N-(2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-3H-imidazo[4,5-b]pyridine-6-carboxamide | 677341-73-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: N-(2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-3H-imidazo[4,5-b]pyridine-6-carboxamide
• 英文别名: N-(2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1H-imidazo[4,5-b]pyridine-6-carboxamide
• CAS: 677341-73-0
• 化学式: C₁₇H₁₃N₇O
• 分子量: 331.337
• InChiKey: DDCLADNGPFQZSB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.45
• 重原子数：
  25.0
• 可旋转键数：
  1.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  98.63
• 氢给体数：
  2.0
• 氢受体数：
  6.0

反应信息

• 作为产物：
  描述：

  2-(2-aminophenyl)-4,5-dihydro-1H-imidazole 在 benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 生成 N-(2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-3H-imidazo[4,5-b]pyridine-6-carboxamide
  参考文献：
  名称：

  新型2,3-二氢咪唑并[1,2-c]喹唑啉PI3K抑制剂的发现和合成孔径雷达：鉴定帕潘替尼（BAY 80-6946）

  摘要：

  磷酸肌醇3激酶（PI3K）途径在许多疾病状态中都被异常激活，包括肿瘤细胞，无论是通过生长因子受体酪氨酸激酶还是通过关键途径成分的基因突变和扩增。多种PI3K亚型在癌症中起着不同的作用。因此，从新型化合物类别开发PI3K抑制剂应导致不同的药理和药代动力学特征，并允许探索各种适应症，组合和给药方案。旨在鉴定用于治疗炎性疾病的PI3Kγ抑制剂的筛选工作导致发现了新型2,3-二氢咪唑[1,2- c喹唑啉类的PI3K抑制剂。随后针对癌症治疗的前导优化程序着重于抑制PI3Kα和PI3Kβ。在此，描述了此类的初始结构-活性关系发现以及优化方法，该方法导致将copanlisib（BAY 80-6946）鉴定为治疗实体瘤和血液肿瘤的临床候选药物。

  DOI：

  10.1002/cmdc.201600148

文献信息

• [EN] FUSED AZOLE-PYRIMIDINE DERIVATIVES<br/>[FR] DERIVES D'AZOLE-PYRIMIDINES FONDUES
  申请人：BAYER HEALTHCARE AG

  公开号：WO2004029055A1

  公开（公告）日：2004-04-08

  The present invention relates to hovel fused azolepyrimidine derivatives, processes for preparing them and pharmaceutical preparations containing them. The fused azolepyrimidine derivatives of the present invention exhibit enhanced potency for phosphotidylinositol-3-kinase (P13K) inhibition, especially for PI3K-Ϝ inhibition and can be used for the prophylaxis and treatment of diseases associated with P13K and particularly with P13K-Ϝ activity. More specifically, the azole derivatives of the present invention are useful for treatment and prophylaxis of diseases as follows: inflammatory and immunoregulatory disorders, such as asthma, atopic dermatitis, rhinitis, allergic diseases, chronic obstructive pulmonary disease (COPD), septic shock, joint diseases, autoixnmune pathologies such as rheumatoid arthritis, and Graves' disease, cancer, myocardial contractility disorders, heart failure, thromboembolism, ischemia, and atherosclerosis. The compounds of the present invention are also useful for pulmonary hypertension, renal failure, cardiac hypertrophy, as well as neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, diabetes and focal ischemia, since the diseases also relate to P13K activity in a human or animal subject.

  本发明涉及杂环嘧啶衍生物，其制备方法以及含有它们的药物制剂。本发明的杂环嘧啶衍生物对磷脂酰肌醇-3-激酶（PI3K）抑制具有增强的效力，尤其对PI3K-Ϝ抑制效果显著，可用于预防和治疗与PI3K以及特别是PI3K-Ϝ活性相关的疾病。具体而言，本发明的杂环衍生物可用于治疗和预防以下疾病：炎症和免疫调节性疾病，如哮喘、特应性皮炎、鼻炎、过敏性疾病、慢性阻塞性肺病（COPD）、脓毒性休克、关节疾病、风湿性关节炎、Graves病、癌症、心肌收缩功能障碍、心力衰竭、血栓栓塞、缺血和动脉粥样硬化。本发明的化合物还可用于肺动脉高压、肾功能衰竭、心肌肥大，以及神经退行性疾病，如帕金森病、阿尔茨海默病、糖尿病和局灶性缺血，因为这些疾病也与人类或动物主体的PI3K活性有关。
• Combinations of substituted 2,3-dihydroimidazo[1,2-c]quinazolines
  申请人：Bayer Schering Pharma Aktiengesellschaft

  公开号：EP2168582A1

  公开（公告）日：2010-03-31

  The present invention relates to the use of 2,3-dihydroimidazo[1,2-c]quinazoline compounds, and of pharmaceutical compositions containing such compounds, for the treatment or prophylaxis of multiple myeloma, as a sole agent or in combination with other one or more other active ingredients.

  本发明涉及使用2,3-二氢咪唑[1,2-c]喹唑啉化合物，以及含有这种化合物的药物组合物，用于治疗或预防多发性骨髓瘤，作为单一药剂或与其他一个或多个其他活性成分联合使用。
• Use of substituted 2,3-dihydroimidazo[1,2-c]quinazolines for the treatment of myeloma
  申请人：Bayer Schering Pharma Aktiengesellschaft

  公开号：EP2168583A1

  公开（公告）日：2010-03-31

  The present invention relates to the use of 2,3-dihydroimidazo[1,2-c]quinazoline compounds, and of pharmaceutical compositions containing such compounds, for the treatment or prophylaxis of multiple myeloma, as a sole agent or in combination with other one or more other active ingredients.

  本发明涉及使用2,3-二氢咪唑[1,2-c]喹唑啉化合物以及含有这种化合物的药物组合物，用于治疗或预防多发性骨髓瘤，作为唯一药剂或与其他一种或多种其他活性成分联合使用。
• [EN] USE OF SUBSTITUTED 2,3-DIHYDROIMIDAZO[1,2-C]QUINAZOLINES<br/>[FR] UTILISATION DE 2,3-DIHYDROIMIDAZO[1,2-C]QUINAZOLINES SUBSTITUÉES
  申请人：BAYER PHARMA AG

  公开号：WO2016142313A1

  公开（公告）日：2016-09-15

  The present invention relates to : - use of a 2,3-dihydroimidazo[1,2-c]quinazoline compound, or of a pharmaceutical composition containing same, as a sole active agent, or of a combination of a) said compound or a pharmaceutical composition containing said compound and b) one or more further active agents, for the preparation of a medicament for the treatment or prophylaxis of endometrial cancer (hereinafter abbreviated to "EC"), particularly 1st line, 2nd line, relapsed, refractory, type I or type II EC, or endometriosis; - combinations of a) said compound and b) one or more further active agents; - a pharmaceutical composition comprising said compound as a sole active agent for the treatment of endometrial cancer (hereinafter abbreviated to "EC"), particularly 1st line, 2nd line, relapsed, refractory, type I or type II EC, or endometriosis; - a pharmaceutical composition comprising a combination of a) said compound and b) one or more further active agents; - use of biomarkers which is the loss of tumor suppressor PTEN or FBXW7, for predicting the sensitivity and/or resistance of a cancer patient to said compound and providing a rationale-based dosage to increase sensitivity and/or to overcome resistance; - a method of determining the loss of tumor suppressor PTEN or FBXW7; and - a method for determining perturbations in PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, FGFR1, FGFR2, FGFR3 and/or FGFR4.

  本发明涉及以下内容：- 使用2,3-二氢咪唑[1,2-c]喹唑啉化合物或含有该化合物的药物组成物作为唯一活性剂，或使用a) 该化合物或含有该化合物的药物组成物和b) 一种或多种进一步的活性剂的组合，用于制备治疗或预防子宫内膜癌（以下简称“EC”），特别是1线、2线、复发、难治、I型或II型EC或子宫内膜异位症的药物；- a) 该化合物和b) 一种或多种进一步的活性剂的组合；- 仅包含该化合物作为唯一活性剂的药物组成物，用于治疗子宫内膜癌（以下简称“EC”），特别是1线、2线、复发、难治、I型或II型EC或子宫内膜异位症；- 包含a) 该化合物和b) 一种或多种进一步的活性剂的药物组成物；- 使用生物标志物，即肿瘤抑制剂PTEN或FBXW7的丧失，来预测癌症患者对该化合物的敏感性和/或抗药性，并提供基于理性的剂量以增加敏感性和/或克服抗药性；- 确定肿瘤抑制剂PTEN或FBXW7的丧失的方法；以及- 确定PIK3CA、PIK3CB、PIK3CD、PIK3CG、PIK3R1、PIK3R2、PIK3R3、PIK3R4、PIK3R5、FGFR1、FGFR2、FGFR3和/或FGFR4扰动的方法。
• [EN] USE OF SUBSTITUTED 2,3-DIHYDROIMIDAZO[1,2-C]QUINAZOLINES FOR TREATING LYMPHOMAS<br/>[FR] UTILISATION DE 2,3-DIHYDROIMIDAZO[1,2-C]QUINAZOLINES SUBSTITUÉES POUR LE TRAITEMENT DE LYMPHOMES
  申请人：BAYER PHARMA AKTIENGESLLSCHAFT

  公开号：WO2014166820A1

  公开（公告）日：2014-10-16

  - use of a 2,3-dihydroimidazo[l,2-c]quinazoline compound, or of a pharmaceutical composition containing same, as a sole active agent, or of a combination of a) said compound or a pharmaceutical composition containing said compound and b) one or more fu rther active agents, for the preparation of a medicament for the treatment or prophylaxis of non-Hodgkin's lymphoma (NHL), particularly 1st line, 2nd line, relapsed, refractory, indolent or agressive non-Hodgkin's lymphoma (NHL), in particular follicular lymphoma (FL), chronic lymphocytic leukaemia (CLL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), or peripheral T-cell lymphoma (PTCL); - combinations of a) said compound and b) one or more further active agents; - a pharmaceutical composition comprising said compound as a sole active agent for the treatment of non-Hodgkin's lymphoma (NHL), particularly 1st line, 2nd line, relapsed, refractory, indolent or agressive non-Hodgkin's lymphoma (NHL), in particular follicular lymphoma (FL), chronic lymphocytic leukaemia (CLL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), or peripheral T-cell lymphoma (PTCL); - a pharmaceutical composition comprising a combination of a) said compound and b) one or more further active agents; - use of biomarkers involved in the modification of the expression of PI3K isoforms, BTK and IKK,, BCR activation, BCR downstream activation of NFKB pathway, c-Myc, EZH2, for predicting the sensitivity and/or resistance of a cancer patient to said compound and providing a rationale-based synergistic combination as defined herein to increase sensitivity and/or to overcome resistance; and - a method of determining the level of a component of one or more of the expression of PI3K isoforms, BTK and IKK„ BCR activation, BCR downstream activation of NFKB pathway, c-Myc, EZH2.

  使用2,3-二氢咪唑[1,2-c]喹唑啉化合物或含有该化合物的药物组合物作为唯一活性剂，或使用a)该化合物或含有该化合物的药物组合物和b)一个或多个其他活性剂的组合，用于制备用于治疗或预防非霍奇金淋巴瘤（NHL）的药物，特别是一线、二线、复发、难治、慢性或侵袭性非霍奇金淋巴瘤（NHL），特别是滤泡性淋巴瘤（FL）、慢性淋巴细胞白血病（CLL）、边缘区淋巴瘤（MZL）、弥漫性大B细胞淋巴瘤（DLBCL）、曼托细胞淋巴瘤（MCL）、转化淋巴瘤（TL）或外周T细胞淋巴瘤（PTCL）；a)该化合物和b)一个或多个其他活性剂的组合；仅包含该化合物作为唯一活性剂的药物组合物，用于治疗非霍奇金淋巴瘤（NHL），特别是一线、二线、复发、难治、慢性或侵袭性非霍奇金淋巴瘤（NHL），特别是滤泡性淋巴瘤（FL）、慢性淋巴细胞白血病（CLL）、边缘区淋巴瘤（MZL）、弥漫性大B细胞淋巴瘤（DLBCL）、曼托细胞淋巴瘤（MCL）、转化淋巴瘤（TL）或外周T细胞淋巴瘤（PTCL）；仅包含a)该化合物和b)一个或多个其他活性剂的药物组合物；使用涉及PI3K亚型、BTK和IKK、BCR激活、BCR下游NFKB通路激活、c-Myc、EZH2表达修饰的生物标志物，预测癌症患者对该化合物的敏感性和/或耐药性，并提供基于理性的协同组合，以增加敏感性和/或克服耐药性；以及确定PI3K亚型、BTK和IKK、BCR激活、BCR下游NFKB通路激活、c-Myc、EZH2表达的一个或多个组分水平的方法。