3-(tert-butyl)-5-isocyanato-1-phenyl-1H-pyrazole | 443912-83-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 3-(tert-butyl)-5-isocyanato-1-phenyl-1H-pyrazole
• 英文别名: 3-tert-Butyl-5-isocyanato-1-phenyl-1H-pyrazole；3-tert-butyl-5-isocyanato-1-phenylpyrazole
• CAS: 443912-83-2
• 化学式: C₁₄H₁₅N₃O
• 分子量: 241.293
• InChiKey: GLVIGPBCFGTMEU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  18
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  47.2
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  2,3-二甲基苯胺 、 3-(tert-butyl)-5-isocyanato-1-phenyl-1H-pyrazole 以 二氯甲烷 为溶剂， 生成 1-(5-Tert-butyl-2-phenylpyrazol-3-yl)-3-(2,3-dimethylphenyl)urea
  参考文献：
  名称：

  Pyrazole Urea-Based Inhibitors of p38 MAP Kinase:  From Lead Compound to Clinical Candidate

  摘要：

  We report on a series of N-pyrazole, N'-aryl ureas and their mode of binding to p38 mitogen activated protein kinase. Importantly, a key binding domain that is distinct from the adenosine 5'-triphoshate (ATP) binding site is exposed when the conserved activation loop, consisting in part of Asp168-Phe169-Gly170, adopts a conformation permitting lipophilic and hydrogen bonding interactions between this class of inhibitors and the protein. We describe the correlation of the structure-activity relationships and crystallographic structures of these inhibitors with p38. In addition, we incorporated another binding pharmacophore that forms a hydrogen bond at the ATP binding site. This modification affords significant improvements in binding, cellular, and in vivo potencies resulting in the selection of 45 (BIRB 796) as a clinical candidate for the treatment of inflammatory diseases.

  DOI：

  10.1021/jm020057r
• 作为产物：
  描述：

  三甲基乙酸乙酯 在 sodium hydride 作用下， 以 四氢呋喃 、 乙醇 为溶剂， 反应 7.0h， 生成 3-(tert-butyl)-5-isocyanato-1-phenyl-1H-pyrazole
  参考文献：
  名称：

  Drug Discovery against Psoriasis: Identification of a New Potent FMS-like Tyrosine Kinase 3 (FLT3) Inhibitor, 1-(4-((1H-Pyrazolo[3,4-d]pyrimidin-4-yl)oxy)-3-fluorophenyl)-3-(5-(tert-butyl)isoxazol-3-yl)urea, That Showed Potent Activity in a Psoriatic Animal Model

  摘要：

  Psoriasis is a chronic T-cell-mediated autoimmune disease, and FMS-like tyrosine kinase 3 (FLT3) has been considered as a potential molecular target for the treatment of psoriasis. In this investigation, structural optimization was performed on a lead compound, 1-(4-(1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea (1), which showed a moderate inhibitory activity againt FLT3. A series of pyrazolo[3,4-d]pyrimidine derivatives were synthesized, and structureactivity relationship analysis led to the discovery of a number of potent FLT3 inhibitors. One of the most active compounds, 1-(4-(1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3-fluorophenyl)-3-(5-tert-butylisoxazol-3-yl)urea (18b), was then chosen for in-depth antipsoriasis studies because this compound displayed the highest potency in a preliminary antipsoriasis test. Compound 18b exhibited significant antipsoriatic effects in the K14-VEGF transgenic mouse model of psoriasis, and no recurrence was found 15 days later after the last administration. Detailed mechanisms of action of compound 18b were also investigated. Collectively, compound 18b could be a potential drug candidate for psoriasis treatment.

  DOI：

  10.1021/acs.jmedchem.6b00604

文献信息

• [EN] NOVEL COMPOUNDS AS REARRANGED DURING TRANSFECTION (RET) INHIBITORS<br/>[FR] NOUVEAUX COMPOSÉS UTILISÉS COMME INHIBITEURS DE LA KINASE RÉARRANGÉE AU COURS DE LA TRANSFECTION (RET)
  申请人：GLAXOSMITHKLINE IP DEV LTD

  公开号：WO2016037578A1

  公开（公告）日：2016-03-17

  This invention relates to novel compounds which are inhibitors of the Rearranged during Transfection (RET) kinase, to pharmaceutical compositions containing them, to processes for their preparation, and to their use in therapy, alone or in combination, for the normalization of gastrointestinal sensitivity, motility and/or secretion and/or abdominal disorders or diseases and/or treatment related to diseases related to RET dysfunction or where modulation of RET activity may have therapeutic benefit including but not limited to all classifications of irritable bowel syndrome (IBS) including diarrhea-predominant, constipation-predominant or alternating stool pattern, functional bloating, functional constipation, functional diarrhea, unspecified functional bowel disorder, functional abdominal pain syndrome, chronic idiopathic constipation, functional esophageal disorders, functional gastroduodenal disorders, functional anorectal pain, inflammatory bowel disease, proliferative diseases such as non-small cell lung cancer, hepatocellular carcinoma, colorectal cancer, medullary thyroid cancer, follicular thyroid cancer, anaplastic thyroid cancer, papillary thyroid cancer, brain tumors, peritoneal cavity cancer, solid tumors, other lung cancer, head and neck cancer, gliomas, neuroblastomas, Von Hippel-Lindau Syndrome and kidney tumors, breast cancer, fallopian tube cancer, ovarian cancer, transitional cell cancer, prostate cancer, cancer of the esophagus and gastroesophageal junction, biliary cancer, adenocarcinoma, and any malignancy with increased RET kinase activity.

  这项发明涉及一种新型化合物，这些化合物是重排转位过程中的抑制剂（RET）激酶，包含它们的药物组合物，它们的制备方法，以及它们在治疗中的使用，单独或结合使用，用于规范胃肠敏感性、蠕动和/或分泌以及/或腹部紊乱或疾病和/或与RET功能障碍相关的疾病或调节RET活性可能具有治疗益处的治疗，包括但不限于所有分类的肠易激综合征（IBS），包括以腹泻为主、以便秘为主或交替排便模式、功能性腹胀、功能性便秘、功能性腹泻、未特指的功能性肠道障碍、功能性腹痛综合征、慢性特发性便秘、功能性食管障碍、功能性胃十二指肠障碍、功能性肛门疼痛、炎症性肠病、非小细胞肺癌、肝细胞癌、结肠癌、髓样甲状腺癌、滤泡性甲状腺癌、间变性甲状腺癌、乳头状甲状腺癌、脑肿瘤、腹腔癌、实体肿瘤、其他肺癌、头颈癌、神经胶质瘤、神经母细胞瘤、冯·希普-林道氏综合征和肾肿瘤、乳腺癌、输卵管癌、卵巢癌、移行细胞癌、前列腺癌、食管和食管胃交界处癌症、胆道癌、腺癌，以及任何具有增加RET激酶活性的恶性肿瘤。
• [EN] ARYL-QUINOLYL COMPOUNDS AND THEIR USE<br/>[FR] COMPOSÉS ARYL-QUINOLÉYLE ET LEUR UTILISATION
  申请人：CANCER REC TECH LTD

  公开号：WO2009130487A1

  公开（公告）日：2009-10-29

  The present invention pertains generally to the field of therapeutic compounds for treating proliferative disorders, cancer, etc., and more specifically to certain aryl-quinolyl compounds, as described herein, which, inter alia, inhibit RAF (e.g., B-RAF) activity. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit RAF (e.g., BRAF) activity, to inhibit receptor tyrosine kinase (RTK) activity, to inhibit cell proliferation, and in the treatment of diseases and disorders that are ameliorated by the inhibition of RAF, RTK, etc., proliferative disorders such as cancer (e.g., colorectal cancer, melanoma), etc.

  本发明一般涉及治疗增殖性疾病、癌症等的治疗化合物领域，更具体地涉及本文所述的某些芳基喹啉化合物，该化合物在诸多方面抑制了RAF（例如B-RAF）活性。本发明还涉及包含这种化合物的药物组合物，以及利用这种化合物和组合物在体外和体内抑制RAF（例如BRAF）活性，抑制受体酪氨酸激酶（RTK）活性，抑制细胞增殖，并用于治疗通过抑制RAF、RTK等而得到改善的疾病和疾病，如癌症（例如结直肠癌、黑色素瘤）等。
• [EN] PYRIDO[2,3-B]PYRAZINE-8-SUBSTITUTED COMPOUNDS AND THEIR USE<br/>[FR] COMPOSÉS PYRIDO[2,3-B]PYRAZINE SUBSTITUÉS EN POSITION 8 ET LEUR UTILISATION
  申请人：CANCER REC TECH LTD

  公开号：WO2009077766A1

  公开（公告）日：2009-06-25

  The present invention pertains generally to the field of therapeutic compounds for treating proliferative disorders, cancer, etc., and more specifically to certain pyrido[2,3-b]pyrazin-8-substituted compounds, as described herein, which, inter alia, inhibit RAF (e.g., B RAF) activity. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit RAF (e.g., BRAF) activity, to inhibit receptor tyrosine kinase (RTK) activity, to inhibit cell proliferation, and in the treatment of diseases and disorders that are ameliorated by the inhibition of RAF, RTK, etc., proliferative disorders such as cancer (e.g., colorectal cancer, melanoma), etc.

  本发明一般涉及用于治疗增殖性疾病、癌症等的治疗化合物领域，更具体地涉及到本文所述的某些吡啶并[2,3-b]吡嗪-8-取代化合物，该化合物在某些情况下抑制RAF（例如BRAF）活性。本发明还涉及包含这些化合物的药物组合物，以及利用这些化合物和组合物在体内外抑制RAF（例如BRAF）活性、抑制受体酪氨酸激酶（RTK）活性、抑制细胞增殖，并用于治疗通过抑制RAF、RTK等而得到改善的疾病和疾患，如癌症（例如结直肠癌、黑色素瘤）等。
• Structural Optimization and Structure–Activity Relationship Studies of 6,6-Dimethyl-4-(phenylamino)-6<i>H</i>-pyrimido[5,4-<i>b</i>][1,4]oxazin-7(8<i>H</i>)-one Derivatives as A New Class of Potent Inhibitors of Pan-Trk and Their Drug-Resistant Mutants
  作者：Shulei Pan、Liting Zhang、Xinling Luo、Jinshan Nan、Wei Yang、Huachao Bin、Yang Li、Qiao Huang、Tianqi Wang、Zhiling Pan、Bo Mu、Falu Wang、Chenyu Tian、Yang Liu、Linli Li、Shengyong Yang

  DOI：10.1021/acs.jmedchem.1c01597

  日期：2022.2.10

  the drug-resistance mutations of Trks have already emerged, which calls for new-generation Trks inhibitors. Herein, we report the structural optimization and structure–activity relationship studies of 6,6-dimethyl-4-(phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one derivatives as a new class of pan-Trk inhibitors. The prioritized compound 11g exhibited low nanomolar IC50 values against TrkA, TrkB

  原肌球蛋白受体激酶（TrkA、TrkB 和 TrkC）是多种癌症的有吸引力的治疗靶点。两种第一代小分子 Trks 抑制剂 larotrectinib 和 entrectinib 刚刚被批准用于临床。然而，Trks的耐药突变已经出现，这就需要新一代的Trks抑制剂。在此，我们报告了 6,6-dimethyl-4-(phenylamino)-6 H -pyrimido[5,4- b ][1,4]oxazin-7(8 H )-的结构优化和构效关系研究一种衍生物作为一类新的泛 Trk 抑制剂。优先化合物11g表现出低纳摩尔 IC 50对 TrkA、TrkB 和 TrkC 以及各种耐药突变体的值。它还显示出良好的激酶选择性。11g在完整细胞中表现出优异的体外抗肿瘤活性并强烈抑制 Trk 介导的信号通路。在体内研究中，化合物11g在 BaF3-TEL-TrkA 和 BaF3-TEL-TrkC G623
• Pyridinone Pyrazole Urea and Pyrimidinone Pyrazole Urea Derivatives
  申请人：Devadas Balekudru

  公开号：US20090270350A1

  公开（公告）日：2009-10-29

  This invention is directed generally to substituted pyridinone and pyrimidinone compounds that generally inhibit p38 kinase, TNF, and/or cyclooxygeπase activity. Such substituted pyridinone and pyrimidinone compounds include compounds generally corresponding in structure to the following formula: wherein Z, n, R 1 , R 2a , R 2b , R 2c , R 2d , R 2e , R 3a , R 3b , R 3c , R 3d , R 4 , R 5 , R 6 , R 7a , R 7b , R 7c , R 7d and R 7e are as defined in this specification. This invention also is directed to compositions of such substituted pyridinones and pyrimidinones (particularly pharmaceutical compositions), and methods for treating disorders (typically pathological disorders) associated with p38 kinase activity, TNF activity, and/or cyclooxygenase-2 activity.

  本发明通常涉及取代的吡啶酮和嘧啶酮化合物，它们通常抑制p38激酶、TNF和/或环氧合酶活性。这些取代的吡啶酮和嘧啶酮化合物包括通常对应于以下结构公式的化合物：其中Z、n、R1、R2a、R2b、R2c、R2d、R2e、R3a、R3b、R3c、R3d、R4、R5、R6、R7a、R7b、R7c、R7d和R7e如本说明书所定义。本发明还涉及这些取代的吡啶酮和嘧啶酮（特别是药物组成物）的组成物，以及用于治疗与p38激酶活性、TNF活性和/或环氧合酶-2活性相关的疾病（通常是病理性疾病）的方法。