CN104968667A - 四并环激酶抑制剂 - Google Patents
四并环激酶抑制剂 Download PDFInfo
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- CN104968667A CN104968667A CN201480007591.3A CN201480007591A CN104968667A CN 104968667 A CN104968667 A CN 104968667A CN 201480007591 A CN201480007591 A CN 201480007591A CN 104968667 A CN104968667 A CN 104968667A
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- Prior art keywords
- alkyl
- cancer
- carcinoma
- cycloalkyl
- amino
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- MUUHXGOJWVMBDY-UHFFFAOYSA-L tetrazolium blue Chemical compound [Cl-].[Cl-].COC1=CC(C=2C=C(OC)C(=CC=2)[N+]=2N(N=C(N=2)C=2C=CC=CC=2)C=2C=CC=CC=2)=CC=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 MUUHXGOJWVMBDY-UHFFFAOYSA-L 0.000 description 1
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- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
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- 125000001544 thienyl group Chemical group 0.000 description 1
- XSROQCDVUIHRSI-UHFFFAOYSA-N thietane Chemical compound C1CSC1 XSROQCDVUIHRSI-UHFFFAOYSA-N 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
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- 238000005406 washing Methods 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims (1)
- 权 利 要 求 通式( I )所示的化合物或其立体异构体、 或者其药学上可接受其中,Ai, A2和 A4分别独立地选自 C或 N, 且 Α2和 Α4不同时为 Ν; Α3选自 C;R1选自氢, 羟基, 羧基, 氨基, 烷基 )2氨基, 氰基, C1-6烷基, (^_6烷氧基, 3〜14元环烷基, 卤素原子, C2_6烯基, C2_6炔基或硝基;R2和 R4分别独立地选自氢, 羟基, 羧基, 氨基, (C1-6烷基 )2氨基, C 6烷基, C^6烷氧基, 3~14元环烷基, 卤素原子, C2-6烯基, C2-6 炔基或硝基;R3选自氢, , 羟基, 氨基, 鹵素原子, C1-6烷基, C1-6烷氧基, 3~14元环烷基, 烯基或 C2_6炔基,其中所述的 C1-6烷基、 C 烷氧基、 3-14元环烷基、 C2_6烯基和 (¾_6炔基可独立地任选被一至多个下列取代基 取代: 羟基, , 卤素原子, 硝基或 3~14元杂环基;M选自 O, S, NH或 N-R8, 其中 R8选自 C1-6烷基、 C1-6烷氧基、 C2-6 烯基或 C2_6炔基, 其中所述的 C1-6烷基、 C2-6烯基和 C2_6炔基可独立地任 选被 C1-6烷氧基取代;R5和 R6分别独立地选自氢, ^6烷基, (^_6烷氧基, 羟基 C 烷基, 卤素原子, C2-6烯基或 C2-6块基,或 R5和 R6相互连接, 与它们所连接的碳原子一起形成 3~14元杂环 基或 3~14元环烷基;Y选自 N或 CH;X选自 O, S或 N-R9, 其中 R9选自( 1 )氢、 氰基、 C1-6烷基、 硝基、 羰基,( 2 )氨基、 磺酰基, ( 3 ) C1-6烷氧基、 C1-6烷基硫基,( 4 ) C2-6烯基、 C2-6炔基,( 5 )3-14元环烷基、 3-14元杂环基、 5-15元杂芳基或 6~14元芳基, 其中所述的 C1-6烷基、 羰基、 氨基、 磺酰基、 C1-6烷氧基、 C1-6烷基 硫基、 C2_6烯基、 C2-6炔基、 3~14元环烷基、 3〜14元杂环基、 5〜15元杂 芳基和 6〜14元芳基可独立地任选被一至三个下列取代基取代: 羟基、 C1-6 烷基、 C1-6烷氧基、 3~14元杂环基、 C1-6烷基磺酰基、 羧基、 3~8元环烷 基、 (C1-6烷基 )2氨基、 3~14元杂环基取代的 3~14元杂环基、 3~14元杂环 基取代的 C 6烷基、 或 (C 6烷基) 2氨基取代的 烷基;Q选自 3〜8元单环杂环基或 5~7元单环杂芳基;R7选自下列基团:(1) 氢、 、 硝基、 C1-6烷氧基、 羟基、 卤素原子,(2)任选被 R1Q取代的氨基、 羰基、 烷基、 羟基 C1-6烷基、 C2-6烯 基、 C2-6炔基、 磺酰基、 氨基磺酰基、 氨基羰基、 磺酰基氨基或 3~8元单 环环烷基,其中所述的 3〜8元单环环烷基的环碳原子可任选被 S02、 SO、 0、 S、 N、 NH或羰基取代,R1Q选自卤素原子、氨基、 C^6烷基、羟基、硝基、 3~8元单环环烷基、 羟基 C1-6烷基、 羟基 C1-6烷氧基、 3~8元单环杂环基、 氨基磺酰基、 C1-6 烷基磺酰基、 卤代 (^6烷基、 氨基磺酰基氨基、 或 (C1-6烷基 )2氨基取代的Ci— 6燒基,n选自 0, 1 , 2, 3, 4, 5或 6, 且 n为 0时, R7不存在, n≥ 2时, R7可以相同或不同。2. 如权利要求 1所述的化合物或其立体异构体、 或者其药学上可接 受的盐、 酯或溶剂化物:其中,Ai, A2、 A3和 A4分别选自 C;R1选自氢, CM垸基或卤素原子;R2和 R4分别独立地选自氢, CM烷基, 3~8元环烷基或 素原子; R3选自 , 羟基, 氨基, 卤素原子, C1-6烷基或 3~8元环烷基; M选自 O, S, NH或 N-R8, 其中 R8选自 C1-6烷基或 C1-6烷氧基, 其 中所述的(^_6烷基可任选被 C!_6烷氧基取代;R5和 R6分别独立地选自 ^6烷基, ^6烷氧基,羟基 烷基或卤素 原子,或 R5和 R6相互连接, 与它们连接的碳原子一起形成 5〜6元杂环基或 3-8元环烷基;X为 0, S或 N-R9, R9选自氢、 CM烷基或氨基,Q选自 3~6元单环杂环基或 5〜6元单环杂芳基;R7选自下列基团(1) 氢、 CM烷氧基或羟基,(2) CM烷基、 羟基 CM烷基或 3~6元单环环烷基, 其中所述的 3〜6 元单环环烷基的环碳原子可任选被 S02、 SO、 0、 S、 N、 NH或羰基取代, n选自 0, 1, 2或 3, 且 n为 0时, R7不存在, n≥2时, R7可以相同 或不同。3. 如权利要求 2所述的化合物或其立体异构体、 或者其药学上可接 受的盐、 酯或溶剂化物:其中,R R2和 R4分别独立地选自氢或 CM烷基;R3选自氰基, 羟基, 氨基, 氟原子, 氯原子或 CM烷基;M选自 NH或 N-R8, 其中 R8选自 ^ 0\;R5和 R6分别选自 CM烷基;—(R7)n选自4. 如权利要求 1所述的化合物或其立体异构体、 或者其药学上可接 受的盐、 酯或溶剂化物, 其中,Q选自 4〜7元单环杂环基;R7选自氢、 CM烷基、 C1-6烷氧基或 3~7元单环环烷基, 其中所述的 3~7元单环环烷基的环碳原子可任选被 0、 N或 NH取代;n选自 1。5. 如权利要求 1所述的化合物或其立体异构体、 或者其药学上可接 受的盐、 酯或溶剂化物, 其中,Ax. A2、 A3和 A4为 C;R R2和 R4分别独立地选自氢和 C1-6烷基;R3选自氰基,M选自 NH;R5和 R6分别独立地选自氢和 C1-6烷基;Y选自 N;X选自 S;Q选自 4~7元单环杂环基;R7选自氢、 CM烷基、 ^6烷氧基或 3~7元单环环烷基, 其中所述的 3〜7元单环环垸基的环碳原子可任选被 0、 N或 NH取代;π选 I) 1。6. 如权利要求 1所述的化合物或其立体异构体、 或者其药学上可接 受的盐、 酯或溶剂化物, 其中,7. 如权利要求 1所述的化合物或其立体异构体、 或者其药学上可接 受的盐、 酯或溶剂化物, 其中,Αγ. A2、 A3和 A4为 C;R1, R2和 R4分别独立地选自氢和 C^6烷基;R3选自氰基,M选自 NH;R5和 R6分别独立地选自氢和 烷基;Y选自 N;X选自 S;Q选自8. 如权利要求 1所述的化合物或其立体异构体、 或者其药学上可接 受的 :9. 一种药物组合物, 其包括权利要求 1-8中任一项所述的化合物或 其立体异构体、或者其药学上可接受的盐、 酯或溶剂化物与一种或多种药 用载体和 /或稀释剂。10. 权利要求 9所述的药物组合物, 其特征在于还可含有一种或多 种抗肿瘤剂和免疫抑制剂, 所述的抗肿瘤剂和免疫抑制剂选自曱氨蝶呤、 卡培他滨、吉西他滨、去氧氟尿苷、培美曲塞二钠、帕唑帕尼、伊马替尼、 埃罗替尼、 拉帕替尼、 吉非替尼、 凡德他尼、 赫赛汀、 贝伐单抗、 利妥昔 单抗、 曲妥珠单抗、 紫杉醇、 长春瑞滨、 多西他赛、 多柔比星、 羟基喜树 碱、 丝裂霉素、 表柔比星、 吡柔比星、 博来霉素、 来曲唑、 他莫西芬、 氟 维司群、曲谱瑞林、氟他胺、亮丙瑞林、阿那曲唑、异环磷酰胺、白消安、 环磷酰胺、 卡莫司汀、 尼莫司汀、 司莫司汀、 氮芥、 马法兰、 瘤可宁、 卡 铂、 顺铂、 奥沙利铂、 络铂、 拓朴特肯、 喜树碱、 拓朴替康、 依维莫司、 西罗莫斯、 特癌适、 6-琉基嘌呤、 6-硫鸟嘌呤、 硫唑嘌呤、 菌素 D、 柔红 霉素、 阿霉素、 米托蒽服、 争光霉素、 普卡霉素或氨鲁米特。11. 权利要求 1-8中任一项所述的化合物或其立体异构体、或者其药 学上可接受的盐、 酯或溶剂化物或者权利要求 9-10中任一项所述的药物 组合物在制备用于治疗和 /或预防 ALK介导的癌症相关疾病的药物中的应 用, 所述 ALK介导的癌症相关的疾病选自: 脑瘤、 非小细胞性肺癌、 鳞 状上皮细胞癌、 膀胱癌、 胃癌、 卵巢癌、 腹膜癌、 胰腺癌、 乳腺癌、 头颈 癌、 子宫颈癌、 子宫内膜癌、 直肠癌、 肝癌、 肝母细胞瘤、 乳头状肾细胞 瘤、头颈部鳞状细胞瘤、肾母细胞瘤、肾癌、食管腺癌、食管鳞状细胞癌、 雌性生殖道癌、 原位癌、 淋巴瘤、 成神经细胞瘤、 神经纤维瘤病、 曱状腺 癌、 骨癌、 皮肤癌、 结肠癌、 睾丸癌、 小细胞肺癌、 胃肠道间盾瘤、 前列 腺肿瘤、 肥大细胞肿瘤、 多发性骨髓瘤、 黑色素瘤或神经胶质瘤。12. 权利要求 1-8中任一项所述的化合物或其立体异构体、或者其药 学上可接受的盐、 酯或溶剂化物或者权利要求 9-10中任一项所述的药物 组合物, 其用于治疗和 /或预防 ALK介导的癌症相关疾病, 所述 ALK介 导的癌症相关的疾病选自: 脑瘤、 非小细胞性肺癌、 鳞状上皮细胞癌、 膀 胱癌、 胃癌、 卵巢癌、 腹膜癌、 胰腺癌、 乳腺癌、 头颈癌、 子宫颈癌、 子 宫内膜癌、 直肠癌、 肝癌、 肝母细胞瘤、 乳头状肾细胞瘤、 头颈部鳞状细 胞瘤、 肾母细胞瘤、 肾癌、 食管腺癌、 食管鳞状细胞癌、 雌性生殖道癌、 原位癌、 淋巴瘤、 成神经细胞瘤、 神经纤维瘤病、 曱状腺癌、 骨癌、 皮肤 癌、 结肠癌、 睾丸癌、 小细胞肺癌、 胃肠道间质瘤、 前列腺肿瘤、 肥大细 胞肿瘤、 多发性骨髓瘤、 黑色素瘤或神经胶质瘤。13. 一种治疗和 /或预防 ALK介导的癌症相关疾病的方法, 包括给 予需要其的患者治疗有效量的权利要求 1-8中任一项所述的化合物或其立 体异构体、 或者其药学上可接受的盐、 酯或溶剂化物或者权利要求 9-10 中任一项所述的药物组合物 ,其中所述 ALK介导的癌症相关的疾病选自:脑瘤、非小细胞性肺癌、 鳞状上皮细胞癌、 膀胱癌、 胃癌、 卵巢癌、 腹膜癌、 胰腺癌、 乳腺癌、 头 颈癌、 子宫颈癌、 子宫内膜癌、 直肠癌、 肝癌、 肝母细胞瘤、 乳头状肾细 胞瘤、 头颈部鳞状细胞瘤、 肾母细胞瘤、 肾癌、 食管腺癌、 食管鳞状细胞 癌、 雌性生殖道癌、 原位癌、 淋巴瘤、 成神经细胞瘤、 神经纤维瘤病、 曱 状腺癌、 骨癌、 皮肤癌、 结肠癌、 睾丸癌、 小细胞肺癌、 胃肠道间质瘤、 前列腺肿瘤、 肥大细胞肿瘤、 多发性骨髓瘤、 黑色素瘤或神经胶质瘤。
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CN101765596A (zh) * | 2007-05-18 | 2010-06-30 | 拜耳先灵制药股份公司 | 用于治疗过增生症状和与血管生成有关疾病的缺氧诱导因子(hif)抑制剂 |
CN102459172A (zh) * | 2009-06-10 | 2012-05-16 | 中外制药株式会社 | 四环化合物 |
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WO2008021369A2 (en) * | 2006-08-14 | 2008-02-21 | Chembridge Research Laboratories, Inc. | Tricyclic compounds and its use as tyrosine kinase modulators |
CN101535276A (zh) * | 2006-10-23 | 2009-09-16 | 赛福伦公司 | 作为ALK和c-MET抑制剂的2,4-二氨基嘧啶稠合双环衍生物 |
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Effective date of registration: 20201116 Address after: High tech Zone Tianchen road Ji'nan City, Shandong province 250101 No. 2518 Patentee after: XUANZHU PHARMA Co.,Ltd. Patentee after: Xuanzhu Biotechnology Co.,Ltd. Address before: 050000 Beijing Tianjin Hebei Collaborative Innovation Demonstration Park, 769 Taihang street, high tech Zone, Shijiazhuang City, Hebei Province 203c507 Patentee before: Xuanzhu Biotechnology Co.,Ltd. |
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Address after: No. 2518, Tianchen Road, Ji'nan high tech Zone, Shandong, Shandong Patentee after: XUANZHU PHARMA Co.,Ltd. Patentee after: Xuanzhu Biotechnology Co.,Ltd. Address before: No. 2518, Tianchen Road, Ji'nan high tech Zone, Shandong, Shandong Patentee before: XUANZHU PHARMA Co.,Ltd. Patentee before: Xuanzhu Biotechnology Co.,Ltd. |
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