Stereochemically /Structurally Diverse Pilot Scale Libra

描述(由申请人提供)：我们计划利用我们在以多样性为导向的小分子化合物合成方面的集体长期专业知识，制备一系列20-26种结构独特的药效团。建议的策略和合成方法将以可预见的方式导致多种化学探针的多样性，并将产生多种化合物类型。我们将使用固相法和溶液相法。将采取的综合办法虽然直接和富有成效，但具有很强的实用性和可重复性。因此，目标化合物将是独一无二的，并将利用我们在利用合成“简单性”进行设计和成功地平行合成大量化合物方面的优势。 因此，我们将使用不同的策略以多样性为导向合成各种独特的杂环化合物，这将丰富MLSMR小分子的集合。化合物将包括不同的二氮杂和三氮杂环化合物，以及各种稠合杂环化合物，如三氮苯咪唑和新型稠合四环和五环o-Caroline[原文如此]。此外，我们将在这一应用中使用的方法之一是针对受欢迎的药效团文库，并使用杂原子合并策略(HIS)来使用面向多样性的合成来生成新的文库。 图书馆的设计以平衡大小、多样性、复杂性和纯净性的方式进行。这对于避免筛查过程中的假阳性至关重要。所有提出的小分子文库都是根据已知的类药物规则设计的，包括“利平斯基五规则”。 所有结构独特的文库将分别由100-200个单独的化合物组成，并将以等于或高于90%的纯度制备。按照RFA的要求，每种化合物将制备10至20毫克，并转移到NIH小分子储存库，提供详细的合成实验信息和溶解性能。建议的文库是以一种平衡分子量、多样性、复杂性和纯度的方式设计的。选择这些化合物的方式不会在化学空间与PubChem数据库中当前的分子重叠。大多数化学反应都是在PI和Co-PI的实验室中建立起来的。Torrey Pines分子研究所的PI与作为分子图书馆筛选中心网络(MLSCN)一部分的伯纳姆医学研究所之间存在并将继续存在长期的协作互动。因此，我们随时可以接触到这两个组织和MLSCN的设备和人员。

DESCRIPTION (provided by applicant): We plan to use our collective long standing expertise in the diversity oriented synthesis of small molecule compounds for the preparation of a range of 20-26 structurally unique pharmacophores. The proposed strategies and synthetic approaches will lead in a predictable fashion to diversities of multiple chemical probes and will generate a variety of compound types. We will employ both solid and solution phase methods. The synthetic approaches to be pursued while direct and productive, are highly practical and reproducible. The target compounds will therefore be unique and will capitalize on our strength in the utilization of synthetic "simplicity" for the design and the successful parallel synthesis of large numbers of compounds. Thus, we will use different strategies for the diversity-oriented synthesis of a variety of unique heterocyclic compounds that will enrich the MLSMR collection of small molecules. Compounds will include differing diaza and triazacyclic compounds and diverse fused heterocyclic compounds such as triazinobenzimidazoles and novel fused tetra and pentacyclic o-carbolines [sic]. In addition, one of the approaches we will use in this application is to target libraries of Favored Pharmacophores and employ the Heteroatom Incorporation Strategy (HIS) to generate novel libraries using diversity-oriented synthesis. The libraries are designed in a manner to balance size, diversity, complexity and purity. This is essential to avoid false positives during the screening process. All proposed small molecule libraries are designed with regard to known drug-likeness rules including 'Lipinski's Rule of Five'. All structurally unique libraries will consist of 100-200 individual compounds each and will be prepared with purity equal or higher than 90%. As required by the RFA, 10 to 20 mg of each compound will be prepared and transferred to the NIH small Molecule Repository with the detailed synthetic experimental information and solubility properties. The libraries proposed are designed in a manner which balances molecular weight, diversity, complexity and purity. These have been chosen in a manner which does not overlap in chemical space with molecules currently in the PubChem database. The majority of the chemistries are well established in the PI's and Co-PI's laboratories. There has been and continues to be, a longstanding collaborative interaction between the PIs at Torrey Pines Institute for Molecular Studies and the Burnham Institute for Medical Research, which is part of the Molecular Library Screening Center Network (MLSCN). We thus have ready access to equipment and personnel at both organizations and to the MLSCN.