-c2c(C)[o]nc2C)ccc1C Chemical compound CCN(c(cc1)ccc1-[n]1nncc1)c1cc(-c2c(C)[o]nc2C)ccc1C KROHNJAXRAQACN-UHFFFAOYSA-N 0.000 description 1
- OASQNZXSDFURIR-UHFFFAOYSA-N CCN(c(cc1)ccc1-c1c(C)[o]nc1C)c1c(C)ccc(-c2c(C)[o]nc2C)c1 Chemical compound CCN(c(cc1)ccc1-c1c(C)[o]nc1C)c1c(C)ccc(-c2c(C)[o]nc2C)c1 OASQNZXSDFURIR-UHFFFAOYSA-N 0.000 description 1
- VLOHNTWGRYNCMX-UHFFFAOYSA-N CCN(c(cc1)ccc1-c1c[s]c(N)n1)c1c(C)ccc(-c2c(C)[o]nc2C)c1 Chemical compound CCN(c(cc1)ccc1-c1c[s]c(N)n1)c1c(C)ccc(-c2c(C)[o]nc2C)c1 VLOHNTWGRYNCMX-UHFFFAOYSA-N 0.000 description 1
- IWLRCNIJDJCDLL-UHFFFAOYSA-N CCN(c(cc1)ccc1-c1cnc[nH]1)c1cc(-c2c(C)[o]nc2C)ccc1C Chemical compound CCN(c(cc1)ccc1-c1cnc[nH]1)c1cc(-c2c(C)[o]nc2C)ccc1C IWLRCNIJDJCDLL-UHFFFAOYSA-N 0.000 description 1
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- WGRDPNSIGPOTII-UHFFFAOYSA-N CCN(c(cc1)ccc1-c1n[o]cn1)c1cc(-c2c(C)[o]nc2C)ccc1C Chemical compound CCN(c(cc1)ccc1-c1n[o]cn1)c1cc(-c2c(C)[o]nc2C)ccc1C WGRDPNSIGPOTII-UHFFFAOYSA-N 0.000 description 1
- HZQCFPAOJUSEEL-STZFKDTASA-N CCN(c(cc1)ccc1/C(/N)=C/N(C)N)c1c(C)ccc(-c2c(C)[o]nc2C)c1 Chemical compound CCN(c(cc1)ccc1/C(/N)=C/N(C)N)c1c(C)ccc(-c2c(C)[o]nc2C)c1 HZQCFPAOJUSEEL-STZFKDTASA-N 0.000 description 1
- QIEMHALQPYKSTD-MOSHPQCFSA-N CCN(c(cc1)ccc1/C(/N)=C/SN)c1cc(-c2c(C)[o]nc2C)ccc1C Chemical compound CCN(c(cc1)ccc1/C(/N)=C/SN)c1cc(-c2c(C)[o]nc2C)ccc1C QIEMHALQPYKSTD-MOSHPQCFSA-N 0.000 description 1
- FZGZLVYUHAQWNG-UHFFFAOYSA-N CCN(c(cc1)ccc1N)c1cc(-c2c(C)[o]nc2C)ccc1C Chemical compound CCN(c(cc1)ccc1N)c1cc(-c2c(C)[o]nc2C)ccc1C FZGZLVYUHAQWNG-UHFFFAOYSA-N 0.000 description 1
- WUEVLLCEBBZRQM-UHFFFAOYSA-N CCN(c(cc1)ccc1OC)c1c(C)ccc(-c2c(C)[o]nc2C)c1 Chemical compound CCN(c(cc1)ccc1OC)c1c(C)ccc(-c2c(C)[o]nc2C)c1 WUEVLLCEBBZRQM-UHFFFAOYSA-N 0.000 description 1
- FGBOGVVQQAGDHL-UHFFFAOYSA-N CCN(c(cc1)ccc1[N+]([O-])=O)c1cc(-c2c(C)[o]nc2C)ccc1C Chemical compound CCN(c(cc1)ccc1[N+]([O-])=O)c1cc(-c2c(C)[o]nc2C)ccc1C FGBOGVVQQAGDHL-UHFFFAOYSA-N 0.000 description 1
- HGCLUNJEUQLSFK-UHFFFAOYSA-N CCN(c1ccc(C(C)(C)C#N)cc1)c1c(C)ccc(-c2c(C)[O](CCN(c(cc3)ccc3OC(F)(F)F)c3cc(-c4c(C)[o]nc4C)ccc3C)nc2C)c1 Chemical compound CCN(c1ccc(C(C)(C)C#N)cc1)c1c(C)ccc(-c2c(C)[O](CCN(c(cc3)ccc3OC(F)(F)F)c3cc(-c4c(C)[o]nc4C)ccc3C)nc2C)c1 HGCLUNJEUQLSFK-UHFFFAOYSA-N 0.000 description 1
- AUADXQAQYRTXOT-UHFFFAOYSA-N CCN(c1ccc(C2(CC2)C#N)cc1)c1cc(-c2c(C)[o]nc2C)ccc1C Chemical compound CCN(c1ccc(C2(CC2)C#N)cc1)c1cc(-c2c(C)[o]nc2C)ccc1C AUADXQAQYRTXOT-UHFFFAOYSA-N 0.000 description 1
- IZGSBPAZVQXEFB-UHFFFAOYSA-N CCN(c1ccc(C2(CCC2)C#N)cc1)c1cc(-c2c(C)[o]nc2C)ccc1C Chemical compound CCN(c1ccc(C2(CCC2)C#N)cc1)c1cc(-c2c(C)[o]nc2C)ccc1C IZGSBPAZVQXEFB-UHFFFAOYSA-N 0.000 description 1
- PXHGVLRBXVOVRB-UHFFFAOYSA-N CCN(c1ccc2[nH]ncc2c1)c1cc(-c2c(C)[o]nc2C)ccc1C Chemical compound CCN(c1ccc2[nH]ncc2c1)c1cc(-c2c(C)[o]nc2C)ccc1C PXHGVLRBXVOVRB-UHFFFAOYSA-N 0.000 description 1
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- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A61K31/42—Oxazoles
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4245—Oxadiazoles
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- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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Abstract
Description
化合物 | IC 50(μM) |
2 | 0.78 |
14 | 1.5 |
27 | 0.89 |
29 | 0.45 |
31 | 2.1 |
45 | 1.7 |
83 | 0.83 |
104 | 1.3 |
110 | 1.6 |
111 | 1.6 |
116 | 4.9 |
127 | 3.4 |
化合物 | IC 50(μM) |
27 | 4.1 |
31 | 6.3 |
45 | 1.9 |
83 | 6.7 |
Claims (10)
- 式Ⅰ所示化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物、或其互变异构体、或其内消旋体、或其外消旋体、或其对映异构体、或其非对映异构体、或其混合物形式、或其代谢产物、或其代谢前体、或其同位素替代形式:其中,环A、B、C各自独立地选自无、取代或未取代的不饱和杂环、取代或未取代的不饱和碳环、取代或未取代的稠环;优选为无、取代或未取代的单环芳环、取代或未取代的单环杂芳环、取代或未取代的稠环;更优选为无、取代或未取代的3~8元单环芳环、取代或未取代的3~8元单环杂芳环、取代或未取代的杂芳环并杂芳环、取代或未取代的苯并芳环、取代或未取代的苯并杂芳环、取代或未取代的苯并饱和碳环、取代或未取代的苯并饱和杂环;环A、B、C不同时为无;上述A、B、C环上的取代基各自独立地选自氘、卤素、-CN、羟基、硝基、氨基、 -L 0-OH、-L 3-C(O)R 7、-L 4-CO(O)R 8、-L 5-(O)COR 9、-L 6-NHC(O)R 10、-L 7-C(O)NHR 11、-L 8-CN、被一个或多个R 12取代的烯基、被一个或多个R 13取代的炔基、被一个或多个R 1取代的烷基、被一个或多个R 2取代的烷氧基、被一个或多个R 3取代的芳基或杂芳基、被一个或多个R 5取代的环烷基、被一个或多个R 6取代的杂环基,所述R X、R 1、R 2、R 3、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13各自独立地选自H、氘、卤素、-CN、羟基、硝基、氨基、烷基或其氘代或卤代物、-L 0-OH,其中L 0、L 3、L 4、L 5、L 6、L 7、L 8各自独立地选自无、C 1-C 8烷基、环烷基;R 4选自氢、氘、卤素、-CN、羟基、硝基、氨基、 -L 0-OH、-L 3-C(O)R 7、-L 4-CO(O)R 8、-L 5-(O)COR 9、-L 6-NHC(O)R 10、-L 7-C(O)NHR 11、被一个或多个R 12取代的烯基、被 一个或多个R 13取代的炔基、被一个或多个R 1取代的烷基、被一个或多个R 2取代的烷氧基、被一个或多个R 3取代的芳基或杂芳基、被一个或多个R 5取代的环烷基、被一个或多个R 6取代的杂环基,所述R X、R 1、R 2、R 3、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13各自独立地选自H、氘、卤素、-CN、羟基、硝基、氨基、烷基或其氘代或卤代物、-L 0-OH,其中L 0、L 3、L 4、L 5、L 6、L 7各自独立地选自0-8个亚甲基;或,上述A、B、C环上的取代基、R 4中的任意两个基团与其连接的被取代原子一起连接成环。
- 根据权利要求1所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物、或其互变异构体、或其内消旋体、或其外消旋体、或其对映异构体、或其非对映异构体、或其混合物形式、或其代谢产物、或其代谢前体、或其同位素替代形式,其特征在于:所述化合物具有如式II所示的结构:B 1、B 2、B 3、B 4、B 5、B 6、A 1、A 2、A 3、A 4、A 5、A 6各自独立地选自CR 0或N,R 0选自H、-CN、氨基、硝基、卤素、-L 0-OH、 -C(O)NHR 11、C 1~C 5烷基或其氘代或卤代物或氰基取代物、C 1~C 5烷氧基或其氘代或卤代物或氰基取代物、取代或未取代的3~6元环烷基、取代或未取代的3~6元环烷基,或,环上相邻的两个取代基与其连接的被取代原子一起形成取代或未取代的3~6元杂环;其中,所述3~6元环烷基、3~6元环烷基上的取代基各自独立地选自-CN、氨基、硝基、卤素、C 1~C 3烷基或其氘代或卤代物、-L 1-OH,所述L 0、L 1各自独立地选自0-5个亚甲基,所述R x、R 11各自独立地选自H、C 1~C 3烷基;C环、R 4如权利要求1所述。
- 根据权利要求2所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物、或其互变异构体、 或其内消旋体、或其外消旋体、或其对映异构体、或其非对映异构体、或其混合物形式、或其代谢产物、或其代谢前体、或其同位素替代形式,其特征在于:所述化合物具有如式III-A所示的结构:其中,R a4、R a6各自独立地选自氢、卤素、取代或未取代的五元不饱和杂环;其中所述五元不饱和杂环上的取代基选自氘代或未氘代的C 1~C 2烷基、-L 1-OH,L 1选自0-2个亚甲基;R 4选自氢、氘代或未氘代的C 1~C 2烷基、-L 2-OH,L 2选自0-5个亚甲基;B 1选自CH、N;R b2选自氘代或未氘代的甲基;
- 根据权利要求2所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物、或其互变异构体、或其内消旋体、或其外消旋体、或其对映异构体、或其非对映异构体、或其混合物形式、或其代谢产物、或其代谢前体、或其同位素替代形式,其特征在于:所述化合物具有如式III-B所示的结构:其中,C环选自 C 3选自O、S或NR c3,R c2、R c3、R c5各自独立地选自氢、卤素、C 1~C 3烷基或其氘代或卤代物、-L 0-OH,L 0选自0-5个亚甲基;B 1、B 3、B 5各自独立地选自CH、N;R b0选自氢、卤素、C 1~C 3烷基或其氘代或卤代物;R 4选自氢、C 1~C 2烷基或其氘代或卤代物、-L 2-OH,L 2选自0-5个亚甲基;A 1、A 2、A 3、A 4各自独立地选自N、CR a0,A 5为C,A 6选自N、CR a6,其中,R a0、R a6各自独立地选自H、-CN、氨基、硝基、卤素、 -C(O)NHR 11、C 1~C 3烷基或其氘代或卤代物或氰基取代物、C 1~C 3烷氧基或其氘代或卤代物或氰基取代物、取代或未取代的3~6元环烷基、取代或未取代的5元杂环基,或,R a6、R a6邻位的取代基、与其连接的被取代原子一起形成取代或未取代的5元杂环;其中,所述5元杂环、3~6元环烷基、5元杂环基上的取代基各自独立地选自-CN、氨基、硝基、卤素、C 1~C 2烷基或其氘代或卤代物、-L 1-OH,L 1选自0-2个亚甲基,所述R x、R 11各自独立地选自H、C 1~C 2烷基;优选地,上述5元杂环为5元不饱和杂环,5元杂环基为5元 不饱和杂环基,杂原子选自N、S、O;上述3~6元环烷基为3~6元饱和环烷基。
- 根据权利要求4所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物、或其互变异构体、或其内消旋体、或其外消旋体、或其对映异构体、或其非对映异构体、或其混合物形式、或其代谢产物、或其代谢前体、或其同位素替代形式,其特征在于:所述化合物具有如式III-B1所示的结构:其中,C 3选自O、S或NR c3,R c2、R c5、R c3各自独立地选自氢、卤素、C 1~C 3烷基或其氘代或卤代物、-L 0-OH,L 0选自0-5个亚甲基;B 1、B 3、B 5各自独立地选自CH、N;R b2选自氘代或未氘代的甲基;R 4选自氢、氘代或未氘代的C 1~C 2烷基、-L 2-OH,L 2选自0-5个亚甲基;A 1、A 2、A 3、A 4各自独立地选自N、CR a0,其中,R a0、R a6各自独立地选自H、-CN、氨基、硝基、卤素、 -C(O)NHR 11、C 1~C 3烷基或其氘代或卤代物或氰基取代物、C 1~C 3烷氧基或其氘代或卤代物或氰基取代物、取代或未取代的3~6元饱和环烷基、取代或未取代的5元不饱和杂环基,或,R a6、R a6邻位的取代基、与其连接的被取代原子一起形成取代或未取代的五元不饱和杂环;其中,所述5元不饱和杂环基、五元不饱和杂环上的取代基各自独立地选自-CN、氨基、硝基、卤素、C 1~C 2烷基或其氘代或卤代物、-L 1-OH,L 1选自0-2个亚甲基,所述3~6元饱和环烷基上的取代基选自-CN,所述R x、R 11各自独立地选自H、C 1~C 2烷基。
- 根据权利要求5所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物、或其互变异构体、 或其内消旋体、或其外消旋体、或其对映异构体、或其非对映异构体、或其混合物形式、或其代谢产物、或其代谢前体、或其同位素替代形式,其特征在于:所述化合物具有如式III-B1a所示的结构:其中,C 3选自O或S;R c2、R c5各自独立地选自氢、C 1~C 3烷基或其氘代或卤代物,优选地,R c2、R c5选自甲基;B 1、B 3、B 5各自独立地选自CH、N;R b2选自氘代或未氘代的甲基;R 4选自氢、氘代或未氘代的C 1~C 2烷基、-L 2-OH,L 2选自0-5个亚甲基;A 1、A 2、A 3、A 4各自独立地选自N、CR a0,其中,R a0、R a6各自独立地选自H、-CN、氨基、硝基、卤素、 -C(O)NHR 11、C 1~C 3烷基或其氘代或卤代物或氰基取代物、C 1~C 3烷氧基或其氘代或卤代物或氰基取代物、取代或未取代的3~6元饱和环烷基、取代或未取代的5元不饱和杂环基,或,R a6、R a6邻位的取代基、与其连接的被取代原子一起形成取代或未取代的五元不饱和杂环;其中,所述5元不饱和杂环基、五元不饱和杂环上的取代基各自独立地选自-CN、氨基、硝基、卤素、C 1~C 2烷基或其氘代或卤代物、-L 1-OH,L 1选自0-2个亚甲基,所述3~6元饱和环烷基上的取代基选自-CN,所述R x、R 11各自独立地选自H、C 1~C 2烷基;或,所述化合物具有如式III-B1b所示的结构:其中,R c2、R c3、R c5各自独立地选自氢、C 1~C 3烷基或其氘代或卤代物、-L 0-OH;优选地,R c3选自氢、C 1~C 3烷基或其氘代或卤代物、-L 0-OH,R c2、R c5选自甲基;其中L 0选自0-5个亚甲基;R 4选自氢、氘代或未氘代的C 1~C 2烷基、-L 2-OH,L 2选自0-5个亚甲基;R b2选自氘代或未氘代的甲基;A 2选自N或CH;R a4、R a6各自独立地选自H、-CN、氨基、硝基、卤素、 -C(O)NHR 11、C 1~C 3烷基或其氘代或卤代物或氰基取代物、C 1~C 3烷氧基或其氘代或卤代物或氰基取代物、取代或未取代的3~6元饱和环烷基、取代或未取代的5元不饱和杂环基,或,R a6、R a6邻位的取代基、与其连接的被取代原子一起形成取代或未取代的五元不饱和杂环;其中,所述5元不饱和杂环基、五元不饱和杂环上的取代基各自独立地选自-CN、氨基、硝基、卤素、C 1~C 2烷基或其氘代或卤代物、-L 1-OH,L 1选自0-2个亚甲基,所述3~6元饱和环烷基上的取代基选自-CN,所述R x、R 11各自独立地选自H、C 1~C 2烷基。
- 根据权利要求4所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物、或其互变异构体、或其内消旋体、或其外消旋体、或其对映异构体、或其非对映异构体、或其混合物形式、或其代谢产物、或其代谢前体、或其同位素替代形式,其特征在于:所述化合物具有如式III-B2所示的结构:R 4选自氢、氘代或未氘代的C 1~C 2烷基、-L 2-OH,L 2选自0-5个亚甲基;R b2选自氘代或未氘代的甲基;R a4、R a6各自独立地选自H、-CN、氨基、硝基、卤素、 -C(O)NHR 11、C 1~C 3烷基或其氘代或卤代物或氰基取代物、C 1~C 3烷氧基或其氘代或卤代物或氰基取代物、取代或未取代的3~6元饱和环烷基、取代或未取代的5元不饱和杂环基,或,R a6、R a6邻位的取代基、与其连接的被取代原子一起形成取代或未取代的五元不饱和杂环;其中,所述5元不饱和杂环基、五元不饱和杂环上的取代基各自独立地选自-CN、氨基、硝基、卤素、C 1~C 2烷基或其氘代或卤代物、-L 1-OH,L 1选自0-2个亚甲基,所述3~6元饱和环烷基上的取代基选自-CN,所述R x、R 11各自独立地选自H、C 1~C 2烷基。
- 权利要求1-8任一所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物、或其互变异构体、或其内消旋体、或其外消旋体、或其对映异构体、或其非对映异构体、或其混合物形式、或其代谢产物、或其代谢前体、或其同位素替代形式在制备AR和/或BRD4抑制剂,和/或蛋白降解靶向嵌合体中的用途;优选地,所述抑制剂和/或蛋白降解靶向嵌合体为治疗与AR和/或BRD4相关疾病的药物;所述药物优选为治疗前列腺癌的药物,所述前列腺癌优选为对恩杂鲁胺耐药的前列腺癌。
- 根据权利要9所述的用途,其特征在于:所述蛋白降解靶向嵌合体能够靶向降解AR和/或BRD4,和/或下调全长雄激素受体和/或变异雄激素受体表达。
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104918919A (zh) * | 2012-11-21 | 2015-09-16 | Ptc医疗公司 | 取代的反向嘧啶Bmi-1抑制剂 |
CN107814785A (zh) * | 2016-09-14 | 2018-03-20 | 四川大学 | 雄激素受体拮抗剂及其制备方法和用途 |
CN108697710A (zh) * | 2016-01-22 | 2018-10-23 | 杨森制药有限公司 | 作为nik抑制剂的新颖的经取代的氰基吲哚啉衍生物 |
CN109608394A (zh) * | 2018-12-03 | 2019-04-12 | 湖南大学 | 氮杂芳胺类化合物的合成方法和氮杂芳胺类化合物 |
WO2020063968A1 (zh) * | 2018-09-30 | 2020-04-02 | 四川大学 | Ar和bet双重抑制剂及其用途 |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3227281A4 (en) * | 2014-12-01 | 2018-05-30 | Zenith Epigenetics Ltd. | Substituted pyridinones as bromodomain inhibitors |
CA2966303A1 (en) * | 2014-12-01 | 2016-06-09 | Zenith Epigenetics Ltd. | Substituted pyridines as bromodomain inhibitors |
WO2017133681A1 (zh) * | 2016-02-05 | 2017-08-10 | 正大天晴药业集团股份有限公司 | 溴区结构域蛋白抑制剂的三环类化合物及其制备、药物组合物和用途 |
-
2020
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Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104918919A (zh) * | 2012-11-21 | 2015-09-16 | Ptc医疗公司 | 取代的反向嘧啶Bmi-1抑制剂 |
CN108697710A (zh) * | 2016-01-22 | 2018-10-23 | 杨森制药有限公司 | 作为nik抑制剂的新颖的经取代的氰基吲哚啉衍生物 |
CN107814785A (zh) * | 2016-09-14 | 2018-03-20 | 四川大学 | 雄激素受体拮抗剂及其制备方法和用途 |
WO2020063968A1 (zh) * | 2018-09-30 | 2020-04-02 | 四川大学 | Ar和bet双重抑制剂及其用途 |
CN109608394A (zh) * | 2018-12-03 | 2019-04-12 | 湖南大学 | 氮杂芳胺类化合物的合成方法和氮杂芳胺类化合物 |
Non-Patent Citations (3)
Title |
---|
DATABASE Registry 9 August 1996 (1996-08-09), ANONYMOUS: "4-Pyrimidinamine, 2-(1H-imidazol-1-yl)-5,6-dimethyl-N-phenyl-,hydrochloride", XP055740406, retrieved from STN Database accession no. RN 179336-31-3 * |
XIA WANG, YANG QIU-XIA, LONG CHENG-YU, TAN YAN, QU YI-XIN, SU MIN-HUI, HUANG SI-JIE, TAN WEIHONG, WANG XUE-QIANG: "Anticancer-Active N-Heteroaryl Amines Syntheses: Nucleophilic Amination of N-Heteroaryl Alkyl Ethers with Amines", ORGANIC LETTERS, vol. 21, no. 13, 14 June 2019 (2019-06-14), pages 5111 - 5115, XP055740350, ISSN: 1523-7060, DOI: 10.1021/acs.orglett.9b01711 * |
YU JIANG; ZHANG LANXI; YAN GUOYI; ZHOU PEITING; CAO CHAOGUO; ZHOU FEI; LI XINGHAI; CHEN YUANWEI: "Discovery and biological evaluation of novel androgen receptor antagonist for castration-resistant prostate cancer", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 171, 1 June 2019 (2019-06-01), pages 265 - 281, XP085661306, ISSN: 0223-5234, DOI: 10.1016/j.ejmech.2019.03.041 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11613548B2 (en) | 2021-02-19 | 2023-03-28 | Sudo Biosciences Limited | Substituted pyridines, pyridazines, pyrimidines, and 1,2,4-triazines as TYK2 inhibitors |
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