索拉非尼 | 284461-73-0

• 物质功能分类: 原料药 - 循环系统用药 - 抗高血压病药
• 分子结构分类: 有机化合物 - 有机氧化合物
• 中文名称: 索拉非尼
• 中文别名: Raf抑制剂；4-{4-[3-(4-氯-3-三氟甲基苯基)酰脲]苯氧基}吡啶-2-甲酰胺；索拉菲尼；索拉菲尼单体；索拉非尼碱
• 英文名称: sorafenib
• 英文别名: bay 43-9006；4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy)-N-methylpicolinamide；regorafenib；Nexavar；4-(4-((4-chloro-3-(trifluoromethyl)phenyl)carbamoylamino)phenoxy)-N-methylpyridine-2-carboxamide；4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-N-methylpyridine-2-carboxamide；N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-(methyl)aminoformyl)-4-pyridyloxy)phenyl)urea；cm4306；SRF；Sor；4-[4-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]phenoxy]-N-methyl-2-pyridinecarboxamide；4-(4-{3-[4-chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-n²-methylpyridine-2-carboxamide；4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy)-N-methylpyridine-2-carboxamide；BAY 93-4006；SFN；4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methylpyridine-2-carboxamide
• CAS: 284461-73-0
• 化学式: C₂₁H₁₆ClF₃N₄O₃
• mdl: MFCD06411450
• 分子量: 464.831
• InChiKey: MLDQJTXFUGDVEO-UHFFFAOYSA-N

物化性质

• 熔点：
  202-204°C
• 沸点：
  523.3±50.0 °C(Predicted)
• 密度：
  1.454±0.06 g/cm3(Predicted)
• 溶解度：
  可溶于氯仿（少许）、DMSO（少许）
• LogP：
  3.3 at 25℃
• 物理描述：
  Solid
• 颜色/状态：
  White solid
• 蒸汽密度：
  4.11X10-14 mm Hg at 25 °C (est)
• 稳定性/保质期：
  Stable if stored as directed; avoid strong oxidizing agents. /Sorafenib tosylate/
• 分解：
  Dangerous products of decomposition: thermal ecomposition may produce toxic gases such as carbon monoxide, carbon dioxide, and nitrogen oxides. /Sorafenib tosylate/

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  32
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.095
• 拓扑面积：
  92.4
• 氢给体数：
  3
• 氢受体数：
  7

ADMET

代谢

索拉非尼主要在肝脏代谢，经历由CYP3A4介导的氧化代谢，以及由UGT1A9介导的葡萄糖醛酸化。在稳态下，索拉非尼占血浆中循环分析物的约70-85%。已经鉴定出索拉非尼的八个代谢物，其中五个已在血浆中检测到。索拉非尼在血浆中的主要循环代谢物是吡啶N-氧化物，其体外活性与索拉非尼相似。在稳态下，这种代谢物大约占循环分析物的9-16%。

Sorafenib is metabolized primarily in the liver, undergoing oxidative metabolism, mediated by CYP3A4, as well as glucuronidation mediated by UGT1A9. Sorafenib accounts for approximately 70-85% of the circulating analytes in plasma at steady- state. Eight metabolites of sorafenib have been identified, of which five have been detected in plasma. The main circulating metabolite of sorafenib in plasma, the pyridine N-oxide, shows <i>in vitro</i> potency similar to that of sorafenib. This metabolite comprises approximately 9-16% of circulating analytes at steady-state.

来源:DrugBank

代谢

索拉非尼通过肝脏CYP3A4进行氧化代谢，同时也通过UGT1A9进行葡萄糖醛酸化。CYP3A4活性的诱导剂可以减少索拉非尼的系统暴露。在稳态下，索拉非尼占血浆中循环分析物的约70-85%。已经确定了索拉非尼的八个代谢物，其中五个在血浆中被检测到。索拉非尼的主要循环代谢物是吡啶N-氧化物，在稳态下占循环分析物的约9-16%，其体外效力与索拉非尼相似。

Sorafenib undergoes oxidative metabolism by hepatic CYP3A4, as well as glucuronidation by UGT1A9. Inducers of CYP3A4 activity can decrease the systemic exposure of sorafenib. Sorafenib accounted for approximately 70-85% of the circulating analytes in plasma at steady-state. Eight metabolites of sorafenib have been identified, of which 5 have been detected in plasma. The main circulating metabolite of sorafenib, the pyridine N-oxide that comprises approximately 9-16% of circulating analytes at steady-state, showed in vitro potency similar to that of sorafenib.

来源:Hazardous Substances Data Bank (HSDB)

代谢

索拉非尼已知的人体代谢物包括A-D-葡萄糖苷酸已停产和索拉非尼。

Sorafenib has known human metabolites that include A-D-GlucuronideDISCONTINUED and Sorafenib.

来源:NORMAN Suspect List Exchange

代谢

索拉非尼主要在肝脏代谢，经历由CYP3A4介导的氧化代谢，以及由UGT1A9介导的葡萄糖醛酸化。在稳态下，索拉非尼约占血浆中循环分析物的70-85%。已经鉴定出索拉非尼的八个代谢物，其中五个在血浆中被检测到。索拉非尼在血浆中的主要循环代谢物是吡啶N-氧化物，其体外活性与索拉非尼相似。在稳态下，这种代谢物大约占循环分析物的9-16%。 消除途径：口服100毫克溶液制剂的索拉非尼后，14天内回收了96%的剂量，其中77%的剂量通过粪便排出，19%的剂量以葡萄糖醛酸化代谢物的形式通过尿液排出。 半衰期：25-48小时

Sorafenib is metabolized primarily in the liver, undergoing oxidative metabolism, mediated by CYP3A4, as well as glucuronidation mediated by UGT1A9. Sorafenib accounts for approximately 70-85% of the circulating analytes in plasma at steady- state. Eight metabolites of sorafenib have been identified, of which five have been detected in plasma. The main circulating metabolite of sorafenib in plasma, the pyridine N-oxide, shows <i>in vitro</i> potency similar to that of sorafenib. This metabolite comprises approximately 9-16% of circulating analytes at steady-state. Route of Elimination: Following oral administration of a 100 mg dose of a solution formulation of sorafenib, 96% of the dose was recovered within 14 days, with 77% of the dose excreted in feces, and 19% of the dose excreted in urine as glucuronidated metabolites. Half Life: 25-48 hours

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

索拉非尼与多种细胞内（CRAF、BRAF和突变型BRAF）和细胞表面激酶（KIT、FLT-3、VEGFR-2、VEGFR-3和PDGFR-β）相互作用。这些激酶中有许多被认为参与血管生成，因此索拉非尼减少了流向肿瘤的血液。索拉非尼在靶向Raf/Mek/Erk途径方面是独特的。通过抑制这些激酶，涉及细胞增殖和血管生成的遗传转录被抑制。

Sorafenib interacts with multiple intracellular (CRAF, BRAF and mutant BRAF) and cell surface kinases (KIT, FLT-3, VEGFR-2, VEGFR-3, and PDGFR-&szlig;). Several of these kinases are thought to be involved in angiogenesis, thus sorafenib reduces blood flow to the tumor. Sorafenib is unique in targeting the Raf/Mek/Erk pathway. By inhibiting these kinases, genetic transcription involving cell proliferation and angiogenesis is inhibited.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 肝毒性

在大规模临床试验中，使用索拉非尼的患者中，血清转氨酶水平升高是常见的现象，发生在多达一半的患者中，但是超过正常上限5倍（ULN）的情况仅发生在1%到3%的治疗对象中。此外，还有几个单一病例报告显示，在索拉非尼治疗期间出现了临床上明显的肝损伤，这种情况往往是严重的，偶尔是致命的。急性肝损伤的出现时间从开始使用索拉非尼的几天到8周不等，损伤的模式通常是肝细胞型的，血清转氨酶水平显著升高。免疫过敏和自身免疫特征缺失。一旦停止使用索拉非尼，恢复通常很快，但有些病例与进行性肝损伤和肝衰竭有关。大多数严重肝损伤的报告发生在治疗肝细胞癌的患者中，这些患者通常还患有肝硬化，或者在接受其他可能对肝脏有毒性的药物的患者中。

In large clinical trials of sorafenib, elevations in serum aminotransferase levels were common, occurring in up to half of patients, but values greater than 5 times the upper limit of normal (ULN) occurred in only 1% to 3% of treated subjects. In addition, there have been several single case reports of clinically apparent liver injury arising during sorafenib therapy which was often severe and occasionally fatal. The onset of acute liver injury ranged from a few days to 8 weeks of starting sorafenib, and the pattern of injury was typically hepatocellular with marked elevations in serum aminotransferase levels. Immunoallergic and autoimmune features were absent. Recovery was usually rapid once sorafenib was stopped, but some cases were associated with progressive liver injury and hepatic failure. Most of the reports of severe liver injury occurred in patients being treated for hepatocellular carcinoma who also had cirrhosis or in patients receiving other potentially hepatotoxic drugs31.

来源:LiverTox

毒理性

• 药物性肝损伤

化合物：索拉非尼

Compound:sorafenib

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注解：最令人关注的药物性肝损伤

DILI Annotation:Most-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

严重等级：8

Severity Grade:8

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

口服给药后，索拉非尼在3小时内达到血浆峰值。与空腹状态相比，高脂肪餐会使生物利用度降低29%。

The mean relative bioavailability is 38-49% for the tablet form, when compared to an oral solution. Sorafenib reached peak plasma levels in 3 hours following oral administration. With a high-fat meal, bioavailability is reduced by 29% compared to administration in the fasted state.

来源:DrugBank

吸收、分配和排泄

• 排除途径

在口服100毫克剂量的索拉非尼溶液制剂后，14天内回收了剂量的96%，其中77%的剂量通过粪便排出，19%的剂量以葡萄糖苷酸化代谢物的形式通过尿液排出。

Following oral administration of a 100 mg dose of a solution formulation of sorafenib, 96% of the dose was recovered within 14 days, with 77% of the dose excreted in feces, and 19% of the dose excreted in urine as glucuronidated metabolites.

来源:DrugBank

吸收、分配和排泄

在口服100毫克剂量的索拉非尼溶液制剂后，14天内96%的剂量被回收，其中77%的剂量通过粪便排出，19%的剂量通过尿液以葡萄糖苷酸化代谢物的形式排出。未改变的索拉非尼，占剂量的51%，在粪便中找到，但在尿液中未找到。

Following oral administration of a 100 mg dose of a solution formulation of sorafenib, 96% of the dose was recovered within 14 days, with 77% of the dose excreted in feces and 19% of the dose excreted in urine as glucuronidated metabolites. Unchanged sorafenib, accounting for 51% of the dose, was found in feces but not in urine.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

Nexavar片给药后，与口服溶液相比，平均相对生物利用度为38-49%。口服给药后，索拉非尼在约3小时内达到血浆峰值。在进食能量适中含脂肪的饮食（30%脂肪；700卡路里）后，生物利用度与空腹状态相似。在进食高脂肪饮食（50%脂肪；900卡路里）后，与空腹状态相比，生物利用度降低了29%。建议在空腹时给药Nexavar。平均Cmax和AUC在每日两次口服400mg剂量以上的增加不到成比例。索拉非尼与人血浆蛋白的体外结合率为99.5%。

After administration of Nexavar tablets, the mean relative bioavailability was 38-49% when compared to an oral solution. Following oral administration, sorafenib reached peak plasma levels in approximately 3 hours. With a moderate-fat meal (30% fat; 700 calories), bioavailability was similar to that in the fasted state. With a high-fat meal (50% fat; 900 calories), bioavailability was reduced by 29% compared to that in the fasted state. It is recommended that Nexavar be administered without food. Mean Cmax and AUC increased less than proportionally beyond oral doses of 400 mg administered twice daily. In vitro binding of sorafenib to human plasma proteins was 99.5%.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在雌性CD-1小鼠、雄性Wistar大鼠和雌性比格犬中评估了单次给予索拉非尼甲磺酸盐的吸收和基本药代动力学。为了确定大鼠中索拉非尼的吸收，使用了胆管插管的大鼠（每组5只）。手术后24小时，将(14)C-索拉非尼甲磺酸盐以5 mg/kg索拉非尼的剂量口服或静脉给予大鼠。索拉非尼在雌性CD-1小鼠（78.6%）和雄性Wistar大鼠（79.2%）中的吸收几乎完全。在比格犬中，吸收（67.6%，根据静脉和口服给药后的AUC归一化值计算）和绝对生物利用度（59.9%）低于啮齿类动物。在所有物种中，口服给药后1.5小时至2小时观察到放射性物质的最大血浆浓度。将(14)C-索拉非尼甲磺酸盐静脉给予小鼠、大鼠和犬后，从血浆中消除放射性物质的末端半衰期相似，分别为6.8、8.8和7.3小时。口服给药后放射性物质的末端半衰期在小鼠中为6.1小时，在犬中为5.8小时。在大鼠中，口服给药后的末端半衰期（11.2小时）长于静脉给药。在大鼠中，未改变化合物的消除较慢（半衰期：9.3小时），慢于小鼠（半衰期：6.5小时）和犬（半衰期：4.3小时）。大鼠的总血浆清除率为0.044 L/(小时/kg)，相应的血液清除率为0.049 L/(小时/kg)。在小鼠和犬中，总血浆清除率分别为0.13和0.15 L/(小时/kg)。稳态下的分布体积从0.65 L/kg到0.74 L/kg不等，取决于物种。

The absorption and the basic pharmacokinetics following a single dose of sorafenib tosylate were evaluated in female CD-1 mice, male Wistar rats, and female Beagle dogs. For the determination of the absorption of sorafenib in rats, bile duct-cannulated rats (n=5/group) were used. Twenty-four hours after surgery (14)C-sorafenib tosylate was administered orally or intravenously to the rats at a dose of 5 mg/kg sorafenib. The absorption of sorafenib was almost complete in female CD-1 mice (78.6%) and male Wistar rats (79.2%). In Beagle dogs the absorption (67.6 %, calculated from AUC norm values after intravenous and oral administration) and the absolute bioavailability (59.9 %) were lower than in rodents. Maximum plasma concentrations of radioactivity between 1.5 hr and 2 hr after oral administration were observed in all species. After intravenous administration of (14)C-sorafenib tosylate to mice, rats, and dogs the elimination of the radioactivity from plasma occurred with similar terminal half-lives of 6.8, 8.8, and 7.3 hours, respectively. The terminal half-lives of radioactivity after oral administration were 6.1 hours in mice and 5.8 hours in dogs. In rats, terminal half-live after oral administration was longer (11.2 hr) than after intravenous administration. In rats, the elimination of the unchanged compound was slower (half life: 9.3 hr) than in the mice (half life: 6.5 hr) and dogs (half life:4.3 hr). The total plasma clearance in rats was 0.044 L/(hr/kg) corresponding to a blood clearance of 0.049 L/(hr/kg). In mice and dogs the total plasma clearance was 0.13 and 0.15 lL/(hr/kg) respectively. The volume of distribution at steady state ranged from 0.65 l/kg to 0.74 l/kg, depending on the species.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 安全说明：
  S26,S37/39
• 危险类别码：
  R36/37/38,R68/20/21/22,R37/38
• 海关编码：
  29350090
• WGK Germany：
  2
• 危险品标志：
  Xi
• RTECS号：
  HM1650000
• 包装等级：
  III
• 危险类别：
  9
• 危险性防范说明：
  P201,P202,P260,P263,P264,P270,P273,P280,P308+P313,P391,P405,P501
• 危险品运输编号：
  3077
• 危险性描述：
  H360,H362,H372,H410
• 储存条件：
  -20°C冷冻库

制备方法与用途

索拉菲尼简介

索拉菲尼（Sorafenib，商品名：多吉美）是一种分子靶向治疗新药。作为一种口服、多靶点、多激酶抑制剂，它能够靶向作用于肿瘤细胞及肿瘤血管上的丝氨酸/苏氨酸激酶和受体酪氨酸激酶等。索拉菲尼通过以下两种机制发挥作用：

1. 抑制受体酪氨酸激酶KIT和FLT-3以及Raf /MEK/ERK途径中的丝氨酸/苏氨酸激酶，有效抑制肿瘤细胞的增生。
2. 上游抑制VEGFR和PDGFR，及下游抑制Raf /MEK/ERK途径中的丝氨酸/苏氨酸激酶，明显抑制肿瘤血管生成。

因此，索拉菲尼能够双管齐下，同时发挥抗血管生成和抗肿瘤细胞增殖的双重作用。

药理作用

索拉菲尼是一种多激酶抑制剂。临床前研究显示，它能同时抑制多种存在于细胞内和细胞表面的激酶，包括RAF激酶、血管内皮生长因子受体-2（VEGF-2）、血管内皮生长因子受体-3（VEGF-3）、血小板衍生生长因子受体-β（PDGFR-β）、KIT和FLT-3。这种双重作用机制使索拉菲尼能够通过以下途径发挥抗肿瘤效应：

1. 抑制RAF/MEK/ERK信号传导通路，直接抑制肿瘤生长。
2. 通过抑制VEGFR和PDGFR阻断肿瘤新生血管的形成，间接抑制肿瘤细胞的生长。

甲苯磺酸索拉菲尼

甲苯磺酸索拉菲尼是一种新型多靶点抗肿瘤药物。作为由德国拜耳制药公司研制成功的药物，它能够同时作用于肿瘤细胞和肿瘤血管。它的双重抗肿瘤作用包括：

1. 阻断由RAF/MEK/ERK介导的细胞信号传导通路，直接抑制肿瘤细胞增殖。
2. 抑制VEGF和血小板衍生生长因子（PDGF）受体，阻断肿瘤新生血管形成，间接抑制肿瘤细胞的生长。

在临床前动物试验中，索拉菲尼显示了广泛的抗肿瘤活性。在美国和欧洲进行的一项治疗晚期肾癌的III期随机临床研究中，903例接受过一次系统治疗（生物免疫或化疗）失败的患者被分为两组：一组服用甲苯磺酸索拉菲尼，另一组服用安慰剂。结果显示，Sorafenib组客观有效率为10%，而安慰剂组为2%；延缓疾病发展时间73%。

用途

索拉非尼是一种新型多靶向性的口服药物，用于治疗多种类型的肿瘤。

副作用

服用索拉菲尼可能出现以下副作用：

• 出血（常见）、胃肠道出血、呼吸道出血（少数可威胁生命）
• 恶心、呕吐、腹泻、乏力
• 手足皮肤反应、脱发、淋巴细胞减少
• 脂肪酶和淀粉酶增加、低磷血症
• 瘙痒、厌食、便秘、轻中度高血压
• 感觉神经病变、贫血、中性粒细胞减少、血小板减少、转氨酶一过性升高
• 极罕见高血压危象，胰腺炎不常见

请注意，在使用索拉菲尼前应咨询专业医生以获取详细信息和建议。

反应信息

• 作为反应物：
  描述：

  索拉非尼 在 硫酸 作用下， 以 乙醇 、 水 为溶剂， 反应 12.0h， 以89%的产率得到4-(4-{3-[4-chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-N-methylpyridine-2-carboxamide sulphate
  参考文献：
  名称：

  [EN] POLYMORPHS OF SORAFENIB ACID ADDITION SALTS
  [FR] POLYMORPHES DE SELS D'ADDITION ACIDE DE SORAFÉNIB

  摘要：

  本发明提供索拉非尼的非晶态和晶态酸盐形式，包括它们的药物组合物并用于癌症治疗。本发明还提供制备索拉非尼酸盐的工艺。

  公开号：

  WO2011036648A1
• 作为产物：
  描述：

  4-氯-2-吡啶羰酰氯盐酸盐 在 potassium tert-butylate 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 36.0h， 生成 索拉非尼
  参考文献：
  名称：

  ARYL UREAS WITH ANGIOGENISIS INHIBITING ACTIVITY

  摘要：

  这项发明涉及使用芳基脲类化合物治疗由异常血管生成或高渗透性过程特征的VEGF诱导信号转导通路介导的疾病的方法。

  公开号：

  US20160015697A1

文献信息

• [EN] ACC INHIBITORS AND USES THEREOF<br/>[FR] INHIBITEURS DE L'ACC ET UTILISATIONS ASSOCIÉES
  申请人：GILEAD APOLLO LLC

  公开号：WO2017075056A1

  公开（公告）日：2017-05-04

  The present invention provides compounds I and II useful as inhibitors of Acetyl CoA Carboxylase (ACC), compositions thereof, and methods of using the same.

  本发明提供了化合物I和II，这些化合物可用作乙酰辅酶A羧化酶（ACC）的抑制剂，以及它们的组合物和使用方法。
• DISUBSTITUTED TRIFLUOROMETHYL PYRIMIDINONES AND THEIR USE
  申请人：BAYER PHARMA AKTIENGESELLSCHAFT

  公开号：US20160221965A1

  公开（公告）日：2016-08-04

  The present application relates to novel 2,5-disubstituted 6-(trifluoromethyl)pyrimidin-4(3H)-one derivatives, to processes for their preparation, to their use alone or in combinations for the treatment and/or prevention of diseases, and to their use for preparing medicaments for the treatment and/or prevention of diseases, in particular for treatment and/or prevention of cardiovascular, renal, inflammatory and fibrotic diseases.

  本申请涉及新颖的2,5-二取代6-(三氟甲基)嘧啶-4(3H)-酮衍生物，其制备方法，其单独或与其他药物联合用于治疗和/或预防疾病，以及用于制备治疗和/或预防疾病的药物，特别是用于治疗和/或预防心血管、肾脏、炎症和纤维化疾病。
• [EN] 2-QUINOLONE DERIVED INHIBITORS OF BCL6<br/>[FR] INHIBITEURS DE BCL6 DÉRIVÉS DE 2-QUINOLONE
  申请人：CANCER RESEARCH TECH LTD

  公开号：WO2018215798A1

  公开（公告）日：2018-11-29

  The present invention relates to compounds of formula I that function as inhibitors of BCL6(B- cell lymphoma 6) activity: Formula I wherein X1, X2, X3, R1, R2, R3, R4 and R5 are each as defined herein. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of proliferative disorders, such as cancer,as well as other diseases or conditions in which BCL6 activity is implicated.

  本发明涉及作为BCL6（B细胞淋巴瘤6）活性抑制剂的I式化合物：式中X1、X2、X3、R1、R2、R3、R4和R5分别如本文所定义。本发明还涉及制备这些化合物的方法，包括含有它们的药物组合物，以及它们在治疗增生性疾病（如癌症）以及其他BCL6活性所涉及的疾病或病况中的用途。
• [EN] DIHYDROPYRROLONAPHTYRIDINONE COMPOUNDS AS INHIBITORS OF JAK<br/>[FR] COMPOSÉS DE DIHYDROPYRROLONAPHTYRIDINONE COMME INHIBITEURS DE JAK
  申请人：TAKEDA PHARMACEUTICAL

  公开号：WO2010144486A1

  公开（公告）日：2010-12-16

  Disclosed are JAK inhibitors of formula (I) where G1, R1, R2, R3, R4, R5, R6, and R7 are defined in the specification. Also disclosed are pharmaceutical compositions, kits and articles of manufacture which contain the compounds, methods and materials for making the compounds, and methods of using the compounds to treat diseases, disorders, and conditions involving the immune system and inflammation, including rheumatoid arthritis, hematological malignancies, epithelial cancers (i.e., carcinomas), and other diseases, disorders or conditions associated with JAK.

  揭示了式(I)的JAK抑制剂，其中G1、R1、R2、R3、R4、R5、R6和R7在规范中定义。还披露了含有这些化合物的药物组合物、试剂盒和制造物品，制备这些化合物的方法和材料，以及使用这些化合物治疗涉及免疫系统和炎症的疾病、紊乱和症状的方法，包括类风湿关节炎、血液恶性肿瘤、上皮癌（即癌症）和其他与JAK相关的疾病、紊乱或症状。
• SULFONAMIDE, SULFAMATE, AND SULFAMOTHIOATE DERIVATIVES
  申请人：Wang Zhong

  公开号：US20120077814A1

  公开（公告）日：2012-03-29

  The disclosure provides biologically active compounds of formula (I): and pharmaceutically acceptable salts thereof, compositions containing these compounds, and methods of using these compounds in a variety applications, such as treatment of diseases or disorders associated with E1 type activating enzymes, and with Nedd8 activating enzyme (NAE) in particular.

  该披露提供了化学式(I)的生物活性化合物及其药用盐，含有这些化合物的组合物，以及在各种应用中使用这些化合物的方法，例如用于治疗与E1型激活酶相关的疾病或紊乱，特别是与Nedd8激活酶(NAE)相关的疾病或紊乱。