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TW201805284A - Imidazo[4,5-C]quinolin-2-one compounds and their use in treating cancer - Google Patents

Imidazo[4,5-C]quinolin-2-one compounds and their use in treating cancer Download PDF

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TW201805284A
TW201805284A TW106115396A TW106115396A TW201805284A TW 201805284 A TW201805284 A TW 201805284A TW 106115396 A TW106115396 A TW 106115396A TW 106115396 A TW106115396 A TW 106115396A TW 201805284 A TW201805284 A TW 201805284A
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pharmaceutically acceptable
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cancer
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伯納德 克里斯多夫 巴蘭
科特 高登 派克
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阿斯特捷利康公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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Abstract

The specification generally relates to compounds of Formula (I): (I) and pharmaceutically acceptable salts thereof, where R1is 4-fluoropiperidin-1-yl or 3-fluoropyrrolidin-1-yl and R2 is methyl or hydro; the use of compounds of Formula (I) or pharmaceutically acceptable salts thereof to treat or prevent ATM mediated disease, including cancer; pharmaceutical compositions comprising substituted imidazo[4,5-c]quinolin-2-one compounds or pharmaceutically acceptable salts thereof; kits comprising compounds of Formula (I) or pharmaceutically acceptable salts thereof; methods of manufacture of compounds of Formula (I) or pharmaceutically acceptable salts thereof; and intermediates useful in such manufacture.

Description

咪唑并［4，5－C］喹啉－2酮化合物及其治療癌症之用途Imidazo [4,5-C] quinoline-2one compound and its use in treating cancer

本說明書係關於經取代之咪唑并[4,5-c]喹啉-2-酮化合物及其醫藥上可接受之鹽。該等化合物及鹽選擇性調節共濟失調毛細血管擴張症突變(「ATM」)激酶，且因此，本說明書亦係關於其用於治療或預防ATM介導之疾病(包括癌症)之用途。本說明書進一步係關於包含經取代之咪唑并[4,5-c]喹啉-2-酮化合物及其醫藥上可接受之鹽之醫藥組合物；包含該等化合物及鹽之套組；該等化合物及鹽之製造方法；及可用於該製造之中間體。This specification relates to substituted imidazo [4,5-c] quinolin-2-one compounds and their pharmaceutically acceptable salts. These compounds and salts selectively modulate ataxia telangiectasia mutant ("ATM") kinases, and therefore, this specification also pertains to their use for treating or preventing ATM-mediated diseases, including cancer. This specification further relates to pharmaceutical compositions containing substituted imidazo [4,5-c] quinolin-2-one compounds and pharmaceutically acceptable salts thereof; kits containing these compounds and salts; these Compound and salt production methods; and intermediates that can be used in the production.

ATM激酶係最初鑑別為共濟失調毛細血管擴張症中突變之基因之產物的絲胺酸蘇胺酸激酶。共濟失調毛細血管擴張症位於人類染色體11q22-23上並編碼約350 kDa之大蛋白，其特徵在於存在側接調節ATM激酶活性及功能之FRAP-ATM-TRRAP及FATC結構域之磷脂醯肌醇(「PI」)3-激酶樣絲胺酸/蘇胺酸激酶結構域。ATM激酶已鑑別為由雙鏈斷裂引發之DNA損害反應之主要參與者。其主要在S/G2/M細胞週期過渡中及在崩塌複製叉處起作用以起始細胞週期檢查點、染色質改質、HR修復及促存活信號傳導級聯，以便在DNA損害後維持細胞完整性(Lavin, M. F.；Rev. Mol. Cell Biol. 2008 ,759-769)。 ATM激酶信號傳導可大概分成兩類：正準路徑，其與來自雙鏈斷裂之Mre11-Rad50-NBS1複合物一起傳導信號並活化DNA損害檢查點；及若干非正準活化模式，其係由其他形式之細胞應力活化(Cremona等人，Oncogene 2013 ,3351-3360)。 ATM激酶因應雙鏈斷裂快速且穩健地經活化且據報導能在超過800種受質中磷酸化(Matsuoka等人，Science 2007 , 1160-1166)，從而協調多個應力反應路徑(Kurz及Lees Miller,DNA Repair 2004 , 889-900)。ATM激酶主要以無活性同二聚體形式存在細胞核中，但在感測DNA雙鏈斷裂(正準途徑)後在Ser1981上自身磷酸化，從而導致解離成具有完全激酶活性之單體(Bakkenist等人，Nature 2003 , 499-506)。此係關鍵活化事件，且因此，ATM磷酸-Ser1981係用於腫瘤路徑依賴性之直接藥效學及患者選擇生物標記。 ATM激酶對於由常見抗癌治療(例如電離輻射及拓樸異構酶-II抑制劑)引起之直接雙鏈斷裂有反應，且亦經由複製期間單鏈斷裂至雙鏈斷裂之轉化對拓樸異構酶-I抑制劑有反應。ATM激酶抑制可增強任何該等試劑之活性，且因此，預計ATM激酶抑制劑可用於治療癌症。 CN102372711A報導某些咪唑并[4,5-c]喹啉-2-酮化合物，其經提及為PI 3-激酶α及雷帕黴素(「mTOR」)激酶之哺乳動物靶標之雙重抑制劑，包括：

Figure TW201805284AD00001
CN102372711A 中報導之某些化合物 CN102399218A報導某些咪唑并[4,5-c]喹啉-2-酮化合物，其經提及為PI 3-激酶α抑制劑。CN102399218A中報導之化合物尤其係以下：
Figure TW201805284AD00002
CN102399218A 中報導之某些化合物 儘管據報導CN102372711A及CN102399218A之化合物具有針對PI 3-激酶α且在一些情形下mTOR激酶之活性，但仍需要研發更有效針對不同激酶(例如ATM激酶)之新化合物。進一步需要以高度選擇性方式針對某些激酶(如ATM激酶)起作用(即藉由比其他生物靶標更有效地調節ATM)的新化合物。 如本說明書中別處(例如實驗部分中所述之基於細胞之分析中)所展現，本說明書之化合物通常具有極強效ATM激酶抑制活性，但針對其他酪胺酸激酶(例如PI 3-激酶α、mTOR激酶、共濟失調毛細血管擴張症及Rad3相關蛋白(「ATR」)激酶及DNA依賴性蛋白激酶(「DNAPK」))具有遠較不強效活性。因此，本說明書之化合物不僅抑制ATM激酶，且亦可認為係ATM激酶之高度選擇性抑制劑。 由於本說明書之化合物之高度選擇性質，預計其尤其可用於治療如下疾病：ATM激酶參與(例如，用於癌症之治療)、但其中期望最小化可能由於其他酪胺酸激酶(例如種類PI 3-激酶α、mTOR激酶、ATR激酶及/或DNAPK)之抑制引起之脫靶效應或毒性。ATM kinase is a serine threonine kinase originally identified as the product of a mutated gene in ataxia telangiectasia. Ataxic telangiectasia is located on human chromosome 11q22-23 and encodes a large protein of approximately 350 kDa, which is characterized by the presence of phosphatide inositol flanked by FRAP-ATM-TRRAP and FATC domains that regulate ATM kinase activity and function ("PI") 3-kinase-like serine / threonine kinase domain. ATM kinase has been identified as a major player in the DNA damage response caused by double-strand breaks. It mainly functions in the S / G2 / M cell cycle transition and at the collapse replication fork to initiate cell cycle checkpoints, chromatin modification, HR repair, and pro-survival signaling cascades to maintain cells after DNA damage Integrity (Lavin, MF; Rev. Mol. Cell Biol. 2008 , 759-769). ATM kinase signaling can be roughly divided into two categories: positive and quasi-pathways, which together with the Mre11-Rad50-NBS1 complex from double-strand breaks conduct signals and activate DNA damage checkpoints; and several non-positive and quasi-activation modes, which are caused by Form of cell stress activation (Cremona et al., Oncogene 2013 , 3351-3360). ATM kinase is rapidly and robustly activated in response to double-strand breaks and reportedly phosphorylated in more than 800 substrates (Matsuoka et al., Science 2007 , 1160-1166), thereby coordinating multiple stress response pathways (Kurz and Lees Miller , DNA Repair 2004 , 889-900). ATM kinase mainly exists in the cell nucleus in the form of inactive homodimer, but after sensing DNA double-strand break (positive quasi-pathway), it is phosphorylated on Ser1981, resulting in dissociation into monomers with complete kinase activity (Bakkenist et al. People, Nature 2003 , 499-506). This is a key activation event, and therefore, ATM phosphate-Ser1981 is used for tumor path-dependent direct pharmacodynamics and patient selection biomarkers. ATM kinases respond to direct double-strand breaks caused by common anti-cancer treatments (such as ionizing radiation and topoisomerase-II inhibitors), and also to topological differences through the conversion of single-strand breaks to double-strand breaks during replication Structural enzyme-I inhibitors respond. ATM kinase inhibition can enhance the activity of any of these agents, and therefore, it is expected that ATM kinase inhibitors can be used to treat cancer. CN102372711A reports certain imidazo [4,5-c] quinolin-2-one compounds, which are mentioned as dual inhibitors of the mammalian targets of PI 3-kinase alpha and rapamycin ("mTOR") kinase ,include:
Figure TW201805284AD00001
Certain compounds reported in the CN102399218A CN102372711A reported certain imidazo [4,5-c] quinolin-2-one compound, which was referred to as α PI 3- kinase inhibitor. The compounds reported in CN102399218A are especially the following:
Figure TW201805284AD00002
Certain compounds reported in the CN102399218A Although compounds according to the reported CN102372711A and CN102399218A new compounds for α and PI 3- kinase activity of mTOR kinase in some cases, there remains a need to develop more effective against different kinases (e.g. ATM kinase) of. There is a further need for new compounds that act against certain kinases (such as ATM kinases) in a highly selective manner (ie, by modulating ATM more efficiently than other biological targets). As demonstrated elsewhere in this specification (such as in cell-based assays described in the experimental section), the compounds of this specification generally have very potent ATM kinase inhibitory activity, but are directed against other tyrosine kinases (such as PI 3-kinase alpha , MTOR kinase, ataxia telangiectasia and Rad3 related protein ("ATR") kinase and DNA-dependent protein kinase ("DNAPK") have far less potent activity. Therefore, the compound of the present specification not only inhibits ATM kinase, but can also be regarded as a highly selective inhibitor of ATM kinase. Due to the highly selective nature of the compounds of the present specification, they are expected to be particularly useful for the treatment of the following diseases: ATM kinase involvement (for example, for the treatment of cancer), but the desire to minimize it may be due to other tyrosine kinases (for example, PI 3- Off-target effects or toxicity caused by inhibition of kinase α, mTOR kinase, ATR kinase and / or DNAPK).

簡言之，本說明書部分闡述式(I) 化合物：

Figure TW201805284AD00003
(I) 或其醫藥上可接受之鹽，其中：R1 係4-氟六氫吡啶-1-基或3-氟吡咯啶-1-基；且R2 係甲基或氫。 本說明書亦部分闡述包含式(I) 化合物或其醫藥上可接受之鹽及至少一種醫藥上可接受之賦形劑的醫藥組合物。 本說明書亦部分闡述式(I) 化合物或其醫藥上可接受之鹽，其用於療法中。 本說明書亦部分闡述式(I) 化合物或其醫藥上可接受之鹽，其用於治療癌症。 本說明書亦部分闡述式(I) 化合物或其醫藥上可接受之鹽之用途，其用於製造用於治療癌症之藥劑。 本說明書亦部分闡述用於治療需要該治療之溫血動物之癌症的方法，其包含向該溫血動物投與治療有效量之式(I) 化合物或其醫藥上可接受之鹽。In short, the part of the specification explains the compound of formula (I) :
Figure TW201805284AD00003
(I) or a pharmaceutically acceptable salt thereof, wherein: R 1 is 4-fluorohexahydropyridin-1-yl or 3-fluoropyrrolidin-1-yl; and R 2 is methyl or hydrogen. The specification also partially describes a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. This specification also partially describes the compound of formula (I) or a pharmaceutically acceptable salt thereof for use in therapy. The specification also partially describes the compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of cancer. This specification also partially describes the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of cancer. This specification also partially describes a method for treating cancer in warm-blooded animals in need of such treatment, which comprises administering to the warm-blooded animal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

許多實施例詳述於本說明書中且對於熟習此項技術之讀者應顯而易見。該等實施例不應解釋為具有限制性。 在第一實施例中，提供式(I) 化合物：

Figure TW201805284AD00004
(I) 或其醫藥上可接受之鹽，其中：R1 係4-氟六氫吡啶-1-基或3-氟吡咯啶-1-基；且R2 係甲基或氫。 「氫」基團等效於氫原子。附接有氫基團之原子可視為未經取代。 3-氟吡咯啶-1-基可以兩種鏡像異構形式、即(S )-3-氟吡咯啶-1-基及(R )-3-氟吡咯啶-1-基存在，具有下文所示結構。
Figure TW201805284AD00005
術語「醫藥上可接受之」用於指定目標(例如鹽、劑型或賦形劑)適用於患者。醫藥上可接受之鹽之實例清單可參見Handbook of Pharmaceutical Salts: Properties, Selection and Use, P. H. Stahl及C. G. Wermuth編輯，Weinheim/z ürich:Wiley-VCH/VHCA, 2002。式(I) 化合物之適宜醫藥上可接受之鹽係(例如)酸加成鹽。式(I) 化合物之酸加成鹽可藉由使化合物與適宜無機或有機酸在熟習此項技術者已知之條件下接觸來形成。酸加成鹽可(例如)使用選自鹽酸、氫溴酸、硫酸及磷酸之無機酸來形成。酸加成鹽亦可使用選自三氟乙酸、檸檬酸、馬來酸、草酸、乙酸、甲酸、苯甲酸、富馬酸、琥珀酸、酒石酸、乳酸、丙酮酸、甲磺酸、苯磺酸及對甲苯磺酸之有機酸來形成。 因此，在一個實施例中，提供式(I) 化合物或其醫藥上可接受之鹽，其中醫藥上可接受之鹽係鹽酸、氫溴酸、硫酸、磷酸、三氟乙酸、檸檬酸、馬來酸、草酸、乙酸、甲酸、苯甲酸、富馬酸、琥珀酸、酒石酸、乳酸、丙酮酸、甲磺酸、苯磺酸或對甲苯磺酸鹽。在一個實施例中，提供式(I) 化合物或其醫藥上可接受之鹽，其中醫藥上可接受之鹽係甲磺酸鹽。在一個實施例中，提供式(I) 化合物或其醫藥上可接受之鹽，其中醫藥上可接受之鹽係單- 甲磺酸鹽，即式(I) 化合物對甲磺酸之化學計量係1:1。 又一實施例提供本文中定義之實施例(例如技術方案1之實施例)，條件係個別地放棄一或多個選自實例1、2及3之具體實例(例如1、2或3個具體實例)。 式(I) 中之可變基團之一些值如下。該等值可與本文中定義之定義、申請專利範圍(例如技術方案1)或實施例組合使用以提供其他實施例。 a)R1 係4-氟六氫吡啶-1-基。 b)R1 係3-氟吡咯啶-1-基。 c)R1 係(S )-3-氟吡咯啶-1-基。 d)R1 係(R )-3-氟吡咯啶-1-基。 e)R2 係甲基。 f)R2 係氫。 在一個實施例中，提供式(I) 化合物或其醫藥上可接受之鹽，其中：R1 係四氫吡喃-3-基；R2 係甲基或氫；R3 係氫或氟；R4 係氫或氟；且R5 係甲基。 在一個實施例中，提供式(I) 化合物或其醫藥上可接受之鹽，其中該化合物選自： 8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮； (S )-8-(6-(3-(3-氟吡咯啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮；及 (R )-8-(6-(3-(3-氟吡咯啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮。 在一個實施例中，提供任何式(I) 化合物或其醫藥上可接受之鹽，其可根據實例部分中之實驗詳情來製備。 在一個實施例中，提供8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮或其醫藥上可接受之鹽。 在一個實施例中，提供8-(6-(3-(4氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮。 在一個實施例中，提供8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮之醫藥上可接受之鹽。 在一個實施例中，提供(S )-8-(6-(3-(3-氟吡咯啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮或其醫藥上可接受之鹽。 在一個實施例中，提供(S )-8-(6-(3-(3-氟吡咯啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮。 在一個實施例中，提供(S )-8-(6-(3-(3-氟吡咯啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮之醫藥上可接受之鹽。 在一個實施例中，提供(R )-8-(6-(3-(3-氟吡咯啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮或其醫藥上可接受之鹽。 在一個實施例中，提供(R )-8-(6-(3-(3-氟吡咯啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮。 在一個實施例中，提供(R )-8-(6-(3-(3-氟吡咯啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮之醫藥上可接受之鹽。 本說明書中所述之化合物及鹽可以溶劑化形式及非溶劑化形式存在。舉例而言，溶劑化形式可為水合形式，例如半-水合物、單-水合物、二-水合物、三-水合物或其替代量。本發明涵蓋式(I) 化合物之所有該等溶劑化及非溶劑化形式，尤其至該等形式具有ATM激酶抑制活性之程度，如例如使用本文所述測試所量測。 本說明書中所述之化合物及鹽之原子可以其同位素形式存在。本發明涵蓋所有式(I) 化合物，其中原子由一或多個其同位素置換(例如式(I) 化合物，其中一或多個碳原子係11 C或13 C碳同位素，或其中一或多個氫原子係2 H或3 H同位素)。 本說明書中所述之化合物及鹽可以互變異構物之混合物形式存在。「互變異構物」係由於氫原子之遷移平衡存在之結構異構物。本發明包括式(I) 化合物之所有互變異構物，尤其至該等互變異構物具有ATM激酶抑制活性之程度。 本說明書中所述之化合物及鹽由於不對稱碳原子以光學活性或外消旋形式存在。本發明包括式(I) 化合物之任何光學活性或外消旋形式，其具有ATM激酶抑制活性，如例如使用本文所述測試所量測。可藉由業內熟知之有機化學的標準技術、例如藉由使用光學活性材料合成或藉由外消旋形式之拆分實施光學活性形式之合成。 因此，在一個實施例中，提供式(I) 化合物或其醫藥上可接受之鹽，其係鏡像異構過量(%ee)為≥ 95%、≥ 98%或≥ 99%之單一光學異構物。在一個實施例中，單一光學異構物係以≥ 99%之鏡像異構過量(%ee)存在。 在一個實施例中，提供式(I) 化合物或其醫藥上可接受之鹽，其係鏡像異構過量(%ee)為≥ 95%、≥ 98%或≥ 99%之(S )-光學異構物。在一個實施例中，(S )-光學異構物係以≥ 99%之鏡像異構過量(%ee)存在。 在一個實施例中，提供式(I) 化合物或其醫藥上可接受之鹽，其係鏡像異構過量(%ee)為≥ 95%、≥ 98%或≥ 99%之(R )-光學異構物。在一個實施例中，(R )-光學異構物係以≥ 99%之鏡像異構過量(%ee)存在。 本說明書中所述之化合物及鹽可為結晶，且可展現一或多個結晶型。本發明涵蓋式(I) 化合物之任何結晶或非晶型、或該等形式之混合物，其具有ATM激酶抑制活性。 通常已知，可使用習用技術(例如X-射線粉末繞射(XRPD)、差示掃描量熱法(DSC)、熱重分析(TGA)、漫反射紅外傅立葉轉變(Diffuse Reflectance Infrared Fourier Transform，DRIFT)光譜、近紅外(NIR)光譜、溶液及/或固態核磁共振光譜)表徵結晶材料。結晶材料之水含量可藉由Karl Fischer分析來測定。 本文所述結晶型提供與各圖中所示之XRPD圖案實質上相同之XRPD圖案，且具有如本文包括之表中所示之不同2θ值。熟習此項技術者應瞭解，可獲得XRPD圖案或繞射圖，根據記錄條件(例如所用設備或機器)，其具有一或多個量測誤差。類似地，通常已知，XRPD圖案中之強度可由於較佳定向根據量測條件或試樣製備而波動。熟習XRPD之領域之人員應進一步認識到，峰之相對強度亦可受(例如)大小高於30µm及非單一縱橫比之晶粒影響。熟習此項技術者應瞭解，反射位置可受試樣位於繞射儀中之精確高度亦及繞射儀之零校正影響。試樣之表面平面性亦可具有較小影響。 由於該等考慮因素，並不將所提供繞射圖案數據取為絕對值(Jenkins, R及Snyder, R.L. 「Introduction to X-Ray Powder Diffractometry 」 John Wiley & Sons 1996；Bunn, C.W. (1948), 「Chemical Crystallography 」 , Clarendon Press, London；Klug, H. P.及Alexander, L. E. (1974), 「X-Ray Diffraction Procedures 」 )。相應地應理解，固體形式並不限於提供與各圖中所示之XRPD圖案相同之XRPD圖案的晶體，且提供與各圖中所示之XRPD圖案實質上相同之XRPD圖案的任何晶體亦屬本發明之範疇內。熟習XRPD領域之人員能判斷XRPD圖案之實質相同性。通常，XRPD中之繞射角之量測誤差係約加或減0.2° 2θ，且在考慮圖中之X射線粉末繞射圖案時及在讀取包含於本文中包括之表中的數據時，應慮及此量測誤差度數。 實例1之化合物展現結晶性質，且本文中表徵三個結晶型。 因此，在一個實施例中，提供8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮之結晶型形式A。 在一個實施例中，提供8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮之結晶型形式A，其X射線粉末繞射圖案具有至少一個在約2θ = 10.9º處之特異峰。 在一個實施例中，提供8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮之結晶型形式A，其X射線粉末繞射圖案具有至少一個在約2θ = 20.6º處之特異峰。 在一個實施例中，提供8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮之結晶型形式A，其X射線粉末繞射圖案具有至少兩個在約2θ = 10.9及20.6°處之特異峰。 在一個實施例中，提供8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮之結晶型形式A，其X射線粉末繞射圖案具有在約2θ = 3.6、10.9、12.6、14.4、17.3、18.0、19.6、20.3、20.6及23.5º處之特異峰。 在一個實施例中，提供8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮之結晶型形式A，其X射線粉末繞射圖案與圖1中所示之X射線粉末繞射圖案實質上相同。 在一個實施例中，提供8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮之結晶型形式A，其X射線粉末繞射圖案具有至少一個在2θ = 10.9º加或減0.2º 2θ處之特異峰。 在一個實施例中，提供8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮之結晶型形式A，其X射線粉末繞射圖案具有至少一個在2θ = 20.6º加或減0.2º 2θ處之特異峰。 在一個實施例中，提供8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮之結晶型形式A，其X射線粉末繞射圖案具有至少兩個在2θ = 7.0及9.2º處之特異峰，其中兩個2θ值皆加或減0.2º 2θ。 在一個實施例中，提供8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮之結晶型形式A，其X射線粉末繞射圖案具有在2θ = 3.6、10.9、12.6、14.4、17.3、18.0、19.6、20.3、20.6及23.5º處之特異峰，其中所有2θ值皆加或減0.2º 2θ。 8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮之形式A之DSC分析顯示157.8℃開始且在158.9℃下具有峰之熔融吸熱，該吸熱之前係59.0℃下的小的吸熱(圖2)。 熟習此項技術者應理解，特定化合物之DSC溫度記錄圖中所觀察之值或值之範圍將在不同純度之批次之間顯示變化。因此，同時對於一種化合物，範圍可較小，對於其他化合物，範圍可相當大。通常，DSC熱事件中之繞射角之量測誤差係約加或減5℃，且在考慮本文中包括之DSC數據時，應慮及此量測誤差度數。 因此，在一個實施例中，提供8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮之結晶型形式A，其DSC吸熱在約157.8℃下開始熔融且在約158.9℃下具有峰。 在一個實施例中，提供8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮之結晶型形式A，其DSC吸熱在157.8℃加或減5℃下開始熔融且在158.9℃加或減5℃下具有峰。 在一個實施例中，提供8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮之結晶型形式A，其DSC吸熱在157.8℃下開始熔融且在158.9℃下具有峰。 在一個實施例中，提供8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮之結晶型形式A，其具有實質上如圖2中所示之DSC溫度記錄圖。 在一個實施例中，提供8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮之結晶型形式C。 在一個實施例中，提供8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮之結晶型形式C，其X射線粉末繞射圖案具有在約2θ = 6.8º處之至少一個特異峰。 在一個實施例中，提供8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮之結晶型形式C，其X射線粉末繞射圖案具有在約2θ = 13.5º處之至少一個特異峰。 在一個實施例中，提供8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮之結晶型形式C，其X射線粉末繞射圖案具有至少兩個在約2θ = 6.8及13.5°處之特異峰。 在一個實施例中，提供8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮之結晶型形式C，其X射線粉末繞射圖案具有在約2θ = 6.8、11.2、13.3、13.5、16.5、17.6、18.5、21.7、25.0及25.8º處之特異峰。 在一個實施例中，提供8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮之結晶型形式C，其X射線粉末繞射圖案與圖3中所示之X射線粉末繞射圖案實質上相同。 在一個實施例中，提供8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮之結晶型形式C，其X射線粉末繞射圖案具有至少一個在2θ = 6.8º加或減0.2º 2θ處之特異峰。 在一個實施例中，提供8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮之結晶型形式C，其X射線粉末繞射圖案具有至少一個在2θ = 13.5º加或減0.2º 2θ處之特異峰。 在一個實施例中，提供8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮之結晶型形式C，其X射線粉末繞射圖案具有至少兩個在2θ = 6.8及13.5º處之特異峰，其中兩個2θ值皆加或減0.2º 2θ。 在一個實施例中，提供8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮之結晶型形式C，其X射線粉末繞射圖案具有在2θ = 6.8、11.2、13.3、13.5、16.5、17.6、18.5、21.7、25.0及25.8º處之特異峰，其中所有2θ值皆加或減0.2º 2θ。 8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮之形式C之DSC分析顯示141.1℃開始且在142.0℃下具有峰之熔融吸熱、在143.0℃下之放熱事件、及158.1℃開始且在159.1℃下具有峰之熔融吸熱(圖4)。 因此，在一個實施例中，提供8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮之結晶型形式C，其DSC吸熱在約141.1℃下開始熔融且在約142.0℃下具有峰。 在一個實施例中，提供8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮之結晶型形式C，其DSC吸熱在約141.1℃下開始熔融且在約142.0℃下具有峰且在約143.0℃下具有放熱事件。 在一個實施例中，提供8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮之結晶型形式C，其DSC吸熱在約141.1℃下開始熔融且在約142.0℃下具有峰，在約143.0℃下具有放熱事件，且吸熱在約158.1℃下開始熔融且在約159.1℃下具有峰。 因此，在一個實施例中，提供8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮之結晶型形式C，其DSC吸熱在141.1℃加或減5℃下開始熔融且在142.0℃加或減5℃下具有峰。 在一個實施例中，提供8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮之結晶型形式C，其DSC吸熱在141.1℃加或減5℃下開始熔融且在142.0℃加或減5℃下具有峰且在143.0℃加或減5℃下具有放熱事件。 在一個實施例中，提供8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮之結晶型形式C，其DSC吸熱在141.1℃加或減5℃下開始熔融且在142.0℃加或減5℃下具有峰，在143.0℃加或減5℃下具有放熱事件，且吸熱在158.1℃加或減5℃下開始熔融且在159.1℃加或減5℃下具有峰。 因此，在一個實施例中，提供8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮之結晶型形式C，其DSC吸熱在141.1℃下開始熔融且在142.0℃下具有峰。 在一個實施例中，提供8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮之結晶型形式C，其DSC吸熱在141.1℃下開始熔融且在142.0℃下具有峰且在143.0℃下具有放熱事件。 在一個實施例中，提供8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮之結晶型形式C，其DSC吸熱在141.1℃下開始熔融且在142.0℃下具有峰、在143.0℃下具有放熱事件、且吸熱在158.1℃下開始熔融且在159.1℃下具有峰。 在一個實施例中，提供8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮之結晶型形式C，其具有實質上如圖4中所示之DSC溫度記錄圖。 在一個實施例中，提供8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮之結晶型形式D。 在一個實施例中，提供8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮之結晶型形式D，其X射線粉末繞射圖案具有至少一個在約2θ = 10.2º處之特異峰。 在一個實施例中，提供8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮之結晶型形式D，其X射線粉末繞射圖案具有至少一個在約2θ = 19.2º處之特異峰。 在一個實施例中，提供8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮之結晶型形式C，其X射線粉末繞射圖案具有至少兩個在約2θ = 10.2及19.2°處之特異峰。 在一個實施例中，提供8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮之結晶型形式D，其X射線粉末繞射圖案具有在約2θ = 3.6、10.2、14.3、14.6、18.3、19.2及19.6º處之特異峰。 在一個實施例中，提供8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮之結晶型形式D，其X射線粉末繞射圖案與圖5中所示之X射線粉末繞射圖案實質上相同。 在一個實施例中，提供8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮之結晶型形式D，其X射線粉末繞射圖案具有至少一個在2θ = 10.2º加或減0.2º 2θ處之特異峰。 在一個實施例中，提供8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮之結晶型形式D，其X射線粉末繞射圖案具有至少一個在2θ = 19.2º加或減0.2º 2θ處之特異峰。 在一個實施例中，提供8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮之結晶型形式D，其X射線粉末繞射圖案具有至少兩個在2θ = 7.0及9.2º處之特異峰，其中兩個2θ值皆加或減0.2º 2θ。 在一個實施例中，提供8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮之結晶型形式D，其X射線粉末繞射圖案具有在2θ = 3.6、10.2、14.3、14.6、18.3、19.2及19º處之特異峰，其中所有2θ值皆加或減0.2º 2θ。 8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮之形式D之DSC分析顯示153.4℃開始且在156.9℃下具有峰之熔融吸熱，該吸熱之前係80.0℃下的小的吸熱(圖6)。 因此，在一個實施例中，提供8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮之結晶型形式D，其DSC吸熱在約153.4℃下開始熔融且在約156.9℃下具有峰。 在一個實施例中，提供8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮之結晶型形式D，其DSC吸熱在153.4℃加或減5℃下開始熔融且在156.9℃加或減5℃下具有峰。 在一個實施例中，提供8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮之結晶型形式D，其DSC吸熱在153.4℃下開始熔融且在156.9℃下具有峰。 在一個實施例中，提供8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮之結晶型形式D，其具有實質上如圖6中所示之DSC溫度記錄圖。 在據說實施例係關於結晶型時，結晶度程度可大於約60%。在一些實施例中，結晶度程度大於約80%。在一些實施例中，結晶度程度大於約90%。在一些實施例中，結晶度程度大於約95%。在一些實施例中，結晶度程度大於約98%。「結晶度程度」可係指單一結晶型與存在之所有其他結晶或非晶型相比之百分比；所有結晶型與存在之非晶型相比之百分比。 式(I) 化合物可(例如)藉由如下反應製備：式(II) 化合物：
Figure TW201805284AD00006
(II) 或其鹽，其中R2 係如本文實施例中之任一者中所定義且X 係脫離基(例如鹵素原子，或另一選擇為氟原子)；與式(III) 化合物：
Figure TW201805284AD00007
(III) 或其鹽，其中R1 係如本文實施例中之任一者中所定義。該反應便捷地在適宜溶劑(例如DMF、DMA或THF)中及在存在鹼(例如氫化鈉)下於適宜溫度(例如約20-50℃範圍內之溫度)下實施。 式(II) 化合物及其鹽因此可用作用於製備式(I) 化合物之中間體且提供又一實施例。 在一個實施例中，提供式(II) 化合物或其鹽，其中：R2 係甲基或氫；且X 係脫離基。在一個實施例中，X 係鹵素原子或三氟甲磺酸酯基團。在一個實施例中，X 係氟原子。 在一個實施例中，提供式(II) 化合物或其鹽，其中：R2 係甲基；且X 係脫離基。在一個實施例中，X 係鹵素原子或三氟甲磺酸酯基團。在一個實施例中，X 係氟原子。 在一個實施例中，提供7-氟-8-(6-氟-3-吡啶基)-1-異丙基-3-甲基-咪唑并[4,5-c]喹啉-2-酮或其鹽。 在提及式(II) 化合物或其鹽之實施例中之任一者，應理解，該等鹽無需為醫藥上可接受之鹽。式(II) 化合物之適宜鹽係(例如)酸加成鹽。式(II) 化合物之酸加成鹽可藉由使化合物與適宜無機或有機酸在熟習此項技術者已知之條件下接觸來形成。酸加成鹽可(例如)使用選自由鹽酸、氫溴酸、硫酸及磷酸組成之群之無機酸來形成。酸加成鹽亦可使用選自由三氟乙酸、檸檬酸、馬來酸、草酸、乙酸、甲酸、苯甲酸、富馬酸、琥珀酸、酒石酸、乳酸、丙酮酸、甲磺酸、苯磺酸及對甲苯磺酸組成之群之有機酸來形成。 因此，在一個實施例中，提供式(II) 化合物或其鹽，其中該鹽係鹽酸、氫溴酸、硫酸、磷酸、三氟乙酸、檸檬酸、馬來酸、草酸、乙酸、甲酸、苯甲酸、富馬酸、琥珀酸、酒石酸、乳酸、丙酮酸、甲磺酸、苯磺酸或對甲苯磺酸鹽。 在一個實施例中，提供實驗部分中所述之新穎中間體中之任一者。 式(I) 化合物及其醫藥上可接受之鹽由於其ATM激酶抑制活性，預計其可用於療法中，例如用於治療至少部分由ATM激酶介導之疾病或醫學病況、包括癌症。 在提及「癌症」時，此包括非轉移癌症亦及轉移癌症，使得治療癌症涉及原發性腫瘤亦及腫瘤轉移二者之治療。 「ATM激酶抑制活性」係指相對於在不存在式(I) 化合物或其醫藥上可接受之鹽下ATM激酶之活性，作為對於存在式(I) 化合物或其醫藥上可接受之鹽之直接或間接反應之ATM激酶活性的減小。該活性減小可由於式(I) 化合物或其醫藥上可接受之鹽與ATM激酶之直接相互作用、或由於式(I) 化合物或其醫藥上可接受之鹽與一或多個又影響ATM激酶活性之其他因子之相互作用。舉例而言，式(I) 化合物或其醫藥上可接受之鹽可藉由直接結合至ATM激酶、藉由引起(直接或間接)另一因子以減小ATM激酶活性、或藉由(直接或間接)減少細胞或生物體中存在之ATM激酶之量來減少ATM激酶。 術語「療法」意欲具有治療疾病以完全或部分減輕其一種、一些或全部症狀或校正或補償潛在病因之其正常含義。除非明確指明相反之情況，否則術語「療法」亦包括「預防」。術語「治療性」及「治療地」應以相應方式進行解釋。 術語「預防」意欲具有其正常含義且包括用以防止疾病發生之初級預防及二級預防(其中疾病已經發生且暫時或永久保護患者抵抗疾病加劇或惡化或抵抗與該疾病相關之新症狀發生)。 術語「治療」與「療法」同義使用。類似地，術語「治療」可視為「施加療法」，其中「療法」係如本文中所定義。 在一個實施例中，提供式(I) 化合物或其醫藥上可接受之鹽，其用於療法中。 在一個實施例中，提供式(I) 化合物或其醫藥上可接受之鹽之用途，其用於製造藥劑。 在一個實施例中，提供式(I) 化合物或其醫藥上可接受之鹽，其用於治療由ATM激酶介導之疾病。 在一個實施例中，提供式(I) 化合物或其醫藥上可接受之鹽，其用於治療由ATM激酶介導之疾病，其中該由ATM激酶介導之疾病係癌症。 在一個實施例中，提供式(I) 化合物或其醫藥上可接受之鹽，其用於治療由ATM激酶介導之疾病，其中該由ATM激酶介導之疾病係結腸直腸癌、神經膠母細胞瘤、胃癌、卵巢癌、瀰漫性大B細胞淋巴瘤、慢性淋巴球性白血病、急性骨髓樣白血病、頭頸部鱗狀細胞癌、乳癌、肝細胞癌、小細胞肺癌或非小細胞肺癌。 在一個實施例中，提供式(I) 化合物或其醫藥上可接受之鹽，其用於治療由ATM激酶介導之疾病，其中該由ATM激酶介導之疾病係結腸直腸癌。 在一個實施例中，提供式(I) 化合物或其醫藥上可接受之鹽，其用於治療癌症。 在一個實施例中，提供式(I) 化合物或其醫藥上可接受之鹽，其用於治療結腸直腸癌、神經膠母細胞瘤、胃癌、卵巢癌、瀰漫性大B細胞淋巴瘤、慢性淋巴球性白血病、急性骨髓樣白血病、頭頸部鱗狀細胞癌、乳癌、肝細胞癌、小細胞肺癌或非小細胞肺癌。 在一個實施例中，提供式(I) 化合物或其醫藥上可接受之鹽，其用於治療結腸直腸癌。 在一個實施例中，提供式(I) 化合物或其醫藥上可接受之鹽，其用於治療杭丁頓氏病(Huntingdon’s disease)。 在一個實施例中，提供式(I) 化合物或其醫藥上可接受之鹽，其用作神經保護劑。 「神經保護劑」係保存神經元結構及/或功能之試劑。 在一個實施例中，提供式(I) 化合物或其醫藥上可接受之鹽之用途，其用於製造用於治療由ATM激酶介導之疾病之藥劑。 在一個實施例中，提供式(I) 化合物或其醫藥上可接受之鹽之用途，其用於製造用於治療由ATM激酶介導之疾病之藥劑，其中該由ATM激酶介導之疾病係癌症。 在一個實施例中，提供式(I) 化合物或其醫藥上可接受之鹽之用途，其用於製造用於治療由ATM激酶介導之疾病之藥劑，其中該由ATM激酶介導之疾病係結腸直腸癌、神經膠母細胞瘤、胃癌、卵巢癌、瀰漫性大B細胞淋巴瘤、慢性淋巴球性白血病、急性骨髓樣白血病、頭頸部鱗狀細胞癌、乳癌、肝細胞癌、小細胞肺癌及非小細胞肺癌。 在一個實施例中，提供式(I) 化合物或其醫藥上可接受之鹽之用途，其用於製造用於治療由ATM激酶介導之疾病之藥劑，其中該由ATM激酶介導之疾病係結腸直腸癌。 在一個實施例中，提供式(I) 化合物或其醫藥上可接受之鹽之用途，其用於製造用於治療癌症之藥劑。 在一個實施例中，提供式(I) 化合物或其醫藥上可接受之鹽之用途，其用於製造用於治療結腸直腸癌、神經膠母細胞瘤、胃癌、卵巢癌、瀰漫性大B細胞淋巴瘤、慢性淋巴球性白血病、急性骨髓樣白血病、頭頸部鱗狀細胞癌、乳癌、肝細胞癌、小細胞肺癌或非小細胞肺癌之藥劑。 在一個實施例中，提供式(I) 化合物或其醫藥上可接受之鹽之用途，其用於製造用於治療結腸直腸癌之藥劑。 在一個實施例中，提供式(I) 化合物或其醫藥上可接受之鹽之用途，其用於製造用於治療杭丁頓氏病之藥劑。 在一個實施例中，提供式(I) 化合物或其醫藥上可接受之鹽之用途，其用於製造用作神經保護劑之藥劑。 在一個實施例中，提供用於治療需要該治療之溫血動物之ATM激酶之抑制有益之疾病的方法，該方法包含向該溫血動物投與治療有效量之式(I) 化合物或其醫藥上可接受之鹽。 術語「治療有效量」係指如本文實施例中任一者中所述之式(I) 化合物之量，其在個體中有效提供「療法」或在個體中「治療」疾病或病症。在癌症之情形下，治療有效量可在個體中引起可觀察或可量測之變化中之任一者，如上文「療法」、「治療」及「預防」之定義中所述。舉例而言，有效量可減少癌症或腫瘤細胞之數目；減小整體腫瘤大小；抑制或停止腫瘤細胞浸潤至外周器官(包括例如軟組織及骨)中；抑制並停止腫瘤轉移；抑制並停止腫瘤生長；將與癌症相關之症狀中之一或多者減輕至一定程度；降低發病率及死亡率；改良生活品質；或該等效應之組合。有效量可為足以減少對ATM激酶活性之抑制有反應之疾病之症狀的量。對於癌症療法而言，可(例如)藉由評價存活持續時間、疾病進展時間(TTP)、反應速率(RR)、反應持續時間及/或生命品質來量測活體內功效。如由熟習此項技術者所認識到，有效量可根據投與途徑、賦形劑使用及與其他試劑之共使用而變化。舉例而言，在使用組合療法時，本說明書中所述之式(I) 化合物或醫藥上可接受之鹽之量及其他醫藥活性劑之量在組合時共同有效地治療動物患者之靶向病症。在此上下文中，若組合量在組合時足以減少如上文所述對ATM活性之抑制有反應之疾病之症狀，則其係呈「治療有效量」。通常，該等量可熟習此項技術者藉由(例如)對於式(I) 化合物或其醫藥上可接受之鹽以本說明書中所述之劑量範圍及經批准或以其他方式公開之劑量範圍之其他醫藥活性化合物開始來測定。 「溫血動物」包括(例如)人類。 在一個實施例中，提供用於治療需要該治療之溫血動物之ATM激酶之抑制有益之疾病的方法，該方法包含向該溫血動物投與治療有效量之式(I) 化合物或其醫藥上可接受之鹽，且其中ATM激酶之抑制有益之疾病係癌症。 在一個實施例中，提供用於治療需要該治療之溫血動物之ATM激酶之抑制有益之疾病的方法，該方法包含向該溫血動物投與治療有效量之式(I) 化合物或其醫藥上可接受之鹽，且其中ATM激酶之抑制有益之疾病係結腸直腸癌、神經膠母細胞瘤、胃癌、卵巢癌、瀰漫性大B細胞淋巴瘤、慢性淋巴球性白血病、急性骨髓樣白血病、頭頸部鱗狀細胞癌、乳癌、肝細胞癌、小細胞肺癌或非小細胞肺癌。 在一個實施例中，提供用於治療需要該治療之溫血動物之疾病之方法，其中ATM激酶之抑制有益，該方法包含向該溫血動物投與治療有效量之式(I) 化合物或其醫藥上可接受之鹽，且其中ATM激酶之抑制有益之疾病係結腸直腸癌。 在一個實施例中，提供用於治療需要該治療之溫血動物之疾病之方法，其中ATM激酶之抑制有益，該方法包含向該溫血動物投與治療有效量之式(I) 化合物或其醫藥上可接受之鹽，且其中ATM激酶之抑制有益之疾病係杭丁頓氏病。 在一個實施例中，提供用於治療需要該治療之溫血動物之癌症的方法，其包含向該溫血動物投與治療有效量之式(I) 化合物或其醫藥上可接受之鹽。 在一個實施例中，提供用於治療需要該治療之溫血動物之結腸直腸癌、神經膠母細胞瘤、胃癌、卵巢癌、瀰漫性大B細胞淋巴瘤、慢性淋巴球性白血病、急性骨髓樣白血病、頭頸部鱗狀細胞癌、乳癌、肝細胞癌、小細胞肺癌或非小細胞肺癌的方法，其包含向該溫血動物投與治療有效量之式(I) 化合物或其醫藥上可接受之鹽。 在一個實施例中，提供用於治療需要該治療之溫血動物之結腸直腸癌的方法，其包含向該溫血動物投與治療有效量之式(I) 化合物或其醫藥上可接受之鹽。 在一個實施例中，提供用於治療需要該治療之溫血動物之杭丁頓氏病的方法，其包含向該溫血動物投與治療有效量之式(I) 化合物或其醫藥上可接受之鹽。 在一個實施例中，提供用於實現需要該治療之溫血動物之神經保護的方法，其包含向該溫血動物投與治療有效量之式(I) 化合物或其醫藥上可接受之鹽。 在一個實施例中，提供用於治療需要該治療之溫血動物之癌症的方法，其包含向該溫血動物投與治療有效量之式(I) 化合物或其醫藥上可接受之鹽。在一個實施例中，該癌症選自結腸直腸癌、神經膠母細胞瘤、胃癌、卵巢癌、瀰漫性大B細胞淋巴瘤、慢性淋巴球性白血病、急性骨髓樣白血病、頭頸部鱗狀細胞癌、乳癌、肝細胞癌、小細胞肺癌及非小細胞肺癌。在一個實施例中，該癌症選自結腸直腸癌、神經膠母細胞瘤、胃癌、卵巢癌、瀰漫性大B細胞淋巴瘤、慢性淋巴球性白血病、頭頸部鱗狀細胞癌及肺癌。在一個實施例中，該癌症係結腸直腸癌。 在癌症係以一般含義提及之任一實施例中，該癌症可選自結腸直腸癌、神經膠母細胞瘤、胃癌、卵巢癌、瀰漫性大B細胞淋巴瘤、慢性淋巴球性白血病、急性骨髓樣白血病、頭頸部鱗狀細胞癌、乳癌、肝細胞癌、小細胞肺癌及非小細胞肺癌。 在癌症係以一般含義提及之任一實施例中，以下實施例可適用： 在一個實施例中，癌症係結腸直腸癌。 在一個實施例中，癌症係神經膠母細胞瘤。 在一個實施例中，癌症係胃癌。 在一個實施例中，癌症係食管癌。 在一個實施例中，癌症係卵巢癌。 在一個實施例中，癌症係子宮內膜癌。 在一個實施例中，癌症係子宮頸癌。 在一個實施例中，癌症係瀰漫性大B細胞淋巴瘤。 在一個實施例中，癌症係慢性淋巴球性白血病。 在一個實施例中，癌症係急性骨髓樣白血病。 在一個實施例中，癌症係頭頸部鱗狀細胞癌。 在一個實施例中，癌症係乳癌。在一個實施例中，癌症係三陰性乳癌。 「三陰性乳癌」係經測試對雌激素受體、助孕酮受體及Her2/neu不呈陽性之任何乳癌。關於該等受體中之每一者測定陽性測試之測試方法為業內所熟知。 在一個實施例中，癌症係肝細胞癌。 在一個實施例中，癌症係肺癌。在一個實施例中，肺癌係小細胞肺癌。在一個實施例中，肺癌係非小細胞肺癌。 在一個實施例中，癌症係轉移癌症。在一個實施例中，轉移癌症包含中樞神經系統之轉移。在一個實施例中，中樞神經系統之轉移包含腦轉移。在一個實施例中，中樞神經系統之轉移包含軟腦膜轉移。 當癌症擴散至腦膜(即覆蓋腦及脊髓之組織層)時出現「軟腦膜轉移」。轉移可經由血液擴散至腦膜或其可自腦轉移開始行進，由流經腦膜之腦脊髓液(CSF)攜帶。在一個實施例中，癌症係非轉移癌症。 本說明書中所述之抗癌治療可用作單一療法，或除式(I) 化合物之投與外亦可涉及習用手術、放射療法或化學療法；或該等額外療法之組合。該等習用手術、放射療法或化學療法可與式(I) 化合物之治療同時、依序或分開投與。 放射療法可包括以下類別之療法中之一或多者： i. 使用電磁輻射之外部放射療法及使用電磁輻射之術中放射療法； ii. 內放射療法或近接治療；包括間質放射療法或管腔內放射療法；或 iii. 全身性放射療法，包括(但不限於)碘131及鍶89。 在一個實施例中，提供式(I) 化合物或其醫藥上可接受之鹽，其用於治療癌症，其中式(I) 化合物或其醫藥上可接受之鹽係與放射療法組合投與。在一個實施例中，放射療法選自上文(i) - (iii)點所列舉之放射療法類別中之一或多者。 在一個實施例中，提供式(I) 化合物或其醫藥上可接受之鹽，其用於治療神經膠母細胞瘤、肺癌(例如小細胞肺癌或非小細胞肺癌)、乳癌(例如三陰性乳癌)、頭頸部鱗狀細胞癌、食管癌、子宮頸癌或子宮內膜癌，其中式(I) 化合物或其醫藥上可接受之鹽係與放射療法組合投與。在一個實施例中，放射療法選自上文(i) - (iii)點所列舉之放射療法類別中之一或多者。 在一個實施例中，提供式(I) 化合物或其醫藥上可接受之鹽，其用於治療神經膠母細胞瘤，其中式(I) 化合物或其醫藥上可接受之鹽係與放射療法組合投與。在一個實施例中，放射療法選自上文(i) - (iii)點所列舉之放射療法類別中之一或多者。 在一個實施例中，提供式(I) 化合物或其醫藥上可接受之鹽，其用於治療轉移癌症，其中式(I) 化合物或其醫藥上可接受之鹽係與放射療法組合投與。在一個實施例中，放射療法選自上文(i) - (iii)點所列舉之放射療法類別中之一或多者。 在一個實施例中，提供式(I) 化合物或其醫藥上可接受之鹽，其用於治療中樞神經系統之轉移，其中式(I) 化合物或其醫藥上可接受之鹽係與放射療法組合投與。在一個實施例中，放射療法選自上文(i) - (iii)點所列舉之放射療法類別中之一或多者。 在一個實施例中，提供式(I) 化合物或其醫藥上可接受之鹽，其用於治療軟腦膜轉移，其中式(I) 化合物或其醫藥上可接受之鹽係與放射療法組合投與。在一個實施例中，放射療法選自上文(i) - (iii)點所列舉之放射療法類別中之一或多者。 在一個實施例中，提供式(I) 化合物或其醫藥上可接受之鹽，其用於治療癌症，其中式(I) 化合物或其醫藥上可接受之鹽係與放射療法同時、分開或依序投與。在一個實施例中，放射療法選自上文(i) - (iii)點所列舉之放射療法類別中之一或多者。 在一個實施例中，提供治療需要該治療之溫血動物之癌症之方法，其包含向該溫血動物投與式(I) 化合物或其醫藥上可接受之鹽及放射療法，其中式(I) 化合物或其醫藥上可接受之鹽及放射療法共同有效產生抗癌效應。在一個實施例中，癌症選自神經膠母細胞瘤、肺癌(例如小細胞肺癌或非小細胞肺癌)、乳癌(例如三陰性乳癌)、頭頸部鱗狀細胞癌、食管癌、子宮頸癌及子宮內膜癌。在一個實施例中，癌症係神經膠母細胞瘤。在一個實施例中，癌症係轉移癌症。在一個實施例中，轉移癌症包含中樞神經系統之轉移。在一個實施例中，中樞神經系統之轉移包含腦轉移。在一個實施例中，中樞神經系統之轉移包含軟腦膜轉移。在任一實施例中，放射療法選自上文(i) - (iii)點所列舉之放射療法類別中之一或多者。 在一個實施例中，提供治療需要該治療之溫血動物之癌症之方法，其包含向該溫血動物投與式(I) 化合物或其醫藥上可接受之鹽且同時、分開或依序投與放射療法，其中式(I) 化合物或其醫藥上可接受之鹽及放射療法共同有效產生抗癌效應。在一個實施例中，癌症係神經膠母細胞瘤。在一個實施例中，癌症係轉移癌症。在一個實施例中，轉移癌症包含中樞神經系統之轉移。在一個實施例中，中樞神經系統之轉移包含腦轉移。在一個實施例中，中樞神經系統之轉移包含軟腦膜轉移。在任一實施例中，放射療法選自上文(i) - (iii)點所列舉之放射療法類別中之一或多者。 化學療法可包括以下類別之抗腫瘤物質中之一或多者： i. 抗瘤劑及其組合，例如DNA烷基化劑(例如順鉑(cisplatin)、奧沙利鉑(oxaliplatin)、卡鉑(carboplatin)、環磷醯胺(cyclophosphamide)、氮芥(如異環磷醯胺(ifosfamide)、苯達莫司汀(bendamustine)、美法侖(melphalan)、氮芥苯丁酸(chlorambucil)、白消安(busulphan)、替莫唑胺(temozolamide))及亞硝基脲(如卡莫司汀(carmustine)))；抗代謝物(例如吉西他濱(gemcitabine)及抗葉酸劑，例如氟嘧啶(如5-氟尿嘧啶(5-fluorouracil)及替加氟(tegafur))、雷替曲塞(raltitrexed)、胺甲喋呤(methotrexate)、胞嘧啶阿拉伯糖苷及羥基脲)；抗腫瘤抗生素(例如蒽環，如阿德力黴素(adriamycin)、博來黴素(bleomycin)、多柔比星(doxorubicin)、脂質體多柔比星、吡柔比星(pirarubicin)、道諾黴素(daunomycin)、戊柔比星(valrubicin)、泛艾黴素(epirubicin)、伊達比星(idarubicin)、絲裂黴素-C (mitomycin-C)、放線菌素D (dactinomycin)、胺柔比星(amrubicin)及光輝黴素(mithramycin))；抗有絲分裂劑(例如長春花生物鹼(vinca alkaloid) (如長春新鹼(vincristine)、長春鹼(vinblastine)、長春地辛(vindesine)及長春瑞濱(vinorelbine))及類紫杉醇(如紫杉醇(taxol)及剋癌易(taxotere))及polo激酶抑制劑)；及拓樸異構酶抑制劑(例如表鬼臼毒素(epipodophyllotoxin) (如依託泊苷(etoposide)及替尼泊苷(teniposide))、安吖啶(amsacrine)、伊立替康(irinotecan)、托泊替康(topotecan)及喜樹鹼(camptothecin))；DNA修復機制抑制劑，例如CHK激酶；DNA依賴性蛋白激酶抑制劑；聚(ADP-核糖)聚合酶之抑制劑(PARP抑制劑，包括奧拉帕尼(olaparib))；及Hsp90抑制劑(例如坦螺旋黴素(tanespimycin)及瑞他黴素(retaspimycin))、ATR激酶抑制劑(例如AZD6738)；及WEE1激酶抑制劑(例如AZD1775/MK-1775)； ii. 抗血管生成劑，例如抑制血管內皮生長因子之效應之彼等，例如抗血管內皮細胞生長因子抗體貝伐珠單抗(bevacizumab)及(例如) VEGF受體酪胺酸激酶抑制劑，例如凡德他尼(vandetanib) (ZD6474)、索拉菲尼(sorafenib)、瓦他拉尼(vatalanib) (PTK787)、舒尼替尼(sunitinib) (SU11248)、阿西替尼(axitinib) (AG-013736)、帕唑帕尼(pazopanib) (GW 786034)及西地尼布(cediranib) (AZD2171)；化合物，例如國際專利申請案WO97/22596、WO 97/30035、WO 97/32856及WO 98/13354中揭示之彼等；及藉由其他機制起作用之化合物(例如利諾胺(linomide)、整聯蛋白αvβ3功能及血管抑素之抑制劑)、或血管生成素及其受體(Tie-1及Tie-2)之抑制劑、PLGF抑制劑、δ樣配體(DLL-4)抑制劑； iii. 免疫療法方法，包括(例如)用以增加患者腫瘤細胞之免疫原性之離體及活體內方法，例如用細胞介素(例如介白素2、介白素4或顆粒球-巨噬細胞群落刺激因子)轉染；用以減少T細胞無反應性或調節性T細胞功能之方法；增強對腫瘤之T細胞反應之方法，例如針對CTLA4之阻斷抗體(例如伊匹單抗(ipilimumab)及曲美目單抗(tremelimumab))、B7H1、PD-1 (例如BMS-936558或AMP-514)、PD-L1 (例如MEDI4736)及針對CD137之激動劑抗體；使用經轉染免疫細胞(例如細胞介素轉染之樹突細胞)之方法；使用細胞介素轉染之腫瘤細胞系之方法、使用針對腫瘤相關抗原之抗體及耗盡靶細胞類型之抗體(例如，未偶聯抗CD20抗體(例如利妥昔單抗(Rituximab))、放射標記之抗CD20抗體百克沙(Bexxar)及澤娃靈(Zevalin)及抗CD54抗體坎帕斯(Campath))之方法；使用抗個體基因型抗體之方法；增強天然殺手細胞功能之方法；及利用抗體-毒素偶聯物(例如抗CD33抗體滅髓瘤(Mylotarg))之方法；免疫毒素，例如莫妥莫單抗(moxetumumab pasudotox)；類鐸(toll-like)受體7或類鐸受體9之激動劑； iv. 效能增強劑，例如甲醯四氫葉酸。 在一個實施例中，提供式(I) 化合物或其醫藥上可接受之鹽，其用於治療癌症，其中式(I) 化合物或其醫藥上可接受之鹽係與至少一種額外抗腫瘤物質組合投與。在一個實施例中，存在一種額外抗腫瘤物質。在一個實施例中，存在兩種額外抗腫瘤物質。在一個實施例中，存在三種或更多種額外抗腫瘤物質。在任一實施例中，額外抗腫瘤物質選自上文(i) - (iv)點所列舉之抗腫瘤物質中之一或多者。 在一個實施例中，提供式(I) 化合物或其醫藥上可接受之鹽，其用於治療癌症，其中式(I) 化合物或其醫藥上可接受之鹽係與至少一種額外抗腫瘤物質同時、分開或依序投與。在一個實施例中，存在一種額外抗腫瘤物質。在一個實施例中，存在兩種額外抗腫瘤物質。在一個實施例中，存在三種或更多種額外抗腫瘤物質。在任一實施例中，額外抗腫瘤物質選自上文(i) - (iv)點所列舉之抗腫瘤物質中之一或多者。 在一個實施例中，提供治療需要該治療之溫血動物之癌症之方法，其包含向該溫血動物投與式(I) 化合物或其醫藥上可接受之鹽及至少一種額外抗腫瘤物質，其中式(I) 化合物或其醫藥上可接受之鹽及額外抗腫瘤物質之量共同有效產生抗癌效應。在任一實施例中，額外抗腫瘤物質選自上文(i) - (iv)點所列舉之抗腫瘤物質中之一或多者。 在一個實施例中，提供治療需要該治療之溫血動物之癌症之方法，其包含向該溫血動物投與式(I) 化合物或其醫藥上可接受之鹽，且同時、分開或依序向該溫血動物投與至少一種額外抗腫瘤物質，其中式(I) 化合物或其醫藥上可接受之鹽及額外抗腫瘤物質之量共同有效產生抗癌效應。在任一實施例中，額外抗腫瘤物質選自上文(i) - (iv)點所列舉之抗腫瘤物質中之一或多者。 在一個實施例中，提供式(I) 化合物或其醫藥上可接受之鹽及至少一種抗瘤劑，其用於治療癌症。在一個實施例中，提供式(I) 化合物或其醫藥上可接受之鹽，其用於治療癌症，其中式(I) 化合物或其醫藥上可接受之鹽係與至少一種抗瘤劑組合投與。在一個實施例中，抗瘤劑選自上文條目(i)中之抗瘤劑之清單。 在一個實施例中，提供式(I) 化合物或其醫藥上可接受之鹽及至少一種抗瘤劑，其用於同時、分開或依序治療癌症。在一個實施例中，提供式(I) 化合物或其醫藥上可接受之鹽，其用於治療癌症，其中式(I) 化合物或其醫藥上可接受之鹽係與至少一種抗瘤劑同時、分開或依序投與。在一個實施例中，抗瘤劑選自上文條目(i)中之抗瘤劑之清單。 在一個實施例中，提供式(I) 化合物或其醫藥上可接受之鹽，其用於治療癌症，其中式(I) 化合物或其醫藥上可接受之鹽係與至少一種選自以下之額外抗腫瘤物質同時、分開或依序投與：順鉑、奧沙利鉑、卡鉑、戊柔比星、伊達比星、多柔比星、吡柔比星、伊立替康、托泊替康、胺柔比星、泛艾黴素、依託泊苷、絲裂黴素、苯達莫司汀、氮芥苯丁酸、環磷醯胺、異環磷醯胺、卡莫司汀、美法侖、博來黴素、奧拉帕尼、MEDI4736、AZD1775及AZD6738。 在一個實施例中，提供式(I) 化合物或其醫藥上可接受之鹽，其用於治療癌症，式(I) 化合物或其醫藥上可接受之鹽係與至少一種選自以下之額外抗腫瘤物質同時、分開或依序投與：順鉑、奧沙利鉑、卡鉑、多柔比星、吡柔比星、伊立替康、托泊替康、胺柔比星、泛艾黴素、依託泊苷、絲裂黴素、苯達莫司汀、氮芥苯丁酸、環磷醯胺、異環磷醯胺、卡莫司汀、美法侖、博來黴素、奧拉帕尼、AZD1775及AZD6738。 在一個實施例中，提供式(I) 化合物或其醫藥上可接受之鹽，其用於治療癌症，其中式(I) 化合物或其醫藥上可接受之鹽與至少一種選自以下之額外抗腫瘤物質同時、分開或依序投與：多柔比星、伊立替康、托泊替康、依託泊苷、絲裂黴素、苯達莫司汀、氮芥苯丁酸、環磷醯胺、異環磷醯胺、卡莫司汀、美法侖、博來黴素及奧拉帕尼。 在一個實施例中，提供式(I) 化合物或其醫藥上可接受之鹽，其用於治療癌症，其中式(I) 化合物或其醫藥上可接受之鹽係與至少一種選自以下之額外抗腫瘤物質同時、分開或依序投與：多柔比星、伊立替康、托泊替康、依託泊苷、絲裂黴素、苯達莫司汀、氮芥苯丁酸、環磷醯胺、異環磷醯胺、卡莫司汀、美法侖及博來黴素。 在一個實施例中，提供式(I) 化合物或其醫藥上可接受之鹽，其用於治療癌症，其中式(I) 化合物或其醫藥上可接受之鹽係與至少一種選自以下之額外抗腫瘤物質同時、分開或依序投與：多柔比星、吡柔比星、胺柔比星及泛艾黴素。 在一個實施例中，提供式(I) 化合物或其醫藥上可接受之鹽，其用於治療急性骨髓樣白血病，其中式(I) 化合物或其醫藥上可接受之鹽係與至少一種選自以下之額外抗腫瘤物質同時、分開或依序投與：多柔比星、吡柔比星、胺柔比星及泛艾黴素。 在一個實施例中，提供式(I) 化合物或其醫藥上可接受之鹽，其用於治療乳癌，其中式(I) 化合物或其醫藥上可接受之鹽係與至少一種選自以下之額外抗腫瘤物質同時、分開或依序投與：多柔比星、吡柔比星、胺柔比星及泛艾黴素。 在一個實施例中，提供式(I) 化合物或其醫藥上可接受之鹽，其用於治療三陰性乳癌，其中式(I) 化合物或其醫藥上可接受之鹽係與至少一種選自以下之額外抗腫瘤物質同時、分開或依序投與：多柔比星、吡柔比星、胺柔比星及泛艾黴素。 在一個實施例中，提供式(I) 化合物或其醫藥上可接受之鹽，其用於治療肝細胞癌，其中式(I) 化合物或其醫藥上可接受之鹽係與至少一種選自以下之額外抗腫瘤物質同時、分開或依序投與：多柔比星、吡柔比星、胺柔比星及泛艾黴素。 在一個實施例中，提供式(I) 化合物或其醫藥上可接受之鹽，其用於治療癌症，其中式(I) 化合物或其醫藥上可接受之鹽係與伊立替康同時、分開或依序投與。 在一個實施例中，提供式(I) 化合物或其醫藥上可接受之鹽，其用於治療結腸直腸癌，其中式(I) 化合物或其醫藥上可接受之鹽係與伊立替康同時、分開或依序投與。 在一個實施例中，提供式(I) 化合物或其醫藥上可接受之鹽，其用於治療結腸直腸癌，其中式(I) 化合物或其醫藥上可接受之鹽係與FOLFIRI同時、分開或依序投與。 FOLFIRI係包括甲醯四氫葉酸、5-氟尿嘧啶及伊立替康之組合之劑量方案。 在一個實施例中，提供式(I) 化合物或其醫藥上可接受之鹽，其用於治療癌症，其中式(I) 化合物或其醫藥上可接受之鹽係與奧拉帕尼同時、分開或依序投與。 在一個實施例中，提供式(I) 化合物或其醫藥上可接受之鹽，其用於治療胃癌，其中式(I) 化合物或其醫藥上可接受之鹽係與奧拉帕尼同時、分開或依序投與。 在一個實施例中，提供式(I) 化合物或其醫藥上可接受之鹽，其用於治療癌症，其中式(I) 化合物或其醫藥上可接受之鹽係與托泊替康同時、分開或依序投與。 在一個實施例中，提供式(I) 化合物或其醫藥上可接受之鹽，其用於治療肺癌，其中式(I) 化合物或其醫藥上可接受之鹽係與托泊替康同時、分開或依序投與。 在一個實施例中，提供式(I) 化合物或其醫藥上可接受之鹽，其用於治療小細胞肺癌，其中式(I) 化合物或其醫藥上可接受之鹽係與托泊替康同時、分開或依序投與。 在一個實施例中，提供式(I) 化合物或其醫藥上可接受之鹽，其用於治療癌症，其中式(I) 化合物或其醫藥上可接受之鹽係與免疫療法同時、分開或依序投與。在一個實施例中，免疫療法係上文條目(iii)下列舉之試劑中之一或多者。 在一個實施例中，提供式(I) 化合物或其醫藥上可接受之鹽，其用於治療癌症，其中式(I) 化合物或其醫藥上可接受之鹽係與抗PD-L1抗體(例如MEDI4736)同時、分開或依序投與。 根據又一實施例，提供包含以下之套組： a) 式(I) 化合物或其醫藥上可接受之鹽，其呈第一單位劑型； b) 又一額外抗腫瘤物質，呈又一單位劑型； c) 用於涵蓋該等第一及又一單位劑型之容器構件；及視情況 d) 使用說明書。在一個實施例中，抗腫瘤物質包含抗瘤劑。 在提及抗瘤劑之任一實施例中，抗瘤劑係上文條目(i)下列舉之試劑中之一或多者。 式(I) 化合物及其醫藥上可接受之鹽可以包含一或多種醫藥上可接受之賦形劑之醫藥組合物形式投與。 因此，在一個實施例中，提供包含式(I) 化合物或其醫藥上可接受之鹽及至少一種醫藥上可接受之賦形劑之醫藥組合物。 經選擇以包括於特定組合物中之賦形劑將取決於諸如投與模式及所提供組合物之形式等因子。適宜醫藥上可接受之賦形劑為熟習此項技術者所熟知且闡述於(例如)Handbook of Pharmaceutical Excipients ，第6版，Pharmaceutical Press，由Rowe, Ray C；Sheskey, Paul J；Quinn, Marian編輯。醫藥上可接受之賦形劑可用作(例如)佐劑、稀釋劑、載劑、穩定劑、矯味劑、著色劑、填充劑、黏合劑、崩解劑、潤滑劑、助流劑、增稠劑及塗佈劑。如熟習此項技術者應瞭解，端視組合物中存在多少賦形劑及組合物中存在何種其他賦形劑而定，某些醫藥上可接受之賦形劑可起一種以上功能且可起替代功能。 醫藥組合物可呈適於經口使用之形式(例如，作為錠劑、菱形劑、硬或軟膠囊、水性或油性懸浮液、乳液、可分散粉劑或顆粒、糖漿或酏劑)、呈適於外敷使用之形式(例如，作為乳霜、軟膏、凝膠、或水性或油性溶液或懸浮液)、呈適於藉由吸入投與之形式(例如，作為精細粉末或液態氣溶膠)、呈適於藉由吹入投與之形式(例如，作為精細粉末)或呈適於非經腸投與之形式(例如，作為無菌水性或油性溶液用於靜脈內、皮下、肌內或肌內給藥)或作為栓劑用於直腸給藥。該等組合物可藉由業內熟知之習用程序獲得。意欲用於經口使用之組合物可含有額外組份，例如一或多種著色劑、甜味劑、矯味劑及/或防腐劑。 式(I) 化合物通常可以2.5-5000 mg/m2 動物體面積範圍內、或大約0.05-100 mg/kg之單位劑量投與溫血動物，且此通常可提供治療有效劑量。單位劑型(例如錠劑或膠囊)通常將含有(例如)0.1-250 mg活性成分。全部劑量必須端視所治療主體、特定投與途徑、共投與之任何療法及所治療疾病之嚴重程度而有所變化。因此，正在治療任何特定患者之醫師可參照藥物之批准標籤決定最佳劑量。 本文所述醫藥組合物包含式(I) 化合物或其醫藥上可接受之鹽，且因此預計可用於療法中。 因此，在一個實施例中，提供用於療法中之醫藥組合物，其包含式(I) 化合物或其醫藥上可接受之鹽及至少一種醫藥上可接受之賦形劑。 在一個實施例中，提供醫藥組合物，其用於治療ATM激酶之抑制有益之疾病，包含式(I) 化合物或其醫藥上可接受之鹽及至少一種醫藥上可接受之賦形劑。 在一個實施例中，提供用於治療癌症之醫藥組合物，其包含式(I) 化合物或其醫藥上可接受之鹽及至少一種醫藥上可接受之賦形劑。 在一個實施例中，提供醫藥組合物，其用於治療ATM激酶之抑制有益之癌症，包含式(I) 化合物或其醫藥上可接受之鹽及至少一種醫藥上可接受之賦形劑。 在一個實施例中，提供醫藥組合物，其用於治療結腸直腸癌、神經膠母細胞瘤、胃癌、卵巢癌、瀰漫性大B細胞淋巴瘤、慢性淋巴球性白血病、急性骨髓樣白血病、頭頸部鱗狀細胞癌、乳癌、肝細胞癌、小細胞肺癌或非小細胞肺癌，包含式(I) 化合物或其醫藥上可接受之鹽及至少一種醫藥上可接受之賦形劑。 實例 以下實例係出於闡釋目的且不應解釋為具有限制性。在實例之製備期間，通常： i. 除非另外指明，否則操作係在環境溫度下、即約17℃至30℃範圍內及在惰性氣體(例如氮)之氣氛下實施； ii. 蒸發係藉由旋轉蒸發或利用真空內Genevac設備實施且後處理程序係在藉由過濾去除殘餘固體後實施。 iii. 使用自Merck, Darmstad, Germany獲得之預先填充Merck正相Si60二氧化矽柱(粒度測定：15-40或40-63µm)、silicycle二氧化矽柱或graceresolv二氧化矽柱在自動化Armen Glider Flash：Spot II Ultimate (Armen儀器，Saint-Ave, France)或自動化Presearch combiflash companion上實施急驟層析純化。 iv. 使用水(含有0.1%氨)與乙腈之極性漸減混合物或水(含有0.1%甲酸)與乙腈之極性漸減混合物作為溶析液在配備有ZMD或ZQ ESCi質譜儀及Waters X-Terra或Waters X-Bridge或Waters SunFire反相管柱(C-18，5微米二氧化矽，19 mm或50 mm直徑，100 mm長度，流速為40 mL/分鐘)之Waters儀器(600/2700或2525)上實施製備型層析； v. 產率(若存在)未必為可獲得之最大值； vi. 式( I) 之終產物之結構係藉由核磁共振(NMR)光譜確認，且NMR化學位移值係在δ標度上量測。質子磁共振光譜係使用Bruker advance 700 (700MHz)、Bruker Avance 500 (500 MHz)、Bruker 400 (400 MHz)或Bruker 300 (300 MHz)儀器測定；19F NMR係於282 MHz或376 MHz下測定；13C NMR係於75 MHz或100 MHz下測定；除非另外規定，否則量測係在20 - 30℃下進行；使用以下縮寫：s，單峰；d，雙峰；t，三重峰；q，四重峰；m，多重峰；dd，雙峰之雙峰；ddd，雙峰之雙峰之雙峰；dt，三重峰之雙峰；bs，寬信號； vii. 亦藉由液相層析後質譜術(LCMS)表徵式(I) 之終產物；LCMS係使用配備有Waters ZQ ESCi或ZMD ESCi質譜儀及X Bridge 5μm C-18管柱(2.1 × 50 mm)之Waters Alliance HT (2790及2795)以2.4 mL/min之流速、使用在4分鐘內95% A + 5% C至95% B + 5% C之溶劑系統來實施，其中A = 水，B = 甲醇，C = 1:1甲醇:水(含有0.2%碳酸銨)；或藉由使用與DAD檢測器、ELSD檢測器及2020 EV質譜儀(或等效物)且配備有Phenomenex Gemini-NX C18 3.0×50 mm, 3.0 μM管柱或等效物(鹼性條件)或Shim堆疊XR - ODS 3.0 × 50 mm, 2.2 μM管柱或Waters BEH C18 2.1 × 50 mm, 1.7 μM管柱或等效物之Shimadzu UFLC或UHPLC使用在4分鐘內95% D + 5% E至95% E + 5% D之溶劑系統來實施，其中D = 水(含有0.05% TFA)，E = 乙腈(含有0.05% TFA) (酸性條件)，或在4分鐘內90% F + 10% G至95% G + 5% F之溶劑系統來實施，其中F = 水(含有6.5 mM碳酸氫銨並藉由添加氨調節至pH10)，G = 乙腈(鹼性條件)； viii. 中間體通常未完全表徵且藉由薄層層析、質譜、HPLC及/或NMR分析評定純度； ix. X射線粉末繞射譜係(使用Bruker D4分析儀器)藉由將結晶材料之試樣安裝於Bruker單矽晶體(SSC)晶圓支架上且藉助顯微鏡載玻片將試樣展開成薄層來測定。使試樣以30轉/分鐘旋轉(以改良計數統計)並用由在40 kV及40 mA下運行之銅長細聚焦管所產生的波長為1.5418埃之X射線輻照。使準直X射線源穿過設定在V20下之自動可變發散狹縫且反射輻射引導穿過5.89 mm防散射狹縫及9.55 mm檢測器狹縫。在2度至40度2θ範圍內以θθ模式將試樣暴露0.03秒/0.00570° 2θ增量(連續掃描模式)。運行時間係3分鐘又36秒。儀器配備有位置靈敏性檢測器(Lynxeye)。藉助利用Diffrac+軟體運行之Dell Optiplex 686 NT 4.0 Workstation進行控制及數據捕捉。 x. 在TA Instruments Q2000 DSC上實施差式掃描量熱法。通常，將含有小於5mg材料且配備有蓋子之標準鋁盤以10℃/分鐘之恆定加熱速率在25℃至300℃之溫度範圍內加熱。以50 ml/分鐘之流速利用使用氮之吹掃氣體。 xi. 使用以下縮寫：h = 小時；r.t. = 室溫(約18-25℃)；conc. = 濃縮；FCC = 使用二氧化矽之急速管柱層析；DCM = 二氯甲烷；DIPEA = 二異丙基乙胺；DMA =N ,N- 二甲基乙醯胺；DMF =N ,N- 二甲基甲醯胺；DMSO = 二甲亞碸；Et2 O = 二乙醚；EtOAc = 乙酸乙酯；EtOH = 乙醇；K2 CO3 = 碳酸鉀；MeOH = 甲醇；MeCN = 乙腈；MTBE = 甲基四丁基醚；MgSO4 = 無水硫酸鎂；Na2 SO4 = 無水硫酸鈉；THF = 四氫呋喃；sat. = 飽和水溶液；且 xii. IUPAC名稱係使用ELN (一種專利程式)或「Canvas」或「IBIS」、AstraZeneca專利程式來生成。 實例18-(6-(3-(4- 氟六氫吡啶 -1- 基 ) 丙氧基 ) 吡啶 -3- 基 )-1- 異丙基 -3- 甲基 -1,3- 二氫 -2H- 咪唑并 [4,5-c] 喹啉 -2- 酮
Figure TW201805284AD00008
於室溫下向氫化鈉(1.046 g, 26.16 mmol)於THF (10 ml)中之攪拌懸浮液中逐滴添加THF (10 ml)中之3-(4-氟六氫吡啶-1-基)丙-1-醇(2.109 g, 13.08 mmol)。將所得懸浮液於室溫下在氮下攪拌10分鐘，隨後添加DMF (30 ml)中之8-(6-氟吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮(2.2 g, 6.54 mmol)並將反應混合物於室溫下攪拌3h。將反應混合物用乙酸乙酯(400 ml)稀釋，並用水(3 × 200 ml)洗滌三次。將有機層經MgSO4 乾燥，過濾並蒸發，以得到粗產物。藉由FCC純化粗產物，溶析梯度為0至4% 2N NH3 /DCM中之MeOH，且將純部分蒸發至乾燥，隨後與二乙醚(20 ml)一起攪拌過夜。過濾固體，用二乙醚洗滌，隨後乾燥，以得到白色固體狀8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮(2.51 g, 80 %)。NMR 譜 ： 1 H NMR (500MHz, DMSO-d6) δ 1.58 - 1.75 (8H, m), 1.76 - 1.99 (4H, m), 2.19 - 2.33 (2H, m), 2.37 - 2.47 (2H, m), 2.51 - 2.57 (2H, m), 3.49 (3H, s), 4.34 (2H, t), 4.5 - 4.85 (1H, m), 5.2 - 5.49 (1H, m), 6.95 (1H, dd), 7.90 (1H, dd), 8.11 (1H, d), 8.16 (1H, dd), 8.37 (1H, d), 8.63 (1H, dd), 8.85 (1H, s)。質譜： m/z (ES+)[M+H]+ = 478。 在使用X射線粉末繞射(XRPD)分析時，發現根據上述程序製備之物質為晶體。實例1形式A之特徵在於提供X射線粉末繞射圖案，實質上如圖1中所顯示。10個X射線粉末繞射峰顯示於表1中。 表1：實例1之形式A之特徵性X射線粉末繞射峰 實例1形式A展現以下熱參數：熔融吸熱以157.8℃開始且在158.9℃下具有峰，之前係59℃下小的吸熱，如以10℃/min之掃描速率藉由DSC所測定(圖2)。 藉由於環境溫度下將上述形式A物質在乙酸乙酯中製成漿液來產生8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮形式C之不同結晶型。將大約20mg形式A物質放置於具有磁力攪拌棒之小瓶中，並添加大約2ml乙酸乙酯。隨後用蓋子將小瓶緊密密封並在磁力攪拌板上攪拌。大約4天後，自板移出試樣，拿下蓋子並使漿液在環境添加下乾燥，之後藉由XRPD及DSC對其進行分析。 實例1形式C之特徵在於提供X射線粉末繞射圖案，實質上如圖3中所顯示。10個X射線粉末繞射峰顯示於表2中。 表2：實例1之形式C之特徵性X射線粉末繞射峰 實例1形式C展現以下熱參數：熔融吸熱以141.1℃開始且在142.0℃下具有峰，之後在143.0℃下放熱事件及隨後吸熱以158.1℃開始且在159.1℃下具有峰，如以10℃/min之掃描速率藉由DSC所測定(圖4)。 藉由於環境溫度下將上述形式A物質在水中製成漿液來產生8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮形式D之不同結晶型。將大約20mg形式A物質放置於具有磁力攪拌棒之小瓶中，並添加大約2ml水。隨後用蓋子將小瓶緊密密封並在磁力攪拌板上攪拌。大約4天後，自板移出試樣，拿下蓋子並使漿液在環境添加下乾燥，之後藉由XRPD及DSC對其進行分析。 實例1形式D之特徵在於提供X射線粉末繞射圖案，實質上如圖5中所顯示。特徵性X射線粉末繞射峰顯示於表3中。 表3：實例1之形式D之特徵性X射線粉末繞射峰 實例1形式C展現以下熱參數：熔融吸熱以141.1℃開始且在142.0℃下具有峰，之後在143.0℃下放熱事件及隨後吸熱以158.1℃開始且在159.1℃下具有峰，如以10℃/min之掃描速率藉由DSC所測定(圖6)。 亦可藉由將游離鹼溶解於少量DCM中並用溶解於少量DCM中之一定當量之甲磺酸處理、去除溶劑且隨後將殘餘物在二乙醚中攪拌、之後過濾將實例1之8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮分離為甲磺酸鹽。NMR 譜 ： 1 H NMR (500MHz, DMSO-d6) δ 1.67 (6H, d), 1.75 - 2.31 (6H, m), 2.31 (3H, s), 2.99 - 3.21 (2H, m), 3.42 - 3.7 (5H, m), 4.42 (2H, t), 4.64 - 5.17 (1H, m), 5.36 (1H, p), 6.99 (1H, dd), 7.97 (1H, dd), 8.15 (1H, d), 8.23 (1H, dd), 8.41 (1H, d), 8.67 (1H, dd), 8.92 (1H, s), 9.25 (1H, s)。質譜： m/z (ES+)[M+H]+ = 478。 自適當醇中間體以類似方式製備以下化合物：
Figure TW201805284AD00009
Figure TW201805284AD00010
 * 將反應物於室溫下攪拌2至3 h。 實例2NMR 譜 ： 1 H NMR (500MHz, DMSO-d6) δ 1.66 (6H, d), 1.76 - 1.98 (3H, m), 2.01 - 2.23 (1H, m), 2.24 - 2.33 (1H, m), 2.51 - 2.68 (3H, m), 2.72 - 2.92 (2H, m), 3.49 (3H, s), 4.37 (2H, t), 5.05 - 5.29 (1H, m), 5.34 (1H, p), 6.96 (1H, dd), 7.91 (1H, dd), 8.12 (1H, d), 8.17 (1H, dd), 8.38 (1H, d), 8.64 (1H, dd), 8.86 (1H, s)。質譜： m/z (ES+)[M+H]+ = 464。 亦可藉由將游離鹼溶解於少量DCM中並用溶解於少量DCM中之一定當量之甲磺酸處理、去除溶劑且隨後將殘餘物在Et2 O中攪拌、之後過濾將(S )-8-(6-(3-(3-氟吡咯啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮分離為甲磺酸鹽。NMR 譜 ： 1 H NMR (500MHz, DMSO-d6) δ 1.67 (6H, d), 2.13 - 2.21 (2H, m), 2.30 (3H, s), 3.50 (3H, s), 3.84 (2H, d), 4.42 (2H, t), 5.35 (1H, p), 5.49 (1H, d), 6.99 (1H, d), 7.95 (1H, dd), 8.15 (1H, d), 8.22 (1H, dd), 8.40 (1H, d), 8.67 (1H, dd), 8.91 (1H, s), 10.01 (1H, d)。質譜 ： m/z (ES+)[M+H]+ = 464。 實例3NMR 譜 ： 1 H NMR (500MHz, DMSO-d6) δ 1.66 (6H, d), 1.75 - 1.98 (3H, m), 2.12 (1H, ddq), 2.29 (1H, q), 2.52 - 2.68 (3H, m), 2.74 - 2.91 (2H, m), 3.49 (3H, s), 4.36 (2H, t), 5.18 (1H, ddd), 5.34 (1H, p), 6.96 (1H, d), 7.91 (1H, dd), 8.11 (1H, d), 8.16 (1H, dd), 8.38 (1H, d), 8.63 (1H, d), 8.86 (1H, s)。質譜： m/z (ES+)[M+H]+ = 464。 亦可藉由將游離鹼溶解於少量DCM中並用溶解於少量DCM中之一定當量之甲磺酸處理、去除溶劑且隨後將殘餘物在Et2 O中攪拌、之後過濾將(R )-8-(6-(3-(3-氟吡咯啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮分離為甲磺酸鹽。NMR 譜 ： 1 H NMR (500MHz, DMSO-d6) δ 1.67 (6H, d), 2.13 - 2.22 (2H, m), 2.30 (3H, s), 3.50 (3H, s), 3.76 (1H, s), 3.94 (1H, s), 4.42 (2H, t), 5.36 (1H, p), 5.49 (1H, d), 6.99 (1H, d), 7.97 (1H, d), 8.15 (1H, d), 8.23 (1H, dd), 8.41 (1H, d), 8.67 (1H, d), 8.93 (1H, s), 10.15 (1H, s)。質譜： m/z (ES+)[M+H]+ = 464。 中間體3-(4-氟六氫吡啶-1-基)丙-1-醇係如下製備：3-(4- 氟六氫吡啶 -1- 基 ) 丙 -1- 醇
Figure TW201805284AD00011
於室溫下在氮下向4-氟六氫吡啶(2.0 g, 19.39 mmol)於無水四氫呋喃(20 ml)中之溶液中添加氫化鈉(1 g, 25.00 mmol)，隨後攪拌30分鐘。逐滴添加(3-溴丙氧基)(第三丁基)二甲基矽烷(6.77 ml, 29.22 mmol)，隨後於室溫下攪拌24 h。將反應混合物用EtOAc (100 ml)稀釋且用水(3 × 50 ml)洗滌三次。將有機層經MgSO4 乾燥，過濾並蒸發，以得到粗產物(矽基)。將粗產物(矽基)裝載至用MeOH洗滌之2 × 50g SCX管柱上且隨後將產物使用2M NH3 /MeOH自管柱溶析，以得到黃色油狀3-(4-氟六氫吡啶-1-基)丙-1-醇(2.226 g, 71.2 %)。NMR 譜 ： 1 H NMR (500MHz,CDCl3 ) δ 1.63 - 1.77 (2H, m), 1.87 (4H, dq), 2.42 - 2.7 (6H, m), 3.74 - 3.87 (2H, m), 4.69 (1H, dt)。 自適當胺以類似方式製備以下中間體：
Figure TW201805284AD00012
Figure TW201805284AD00013
 * 將反應物於室溫下攪拌2至28 h。中間體 A1 ： NMR 譜 ： 1 H NMR (500MHz,CDCl3 ) δ 1.64 - 1.83 (2H, m), 1.95 - 2.24 (2H, m), 2.45 - 2.59 (1H, m), 2.71 - 3 (5H, m), 3.74 - 3.9 (2H, m), 4.99 - 5.34 (1H, m)。中間體 B1 ： NMR 譜 ： 1 H NMR (500MHz,CDCl3 ) δ 1.69 - 1.77 (2H, m), 1.97 - 2.2 (2H, m), 2.48 - 2.56 (1H, m), 2.73 - 2.81 (2H, m), 2.81 - 3.01 (3H, m), 3.77 - 3.85 (2H, m), 4.59 (1H, s), 5.06 - 5.24 (1H, m)。 中間體8-(6-氟-3-吡啶基)-1-異丙基-3-甲基-咪唑并[4,5-c]喹啉-2-酮係如下製備：8-(6- 氟 -3- 吡啶基 )-1- 異丙基 -3- 甲基 - 咪唑并 [4,5-c] 喹啉 -2- 酮
Figure TW201805284AD00014
將8-溴-1-異丙基-3-甲基-咪唑并[4,5-c]喹啉-2-酮(4.57 g, 14.27 mmol)、(6-氟吡啶-3-基)酸(2.61 g, 18.55 mmol)及2M碳酸鉀(22 mL, 44.00 mmol)懸浮於1,4-二噁烷(90 mL)中。將混合物脫氣，隨後添加二氯[1,1’-雙(二-第三丁基膦基)二茂鐵]鈀(II) (0.465 g, 0.71 mmol)並在惰性氣氛下使反應至80℃並保持2 h。將混合物冷卻，用EtOAc (200 mL)稀釋，隨後用水(50 mL)、鹽水洗滌，並將有機相經MgSO4 乾燥，過濾並在真空中濃縮。藉由FCC純化粗產物，溶析梯度為DCM中之0至5% MeOH，以得到物質，隨後將其與二乙醚一起研磨，以得到灰白色固體狀期望物質(4.46 g, 93 %)。NMR 譜 ： 1 H NMR (500MHz, DMSO-d6) δ 1.66 (6H, d), 3.50 (3H, s), 5.36 (1H, p), 7.36 (1H, dd), 7.95 (1H, dd), 8.15 (1H, d), 8.39 - 8.52 (2H, m), 8.72 (1H, d), 8.90 (1H, s)。質譜： m/z (ES+)[M+H]+ = 337。8- 溴 -1- 異丙基 -3- 甲基 -1,3- 二氫 -2H- 咪唑并 [4,5-c] 喹啉 -2- 酮 向8-溴-1-異丙基-3H-咪唑并[4,5-c]喹啉-2-酮(25.00 g, 81.66 mmol)於DMF (375 mL)中之溶液中添加N ,N -二甲基甲醯胺二甲基縮醛(54.2 mL, 408.29 mmol)。將混合物加熱至80℃並保持3 h，隨後使其冷卻至環境溫度並攪拌16 h。藉由過濾收集沈澱，用水(4 × 300 mL)洗滌並在真空下在50℃下乾燥，以得到白色固體狀期望物質(23.82 g, 91 %)。NMR 譜 : 1 H NMR (500MHz, DMSO-d6) δ 1.63 (6H, d), 3.49 (3H, s), 5.15 - 5.23 (1H, m), 7.75 (1H, dd), 7.99 (1H, d), 8.44 (1H, d), 8.91 (1H, s)。質譜 ： m/z (ES+)[M+H]+ = 320。8- 溴 -1- 異丙基 -3H- 咪唑并 [4,5-c] 喹啉 -2- 酮 於環境溫度下向DMF (342 mL)中之6-溴-4-(異丙基胺基)喹啉-3-甲酸(34.22 g, 110.69 mmol)中添加三乙胺(45.3 mL, 332.06 mmol)。於環境溫度下攪拌30分鐘後，添加疊氮磷酸二苯基酯(26.2 mL, 121.76 mmol)並將所得混合物於60℃下攪拌2 h。將反應混合物倒入水(1500 mL)中；藉由過濾收集沈澱，用水(2 × 700 mL)洗滌並在真空下於50℃下乾燥，以得到米色固體狀期望物質(29.6 g, 87 %)，其不經進一步純化即使用。NMR 譜 ： 1 H NMR (500MHz, CDCl3 ) δ 1.64 (6H, d), 5.06 - 5.21 (1H, m), 7.75 (1H, d), 7.98 (1H, d), 8.43 (1H, s), 8.69 (1H, s), 11.57 (1H, s)。質譜： m/z (ES+)[M+H]+ = 3066- 溴 -4-( 異丙基胺基 ) 喹啉 -3- 甲酸 將6-溴-4-(異丙基胺基)喹啉-3-甲酸乙酯(38.0 g, 112.69 mmol)懸浮於甲醇(800 mL)及水(200 mL)中。添加10M氫氧化鈉溶液(33.8 mL, 338.07 mmol)並將混合物於環境溫度下攪拌1 h。添加THF (200 mL)並將所得混合物攪拌16 h。添加水(400 mL)並在減壓下去除有機物。利用2M HCl將所得水溶液酸化至pH 4-5，並藉由過濾收集沈澱，用水洗滌並在真空下乾燥，以得到白色固體狀期望物質(34.7 g, 100 %)。NMR 譜 ： 1 H NMR (500MHz, DMSO-d6) δ 1.33 (6H, d), 4.39 (1H, s), 7.78 (1H, d), 7.92 (1H, dd), 8.38 (1H, d), 8.88 (1H, s)。質譜： m/z (ES+)[M+H]+ = 309。6- 溴 -4-( 異丙基胺基 ) 喹啉 -3- 甲酸乙酯 於0℃下向6-溴-4-氯喹啉-3-甲酸乙酯(36.61 g, 116.38 mmol)及碳酸鉀(32.2 g, 232.77 mmol)於乙腈(250 mL)中之懸浮液中添加丙-2-胺(11.00 ml, 128.02 mmol)。將混合物於54℃下在回流下攪拌3 h。再添加碳酸鉀(10.7 g, 77.6 mmol)及丙-2-胺(3.6 ml, 42.7 mmol)並於48℃下再繼續攪拌16 h。在真空中去除溶劑並將所得殘餘物分配在DCM (400 mL)與水(500 mL)之間。用DCM (2 × 200 mL)再萃取水層；使合併之有機層通過相分離紙並在減壓下濃縮，以得到米色固體狀期望物質(38.6 g, 98 %)。NMR 譜 ： 1 H NMR (500MHz, CDCl3 ) δ 1.40 (6H, d), 1.43 (3H, t), 4.32 - 4.37 (1H, m), 4.40 (2H, q), 7.72 (1H, dd), 7.81 (1H, d), 8.29 (1H, d), 8.95 (1H, d), 9.10 (1H, s)。質譜： m/z (ES+)[M+H]+ = 337。6- 溴 -4- 氯喹啉 -3- 甲酸乙酯 於環境溫度下在空氣下向亞硫醯氯(800mL)中之6-溴-1-[(4-甲氧基苯基)甲基]-4-側氧基喹啉-3-甲酸乙酯(160g, 384.37mmol)中添加DMF (0.119mL, 1.54mmol)。將所得混合物於75℃下攪拌16 h，隨後在減壓下去除溶劑。將所得混合物與甲苯共沸兩次，隨後添加正己烷(500mL)。藉由過濾收集沈澱，用正己烷(200mL)洗滌並在真空下乾燥，以得到褐色固體狀期望物質(100g, 83%)。NMR 譜 ：1 H NMR (400MHz, CDCl3 ) δ 1.47 (3H, t), 4.51 (2H, q), 7.95 (1H, dd), 8.11 (1H, d), 8.60 (1H, d), 9.24 (1H, s)。質譜 ：m/z (ES+)[M+H]+ = 314、316。 以較大規模，向容器中裝入6-溴-1-[(4-甲氧基苯基)甲基]-4-側氧基喹啉-3-甲酸乙酯(5765 g, 13.85 mol)與亞硫醯氯(28.8 L)。觀察到自20-26℃放熱。添加DMF (4.4 mL)，未觀察到放熱，且將批料加熱至75℃並攪拌17 h。HPLC顯示保留1.3%起始材料與98.0%產物。將反應物在真空中濃縮並將殘餘物與甲苯(25 L)共沸。隨後將所得固體在庚烷(18.5 L)中製漿2.5 h，過濾並用庚烷(3 × 4 L)洗滌。在真空下於35℃下乾燥固體，以產生4077 g期望物質(93%粗產率)，藉由HPLC，其除約4%水解產物外亦含有約5% 6-溴-1-[(4-甲氧基苯基)甲基]-4-側氧基喹啉-3-甲酸乙酯(90%純度)。使粗物質(4077 g)返回至容器並用亞硫醯氯(14.5 L)及DMF (2.2 mL)再處理。將混合物加熱至75℃並保持40 h。在真空中去除亞硫醯氯並將殘餘物與甲苯(10 L)一起共沸。於20℃下將殘餘物在庚烷(18 L)中製漿約16 h。藉由過濾收集固體，一份在氮下經過濾並用庚烷(3 L)洗滌，以得到2196 g期望物質(90% NMR分析，藉由HPLC為99%)。將批料之其餘部分在空氣下過濾並用庚烷(3 L)洗滌，以得到1905 g期望物質(88% NMR分析，藉由HPLC為99%)。合併黃色固體用於進一步處理(4101 g，3653 g活性，83%產率，藉由HPLC為99%)。6- 溴 -1-[(4- 甲氧基苯基 ) 甲基 ]-4- 側氧基喹啉 -3- 甲酸乙酯 於環境溫度下經2分鐘之時段向丙酮(1.2 L)中之2-(5-溴-2-氟苯甲醯基)-3-[(4-甲氧基苯基)甲基胺基]丙-2-烯酸乙酯(296.5g, 679.62mmol)中逐滴添加1,8-二氮雜二環[5.4.0]十一-7-烯(102mL, 679.62mmol)。將所得溶液攪拌16 h，隨後藉由過濾去除固體並用MTBE洗滌，以得到淺黃色固體狀期望物質(180g, 64%)。NMR 譜 ：1 H NMR (400MHz, DMSO-d6) δ 1.30 (3H ,t), 3.71 (3H, s), 4.25 (2H ,q), 5.60 ( 2H, s), 6.90-6.95 (2H, m), 7.12-7.25 (2H, m), 7.67 (1H, d), 7.80-7.90 (1H, m), 8.30 (1H, d), 8.92 (1H, s)。質譜： m/z (ES+)[M+H]+ = 418。 以較大規模，於15℃下向容器中裝入2-(5-溴-2-氟苯甲醯基)-3-[(4-甲氧基苯基)甲基胺基]丙-2-烯酸乙酯(8434 g, (7730 g假定活性), 17.71 mol)與丙酮(23.2 L)。經25分鐘添加1,8-二氮雜二環[5.4.0]十一-7-烯(2.8 L, 18.72 mol)，且在添加過程中觀察到自18-23℃放熱。約25分鐘後形成沈澱且批料繼續放熱，1 h後達到最大37℃。將反應物於20℃下攪拌16.5 h，此時HPLC指示消耗起始材料及96.5%產物。藉由過濾洗滌所得沈澱，用MTBE (4× 3.4 L)洗滌。隨後在真空下於40℃下乾燥固體，以產生6033 g白色固體狀期望物質(經3個步驟產率為81.6%，藉由HPLC純度為99.8%)。分析數據與先前批料中獲得之數據一致。2-(5- 溴 -2- 氟苯甲醯基 )-3-[(4- 甲氧基苯基 ) 甲基胺基 ] 丙 -2- 烯酸乙酯 於10℃下經10分鐘之時段向甲苯(800 mL)中之5-溴-2-氟苯甲醯氯(163 g, 685 mmol)及DIPEA (120 mL, 685.00 mmol)中逐份添加(E )-3-(二甲基胺基)丙烯酸乙酯(98 g, 685.00 mmol)。將所得溶液於70℃下攪拌16 h，隨後使其冷卻。於環境溫度下經20分鐘之時段向混合物中添加(4-甲氧基苯基)甲胺(94 g, 685 mmol)。將所得溶液攪拌3 h，隨後將反應混合物用DCM (4 L)稀釋，並用水(3 × 1L)洗滌。將有機相經Na2 SO4 乾燥，過濾並蒸發，以產生褐色油狀期望物質(300 g, 100%)，其不經進一步純化即立刻用於後續反應。質譜： m/z (ES+)[M+H]+ = 436。 以較大規模，向容器中裝入呈甲苯(7.5 L)中之溶液形式之5-溴-2-氟苯甲醯氯(4318 g，4205 g活性，17.71 mol)。添加DIPEA (3150 mL, 18.08 mol)，未觀察到放熱。經30分鐘之時段逐份添加3-(二甲基胺基)丙烯酸乙酯(2532 g, 17.71 mol)，維持批料溫度 ＜40℃。在30分鐘添加期間觀察到自21-24℃放熱，在1 h內進一步緩慢升高至38℃。將反應物於20-30℃下攪拌16.5 h。經30 min逐份添加4-甲氧基苄基胺(2439 g, 17.78 mol)，維持批料溫度＜40℃。在添加期間觀察到25-30℃放熱，由15℃之降低夾套溫度提供冷卻。將反應物於20-30℃下攪拌4 h，其後HPLC指示93.2%期望物質。分開批料用於後處理，每一半混合物用DCM (28.6 L)稀釋並用水(3 × 7.8 L)洗滌。將有機物經MgSO4 (約550 g)乾燥並過濾，用DCM (4 L)洗滌。隨後濃縮合併之有機物，以產生8444 g油狀期望物質(8434 g，106%產率，藉由HPLC純度為94.7%)。分析數據與自先前批料獲得之數據一致。5- 溴 -2- 氟苯甲醯氯 於環境溫度下經1 h之時段向甲苯(1.2 L)及DMF (12mL)中之5-溴-2-氟苯甲酸(150g, 684.91mmol)中逐滴添加亞硫醯氯(75.0mL, 1027.36mmol)。將所得混合物於70℃下攪拌16 h，隨後將混合物冷卻並在真空中濃縮，以得到淺黃色油狀期望物質(160g, 98%)，其不經進一步純化即使用。NMR 譜 ：1 H NMR (400MHz, DMSO-d6) δ 7.26 - 7.31 (1H, m), 7.83 (1H, dd), 8.02 (1H, d)。 以較大規模，於20℃下向容器中裝入3-溴-6-氟苯甲酸(3888 g, 17.75 mol)，之後甲苯(29.2 L)。添加亞硫醯氯(1950 ml, 26.88 mol)，之後DMF (310 mL)，未觀察到放熱。將混合物加熱至65-75℃(溶液獲得高於約45℃)，未觀察到放熱及輕微氣體逸出。於此溫度下將反應物攪拌40 h，此時HPLC分析顯示87.6%產物、3.4%起始材料。將反應物在真空中濃縮並與甲苯(18 L)一起共沸，以產生4328 g期望物質(103%產率，藉由HPLC為87.3%)。 生物分析 使用以下分析以量測本發明化合物之效應：a) ATM細胞功效分析；b) PI3K細胞功效分析；c) mTOR細胞功效分析；d) ATR細胞功效分析；e) DNAPK細胞功效分析。在分析之說明期間，通常： i. 使用以下縮寫：4NQO = 4-硝基喹啉N- 氧化物；Ab = 抗體；BSA = 牛血清白蛋白；CO2 = 二氧化碳；DMEM = 杜貝克氏改良鷹氏培養基(Dulbecco's Modified Eagle Medium)；DMSO =二甲亞碸；EDTA = 乙二胺四乙酸；EGTA = 乙二醇四乙酸；ELISA = 酶聯免疫吸附分析；EMEM = 鷹氏最小必需培養基(Eagle's Minimal Essential Medium)；FBS = 胎牛血清；h = 小時；HRP = 辣根過氧化物酶；i.p. = 腹膜內；PBS = 磷酸鹽緩衝鹽水；PBST = 磷酸鹽緩衝鹽水 / Tween；TRIS = 參(羥基甲基)胺基甲烷；MTS試劑： [3-(4,5-二甲基噻唑-2-基)-5-(3-羧基甲氧基苯基)-2-(4-磺苯基)-2H-四唑鎓內鹽，及電子偶合劑(吩嗪硫酸甲酯) PMS；s.c. 皮下。 ii. 使用Genedata中之智能擬合模型計算IC50 值。IC50 值係測試化合物抑制50%生物活性之濃度。 分析a)：ATM細胞功效原理 ： 細胞輻照誘導DNA雙鏈斷裂及絲胺酸1981之快速分子間自磷酸化，其引起二聚體解離及起始細胞ATM激酶活性。在低至0.5 Gy之輻射劑量後，細胞中之大部分ATM分子在此位點上快速磷酸化，且在細胞中僅引入幾個DNA雙鏈斷裂後，磷酸特異性抗體之結合可檢測。 pATM分析之原理係鑑別細胞中之ATM之抑制劑。在X射線輻照之前，將HT29細胞與測試化合物一起培育1hr。1h後，將細胞固定並染色用於pATM (Ser1981)。在陣列掃描成像平臺上讀取螢光。方法詳情 ： 將HT29細胞(ECACC編號85061109)以3500個細胞/孔之密度在40μl含有1% L麩醯胺酸及10% FBS之EMEM培養基中接種至384孔分析板(Costar編號3712)中並使其黏附過夜。次日早上，藉由聲波分配向分析板中添加100% DMSO中之式(I) 化合物。於37℃及5% CO2 下培育1h後，使用X-RAD 320儀器(PXi)利用等效於約600cGy輻照板(一次高達6個)。將板返回至培育器並再保持1h。隨後藉由添加20μl PBS溶液中之3.7%甲醛並於r.t.下培育20分鐘、之後使用Biotek EL405板洗滌器用50μl /孔PBS洗滌來固定細胞。隨後添加20μl PBS中之0.1% Triton X100並於r.t.下培育20分鐘以滲透細胞。隨後將板使用Biotek EL405板洗滌器用50μl /孔PBS洗滌一次。 將磷酸-ATM Ser1981抗體(Millipore編號MAB3806)在含有0.05%聚山梨醇酯/Tween及3% BSA之PBS中稀釋10000倍並向每一孔中添加20μl並於r.t.下培育過夜。次日早上，將板使用Biotek EL405板洗滌器用50μl /孔PBS洗滌三次，且隨後添加20μl二級Ab溶液，其含有具有0.05%聚山梨醇酯/Tween及3% BSA之PBS中之500倍稀釋之Alexa Fluor® 488山羊抗兔IgG (Life Technologies, A11001)及0.002mg/ml Hoeschst染料(Life technologies編號H-3570)。於r.t.下培育1h後，將板使用Biotek EL405板洗滌器用50μl /孔PBS洗滌三次，並將板密封並於4℃下保持於PBS中直至讀數。使用ArrayScan VTI儀器、使用具有10X物鏡之XF53過濾器對板進行讀數。使用雙雷射設定以分析經Hoeschst (405nm)之核染色及pSer1981 (488nm)之二級抗體染色。 分析b)：ATR細胞功效原理 ： ATR係PI 3-激酶相關激酶，其因應複製阻斷期間之DNA損害或複製阻斷磷酸化絲胺酸或蘇胺酸殘基上之多個受質。Chk1 (ATR之下游蛋白激酶)在DNA損害檢查點控制中起關鍵作用。Chk1之活化涉及Ser317及Ser345之磷酸化(後者被視為由ATR磷酸化/活化之優先靶標)。此係藉由在用式(I) 化合物及UV模擬4NQO (Sigma編號N8141)處理後量測HT29細胞中Chk1 (Ser 345)之磷酸化之減少來量測ATR激酶之抑制的基於細胞之分析。方法詳情 ： 將HT29細胞(ECACC編號85061109)以6000個細胞/孔之密度在40μl含有1% L麩醯胺酸及10% FBS之EMEM培養基中接種至384孔分析板(Costar編號3712)中並使其黏附過夜。次日早上，藉由聲波分配向分析板中添加100% DMSO中之式(I) 化合物。於37℃及5% CO2 下培育1h後，藉由聲波分配向所有孔中添加40nl 100% DMSO中之3mM 4NQO，未經4NQO處理以生成無反應對照之最少對照孔除外。將板返回至培育器並再保持1h。隨後藉由添加20μl PBS溶液中之3.7%甲醛及於r.t.下培育20 min固定細胞。隨後添加20μl PBS中之0.1% Triton X100並於r.t.下培育10分鐘以滲透細胞。隨後將板使用Biotek EL405板洗滌器用50μl /孔PBS洗滌一次。 將磷酸-Chk1 Ser 345抗體(Cell Signalling Technology編號2348)在含有0.05%聚山梨醇酯/Tween之PBS中稀釋150倍並向每一孔中添加15μl並於r.t.下培育過夜。次日早上，將板使用Biotek EL405板洗滌器用50μl /孔PBS洗滌三次，且隨後添加20μl二級Ab溶液，其含有PBST中之500倍稀釋之Alexa Fluor® 488山羊抗兔IgG (Molecular Probes編號A-11008)及0.002mg/ml Hoeschst染料(Molecular Probes編號H-3570)。於r.t.下培育2h後，將板使用Biotek EL405板洗滌器用50μl /孔PBS洗滌三次，且隨後將板用黑色板密封件密封直至讀數。使用ArrayScan VTI儀器、使用具有10X物鏡之XF53過濾器對板進行讀數。使用雙雷射設定以分析經Hoeschst (405nm)之核染色及pChk1 (488nm)之二級抗體染色。 分析c)：PI3K細胞功效原理 ： 使用此分析以量測細胞中之PI3K-α抑制。將PDK1鑑別為蛋白激酶B (Akt1)之上游活化環激酶，其對於PKB之活化係必需的。脂質激酶磷酸肌醇3激酶(PI3K)之活化對於PDK1活化PKB係至關重要的。 在受體酪胺酸激酶之配體刺激後，PI3K被活化，其將PIP2轉化成PIP3，由PDK1之PH結構域結合，從而引起PDK1招募至質膜，其中其磷酸化活化環中之Thr308處之AKT。 此基於細胞之作用分析模式旨在鑑別藉由抑制PI3K活性抑制PDK活性或抑制將PDK1招募至膜之化合物。在用化合物處理2h後，BT474c細胞中磷酸-Akt (T308)之磷酸化係PDK1之直接量度及PI3K活性之間接量度。方法詳情 ： 將BT474細胞(人類乳房導管癌，ATCC HTB-20)以5600個細胞/孔之密度在含有10% FBS及1%麩醯胺酸之DMEM中接種至黑色384孔板(Costar，編號3712)中並使其黏附過夜。 次日早上，藉由聲學分配向分析板中添加100% DMSO中之化合物。於37℃及5% CO2 下培育2h後，攪動培養基，並用含有25mM Tris、3mM EDTA、3mM EGTA、50mM氟化鈉、2mM正釩酸鈉、0.27M蔗糖、10mM β-甘油磷酸酯、5mM焦磷酸鈉、0.5% Triton X-100及全蛋白酶抑制劑混合錠劑(Roche編號04 693 116 001，使用1個錠劑/50ml溶解緩衝液)之緩衝液溶解細胞。 20分鐘後，將細胞溶解物轉移至ELISA板(Greiner編號781077)中，該等板經PBS緩衝液中之抗總-AKT抗體預塗佈且利用含有0.05% Tween 20之PBS中之1% BSA阻斷非特異性結合。將板於4℃下培育過夜。次日，將板用含有0.05% Tween 20之PBS緩衝液洗滌並進一步與小鼠單株抗磷酸AKT T308一起培育2h。如上文所述再次洗滌板，之後添加馬抗小鼠-HRP偶聯二級抗體。於r.t.下培育2h後，洗滌板並向每一孔中添加QuantaBlu受質工作溶液(Thermo Scientific編號15169，根據提供者之說明書製備)。60分鐘後藉由向孔中添加停止溶液停止顯影螢光產物。使用Tecan Safire讀板儀分別使用325nm激發及420nm發射波長對板進行讀數。除非指定，否則此ELISA分析中使用來自Cell Signalling (編號7144)之Path Scan Phospho AKT (Thr308)夾心式ELISA套組中所含有之試劑。 分析d)：mTOR細胞功效原理 ： 在MDA-MB-468細胞系(一種無PTEN之乳房腺癌人類細胞系)中實施磷酸化-AKTser473細胞分析。由於缺乏PTEN，pAKT以組成型被活化，其不需要刺激以誘導磷酸化。方法詳情 ： 在由DMEM (杜貝克氏改良鷹氏培養基，編號D6546)、10% (v/v)胎牛血清及1% (v/v) L-麩醯胺酸構成之細胞培養基中培養MDA-MB-468細胞。收穫後，將細胞分配至黑色384孔Costar板(編號3712，Corning)中，以在40µl總體積之細胞培養基中產生1500個細胞/孔，並於37℃、90%相對濕度及5% CO2下在旋轉培育器中培育過夜。隨後藉由兩個分析方案A或B中之一者測試化合物：方案 A ： 隨後將細胞板於37℃下培育2 h，之後藉由添加20µl PBS/A中之3.7%甲醛(1.2%最終濃度)固定，之後40分鐘室溫培育，且隨後使用BioTek ELx406板洗滌器用150µl PBS/A (磷酸鹽緩衝鹽水)洗滌兩次。對細胞進行滲透化處理並於室溫下用20µl分析緩衝液(PBS/A中之0.5% Tween 20 + 1%奶粉)阻斷1h，且隨後用50µl PBS/A洗滌1次。將一級磷酸化-AKT (Ser473) 736E11兔單株抗體(編號3787，Cell Signaling Technology) 1:500稀釋於分析緩衝液中，每孔添加20µl，並將板於4℃下培育過夜。將細胞板用200µl PBS/T (含有0.05% Tween-20之磷酸鹽緩衝鹽水)洗滌3次，隨後每孔添加20µl Alexa Fluor® 488山羊抗兔IgG二級抗體(編號A11008，Molecular Probes，Life Technologies)於分析緩衝液中之1:1000稀釋液與Hoechst 33342之1:5000稀釋液。於室溫下培育2 h後，將板用200µl PBS/T洗滌3次，且每孔添加40µl PBS/A。 用黑色密封件覆蓋經染色細胞板，且隨後在Acumen (TTP Labtech)讀板儀上讀數。使用主要通道(綠色螢光，488nm)設定最大/最小截止值之強度設置，以容許使用染色及「對象(數)中之AKT+:數」數據之每週變化進行分析。分析數據且使用Genedata Screener® 軟體計算IC50。方案 B ： 隨後將細胞板於37℃下培育2 h，之後藉由添加20µl PBS/A中之3.7%甲醛(1.2%最終濃度)固定，之後30分鐘室溫培育，且隨後使用BioTek ELx406板洗滌器用150µl PBS/A洗滌兩次。對細胞進行滲透化處理並於室溫下用20µl分析緩衝液(PBS/A中之0.1% Triton X-100 + 1% BSA)阻斷1h，且隨後用50µl PBS/A洗滌1次。將一級磷酸化-AKT (Ser473) D9E XP®兔單株抗體(編號4060，Cell Signaling Technology) 1:200稀釋於分析緩衝液中，每孔添加20µl，並將板於4℃下培育過夜。將細胞板用200µl PBS/T洗滌3次，隨後每孔添加20µl Alexa Fluor® 488山羊抗兔IgG二級抗體(編號A11008，Molecular Probes，Life Technologies)於分析緩衝液中之1:750稀釋液與Hoechst 33342之1:5000稀釋液。於室溫下培育1 h後，將板用200µl PBS/T洗滌3次，且每孔添加40µl PBS w/o Ca、Mg及Na Bicarb (Gibco編號14190-094)。 用黑色密封件覆蓋經染色細胞板，且隨後在Cell Insight成像平臺(Thermo Scientific)上利用10x物鏡讀數。使用主要通過(Hoechst藍色螢光405nM，BGRFR_386_23)以自動聚焦並對事件數進行計數(此將提供關於所測試化合物之細胞毒性之資訊)。次要通道(綠色488nM，BGRFR_485_20)量測pAKT染色。分析數據且使用Genedata Screener® 軟體計算IC50。 分析e)：DNAPK細胞功效化合物處置 ： 使用Echo 555聲波分配器(Labcyte Inc™)將DNAPK細胞ELISA分析之所有化合物或DMSO (二甲亞碸)自含有100% (v/v) DMSO或100% DMSO中之10mM化合物之來源板直接分配至分析板上。使用固定尖端96-頭Agilent Vprep液體處置器(Agilent Technologies, Santa Clara, CA) 1:100稀釋10mM化合物原液，以產生四個中間體稀釋液(10mM、100µM、1µM、10nM)。藉由Echo使用此中間體板以將化合物及DMSO以12點劑量範圍(30、10、3.125、1.25、0.3、0.1、0.03125、0.0125、0.003、0.001、0.0003125、0.00003µM)直接分配至細胞板中以計算化合物IC50 ，其中分析中之總DMSO濃度為0.3%。方法詳情 ： 在HT29結腸直腸癌細胞系中實施DNA-PK細胞ELISA分析。在由MEM (鷹氏最小必需培養基，Sigma編號M2279)、10% (v/v)胎牛血清及1% (v/v) 200 mM L-麩醯胺酸構成之細胞培養基中培養HT29細胞。收穫後，將細胞分配至黑色384孔Costar板(編號3712，Corning)中，以在40 ul總體積之細胞培養基中產生15,000個細胞/孔，並於37℃、90%相對濕度及5% CO2 下在旋轉培育器中培育過夜。於4℃下將Greiner 781077全黑色高結合384孔ELISA板用0.5 µg/ml PBS中之DNA-PK抗體(Abcam編號ab1832)塗佈過夜。次日，將Greiner ELISA板用PBS-T洗滌3次並用3% BSA/PBS阻斷約2h，之後用PBS-T再洗滌3次。使用Labcyte Echo 555聲波分配器直接向細胞板中投用測試化合物及參考對照。隨後於37℃下將細胞板培育1 h，之後接受8 Gy之輻射劑量(XRAD 320，台高度65)。將細胞再培育1 h，之後去除細胞培養基。將溶解緩衝液(內部製備，添加蛋白酶抑制劑混合錠劑，Roche編號04 693 116 001)以25µl/孔分配並將板於4℃下培育15-20 min。使用CyBio Felix液體處置平臺將細胞溶解物(20µl/孔)轉移至DNA-PK抗體塗佈之ELISA板，並將ELISA板於4℃下培育過夜。次日，將ELISA板用PBS-T洗滌3次並以20µl/孔分配內部pS2056-DNA-PK抗體(0.5µg/ml，於3% BSA/PBS中)。於室溫(RT)下將板與抗體一起培育1.5 h，之後用PBS-T洗滌3次。以20 µl/孔分配山羊抗兔HRP二級抗體(1:2000稀釋液，於3% BSA/PBS中；Cell Signaling編號7074)並將板於室溫下培育1 h，之後用PBS-T洗滌3次。以20 µl/孔分配QuantaBlu工作受質溶液(Thermo Scientific編號15169，根據製造商說明書製備)並將板於室溫下培育1 h，之後再以20 µl/孔分配套組(Thermo Scientific編號15169)中提供之QuantaBlu停止溶液。使用PerkinElmer EnVision讀板儀測定個別孔之螢光強度。分析數據且使用Genedata Screener® 軟體計算IC50。 表4：分析a) - e)中之實例1 - 12之功效數據 表5顯示分析a)至e)中之CN102399218A及CN102372711A之某些化合物的比較數據。 表5：分析a) - e)中之CN102399218A及CN102372711A之某些化合物的功效數據Many embodiments are detailed in this specification and should be obvious to readers familiar with the technology. These embodiments should not be interpreted as limiting. In the first embodiment, the formula(I) Compound:
Figure TW201805284AD00004
(I) Or a pharmaceutically acceptable salt thereof, of which:R 1 Is 4-fluorohexahydropyridin-1-yl or 3-fluoropyrrolidin-1-yl; andR 2 It is methyl or hydrogen. The "hydrogen" group is equivalent to a hydrogen atom. Atoms with hydrogen groups attached can be considered unsubstituted. 3-fluoropyrrolidin-1-yl can be in two mirror-image isomeric forms, namely (S ) -3-fluoropyrrolidine-1-yl and (R ) -3-fluoropyrrolidin-1-yl exists and has the structure shown below.
Figure TW201805284AD00005
The term "pharmaceutically acceptable" is used to specify that the target (eg, salt, dosage form, or excipient) applies to the patient. See the list of examples of pharmaceutically acceptable saltsHandbook of Pharmaceutical Salts: Properties, Selection and Use, PH Stahl and C. Edited by G. Wermuth, Weinheim / z ürich: Wiley-VCH / VHCA, 2002. formula(I) Suitable pharmaceutically acceptable salts of the compounds are, for example, acid addition salts. formula(I) Acid addition salts of compounds can be formed by contacting the compound with a suitable inorganic or organic acid under conditions known to those skilled in the art. The acid addition salt can be formed, for example, using an inorganic acid selected from hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid. Acid addition salts can also be selected from trifluoroacetic acid, citric acid, maleic acid, oxalic acid, acetic acid, formic acid, benzoic acid, fumaric acid, succinic acid, tartaric acid, lactic acid, pyruvic acid, methanesulfonic acid, benzenesulfonic acid And p-toluenesulfonic acid organic acid to form. Therefore, in one embodiment, the formula(I) Compounds or pharmaceutically acceptable salts thereof, wherein the pharmaceutically acceptable salts are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, citric acid, maleic acid, oxalic acid, acetic acid, formic acid, benzoic acid, fumar Acid, succinic acid, tartaric acid, lactic acid, pyruvic acid, methanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid salt. In one embodiment, the provided formula(I) The compound or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is mesylate. In one embodiment, the provided formula(I) Compounds or pharmaceutically acceptable salts thereof, of which pharmaceutically acceptable salts are single- Methanesulfonate(I) The stoichiometry of the compound p-methanesulfonic acid is 1: 1. Yet another embodiment provides embodiments defined herein (for example, the embodiment of technical solution 1), provided that one or more specific examples selected from Examples 1, 2, and 3 (for example, 1, 2, or 3 specific examples) are individually abandoned. Examples). formula(I) Some values of the variable groups in are as follows. These values can be used in combination with the definitions defined herein, the scope of patent applications (eg, technical solution 1), or embodiments to provide other embodiments. a)R 1 It is 4-fluorohexahydropyridin-1-yl. b)R 1 3-fluoropyrrolidine-1-yl. c)R 1 system(S ) -3-fluoropyrrolidin-1-yl. d)R 1 system(R ) -3-fluoropyrrolidin-1-yl. e)R 2 Department of methyl. f)R 2 Department of hydrogen. In one embodiment, the provided formula(I) Compound or its pharmaceutically acceptable salt, in which:R 1 Department of tetrahydropyran-3-yl;R 2 It is methyl or hydrogen;R 3 Department of hydrogen or fluorine;R 4 Is hydrogen or fluorine; andR 5 Department of methyl. In one embodiment, the provided formula(I) A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) -1-iso Propyl-3-methyl-1,3-dihydro-2H-imidazo [4,5-c] quinolin-2-one; (S ) -8- (6- (3- (3-fluoropyrrolidin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1,3-dihydro- 2H-imidazo [4,5-c] quinolin-2-one; and (R ) -8- (6- (3- (3-fluoropyrrolidin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1,3-dihydro- 2H-imidazo [4,5-c] quinolin-2-one. In one embodiment, any formula is provided(I) The compound or its pharmaceutically acceptable salt can be prepared according to the experimental details in the example section. In one embodiment, 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1 is provided , 3-dihydro-2H-imidazo [4,5-c] quinolin-2-one or a pharmaceutically acceptable salt thereof. In one embodiment, 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1 is provided, 3-dihydro-2H-imidazo [4,5-c] quinolin-2-one. In one embodiment, 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1 is provided , 3-Dihydro-2H-imidazo [4,5-c] quinolin-2-one is a pharmaceutically acceptable salt. In one embodiment, providing (S ) -8- (6- (3- (3-fluoropyrrolidin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1,3-dihydro- 2H-imidazo [4,5-c] quinolin-2-one or a pharmaceutically acceptable salt thereof. In one embodiment, providing (S ) -8- (6- (3- (3-fluoropyrrolidin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1,3-dihydro- 2H-imidazo [4,5-c] quinolin-2-one. In one embodiment, providing (S ) -8- (6- (3- (3-fluoropyrrolidin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1,3-dihydro- 2H-imidazo [4,5-c] quinolin-2-one is a pharmaceutically acceptable salt. In one embodiment, providing (R ) -8- (6- (3- (3-fluoropyrrolidin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1,3-dihydro- 2H-imidazo [4,5-c] quinolin-2-one or a pharmaceutically acceptable salt thereof. In one embodiment, providing (R ) -8- (6- (3- (3-fluoropyrrolidin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1,3-dihydro- 2H-imidazo [4,5-c] quinolin-2-one. In one embodiment, providing (R ) -8- (6- (3- (3-fluoropyrrolidin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1,3-dihydro- 2H-imidazo [4,5-c] quinolin-2-one is a pharmaceutically acceptable salt. The compounds and salts described in this specification can exist in solvated and unsolvated forms. For example, the solvated form may be a hydrated form, such as hemi-hydrate, mono-hydrate, di-hydrate, tri-hydrate, or alternative amounts thereof. The present invention covers(I) All such solvated and unsolvated forms of the compound, especially to the extent that these forms have ATM kinase inhibitory activity, as measured, for example, using the tests described herein. The atoms of the compounds and salts described in this specification may exist in their isotopic forms. The present invention covers all types(I) Compounds in which atoms are replaced by one or more of their isotopes (e.g. formula(I) Compounds with one or more carbon atoms11 C or13 C carbon isotope, or one or more hydrogen atom system2 H or3 H isotope). The compounds and salts described in this specification may exist as a mixture of tautomers. "Tautomers" are structural isomers that exist due to the migration balance of hydrogen atoms. The present invention includes(I) All tautomers of the compound, especially to the extent that these tautomers have ATM kinase inhibitory activity. The compounds and salts described in this specification exist in optically active or racemic forms due to asymmetric carbon atoms. The present invention includes(I) Any optically active or racemic form of the compound that has ATM kinase inhibitory activity, as measured, for example, using the tests described herein. The synthesis of optically active forms can be carried out by standard techniques of organic chemistry well known in the industry, for example by synthesis using optically active materials or by resolution of racemic forms. Therefore, in one embodiment, the formula(I) A compound or a pharmaceutically acceptable salt thereof is a single optical isomer with a mirror image isomer excess (% ee) of ≥ 95%, ≥ 98%, or ≥ 99%. In one embodiment, the single optical isomer is present in a mirror image isomer excess (% ee) of ≥ 99%. In one embodiment, the provided formula(I) The compound or its pharmaceutically acceptable salt is a mirror image isomer excess (% ee) of ≥ 95%, ≥ 98% or ≥ 99% (S ) -Optical isomers. In one embodiment, (S ) -Optical isomers exist as a mirror image isomer excess ≥ 99% (% ee). In one embodiment, the provided formula(I) The compound or its pharmaceutically acceptable salt is a mirror image isomer excess (% ee) of ≥ 95%, ≥ 98% or ≥ 99% (R ) -Optical isomers. In one embodiment, (R ) -Optical isomers exist as a mirror image isomer excess ≥ 99% (% ee). The compounds and salts described in this specification may be crystalline and may exhibit one or more crystalline forms. The present invention covers(I) Any crystalline or amorphous form of the compound, or a mixture of these forms, has ATM kinase inhibitory activity. It is generally known that conventional techniques such as X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Diffuse Reflectance Infrared Fourier Transform (DRIFT) ) Spectroscopy, near infrared (NIR) spectroscopy, solution and / or solid state nuclear magnetic resonance spectroscopy) characterize crystalline materials. The water content of the crystalline material can be determined by Karl Fischer analysis. The crystalline forms described herein provide XRPD patterns that are substantially the same as the XRPD patterns shown in the figures, and have different 2θ values as shown in the tables included herein. Those skilled in the art should understand that XRPD patterns or diffraction patterns can be obtained, which have one or more measurement errors depending on the recording conditions (such as the equipment or machine used). Similarly, it is generally known that the intensity in the XRPD pattern can fluctuate due to the preferred orientation depending on the measurement conditions or sample preparation. Those skilled in the field of XRPD should further realize that the relative intensity of peaks can also be affected by, for example, grains with a size greater than 30µm and a non-single aspect ratio. Those skilled in the art should understand that the reflection position can be affected by the precise height of the sample in the diffractometer and the zero correction of the diffractometer. The surface planarity of the sample can also have a small effect. Due to these considerations, the provided diffraction pattern data is not taken as absolute values (Jenkins, R and Snyder, R.L. "Introduction to X-Ray Powder Diffractometry '' John Wiley & Sons 1996; Bunn, C.W. (1948), ``Chemical Crystallography " , Clarendon Press, London; Klug, H. P. and Alexander, L. E. (1974), "X-Ray Diffraction Procedures " ). Accordingly, it should be understood that the solid form is not limited to crystals that provide the same XRPD pattern as the XRPD pattern shown in each figure, and any crystal that provides an XRPD pattern that is substantially the same as the XRPD pattern shown in each figure also belongs to this. Within the scope of invention. Those familiar with the XRPD field can judge the substantial identity of XRPD patterns. Generally, the measurement error of the diffraction angle in XRPD is approximately plus or minus 0.2 ° 2θ, and when considering the X-ray powder diffraction pattern in the figure and when reading the data included in the table included in this article, The degree of measurement error should be considered. The compound of Example 1 exhibits crystalline properties, and three crystal forms are characterized herein. Therefore, in one embodiment, 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl is provided Crystalline form A of -1,3-dihydro-2H-imidazo [4,5-c] quinolin-2-one. In one embodiment, 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1 is provided The crystalline form A of, 3-dihydro-2H-imidazo [4,5-c] quinolin-2-one has an X-ray powder diffraction pattern with at least one specific peak at about 2θ = 10.9º. In one embodiment, 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1 is provided The crystalline form A of, 3-dihydro-2H-imidazo [4,5-c] quinolin-2-one has an X-ray powder diffraction pattern with at least one specific peak at about 2θ = 20.6º. In one embodiment, 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1 is provided , 3-dihydro-2H-imidazo [4,5-c] quinolin-2-one in crystalline form A, its X-ray powder diffraction pattern has at least two of them at about 2θ = 10.9 and 20.6 ° Peculiar peak. In one embodiment, 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1 is provided , 3-dihydro-2H-imidazo [4,5-c] quinolin-2-one, crystalline form A, whose X-ray powder diffraction pattern has a value of about 2θ = 3.6, 10.9, 12.6, 14.4, 17.3 , 18.0, 19.6, 20.3, 20.6 and 23.5º specific peaks. In one embodiment, 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1 is provided , 3-dihydro-2H-imidazo [4,5-c] quinolin-2-one crystalline form A, the X-ray powder diffraction pattern is essentially the same as the X-ray powder diffraction pattern shown in FIG. 1 The same. In one embodiment, 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1 is provided , 3-dihydro-2H-imidazo [4,5-c] quinolin-2-one in crystalline form A, its X-ray powder diffraction pattern has at least one plus or minus 0.2º 2θ at 2θ = 10.9º The specific peak. In one embodiment, 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1 is provided , 3-dihydro-2H-imidazo [4,5-c] quinolin-2-one crystalline form A, the X-ray powder diffraction pattern has at least one plus or minus 0.2º 2θ at 2θ = 20.6º The specific peak. In one embodiment, 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1 is provided , 3-dihydro-2H-imidazo [4,5-c] quinolin-2-one crystalline form A, its X-ray powder diffraction pattern has at least two specificities at 2θ = 7.0 and 9.2º Peak, where both 2θ values add or subtract 0.2º 2θ. In one embodiment, 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1 is provided , 3-dihydro-2H-imidazo [4,5-c] quinolin-2-one crystalline form A, its X-ray powder diffraction pattern has the following 2θ = 3.6, 10.9, 12.6, 14.4, 17.3 The specific peaks at 18.0, 19.6, 20.3, 20.6 and 23.5º, where all 2θ values are added or subtracted by 0.2º 2θ. 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1,3-dihydro-2H -The DSC analysis of Form A of imidazo [4,5-c] quinolin-2-one showed a melting endotherm that started at 157.8 ° C and had a peak at 158.9 ° C, which was a small endotherm at 59.0 ° C before this endotherm (Figure 2 ). Those skilled in the art should understand that the value or range of values observed in the DSC temperature record of a particular compound will show variation between batches of different purity. Therefore, for one compound at the same time, the range can be small, and for other compounds, the range can be quite large. Generally, the measurement error of the diffraction angle in a DSC thermal event is approximately plus or minus 5 ° C, and this measurement error degree should be considered when considering the DSC data included in this article. Therefore, in one embodiment, 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl is provided The crystalline form A of -1,3-dihydro-2H-imidazo [4,5-c] quinolin-2-one has a DSC endotherm that starts melting at about 157.8 ° C and has a peak at about 158.9 ° C. In one embodiment, 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1 is provided , 3-dihydro-2H-imidazo [4,5-c] quinolin-2-one in crystalline form A, its DSC endotherm starts to melt at 157.8 ℃ plus or minus 5 ℃ and at 158.9 ℃ There is a peak at 5 ° C. In one embodiment, 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1 is provided The crystalline form A of, 3-dihydro-2H-imidazo [4,5-c] quinolin-2-one has a DSC endotherm that starts to melt at 157.8 ° C and has a peak at 158.9 ° C. In one embodiment, 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1 is provided The crystalline form A of, 3-dihydro-2H-imidazo [4,5-c] quinolin-2-one has a DSC thermogram substantially as shown in FIG. 2. In one embodiment, 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1 is provided , 3-Dihydro-2H-imidazo [4,5-c] quinolin-2-one in crystalline form C. In one embodiment, 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1 is provided The crystalline form C of, 3-dihydro-2H-imidazo [4,5-c] quinolin-2-one has an X-ray powder diffraction pattern with at least one specific peak at about 2θ = 6.8º. In one embodiment, 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1 is provided The crystalline form C of, 3-dihydro-2H-imidazo [4,5-c] quinolin-2-one has an X-ray powder diffraction pattern with at least one specific peak at about 2θ = 13.5º. In one embodiment, 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1 is provided , 3-dihydro-2H-imidazo [4,5-c] quinolin-2-one in crystalline form C, the X-ray powder diffraction pattern has at least two of them at about 2θ = 6.8 and 13.5 ° Peculiar peak. In one embodiment, 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1 is provided , 3-Dihydro-2H-imidazo [4,5-c] quinolin-2-one, crystalline form C, whose X-ray powder diffraction pattern has a value of about 2θ = 6.8, 11.2, 13.3, 13.5, 16.5 , 17.6, 18.5, 21.7, 25.0 and 25.8º specific peaks. In one embodiment, 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1 is provided , 3-dihydro-2H-imidazo [4,5-c] quinolin-2-one in crystalline form C, the X-ray powder diffraction pattern is essentially the same as the X-ray powder diffraction pattern shown in FIG. 3 The same. In one embodiment, 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1 is provided , 3-dihydro-2H-imidazo [4,5-c] quinolin-2-one in crystalline form C, its X-ray powder diffraction pattern has at least one plus or minus 0.2º 2θ at 2θ = 6.8º The specific peak. In one embodiment, 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1 is provided , 3-dihydro-2H-imidazo [4,5-c] quinolin-2-one in crystalline form C, its X-ray powder diffraction pattern has at least one plus or minus 0.2º 2θ at 2θ = 13.5º The specific peak. In one embodiment, 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1 is provided , 3-dihydro-2H-imidazo [4,5-c] quinolin-2-one in crystalline form C, its X-ray powder diffraction pattern has at least two specificities at 2θ = 6.8 and 13.5º Peak, where both 2θ values add or subtract 0.2º 2θ. In one embodiment, 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1 is provided , 3-dihydro-2H-imidazo [4,5-c] quinolin-2-one in crystalline form C, its X-ray powder diffraction pattern has the following values: 2θ = 6.8, 11.2, 13.3, 13.5, 16.5, The specific peaks at 17.6, 18.5, 21.7, 25.0 and 25.8º, where all 2θ values are added or subtracted by 0.2º 2θ. 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1,3-dihydro-2H -Form DSC analysis of imidazo [4,5-c] quinolin-2-one shows melting endotherm starting at 141.1 ° C and having a peak at 142.0 ° C, exothermic event at 143.0 ° C, and starting at 158.1 ° C and at The melting endotherm with a peak at 159.1 ° C (Figure 4). Therefore, in one embodiment, 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl is provided The crystalline form C of -1,3-dihydro-2H-imidazo [4,5-c] quinolin-2-one has a DSC endotherm that begins to melt at about 141.1 ° C and has a peak at about 142.0 ° C. In one embodiment, 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1 is provided , 3-dihydro-2H-imidazo [4,5-c] quinolin-2-one in crystalline form C, whose DSC endotherm begins to melt at about 141.1 ° C and has a peak at about 142.0 ° C and at about There is an exothermic event at 143.0 ° C. In one embodiment, 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1 is provided , 3-dihydro-2H-imidazo [4,5-c] quinolin-2-one in crystalline form C, its DSC endotherm starts to melt at about 141.1 ° C and has a peak at about 142.0 ° C, at about There is an exothermic event at 143.0 ° C, and the endotherm starts to melt at about 158.1 ° C and has a peak at about 159.1 ° C. Therefore, in one embodiment, 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl is provided Crystalline form C of -1,3-dihydro-2H-imidazo [4,5-c] quinolin-2-one, whose DSC endotherm starts to melt at 141.1 ℃ plus or minus 5 ℃ and add at 142.0 ℃ Or there is a peak at minus 5 ° C. In one embodiment, 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1 is provided , 3-dihydro-2H-imidazo [4,5-c] quinolin-2-one in crystalline form C, the DSC endotherm starts to melt at 141.1 ℃ plus or minus 5 ℃ and at 142.0 ℃ There is a peak at 5 ° C and an exothermic event at 143.0 ° C plus or minus 5 ° C. In one embodiment, 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1 is provided , 3-dihydro-2H-imidazo [4,5-c] quinolin-2-one in crystalline form C, the DSC endotherm starts to melt at 141.1 ℃ plus or minus 5 ℃ and at 142.0 ℃ There is a peak at 5 ° C, an exothermic event at 143.0 ° C plus or minus 5 ° C, and endotherm begins to melt at 158.1 ° C plus or minus 5 ° C and a peak at 159.1 ° C plus or minus 5 ° C. Therefore, in one embodiment, 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl is provided The crystalline form C of -1,3-dihydro-2H-imidazo [4,5-c] quinolin-2-one has a DSC endotherm that starts melting at 141.1 ° C and has a peak at 142.0 ° C. In one embodiment, 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1 is provided , 3-dihydro-2H-imidazo [4,5-c] quinolin-2-one in crystalline form C, whose DSC endotherm starts melting at 141.1 ° C and has a peak at 142.0 ° C and at 143.0 ° C With exothermic events. In one embodiment, 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1 is provided , 3-dihydro-2H-imidazo [4,5-c] quinolin-2-one in crystalline form C, whose DSC endotherm starts melting at 141.1 ° C and has a peak at 142.0 ° C, at 143.0 ° C There is an exothermic event, and the endotherm starts to melt at 158.1 ° C and has a peak at 159.1 ° C. In one embodiment, 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1 is provided The crystalline form C of, 3-dihydro-2H-imidazo [4,5-c] quinolin-2-one has a DSC thermogram substantially as shown in FIG. 4. In one embodiment, 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1 is provided , 3-Dihydro-2H-imidazo [4,5-c] quinolin-2-one in crystalline form D. In one embodiment, 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1 is provided The crystalline form D of 2,3-dihydro-2H-imidazo [4,5-c] quinolin-2-one has an X-ray powder diffraction pattern with at least one specific peak at about 2θ = 10.2º. In one embodiment, 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1 is provided The crystalline form D of 2,3-dihydro-2H-imidazo [4,5-c] quinolin-2-one has an X-ray powder diffraction pattern with at least one specific peak at about 2θ = 19.2º. In one embodiment, 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1 is provided , 3-dihydro-2H-imidazo [4,5-c] quinolin-2-one in crystalline form C, the X-ray powder diffraction pattern has at least two of them at about 2θ = 10.2 and 19.2 ° Peculiar peak. In one embodiment, 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1 is provided , 3-dihydro-2H-imidazo [4,5-c] quinolin-2-one in crystalline form D, whose X-ray powder diffraction pattern has a value of about 2θ = 3.6, 10.2, 14.3, 14.6, 18.3 , The specific peaks at 19.2 and 19.6º. In one embodiment, 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1 is provided , 3-Dihydro-2H-imidazo [4,5-c] quinolin-2-one, crystalline form D, the X-ray powder diffraction pattern is essentially the same as the X-ray powder diffraction pattern shown in FIG. 5 The same. In one embodiment, 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1 is provided , 3-Dihydro-2H-imidazo [4,5-c] quinolin-2-one, crystalline form D, whose X-ray powder diffraction pattern has at least one plus or minus 0.2º 2θ at 2θ = 10.2º The specific peak. In one embodiment, 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1 is provided , 3-Dihydro-2H-imidazo [4,5-c] quinolin-2-one, crystalline form D, its X-ray powder diffraction pattern has at least one plus or minus 0.2º 2θ at 2θ = 19.2º The specific peak. In one embodiment, 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1 is provided , 3-Dihydro-2H-imidazo [4,5-c] quinolin-2-one crystalline form D, its X-ray powder diffraction pattern has at least two specificities at 2θ = 7.0 and 9.2º Peak, where both 2θ values add or subtract 0.2º 2θ. In one embodiment, 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1 is provided , 3-dihydro-2H-imidazo [4,5-c] quinolin-2-one in crystalline form D, its X-ray powder diffraction pattern has the following values: 2θ = 3.6, 10.2, 14.3, 14.6, 18.3, For specific peaks at 19.2 and 19º, all 2θ values are added or subtracted by 0.2º 2θ. 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1,3-dihydro-2H -The DSC analysis of form D of imidazo [4,5-c] quinolin-2-one showed a melting endotherm starting at 153.4 ° C and having a peak at 156.9 ° C, which was a small endotherm at 80.0 ° C before the endotherm ). Therefore, in one embodiment, 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl is provided The crystalline form D of -1,3-dihydro-2H-imidazo [4,5-c] quinolin-2-one has a DSC endotherm that starts melting at about 153.4 ° C and has a peak at about 156.9 ° C. In one embodiment, 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1 is provided , 3-dihydro-2H-imidazo [4,5-c] quinolin-2-one in crystalline form D, whose DSC endotherm starts to melt at 153.4 ° C plus or minus 5 ° C and at 156.9 ° C There is a peak at 5 ° C. In one embodiment, 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1 is provided The crystalline form D of, 3-dihydro-2H-imidazo [4,5-c] quinolin-2-one, whose DSC endotherm starts melting at 153.4 ° C and has a peak at 156.9 ° C In one embodiment, 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1 is provided The crystalline form D of, 3-dihydro-2H-imidazo [4,5-c] quinolin-2-one has a DSC thermogram substantially as shown in FIG. 6. When it is said that the embodiments are related to crystalline forms, the degree of crystallinity may be greater than about 60%. In some embodiments, the degree of crystallinity is greater than about 80%. In some embodiments, the degree of crystallinity is greater than about 90%. In some embodiments, the degree of crystallinity is greater than about 95%. In some embodiments, the degree of crystallinity is greater than about 98%. "Crystallinity" may refer to the percentage of a single crystalline form compared to all other crystalline or amorphous forms present; the percentage of all crystalline forms compared to the existing amorphous form. formula(I) The compound can be prepared, for example, by the following reaction:(II) Compound:
Figure TW201805284AD00006
(II) Or its salts, whereR 2 As defined in any of the embodiments herein andX Depart from the group (such as a halogen atom, or alternatively a fluorine atom); and the formula(III) Compound:
Figure TW201805284AD00007
(III) Or its salts, whereR 1 As defined in any of the embodiments herein. The reaction is conveniently carried out in a suitable solvent (eg DMF, DMA or THF) and in the presence of a base (eg sodium hydride) at a suitable temperature (eg a temperature in the range of about 20-50 ° C). formula(II) Compounds and their salts can therefore be used in the preparation formula(I) Compound intermediates and provide yet another example. In one embodiment, the provided formula(II) Compound or its salt, in which:R 2 Is methyl or hydrogen; andX The system is out of base. In one embodiment,X It is a halogen atom or a triflate group. In one embodiment,X Department of fluorine atoms. In one embodiment, the provided formula(II) Compound or its salt, in which:R 2 Is methyl; andX The system is out of base. In one embodiment,X It is a halogen atom or a triflate group. In one embodiment,X Department of fluorine atoms. In one embodiment, 7-fluoro-8- (6-fluoro-3-pyridyl) -1-isopropyl-3-methyl-imidazo [4,5-c] quinolin-2-one is provided Or its salt. Mentioning(II) Any of the embodiments of the compound or its salt, it should be understood that these salts need not be pharmaceutically acceptable salts. formula(II) Suitable salts of the compound are, for example, acid addition salts. formula(II) Acid addition salts of compounds can be formed by contacting the compound with a suitable inorganic or organic acid under conditions known to those skilled in the art. The acid addition salt can be formed, for example, using an inorganic acid selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid. Acid addition salts can also be selected from trifluoroacetic acid, citric acid, maleic acid, oxalic acid, acetic acid, formic acid, benzoic acid, fumaric acid, succinic acid, tartaric acid, lactic acid, pyruvic acid, methanesulfonic acid, benzenesulfonic acid And p-toluenesulfonic acid to form a group of organic acids. Therefore, in one embodiment, the formula(II) Compound or salt thereof, wherein the salt is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, citric acid, maleic acid, oxalic acid, acetic acid, formic acid, benzoic acid, fumaric acid, succinic acid, tartaric acid, lactic acid Pyruvate, methanesulfonic acid, benzenesulfonic acid or p-toluenesulfonate. In one embodiment, any of the novel intermediates described in the experimental section is provided. formula(I) Due to their ATM kinase inhibitory activity, the compounds and their pharmaceutically acceptable salts are expected to be used in therapy, for example, for the treatment of diseases or medical conditions, including cancer, at least partially mediated by ATM kinase. When referring to "cancer", this includes both non-metastatic cancer and metastatic cancer, so that the treatment of cancer involves both primary tumor and tumor metastasis treatment. "ATM kinase inhibitory activity" refers to the relative(I) The activity of ATM kinase in a compound or its pharmaceutically acceptable salt(I) Decrease of ATM kinase activity in the direct or indirect reaction of the compound or its pharmaceutically acceptable salts. This decrease in activity can be attributed to the formula(I) The direct interaction of the compound or its pharmaceutically acceptable salt with ATM kinase, or due to the formula(I) The interaction of the compound or its pharmaceutically acceptable salt with one or more other factors that affect the activity of ATM kinase. For example, the formula(I) The compound or its pharmaceutically acceptable salt can be reduced by direct binding to ATM kinase, by causing (directly or indirectly) another factor to reduce ATM kinase activity, or by (directly or indirectly) reducing cells or organisms The amount of ATM kinase present reduces ATM kinase. The term "therapy" is intended to have its normal meaning of treating a disease to completely or partially alleviate one, some, or all of its symptoms or to correct or compensate for the underlying cause. Unless the contrary is clearly indicated, the term "therapy" also includes "prevention". The terms "therapeutic" and "therapeutic site" should be interpreted accordingly. The term "prevention" is intended to have its normal meaning and includes primary prevention and secondary prevention used to prevent the occurrence of a disease (where the disease has occurred and temporarily or permanently protects the patient against the aggravation or deterioration of the disease or the occurrence of new symptoms related to the disease) . The term "treatment" is used synonymously with "therapy". Similarly, the term "treatment" can be viewed as "applying therapy", where "therapy" is as defined herein. In one embodiment, the provided formula(I) The compound or a pharmaceutically acceptable salt thereof is used in therapy. In one embodiment, the provided formula(I) The use of a compound or a pharmaceutically acceptable salt thereof for the manufacture of a medicament. In one embodiment, the provided formula(I) The compound or a pharmaceutically acceptable salt thereof is used for the treatment of diseases mediated by ATM kinase. In one embodiment, the provided formula(I) The compound or a pharmaceutically acceptable salt thereof is used for treating a disease mediated by ATM kinase, wherein the disease mediated by ATM kinase is cancer. In one embodiment, the provided formula(I) A compound or a pharmaceutically acceptable salt thereof for the treatment of diseases mediated by ATM kinase, wherein the diseases mediated by ATM kinase are colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse B-cell lymphoma, chronic lymphocytic leukemia, acute myeloid leukemia, squamous cell carcinoma of the head and neck, breast cancer, hepatocellular carcinoma, small cell lung cancer or non-small cell lung cancer. In one embodiment, the provided formula(I) The compound or a pharmaceutically acceptable salt thereof is used for treating a disease mediated by ATM kinase, wherein the disease mediated by ATM kinase is colorectal cancer. In one embodiment, the provided formula(I) The compound or a pharmaceutically acceptable salt thereof is used for the treatment of cancer. In one embodiment, the provided formula(I) Compounds or pharmaceutically acceptable salts thereof for the treatment of colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, acute myeloid leukemia, head and neck Squamous cell carcinoma, breast cancer, hepatocellular carcinoma, small cell lung cancer or non-small cell lung cancer. In one embodiment, the provided formula(I) The compound or a pharmaceutically acceptable salt thereof is used for the treatment of colorectal cancer. In one embodiment, the provided formula(I) The compound or a pharmaceutically acceptable salt thereof is used for the treatment of Huntingdon's disease. In one embodiment, the provided formula(I) The compound or a pharmaceutically acceptable salt thereof is used as a neuroprotective agent. "Neuroprotectant" is a reagent that preserves the structure and / or function of neurons. In one embodiment, the provided formula(I) The use of a compound or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of diseases mediated by ATM kinase. In one embodiment, the provided formula(I) The use of a compound or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a disease mediated by ATM kinase, wherein the disease mediated by ATM kinase is cancer. In one embodiment, the provided formula(I) The use of a compound or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of diseases mediated by ATM kinase, wherein the diseases mediated by ATM kinase are colorectal cancer, glioblastoma, gastric cancer , Ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, acute myeloid leukemia, head and neck squamous cell carcinoma, breast cancer, hepatocellular carcinoma, small cell lung cancer, and non-small cell lung cancer. In one embodiment, the provided formula(I) The use of a compound or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a disease mediated by ATM kinase, wherein the disease mediated by ATM kinase is colorectal cancer. In one embodiment, the provided formula(I) The use of compounds or pharmaceutically acceptable salts thereof for the manufacture of medicaments for the treatment of cancer. In one embodiment, the provided formula(I) The use of the compound or its pharmaceutically acceptable salt for the treatment of colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, acute bone marrow Agents for leukemia, squamous cell carcinoma of the head and neck, breast cancer, hepatocellular carcinoma, small cell lung cancer or non-small cell lung cancer. In one embodiment, the provided formula(I) The use of a compound or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of colorectal cancer. In one embodiment, the provided formula(I) The use of compounds or pharmaceutically acceptable salts thereof for the manufacture of medicaments for the treatment of Huntington's disease. In one embodiment, the provided formula(I) The use of compounds or pharmaceutically acceptable salts thereof for the manufacture of medicaments used as neuroprotective agents. In one embodiment, a method for treating a disease that is beneficial for the inhibition of ATM kinase in a warm-blooded animal in need of the treatment is provided, the method comprising administering a therapeutically effective amount to the warm-blooded animal(I) Compound or its pharmaceutically acceptable salt. The term "therapeutically effective amount" refers to the formula as described in any of the embodiments herein(I) The amount of compound that is effective to provide "therapy" in an individual or "treat" a disease or disorder in an individual. In the case of cancer, a therapeutically effective amount can cause any of the observable or measurable changes in the individual, as described above in the definitions of "therapy", "treatment" and "prevention". For example, an effective amount can reduce the number of cancer or tumor cells; reduce the overall tumor size; inhibit or stop tumor cell infiltration into peripheral organs (including, for example, soft tissue and bone); inhibit and stop tumor metastasis; inhibit and stop tumor growth ; Reduce one or more of the symptoms related to cancer to a certain degree; reduce the morbidity and mortality; improve the quality of life; or a combination of these effects. The effective amount may be an amount sufficient to reduce the symptoms of the disease in response to inhibition of ATM kinase activity. For cancer therapy, in vivo efficacy can be measured, for example, by evaluating survival duration, disease progression time (TTP), response rate (RR), response duration, and / or quality of life. As recognized by those skilled in the art, the effective amount can vary depending on the route of administration, use of excipients, and co-use with other agents. For example, when using combination therapy, the formula described in this specification(I) The amount of compound or pharmaceutically acceptable salt and the amount of other pharmaceutically active agents when combined together are effective in treating targeted disorders in animal patients. In this context, if the combined amount is sufficient to reduce the symptoms of a disease that responds to the inhibition of ATM activity as described above, it is a "therapeutically effective amount". Usually, the same amount can be used by those skilled in the art by (for example)(I) The compound or its pharmaceutically acceptable salt is determined starting from the dosage range described in this specification and other pharmaceutically active compounds within the approved or otherwise disclosed dosage range. "Warm-blooded animals" include, for example, humans. In one embodiment, a method for treating a disease that is beneficial for the inhibition of ATM kinase in a warm-blooded animal in need of the treatment is provided, the method comprising administering a therapeutically effective amount to the warm-blooded animal(I) The compound or a pharmaceutically acceptable salt thereof, and the disease in which the inhibition of ATM kinase is beneficial is cancer. In one embodiment, a method for treating a disease that is beneficial for the inhibition of ATM kinase in a warm-blooded animal in need of the treatment is provided, the method comprising administering a therapeutically effective amount to the warm-blooded animal(I) Compounds or pharmaceutically acceptable salts thereof, and diseases in which the inhibition of ATM kinase is beneficial are colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B cell lymphoma, chronic lymphocytic leukemia, acute Myeloid leukemia, squamous cell carcinoma of the head and neck, breast cancer, hepatocellular carcinoma, small cell lung cancer or non-small cell lung cancer. In one embodiment, a method for treating a disease of a warm-blooded animal in need of the treatment is provided, wherein inhibition of ATM kinase is beneficial, the method comprises administering a therapeutically effective amount to the warm-blooded animal(I) A compound or a pharmaceutically acceptable salt thereof, and a disease in which the inhibition of ATM kinase is beneficial is colorectal cancer. In one embodiment, a method for treating a disease of a warm-blooded animal in need of the treatment is provided, wherein inhibition of ATM kinase is beneficial, the method comprises administering a therapeutically effective amount to the warm-blooded animal(I) The compound or a pharmaceutically acceptable salt thereof, and the disease in which the inhibition of ATM kinase is beneficial is Huntington's disease. In one embodiment, a method for treating cancer in a warm-blooded animal in need of the treatment is provided, which comprises administering a therapeutically effective amount of the formula to the warm-blooded animal(I) Compound or its pharmaceutically acceptable salt. In one embodiment, it provides colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, acute myeloid disease for the treatment of warm-blooded animals in need of such treatment A method for leukemia, squamous cell carcinoma of the head and neck, breast cancer, hepatocellular carcinoma, small cell lung cancer or non-small cell lung cancer, which includes the method of administering a therapeutically effective amount to the warm-blooded animal(I) Compound or its pharmaceutically acceptable salt. In one embodiment, a method for treating colorectal cancer of a warm-blooded animal in need of the treatment is provided, which comprises administering a therapeutically effective amount to the warm-blooded animal(I) Compound or its pharmaceutically acceptable salt. In one embodiment, a method for treating Huntington's disease of a warm-blooded animal in need of the treatment is provided, which comprises administering a therapeutically effective amount to the warm-blooded animal(I) Compound or its pharmaceutically acceptable salt. In one embodiment, a method for achieving neuroprotection of a warm-blooded animal in need of the treatment is provided, which comprises administering a therapeutically effective amount of the formula to the warm-blooded animal(I) Compound or its pharmaceutically acceptable salt. In one embodiment, a method for treating cancer in a warm-blooded animal in need of the treatment is provided, which comprises administering a therapeutically effective amount of the formula to the warm-blooded animal(I) Compound or its pharmaceutically acceptable salt. In one embodiment, the cancer is selected from colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, acute myeloid leukemia, squamous cell carcinoma of the head and neck , Breast cancer, hepatocellular carcinoma, small cell lung cancer and non-small cell lung cancer. In one embodiment, the cancer is selected from colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, squamous cell carcinoma of the head and neck, and lung cancer. In one embodiment, the cancer is colorectal cancer. In any embodiment where the cancer is mentioned in a general sense, the cancer may be selected from colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, acute Myeloid leukemia, squamous cell carcinoma of the head and neck, breast cancer, hepatocellular carcinoma, small cell lung cancer and non-small cell lung cancer. In any embodiment where the cancer is mentioned in a general sense, the following embodiments are applicable: In one embodiment, the cancer is colorectal cancer. In one embodiment, the cancer is glioblastoma. In one embodiment, the cancer is gastric cancer. In one embodiment, the cancer is esophageal cancer. In one embodiment, the cancer is ovarian cancer. In one embodiment, the cancer is endometrial cancer. In one embodiment, the cancer is cervical cancer. In one embodiment, the cancer is diffuse large B-cell lymphoma. In one embodiment, the cancer is chronic lymphocytic leukemia. In one embodiment, the cancer is acute myeloid leukemia. In one embodiment, the cancer is squamous cell carcinoma of the head and neck. In one embodiment, the cancer is breast cancer. In one embodiment, the cancer is triple negative breast cancer. "Triple negative breast cancer" is any breast cancer that has not been tested positive for estrogen receptor, progesterone receptor and Her2 / neu. Test methods for determining a positive test for each of these receptors are well known in the industry. In one embodiment, the cancer is hepatocellular carcinoma. In one embodiment, the cancer is lung cancer. In one embodiment, the lung cancer is small cell lung cancer. In one embodiment, the lung cancer is non-small cell lung cancer. In one embodiment, the cancer is metastatic cancer. In one embodiment, metastatic cancer comprises metastasis of the central nervous system. In one embodiment, central nervous system metastases include brain metastases. In one embodiment, the metastasis of the central nervous system includes pial meningeal metastasis. When the cancer spreads to the meninges (that is, the tissue layers that cover the brain and spinal cord), "pimental metastasis" occurs. Metastasis can spread through the blood to the meninges or it can proceed from brain metastases, carried by the cerebrospinal fluid (CSF) flowing through the meninges. In one embodiment, the cancer is a non-metastatic cancer. The anti-cancer treatment described in this specification can be used as a monotherapy or as a division(I) The administration of the compound may also involve conventional surgery, radiation therapy or chemotherapy; or a combination of these additional therapies. Such conventional surgery, radiation therapy or chemotherapy can be combined with(I) Compound treatments are administered simultaneously, sequentially or separately. Radiation therapy can include one or more of the following types of therapy: i. External radiation therapy using electromagnetic radiation and intraoperative radiation therapy using electromagnetic radiation; ii. Internal radiation therapy or brachytherapy; including interstitial radiation therapy or lumen Internal radiation therapy; or iii. Systemic radiation therapy, including (but not limited to) iodine 131 and strontium 89. In one embodiment, the provided formula(I) A compound or a pharmaceutically acceptable salt thereof for the treatment of cancer, wherein the formula(I) The compound or its pharmaceutically acceptable salt is administered in combination with radiation therapy. In one embodiment, the radiotherapy is selected from one or more of the categories of radiotherapy listed in points (i)-(iii) above. In one embodiment, the provided formula(I) Compounds or pharmaceutically acceptable salts thereof for the treatment of glioblastoma, lung cancer (eg small cell lung cancer or non-small cell lung cancer), breast cancer (eg triple negative breast cancer), head and neck squamous cell carcinoma, esophageal cancer , Cervical cancer or endometrial cancer, Chinese(I) The compound or its pharmaceutically acceptable salt is administered in combination with radiation therapy. In one embodiment, the radiotherapy is selected from one or more of the categories of radiotherapy listed in points (i)-(iii) above. In one embodiment, the provided formula(I) Compound or a pharmaceutically acceptable salt thereof for the treatment of glioblastoma, wherein the formula(I) The compound or its pharmaceutically acceptable salt is administered in combination with radiation therapy. In one embodiment, the radiotherapy is selected from one or more of the categories of radiotherapy listed in points (i)-(iii) above. In one embodiment, the provided formula(I) A compound or a pharmaceutically acceptable salt thereof for use in the treatment of metastatic cancer, where the formula(I) The compound or its pharmaceutically acceptable salt is administered in combination with radiation therapy. In one embodiment, the radiotherapy is selected from one or more of the categories of radiotherapy listed in points (i)-(iii) above. In one embodiment, the provided formula(I) Compounds or pharmaceutically acceptable salts thereof for the treatment of central nervous system metastasis, where the formula(I) The compound or its pharmaceutically acceptable salt is administered in combination with radiation therapy. In one embodiment, the radiotherapy is selected from one or more of the categories of radiotherapy listed in points (i)-(iii) above. In one embodiment, the provided formula(I) Compound or its pharmaceutically acceptable salt, which is used to treat pial meningeal metastasis, wherein(I) The compound or its pharmaceutically acceptable salt is administered in combination with radiation therapy. In one embodiment, the radiotherapy is selected from one or more of the categories of radiotherapy listed in points (i)-(iii) above. In one embodiment, the provided formula(I) A compound or a pharmaceutically acceptable salt thereof for the treatment of cancer, wherein the formula(I) The compound or its pharmaceutically acceptable salt is administered simultaneously, separately or sequentially with radiation therapy. In one embodiment, the radiotherapy is selected from one or more of the categories of radiotherapy listed in points (i)-(iii) above. In one embodiment, a method of treating cancer in a warm-blooded animal in need of such treatment is provided, which comprises administering to the warm-blooded animal(I) Compound or its pharmaceutically acceptable salt and radiotherapy, where the formula(I) The compound or its pharmaceutically acceptable salt and radiation therapy together effectively produce anti-cancer effects. In one embodiment, the cancer is selected from glioblastoma, lung cancer (eg small cell lung cancer or non-small cell lung cancer), breast cancer (eg triple negative breast cancer), head and neck squamous cell carcinoma, esophageal cancer, cervical cancer and Endometrial cancer. In one embodiment, the cancer is glioblastoma. In one embodiment, the cancer is metastatic cancer. In one embodiment, metastatic cancer comprises metastasis of the central nervous system. In one embodiment, central nervous system metastases include brain metastases. In one embodiment, the metastasis of the central nervous system includes pial meningeal metastasis. In any embodiment, the radiotherapy is selected from one or more of the categories of radiotherapy listed in points (i)-(iii) above. In one embodiment, a method of treating cancer in a warm-blooded animal in need of such treatment is provided, which comprises administering to the warm-blooded animal(I) The compound or its pharmaceutically acceptable salt is administered simultaneously, separately or sequentially to radiation therapy, where the formula(I) The compound or its pharmaceutically acceptable salt and radiation therapy together effectively produce anti-cancer effects. In one embodiment, the cancer is glioblastoma. In one embodiment, the cancer is metastatic cancer. In one embodiment, metastatic cancer comprises metastasis of the central nervous system. In one embodiment, central nervous system metastases include brain metastases. In one embodiment, the metastasis of the central nervous system includes pial meningeal metastasis. In any embodiment, the radiotherapy is selected from one or more of the categories of radiotherapy listed in points (i)-(iii) above. Chemotherapy can include one or more of the following classes of anti-tumor substances: i. Anti-tumor agents and combinations thereof, such as DNA alkylating agents (eg cisplatin, oxaliplatin, carboplatin) (carboplatin), cyclophosphamide, cyclophosphamide, nitrogen mustard (such as ifosfamide, bendamustine, melphalan, chlorambucil, Busulphan, temozolamide) and nitrosourea (such as carmustine)); antimetabolites (such as gemcitabine) and antifolates such as fluoropyrimidine (such as 5- 5-fluorouracil and tegafur), raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); antitumor antibiotics (such as anthracycline, such as a Adriamycin, bleomycin, doxorubicin, liposomal doxorubicin, pirarubicin, daunomycin, pentorubicin Valrubicin, epirubicin, idarubicin, mitomycin-C Actinomycin D (dactinomycin), amrubicin (amrubicin), and brightmycin (mithramycin); anti-mitotic agents (such as vinca alkaloid (vinca alkaloid) (such as vincristine (vincristine), vinblastine (vinblastine) ), Vindesine (vindesine) and vinorelbine (vinorelbine) and paclitaxel (such as taxol and taxotere) and polo kinase inhibitors); and topoisomerase inhibitors (such as Epipodophyllotoxin (etoposide and teniposide), amsacrine, irinotecan, topotecan and camptothecin (camptothecin)); inhibitors of DNA repair mechanisms, such as CHK kinase; DNA-dependent protein kinase inhibitors; inhibitors of poly (ADP-ribose) polymerase (PARP inhibitors, including olaparib); and Hsp90 inhibitors (e.g. tanspimycin and retaspimycin), ATR kinase inhibitors (e.g. AZD6738); and WEE1 kinase inhibitors (e.g. AZD1775 / MK-1775); ii. Antiangiogenesis Agents, such as those that inhibit the effects of vascular endothelial growth factor, such as Anti-vascular endothelial growth factor antibodies bevacizumab and (for example) VEGF receptor tyrosine kinase inhibitors, such as vandetanib (ZD6474), sorafenib, tile Vatalanib (PTK787), sunitinib (SU11248), axitinib (AG-013736), pazopanib (GW 786034) and sildenib (cediranib) (AZD2171); compounds such as those disclosed in international patent applications WO97 / 22596, WO 97/30035, WO 97/32856 and WO 98/13354; and compounds that act by other mechanisms (e.g. Linomide, integrin αvβ3 function and angiostatin inhibitors), or angiopoietin and its receptor (Tie-1 and Tie-2) inhibitors, PLGF inhibitors, δ-like ligands ( DLL-4) inhibitors; iii. Immunotherapy methods, including (for example) ex vivo and in vivo methods to increase the immunogenicity of patient tumor cells, such as the use of cytokines (such as interleukin 2, interleukin 4 or granulocyte-macrophage community stimulating factor) transfection; a method for reducing T cell anergy or regulatory T cell function Methods to enhance T cell response to tumors, such as blocking antibodies against CTLA4 (eg ipilimumab and tremelimumab), B7H1, PD-1 (eg BMS-936558 or AMP- 514), PD-L1 (such as MEDI4736) and agonist antibodies against CD137; methods using transfected immune cells (such as dendritic cells transfected with cytokines); tumor cell lines transfected with cytokines Methods, use of antibodies against tumor-associated antigens and antibodies that deplete target cell types (eg, unconjugated anti-CD20 antibodies (eg, Rituximab), radiolabeled anti-CD20 antibodies Bexxar) And Zevalin (Zevalin) and anti-CD54 antibody Campas (Campath) method; anti-idiotype antibody method; enhance natural killer cell function method; and the use of antibody-toxin conjugate (such as anti-CD33 Anti-myeloma (Mylotarg) method; immunotoxins, such as motoxumumab (moxetumumab pasudotox); agonists of toll-like receptor 7 or dorto-like receptor 9; iv. Potency enhancers , Such as methyltetrahydrofolate. In one embodiment, the provided formula(I) A compound or a pharmaceutically acceptable salt thereof for the treatment of cancer, wherein the formula(I) The compound or its pharmaceutically acceptable salt is administered in combination with at least one additional antitumor substance. In one embodiment, there is an additional anti-tumor substance. In one embodiment, there are two additional anti-tumor substances. In one embodiment, there are three or more additional anti-tumor substances. In any embodiment, the additional anti-tumor substance is selected from one or more of the anti-tumor substances listed in points (i)-(iv) above. In one embodiment, the provided formula(I) A compound or a pharmaceutically acceptable salt thereof for the treatment of cancer, wherein the formula(I) The compound or its pharmaceutically acceptable salt is administered simultaneously, separately or sequentially with at least one additional antitumor substance. In one embodiment, there is an additional anti-tumor substance. In one embodiment, there are two additional anti-tumor substances. In one embodiment, there are three or more additional anti-tumor substances. In any embodiment, the additional anti-tumor substance is selected from one or more of the anti-tumor substances listed in points (i)-(iv) above. In one embodiment, a method of treating cancer in a warm-blooded animal in need of such treatment is provided, which comprises administering to the warm-blooded animal(I) Compound or its pharmaceutically acceptable salt and at least one additional antitumor substance, wherein the formula(I) The compound or its pharmaceutically acceptable salt and the amount of additional anti-tumor substance together effectively produce an anti-cancer effect. In any embodiment, the additional anti-tumor substance is selected from one or more of the anti-tumor substances listed in points (i)-(iv) above. In one embodiment, a method of treating cancer in a warm-blooded animal in need of such treatment is provided, which comprises administering to the warm-blooded animal(I) Compound or a pharmaceutically acceptable salt thereof, and at least one additional antitumor substance is administered to the warm-blooded animal simultaneously, separately or sequentially, wherein the formula(I) The compound or its pharmaceutically acceptable salt and the amount of additional anti-tumor substance together effectively produce an anti-cancer effect. In any embodiment, the additional anti-tumor substance is selected from one or more of the anti-tumor substances listed in points (i)-(iv) above. In one embodiment, the provided formula(I) A compound or a pharmaceutically acceptable salt thereof and at least one anti-neoplastic agent, which are used to treat cancer. In one embodiment, the provided formula(I) A compound or a pharmaceutically acceptable salt thereof for the treatment of cancer, wherein the formula(I) The compound or a pharmaceutically acceptable salt thereof is administered in combination with at least one anti-neoplastic agent. In one embodiment, the anti-neoplastic agent is selected from the list of anti-neoplastic agents in item (i) above. In one embodiment, the provided formula(I) The compound or a pharmaceutically acceptable salt thereof and at least one anti-neoplastic agent are used to treat cancer simultaneously, separately or sequentially. In one embodiment, the provided formula(I) A compound or a pharmaceutically acceptable salt thereof for the treatment of cancer, wherein the formula(I) The compound or its pharmaceutically acceptable salt is administered simultaneously, separately or sequentially with at least one anti-neoplastic agent. In one embodiment, the anti-neoplastic agent is selected from the list of anti-neoplastic agents in item (i) above. In one embodiment, the provided formula(I) A compound or a pharmaceutically acceptable salt thereof for the treatment of cancer, wherein the formula(I) The compound or its pharmaceutically acceptable salt is administered simultaneously, separately, or sequentially with at least one additional antitumor substance selected from the group consisting of cisplatin, oxaliplatin, carboplatin, pentorubicin, idarubicin Doxorubicin, Pirarubicin, Irinotecan, Topotecan, Amirubicin, Ubinomycin, Etoposide, Mitomycin, bendamustine, Nitrobenzine, Cyclophosphamide, ifosfamide, carmustine, melphalan, bleomycin, olaparib, MEDI4736, AZD1775 and AZD6738. In one embodiment, the provided formula(I) Compound or its pharmaceutically acceptable salt, which is used to treat cancer, formula(I) The compound or its pharmaceutically acceptable salt is administered simultaneously, separately or sequentially with at least one additional antitumor substance selected from the group consisting of: cisplatin, oxaliplatin, carboplatin, doxorubicin, pirarubicin , Irinotecan, topotecan, amrubicin, pangamycin, etoposide, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide Amine, carmustine, melphalan, bleomycin, olaparib, AZD1775 and AZD6738. In one embodiment, the provided formula(I) A compound or a pharmaceutically acceptable salt thereof for the treatment of cancer, wherein the formula(I) The compound or its pharmaceutically acceptable salt and at least one additional antitumor substance selected from the following are administered simultaneously, separately or sequentially: doxorubicin, irinotecan, topotecan, etoposide, mitomycin , Bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan, bleomycin and olaparib. In one embodiment, the provided formula(I) A compound or a pharmaceutically acceptable salt thereof for the treatment of cancer, wherein the formula(I) The compound or its pharmaceutically acceptable salt is administered simultaneously, separately, or sequentially with at least one additional antitumor substance selected from the group consisting of doxorubicin, irinotecan, topotecan, etoposide, and mitotic Amycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan and bleomycin. In one embodiment, the provided formula(I) A compound or a pharmaceutically acceptable salt thereof for the treatment of cancer, wherein the formula(I) The compound or its pharmaceutically acceptable salt is administered simultaneously, separately, or sequentially with at least one additional antitumor substance selected from the group consisting of doxorubicin, pirarubicin, amrubicin, and panamectin. In one embodiment, the provided formula(I) A compound or a pharmaceutically acceptable salt thereof for the treatment of acute myeloid leukemia, wherein the formula(I) The compound or its pharmaceutically acceptable salt is administered simultaneously, separately, or sequentially with at least one additional antitumor substance selected from the group consisting of doxorubicin, pirarubicin, amrubicin, and panamectin. In one embodiment, the provided formula(I) Compounds or pharmaceutically acceptable salts thereof for the treatment of breast cancer, where the formula(I) The compound or its pharmaceutically acceptable salt is administered simultaneously, separately, or sequentially with at least one additional antitumor substance selected from the group consisting of doxorubicin, pirarubicin, amrubicin, and panamectin. In one embodiment, the provided formula(I) Compound or its pharmaceutically acceptable salt, which is used to treat triple negative breast cancer, wherein the formula(I) The compound or its pharmaceutically acceptable salt is administered simultaneously, separately, or sequentially with at least one additional antitumor substance selected from the group consisting of doxorubicin, pirarubicin, amrubicin, and panamectin. In one embodiment, the provided formula(I) A compound or a pharmaceutically acceptable salt thereof for the treatment of hepatocellular carcinoma, wherein the formula(I) The compound or its pharmaceutically acceptable salt is administered simultaneously, separately, or sequentially with at least one additional antitumor substance selected from the group consisting of doxorubicin, pirarubicin, amrubicin, and panamectin. In one embodiment, the provided formula(I) A compound or a pharmaceutically acceptable salt thereof for the treatment of cancer, wherein the formula(I) The compound or its pharmaceutically acceptable salt is administered simultaneously, separately or sequentially with irinotecan. In one embodiment, the provided formula(I) A compound or a pharmaceutically acceptable salt thereof for the treatment of colorectal cancer, wherein the formula(I) The compound or its pharmaceutically acceptable salt is administered simultaneously, separately or sequentially with irinotecan. In one embodiment, the provided formula(I) A compound or a pharmaceutically acceptable salt thereof for the treatment of colorectal cancer, wherein the formula(I) The compound or its pharmaceutically acceptable salt is administered simultaneously, separately or sequentially with FOLFIRI. FOLFIRI is a dosage regimen that includes a combination of methyltetrahydrofolate, 5-fluorouracil, and irinotecan. In one embodiment, the provided formula(I) A compound or a pharmaceutically acceptable salt thereof for the treatment of cancer, wherein the formula(I) The compound or its pharmaceutically acceptable salt is administered simultaneously, separately or sequentially with olaparib. In one embodiment, the provided formula(I) A compound or a pharmaceutically acceptable salt thereof for the treatment of gastric cancer, wherein the formula(I) The compound or its pharmaceutically acceptable salt is administered simultaneously, separately or sequentially with olaparib. In one embodiment, the provided formula(I) A compound or a pharmaceutically acceptable salt thereof for the treatment of cancer, wherein the formula(I) The compound or its pharmaceutically acceptable salt is administered simultaneously, separately or sequentially with topotecan. In one embodiment, the provided formula(I) Compounds or pharmaceutically acceptable salts thereof, which are used to treat lung cancer, where the formula(I) The compound or its pharmaceutically acceptable salt is administered simultaneously, separately or sequentially with topotecan. In one embodiment, the provided formula(I) A compound or a pharmaceutically acceptable salt thereof for use in the treatment of small cell lung cancer, where the formula(I) The compound or its pharmaceutically acceptable salt is administered simultaneously, separately or sequentially with topotecan. In one embodiment, the provided formula(I) A compound or a pharmaceutically acceptable salt thereof for the treatment of cancer, wherein the formula(I) The compound or its pharmaceutically acceptable salt is administered simultaneously, separately, or sequentially with immunotherapy. In one embodiment, the immunotherapy is one or more of the agents listed under item (iii) above. In one embodiment, the provided formula(I) A compound or a pharmaceutically acceptable salt thereof for the treatment of cancer, wherein the formula(I) The compound or a pharmaceutically acceptable salt thereof is administered simultaneously, separately, or sequentially with an anti-PD-L1 antibody (eg, MEDI4736). According to yet another embodiment, a set including the following is provided: a)(I) The compound or its pharmaceutically acceptable salt, which is in the first unit dosage form; b) another additional antitumor substance, in another unit dosage form; c) the container member used to cover the first and further unit dosage forms; And depending on the situation d) instruction manual. In one embodiment, the anti-tumor substance comprises an anti-tumor agent. In any embodiment where an anti-neoplastic agent is mentioned, the anti-neoplastic agent is one or more of the agents listed under item (i) above. formula(I) The compound and its pharmaceutically acceptable salts can be administered in the form of a pharmaceutical composition containing one or more pharmaceutically acceptable excipients. Therefore, in one embodiment, an inclusive formula is provided(I) A pharmaceutical composition of a compound or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. The excipients selected for inclusion in a particular composition will depend on factors such as the mode of administration and the form of the composition provided. Suitable pharmaceutically acceptable excipients are well known to those skilled in the art and are described in (for example)Handbook of Pharmaceutical Excipients , 6th edition, Pharmaceutical Press, edited by Rowe, Ray C; Sheskey, Paul J; Quinn, Marian. Pharmaceutically acceptable excipients can be used as, for example, adjuvants, diluents, carriers, stabilizers, flavoring agents, coloring agents, fillers, binders, disintegrants, lubricants, glidants, glidants Thickener and coating agent. As those skilled in the art should understand, depending on how many excipients are present in the composition and what other excipients are present in the composition, certain pharmaceutically acceptable excipients can serve more than one function and can Play an alternative function. The pharmaceutical composition may be in a form suitable for oral use (for example, as a lozenge, lozenge, hard or soft capsule, aqueous or oily suspension, emulsion, dispersible powder or granules, syrup or elixir), in a suitable form Forms for topical application (eg, as a cream, ointment, gel, or aqueous or oily solution or suspension), in a form suitable for administration by inhalation (eg, as a fine powder or liquid aerosol), in a suitable form For administration by insufflation (eg, as a fine powder) or in a form suitable for parenteral administration (eg, as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, or intramuscular administration) ) Or as a suppository for rectal administration. These compositions can be obtained by conventional procedures well known in the industry. Compositions intended for oral use may contain additional components, such as one or more colorants, sweeteners, flavoring agents, and / or preservatives. formula(I) Compounds can usually be 2.5-5000 mg / m2 Unit doses within the body area of the animal, or about 0.05-100 mg / kg, are administered to warm-blooded animals, and this usually provides a therapeutically effective dose. Unit dosage forms (eg tablets or capsules) will usually contain (eg) 0.1-250 mg of active ingredient. The total dose must vary depending on the subject being treated, the specific route of administration, any therapies co-administered, and the severity of the disease being treated. Therefore, a physician who is treating any specific patient can refer to the approved label of the drug to determine the optimal dose. The pharmaceutical composition described herein comprises the formula(I) The compound or a pharmaceutically acceptable salt thereof, and therefore is expected to be used in therapy. Therefore, in one embodiment, a pharmaceutical composition for use in therapy is provided, which comprises the formula(I) The compound or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. In one embodiment, a pharmaceutical composition is provided for the treatment of ATM kinase inhibitory beneficial diseases, comprising the formula(I) The compound or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. In one embodiment, a pharmaceutical composition for treating cancer is provided, which comprises the formula(I) The compound or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. In one embodiment, a pharmaceutical composition is provided for use in the treatment of cancers that are beneficial for the inhibition of ATM kinase, including formula(I) The compound or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. In one embodiment, a pharmaceutical composition is provided for the treatment of colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, acute myeloid leukemia, head and neck Squamous cell carcinoma, breast cancer, hepatocellular carcinoma, small cell lung cancer or non-small cell lung cancer, including formula(I) The compound or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. Examples The following examples are for illustrative purposes and should not be interpreted as limiting. During the preparation of the examples, usually: i. Unless otherwise specified, the operation is carried out at ambient temperature, ie in the range of about 17 ° C to 30 ° C and in an atmosphere of an inert gas (such as nitrogen); ii. Evaporation is by Rotary evaporation or the use of Genevac equipment in a vacuum and post-treatment procedures are carried out after removing residual solids by filtration. iii. Use pre-filled Merck normal phase Si60 silica column (size determination: 15-40 or 40-63µm), silicycle silica column or graceresolv silica column obtained from Merck, Darmstad, Germany in automated Armen Glider Flash : Spot II Ultimate (Armen Instruments, Saint-Ave, France) or an automated Presearch combiflash companion to perform flash chromatography purification. iv. Use a decreasingly polar mixture of water (containing 0.1% ammonia) and acetonitrile or a decreasingly polar mixture of water (containing 0.1% formic acid) and acetonitrile as the eluent when equipped with a ZMD or ZQ ESCi mass spectrometer and Waters X-Terra or Waters X-Bridge or Waters SunFire reversed phase column (C-18, 5 micron silica, 19 mm or 50 mm diameter, 100 mm length, flow rate 40 mL / min) on Waters instrument (600/2700 or 2525) Implement preparative chromatography; v. Yield (if present) may not be the maximum value available; vi. Formula( I) The structure of the final product was confirmed by nuclear magnetic resonance (NMR) spectroscopy, and the NMR chemical shift value was measured on the delta scale. Proton magnetic resonance spectroscopy is measured using Bruker advance 700 (700MHz), Bruker Avance 500 (500 MHz), Bruker 400 (400 MHz) or Bruker 300 (300 MHz) instruments; 19F NMR is measured at 282 MHz or 376 MHz; 13C NMR is measured at 75 MHz or 100 MHz; unless otherwise specified, the measurement is performed at 20-30 ° C; the following abbreviations are used: s, singlet; d, doublet; t, triplet; q, quadruple Peak; m, multiple peaks; dd, double peaks of double peaks; ddd, double peaks of double peaks; dt, double peaks of triplets; bs, wide signal; vii. Also by liquid chromatography after mass spectrometry (LCMS) characterization(I) The final product; LCMS uses Waters Alliance HT (2790 and 2795) equipped with Waters ZQ ESCi or ZMD ESCi mass spectrometer and X Bridge 5μm C-18 column (2.1 × 50 mm) at a flow rate of 2.4 mL / min. Implemented within 4 minutes with a solvent system of 95% A + 5% C to 95% B + 5% C, where A = water, B = methanol, C = 1: 1 methanol: water (containing 0.2% ammonium carbonate); Or by using a DAD detector, ELSD detector and 2020 EV mass spectrometer (or equivalent) equipped with Phenomenex Gemini-NX C18 3.0 × 50 mm, 3.0 μM column or equivalent (alkaline conditions) or Shim Stack XR-ODS 3.0 × 50 mm, 2.2 μM column or Waters BEH C18 2.1 × 50 mm, 1.7 μM column or equivalent Shimadzu UFLC or UHPLC using 95% D + 5% E to 95 within 4 minutes % E + 5% D solvent system, where D = water (containing 0.05% TFA), E = acetonitrile (containing 0.05% TFA) (acidic conditions), or 90% F + 10% G to 4 minutes 95% G + 5% F solvent system, where F = water (containing 6.5 mM ammonium bicarbonate and adjusted to pH10 by adding ammonia), G = acetonitrile (basic conditions); viii. Intermediate is usually incomplete Characterization and by thin layer chromatography, quality , HPLC and / or NMR analysis to assess purity; ix. X-ray powder diffraction spectrum (using Bruker D4 analytical instrument) by mounting a sample of crystalline material on a Bruker single silicon crystal (SSC) wafer holder and using a microscope Slide the sample into a thin layer to measure. The sample was rotated at 30 rpm (with improved count statistics) and irradiated with X-rays with a wavelength of 1.5418 Angstroms produced by a copper long thin focusing tube operating at 40 kV and 40 mA. The collimated X-ray source was passed through an automatic variable divergence slit set at V20 and the reflected radiation was directed through a 5.89 mm anti-scatter slit and a 9.55 mm detector slit. The sample is exposed in the θθ mode in the range of 2 degrees to 40 degrees 2θ in 0.03 seconds / 0.00570 ° 2θ increments (continuous scanning mode). The running time is 3 minutes and 36 seconds. The instrument is equipped with a position sensitive detector (Lynxeye). Control and data capture with Dell Optiplex 686 NT 4.0 Workstation running with Diffrac + software. x. Differential scanning calorimetry was performed on TA Instruments Q2000 DSC. Generally, a standard aluminum pan containing less than 5 mg of material and equipped with a lid is heated at a constant heating rate of 10 ° C / min in a temperature range of 25 ° C to 300 ° C. Use a purge gas using nitrogen at a flow rate of 50 ml / minute. xi. Use the following abbreviations: h = hour; rt = room temperature (approximately 18-25 ° C); conc. = concentration; FCC = rapid column chromatography using silica; DCM = dichloromethane; DIPEA = diiso Propylethylamine; DMA =N ,N- Dimethylacetamide; DMF =N ,N- Dimethylformamide; DMSO = dimethylsulfoxide; Et2 O = diethyl ether; EtOAc = ethyl acetate; EtOH = ethanol; K2 CO3 = Potassium carbonate; MeOH = methanol; MeCN = acetonitrile; MTBE = methyl tetrabutyl ether; MgSO4 = Anhydrous magnesium sulfate; Na2 SO4 = Anhydrous sodium sulfate; THF = tetrahydrofuran; sat. = Saturated aqueous solution; and xii. IUPAC name is generated using ELN (a patented program) or "Canvas" or "IBIS" or AstraZeneca patented program. Example 18- (6- (3- (4- Fluorohexahydropyridine -1- base ) Propoxy ) Pyridine -3- base )-1- Isopropyl -3- methyl -1,3- Dihydro -2H- Imidazo [4,5-c] quinoline -2- ketone
Figure TW201805284AD00008
To a stirred suspension of sodium hydride (1.046 g, 26.16 mmol) in THF (10 ml) at room temperature was added 3- (4-fluorohexahydropyridin-1-yl) in THF (10 ml) dropwise Propan-1-ol (2.109 g, 13.08 mmol). The resulting suspension was stirred at room temperature under nitrogen for 10 minutes, and then 8- (6-fluoropyridin-3-yl) -1-isopropyl-3-methyl-1 in DMF (30 ml) was added, 3-Dihydro-2H-imidazo [4,5-c] quinolin-2-one (2.2 g, 6.54 mmol) and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with ethyl acetate (400 ml) and washed three times with water (3 × 200 ml). The organic layer was passed through MgSO4 Dry, filter and evaporate to get crude product. Purify the crude product by FCC with a gradient of 0 to 4% 2N NH3 / MeOH in DCM, and the pure portion was evaporated to dryness, then stirred with diethyl ether (20 ml) overnight. The solid was filtered, washed with diethyl ether, and then dried to give 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) -1-iso as a white solid Propyl-3-methyl-1,3-dihydro-2H-imidazo [4,5-c] quinolin-2-one (2.51 g, 80%).NMR Spectrum : 1 H NMR (500MHz, DMSO-d6) δ 1.58-1.75 (8H, m), 1.76-1.99 (4H, m), 2.19-2.33 (2H, m), 2.37-2.47 (2H, m), 2.51-2.57 ( 2H, m), 3.49 (3H, s), 4.34 (2H, t), 4.5-4.85 (1H, m), 5.2-5.49 (1H, m), 6.95 (1H, dd), 7.90 (1H, dd) , 8.11 (1H, d), 8.16 (1H, dd), 8.37 (1H, d), 8.63 (1H, dd), 8.85 (1H, s).Mass spectrometry: m / z (ES +) [M + H] + = 478. When using X-ray powder diffraction (XRPD) analysis, it was found that the material prepared according to the above procedure was a crystal. Example 1 Form A is characterized by providing an X-ray powder diffraction pattern, substantially as shown in FIG. Ten X-ray powder diffraction peaks are shown in Table 1. Table 1: Characteristic X-ray powder diffraction peaks of Form A of Example 1 Example 1 Form A exhibits the following thermal parameters: the melting endotherm starts at 157.8 ° C and has a peak at 158.9 ° C, which was previously a small endotherm at 59 ° C, as determined by DSC at a scan rate of 10 ° C / min (Figure 2) . By slurrying the above Form A substance in ethyl acetate at ambient temperature to produce 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) The different crystal forms of -1-isopropyl-3-methyl-1,3-dihydro-2H-imidazo [4,5-c] quinolin-2-one Form C Approximately 20 mg of Form A substance was placed in a vial with a magnetic stir bar, and approximately 2 ml of ethyl acetate was added. The vial was then tightly sealed with a lid and stirred on a magnetic stir plate. After about 4 days, the sample was removed from the plate, the lid was removed and the slurry was dried under ambient addition, after which it was analyzed by XRPD and DSC. Example 1 Form C is characterized by providing an X-ray powder diffraction pattern, substantially as shown in FIG. 3. Ten X-ray powder diffraction peaks are shown in Table 2. Table 2: Characteristic X-ray powder diffraction peaks of Form C of Example 1 Example 1 Form C exhibits the following thermal parameters: melting endotherm starts at 141.1 ° C and has a peak at 142.0 ° C, then an exothermic event at 143.0 ° C and then endotherm starts at 158.1 ° C and has a peak at 159.1 ° C, such as The scan rate of min was measured by DSC (Figure 4). 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) -1- is produced by slurrying the above Form A substance in water at ambient temperature Different crystal forms of isopropyl-3-methyl-1,3-dihydro-2H-imidazo [4,5-c] quinolin-2-one Form D. Approximately 20 mg of Form A substance was placed in a vial with a magnetic stir bar, and approximately 2 ml of water was added. The vial was then tightly sealed with a lid and stirred on a magnetic stir plate. After about 4 days, the sample was removed from the plate, the lid was removed and the slurry was dried under ambient addition, after which it was analyzed by XRPD and DSC. Example 1 Form D is characterized by providing an X-ray powder diffraction pattern, substantially as shown in FIG. 5. The characteristic X-ray powder diffraction peaks are shown in Table 3. Table 3: Characteristic X-ray powder diffraction peaks of Form D of Example 1 Example 1 Form C exhibits the following thermal parameters: melting endotherm starts at 141.1 ° C and has a peak at 142.0 ° C, then an exothermic event at 143.0 ° C and then endotherm starts at 158.1 ° C and has a peak at 159.1 ° C, such as The scan rate of min was measured by DSC (Figure 6). It can also be done by dissolving the free base in a small amount of DCM and treating with an equivalent amount of methanesulfonic acid dissolved in a small amount of DCM, removing the solvent and then stirring the residue in diethyl ether, followed by filtration. -(3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1,3-dihydro-2H-imidazo [ 4,5-c] quinolin-2-one is separated into mesylate.NMR Spectrum : 1 H NMR (500MHz, DMSO-d6) δ 1.67 (6H, d), 1.75-2.31 (6H, m), 2.31 (3H, s), 2.99-3.21 (2H, m), 3.42-3.7 (5H, m) , 4.42 (2H, t), 4.64-5.17 (1H, m), 5.36 (1H, p), 6.99 (1H, dd), 7.97 (1H, dd), 8.15 (1H, d), 8.23 (1H, dd ), 8.41 (1H, d), 8.67 (1H, dd), 8.92 (1H, s), 9.25 (1H, s).Mass spectrometry: m / z (ES +) [M + H] + = 478. The following compounds are prepared in a similar manner from the appropriate alcohol intermediate:
Figure TW201805284AD00009
Figure TW201805284AD00010
 * Stir the reaction at room temperature for 2 to 3 h. Example 2NMR Spectrum : 1 H NMR (500MHz, DMSO-d6) δ 1.66 (6H, d), 1.76-1.98 (3H, m), 2.01-2.23 (1H, m), 2.24-2.33 (1H, m), 2.51-2.68 (3H, m), 2.72-2.92 (2H, m), 3.49 (3H, s), 4.37 (2H, t), 5.05-5.29 (1H, m), 5.34 (1H, p), 6.96 (1H, dd), 7.91 (1H, dd), 8.12 (1H, d), 8.17 (1H, dd), 8.38 (1H, d), 8.64 (1H, dd), 8.86 (1H, s).Mass spectrometry: m / z (ES +) [M + H] + = 464. It is also possible by dissolving the free base in a small amount of DCM and treating with an equivalent amount of methanesulfonic acid dissolved in a small amount of DCM, removing the solvent and then dissolving the residue in Et2 Stir in O, then filter (S ) -8- (6- (3- (3-fluoropyrrolidin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1,3-dihydro- 2H-imidazo [4,5-c] quinolin-2-one is separated into mesylate.NMR Spectrum : 1 H NMR (500MHz, DMSO-d6) δ 1.67 (6H, d), 2.13-2.21 (2H, m), 2.30 (3H, s), 3.50 (3H, s), 3.84 (2H, d), 4.42 (2H , t), 5.35 (1H, p), 5.49 (1H, d), 6.99 (1H, d), 7.95 (1H, dd), 8.15 (1H, d), 8.22 (1H, dd), 8.40 (1H, d), 8.67 (1H, dd), 8.91 (1H, s), 10.01 (1H, d).Mass spectrometry : m / z (ES +) [M + H] + = 464. Example 3NMR Spectrum : 1 H NMR (500MHz, DMSO-d6) δ 1.66 (6H, d), 1.75-1.98 (3H, m), 2.12 (1H, ddq), 2.29 (1H, q), 2.52-2.68 (3H, m), 2.74 -2.91 (2H, m), 3.49 (3H, s), 4.36 (2H, t), 5.18 (1H, ddd), 5.34 (1H, p), 6.96 (1H, d), 7.91 (1H, dd), 8.11 (1H, d), 8.16 (1H, dd), 8.38 (1H, d), 8.63 (1H, d), 8.86 (1H, s).Mass spectrometry: m / z (ES +) [M + H] + = 464. It is also possible by dissolving the free base in a small amount of DCM and treating with an equivalent amount of methanesulfonic acid dissolved in a small amount of DCM, removing the solvent and then dissolving the residue in Et2 Stir in O, then filter (R ) -8- (6- (3- (3-fluoropyrrolidin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1,3-dihydro- 2H-imidazo [4,5-c] quinolin-2-one is separated into mesylate.NMR Spectrum : 1 H NMR (500MHz, DMSO-d6) δ 1.67 (6H, d), 2.13-2.22 (2H, m), 2.30 (3H, s), 3.50 (3H, s), 3.76 (1H, s), 3.94 (1H , s), 4.42 (2H, t), 5.36 (1H, p), 5.49 (1H, d), 6.99 (1H, d), 7.97 (1H, d), 8.15 (1H, d), 8.23 (1H, dd), 8.41 (1H, d), 8.67 (1H, d), 8.93 (1H, s), 10.15 (1H, s).Mass spectrometry: m / z (ES +) [M + H] + = 464. The intermediate 3- (4-fluorohexahydropyridin-1-yl) propan-1-ol is prepared as follows:3- (4- Fluorohexahydropyridine -1- base ) C -1- alcohol
Figure TW201805284AD00011
To a solution of 4-fluorohexahydropyridine (2.0 g, 19.39 mmol) in anhydrous tetrahydrofuran (20 ml) was added sodium hydride (1 g, 25.00 mmol) at room temperature under nitrogen, followed by stirring for 30 minutes. (3-Bromopropoxy) (tert-butyl) dimethylsilane (6.77 ml, 29.22 mmol) was added dropwise, followed by stirring at room temperature for 24 h. The reaction mixture was diluted with EtOAc (100 ml) and washed three times with water (3 × 50 ml). The organic layer was passed through MgSO4 Dry, filter and evaporate to get crude product (silyl). The crude product (silicon based) was loaded onto a 2 × 50g SCX column washed with MeOH and then the product was used 2M NH3 / MeOH was eluted from the column to obtain 3- (4-fluorohexahydropyridin-1-yl) propan-1-ol (2.226 g, 71.2%) as a yellow oil.NMR Spectrum : 1 H NMR (500MHz, CDCl3 ) δ 1.63-1.77 (2H, m), 1.87 (4H, dq), 2.42-2.7 (6H, m), 3.74-3.87 (2H, m), 4.69 (1H, dt). The following intermediates are prepared in a similar manner from the appropriate amine:
Figure TW201805284AD00012
Figure TW201805284AD00013
 * Stir the reaction at room temperature for 2 to 28 h.Intermediate A1 : NMR Spectrum : 1 H NMR (500MHz, CDCl3 ) δ 1.64-1.83 (2H, m), 1.95-2.24 (2H, m), 2.45-2.59 (1H, m), 2.71-3 (5H, m), 3.74-3.9 (2H, m), 4.99-5.34 (1H, m).Intermediate B1 : NMR Spectrum : 1 H NMR (500MHz, CDCl3 ) δ 1.69-1.77 (2H, m), 1.97-2.2 (2H, m), 2.48-2.56 (1H, m), 2.73-2.81 (2H, m), 2.81-3.01 (3H, m), 3.77-3.85 (2H, m), 4.59 (1H, s), 5.06-5.24 (1H, m). The intermediate 8- (6-fluoro-3-pyridyl) -1-isopropyl-3-methyl-imidazo [4,5-c] quinolin-2-one is prepared as follows:8- (6- fluorine -3- Pyridyl )-1- Isopropyl -3- methyl - Imidazo [4,5-c] quinoline -2- ketone
Figure TW201805284AD00014
8-Bromo-1-isopropyl-3-methyl-imidazo [4,5-c] quinolin-2-one (4.57 g, 14.27 mmol), (6-fluoropyridin-3-yl)Acid (2.61 g, 18.55 mmol) and 2M potassium carbonate (22 mL, 44.00 mmol) were suspended in 1,4-dioxane (90 mL). The mixture was degassed, followed by the addition of dichloro [1,1'-bis (di-tributylphosphino) ferrocene] palladium (II) (0.465 g, 0.71 mmol) and the reaction was allowed to reach 80 under an inert atmosphere ℃ and maintained for 2 h. The mixture was cooled, diluted with EtOAc (200 mL), then washed with water (50 mL), brine, and the organic phase was passed over MgSO4 Dry, filter and concentrate in vacuo. The crude product was purified by FCC with a gradient of 0 to 5% MeOH in DCM to obtain the material, which was then triturated with diethyl ether to obtain the desired material as an off-white solid (4.46 g, 93%).NMR Spectrum : 1 H NMR (500MHz, DMSO-d6) δ 1.66 (6H, d), 3.50 (3H, s), 5.36 (1H, p), 7.36 (1H, dd), 7.95 (1H, dd), 8.15 (1H, d ), 8.39-8.52 (2H, m), 8.72 (1H, d), 8.90 (1H, s).Mass spectrometry: m / z (ES +) [M + H] + = 337.8- bromine -1- Isopropyl -3- methyl -1,3- Dihydro -2H- Imidazo [4,5-c] quinoline -2- ketone To a solution of 8-bromo-1-isopropyl-3H-imidazo [4,5-c] quinolin-2-one (25.00 g, 81.66 mmol) in DMF (375 mL)N ,N -Dimethylformamide dimethyl acetal (54.2 mL, 408.29 mmol). The mixture was heated to 80 ° C for 3 h, then allowed to cool to ambient temperature and stirred for 16 h. The precipitate was collected by filtration, washed with water (4 × 300 mL) and dried under vacuum at 50 ° C. to obtain the desired substance as a white solid (23.82 g, 91%).NMR Spectrum : 1 H NMR (500MHz, DMSO-d6) δ 1.63 (6H, d), 3.49 (3H, s), 5.15-5.23 (1H, m), 7.75 (1H, dd), 7.99 (1H, d), 8.44 (1H , d), 8.91 (1H, s).Mass spectrometry : m / z (ES +) [M + H] + = 320.8- bromine -1- Isopropyl -3H- Imidazo [4,5-c] quinoline -2- ketone To 6-bromo-4- (isopropylamino) quinoline-3-carboxylic acid (34.22 g, 110.69 mmol) in DMF (342 mL) was added triethylamine (45.3 mL, 332.06 mmol) at ambient temperature . After stirring at ambient temperature for 30 minutes, diphenyl azide phosphate (26.2 mL, 121.76 mmol) was added and the resulting mixture was stirred at 60 ° C for 2 h. The reaction mixture was poured into water (1500 mL); the precipitate was collected by filtration, washed with water (2 × 700 mL) and dried under vacuum at 50 ° C to obtain the desired substance as a beige solid (29.6 g, 87%) , Which was used without further purification.NMR Spectrum : 1 H NMR (500MHz, CDCl3 ) δ 1.64 (6H, d), 5.06-5.21 (1H, m), 7.75 (1H, d), 7.98 (1H, d), 8.43 (1H, s), 8.69 (1H, s), 11.57 (1H, s).Mass spectrometry: m / z (ES +) [M + H] + = 3066- bromine -4- ( Isopropylamino ) quinoline -3- Formic acid Ethyl 6-bromo-4- (isopropylamino) quinoline-3-carboxylate (38.0 g, 112.69 mmol) was suspended in methanol (800 mL) and water (200 mL). 10M sodium hydroxide solution (33.8 mL, 338.07 mmol) was added and the mixture was stirred at ambient temperature for 1 h. THF (200 mL) was added and the resulting mixture was stirred for 16 h. Water (400 mL) was added and organics were removed under reduced pressure. The resulting aqueous solution was acidified to pH 4-5 with 2M HCl, and the precipitate was collected by filtration, washed with water and dried under vacuum to obtain the desired substance as a white solid (34.7 g, 100%).NMR Spectrum : 1 H NMR (500MHz, DMSO-d6) δ 1.33 (6H, d), 4.39 (1H, s), 7.78 (1H, d), 7.92 (1H, dd), 8.38 (1H, d), 8.88 (1H, s ).Mass spectrometry: m / z (ES +) [M + H] + = 309.6- bromine -4- ( Isopropylamino ) quinoline -3- Ethyl formate To a suspension of ethyl 6-bromo-4-chloroquinoline-3-carboxylate (36.61 g, 116.38 mmol) and potassium carbonate (32.2 g, 232.77 mmol) in acetonitrile (250 mL) at 0 ° C was added propane- 2-amine (11.00 ml, 128.02 mmol). The mixture was stirred at 54 ° C under reflux for 3 h. Additional potassium carbonate (10.7 g, 77.6 mmol) and propan-2-amine (3.6 ml, 42.7 mmol) were added and stirring was continued at 48 ° C for 16 h. The solvent was removed in vacuo and the resulting residue was partitioned between DCM (400 mL) and water (500 mL). The aqueous layer was re-extracted with DCM (2 × 200 mL); the combined organic layer was passed through phase separation paper and concentrated under reduced pressure to obtain the desired substance as a beige solid (38.6 g, 98%).NMR Spectrum : 1 H NMR (500MHz, CDCl3 ) δ 1.40 (6H, d), 1.43 (3H, t), 4.32-4.37 (1H, m), 4.40 (2H, q), 7.72 (1H, dd), 7.81 (1H, d), 8.29 (1H, d), 8.95 (1H, d), 9.10 (1H, s).Mass spectrometry: m / z (ES +) [M + H] + = 337.6- bromine -4- Chloroquinoline -3- Ethyl formate Ethyl 6-bromo-1-[(4-methoxyphenyl) methyl] -4-pentoxyquinoline-3-carboxylate in thionyl chloride (800 mL) at ambient temperature under air (160g, 384.37mmol) was added DMF (0.119mL, 1.54mmol). The resulting mixture was stirred at 75 ° C for 16 h, and then the solvent was removed under reduced pressure. The resulting mixture was azeotroped twice with toluene, and then n-hexane (500 mL) was added. The precipitate was collected by filtration, washed with n-hexane (200 mL) and dried under vacuum to obtain the desired substance as a brown solid (100 g, 83%).NMR Spectrum :1 H NMR (400MHz, CDCl3 ) δ 1.47 (3H, t), 4.51 (2H, q), 7.95 (1H, dd), 8.11 (1H, d), 8.60 (1H, d), 9.24 (1H, s).Mass spectrometry :m / z (ES +) [M + H] + = 314, 316. On a larger scale, charge 6-bromo-1-[(4-methoxyphenyl) methyl] -4-oxoquinoline-3-carboxylic acid ethyl ester (5765 g, 13.85 mol) With thionyl chloride (28.8 L). An exotherm was observed from 20-26 ° C. DMF (4.4 mL) was added, no exotherm was observed, and the batch was heated to 75 ° C and stirred for 17 h. HPLC showed that 1.3% of starting material and 98.0% of product were retained. The reaction was concentrated in vacuo and the residue was azeotroped with toluene (25 L). The resulting solid was then slurried in heptane (18.5 L) for 2.5 h, filtered and washed with heptane (3 × 4 L). The solid was dried under vacuum at 35 ° C to produce 4077 g of the desired material (93% crude yield), which by HPLC contained about 5% 6-bromo-1-[(4 -Methoxyphenyl) methyl] -4-oxoquinoline-3-carboxylic acid ethyl ester (90% purity). The crude material (4077 g) was returned to the container and retreated with sulfenyl chloride (14.5 L) and DMF (2.2 mL). The mixture was heated to 75 ° C for 40 h. Thiochloride was removed in vacuo and the residue was azeotroped with toluene (10 L). The residue was slurried in heptane (18 L) for approximately 16 h at 20 ° C. The solid was collected by filtration, and a portion was filtered under nitrogen and washed with heptane (3 L) to obtain 2196 g of the desired substance (90% NMR analysis, 99% by HPLC). The rest of the batch was filtered under air and washed with heptane (3 L) to obtain 1905 g of the desired material (88% NMR analysis, 99% by HPLC). The yellow solids were combined for further processing (4101 g, 3653 g activity, 83% yield, 99% by HPLC).6- bromine -1-[(4- Methoxyphenyl ) methyl ] -4- Pendant quinoline -3- Ethyl formate To 2- (5-bromo-2-fluorobenzyl) -3-[(4-methoxyphenyl) methylamino] in acetone (1.2 L) at ambient temperature over a period of 2 minutes To ethyl prop-2-enoate (296.5 g, 679.62 mmol), 1,8-diazabicyclo [5.4.0] undec-7-ene (102 mL, 679.62 mmol) was added dropwise. The resulting solution was stirred for 16 h, and then the solid was removed by filtration and washed with MTBE to obtain the desired substance as a pale yellow solid (180 g, 64%).NMR Spectrum :1 H NMR (400MHz, DMSO-d6) δ 1.30 (3H, t), 3.71 (3H, s), 4.25 (2H, q), 5.60 (2H, s), 6.90-6.95 (2H, m), 7.12-7.25 (2H, m), 7.67 (1H, d), 7.80-7.90 (1H, m), 8.30 (1H, d), 8.92 (1H, s).Mass spectrometry: m / z (ES +) [M + H] + = 418. Fill the container with 2- (5-bromo-2-fluorobenzyl) -3-[(4-methoxyphenyl) methylamino] propan-2 at 15 ° C on a larger scale -Ethyl enoate (8434 g, (7730 g assumed activity), 17.71 mol) and acetone (23.2 L). 1,8-Diazabicyclo [5.4.0] undec-7-ene (2.8 L, 18.72 mol) was added over 25 minutes, and an exotherm from 18-23 ° C was observed during the addition. A precipitate formed after about 25 minutes and the batch continued to exotherm, reaching a maximum of 37 ° C after 1 h. The reaction was stirred at 20 ° C for 16.5 h, at which point HPLC indicated consumption of starting material and 96.5% product. The resulting precipitate was washed by filtration and washed with MTBE (4 x 3.4 L). The solid was then dried under vacuum at 40 ° C to yield 6033 g of the desired substance as a white solid (yield 81.6% over 3 steps, purity 99.8% by HPLC). The analysis data is consistent with the data obtained in the previous batch.2- (5- bromine -2- Fluorobenzyl ) -3-[(4- Methoxyphenyl ) Methylamino ] C -2- Ethyl enoate Add 5-bromo-2-fluorobenzoyl chloride (163 g, 685 mmol) and DIPEA (120 mL, 685.00 mmol) in toluene (800 mL) in portions over 10 minutes at 10 ° C (E ) -3- (dimethylamino) ethyl acrylate (98 g, 685.00 mmol). The resulting solution was stirred at 70 ° C for 16 h, and then allowed to cool. (4-Methoxyphenyl) methylamine (94 g, 685 mmol) was added to the mixture at ambient temperature over a period of 20 minutes. The resulting solution was stirred for 3 h, then the reaction mixture was diluted with DCM (4 L) and washed with water (3 × 1 L). Pass the organic phase through Na2 SO4 Dry, filter, and evaporate to produce the desired material (300 g, 100%) as a brown oil, which was used in the subsequent reaction immediately without further purification.Mass spectrometry: m / z (ES +) [M + H] + = 436. On a larger scale, the vessel was charged with 5-bromo-2-fluorobenzoyl chloride (4318 g, 4205 g active, 17.71 mol) as a solution in toluene (7.5 L). DIPEA (3150 mL, 18.08 mol) was added and no exotherm was observed. Over a period of 30 minutes, 3- (dimethylamino) ethyl acrylate (2532 g, 17.71 mol) was added in portions to maintain the batch temperature <40 ° C. An exotherm from 21-24 ° C was observed during the 30-minute addition, and it slowly increased to 38 ° C within 1 h. The reaction was stirred at 20-30 ° C for 16.5 h. 4-Methoxybenzylamine (2439 g, 17.78 mol) was added portionwise over 30 min, maintaining the batch temperature <40 ° C. An exotherm of 25-30 ° C was observed during the addition, and cooling was provided by lowering the jacket temperature at 15 ° C. The reaction was stirred at 20-30 ° C for 4 h, after which HPLC indicated 93.2% of the expected material. Separate batches for post-treatment, each half of the mixture was diluted with DCM (28.6 L) and washed with water (3 x 7.8 L). The organic matter through MgSO4 (About 550 g) dried and filtered, washed with DCM (4 L). The combined organics were then concentrated to yield 8444 g of the desired material as an oil (8434 g, 106% yield, purity by HPLC 94.7%). The analysis data is consistent with the data obtained from previous batches.5- bromine -2- Fluorobenzyl chloride To a solution of 5-bromo-2-fluorobenzoic acid (150 g, 684.91 mmol) in toluene (1.2 L) and DMF (12 mL) at ambient temperature over a period of 1 h was added dropwise thiosulfonyl chloride (75.0 mL, 1027.36 mmol). The resulting mixture was stirred at 70 ° C. for 16 h, then the mixture was cooled and concentrated in vacuo to give the desired substance (160 g, 98%) as a pale yellow oil, which was used without further purification.NMR Spectrum :1 H NMR (400MHz, DMSO-d6) δ 7.26-7.31 (1H, m), 7.83 (1H, dd), 8.02 (1H, d). On a larger scale, the container was charged with 3-bromo-6-fluorobenzoic acid (3888 g, 17.75 mol) at 20 ° C, followed by toluene (29.2 L). Thionyl chloride (1950 ml, 26.88 mol) was added, followed by DMF (310 mL), and no exotherm was observed. The mixture was heated to 65-75 ° C (solution obtained above about 45 ° C), no exotherm and slight gas evolution was observed. The reaction was stirred at this temperature for 40 h, at which time HPLC analysis showed 87.6% product, 3.4% starting material. The reaction was concentrated in vacuo and azeotroped with toluene (18 L) to yield 4328 g of the desired material (103% yield, 87.3% by HPLC). Biological analysis The following analyses were used to measure the effect of the compounds of the invention: a) ATM cell efficacy analysis; b) PI3K cell efficacy analysis; c) mTOR cell efficacy analysis; d) ATR cell efficacy analysis; e) DNAPK cell efficacy analysis. During the description of the analysis, usually: i. Use the following abbreviation: 4NQO = 4-nitroquinolineN- Oxide; Ab = antibody; BSA = bovine serum albumin; CO2 = Carbon dioxide; DMEM = Dulbecco's Modified Eagle Medium; DMSO = dimethyl sulfoxide; EDTA = ethylenediaminetetraacetic acid; EGTA = ethylene glycol tetraacetic acid; ELISA = enzyme-linked immunosorbent assay; EMEM = Eagle's Minimal Essential Medium; FBS = fetal bovine serum; h = hour; HRP = horseradish peroxidase; ip = intraperitoneal; PBS = phosphate buffered saline; PBST = phosphate buffered Brine / Tween; TRIS = ginseng (hydroxymethyl) aminomethane; MTS reagent: [3- (4,5-dimethylthiazol-2-yl) -5- (3-carboxymethoxyphenyl)- 2- (4-sulfophenyl) -2H-tetrazolium internal salt, and electronic coupling agent (phenazine methosulfate) PMS; sc subcutaneously. ii. Use the intelligent fitting model in Genedata to calculate IC50 value. IC50 The value is the concentration at which the test compound inhibits 50% of the biological activity. Analysis a): ATM cell efficacyprinciple : Cellular irradiation induces DNA double-strand breaks and rapid intermolecular autophosphorylation of serine 1981, which causes dissociation of the dimer and initiation of cellular ATM kinase activity. After a radiation dose as low as 0.5 Gy, most ATM molecules in the cell are rapidly phosphorylated at this site, and after only a few DNA double-strand breaks are introduced into the cell, the binding of the phosphate-specific antibody can be detected. The principle of pATM analysis is to identify inhibitors of ATM in cells. Prior to X-ray irradiation, HT29 cells were incubated with the test compound for 1 hr. After 1 h, the cells were fixed and stained for pATM (Ser1981). Read the fluorescence on the array scanning imaging platform.Method details : HT29 cells (ECACC No. 85061109) were seeded in 384-well analysis plates (Costar No. 3712) in 40 μl EMEM medium containing 1% L-glutamic acid and 10% FBS at a density of 3500 cells / well. overnight. The next morning, add the formula in 100% DMSO to the analysis board by sound wave distribution(I) Compound. At 37 ℃ and 5% CO2 After incubation for 1 h, the X-RAD 320 instrument (PXi) was used to irradiate plates equivalent to about 600 cGy (up to 6 at a time). Return the plate to the incubator and hold for another 1h. The cells were then fixed by adding 20 μl of 3.7% formaldehyde in PBS solution and incubating at r.t. for 20 minutes, followed by washing with 50 μl / well PBS using a Biotek EL405 plate washer. Then add 20 μl of 0.1% Triton X100 in PBS and incubate at r.t. for 20 minutes to infiltrate the cells. The plate was then washed once with 50 μl / well PBS using a Biotek EL405 plate washer. Phospho-ATM Ser1981 antibody (Millipore code MAB3806) was diluted 10,000-fold in PBS containing 0.05% polysorbate / Tween and 3% BSA and 20 μl was added to each well and incubated overnight at r.t. The next morning, the plate was washed three times with 50 μl / well PBS using a Biotek EL405 plate washer, and then 20 μl secondary Ab solution was added, which contained a 500-fold dilution in PBS with 0.05% polysorbate / Tween and 3% BSA Alexa Fluor® 488 goat anti-rabbit IgG (Life Technologies, A11001) and 0.002mg / ml Hoeschst dye (Life technologies number H-3570). After incubating at r.t. for 1 h, the plate was washed three times with 50 μl / well PBS using a Biotek EL405 plate washer, and the plate was sealed and kept in PBS at 4 ° C until reading. The plate was read using an ArrayScan VTI instrument using an XF53 filter with a 10X objective lens. A dual laser setup was used to analyze nuclear staining by Hoeschst (405 nm) and secondary antibody staining by pSer1981 (488 nm). Analysis b): ATR cell efficacyprinciple : ATR is a PI 3-kinase-related kinase that responds to DNA damage during replication blocking or replication blocking multiple substrates on phosphorylated serine or threonine residues. Chk1 (ATR's downstream protein kinase) plays a key role in DNA damage checkpoint control. The activation of Chk1 involves the phosphorylation of Ser317 and Ser345 (the latter is regarded as a preferential target for phosphorylation / activation by ATR). This is through in-use(I) Cell-based analysis of ATR kinase inhibition was measured by measuring the reduction in phosphorylation of Chk1 (Ser 345) in HT29 cells after treatment with the compound and UV-simulated 4NQO (Sigma number N8141).Method details : HT29 cells (ECACC No. 85061109) were seeded into 384-well analysis plates (Costar No. 3712) in 40 μl EMEM medium containing 1% L-glutamic acid and 10% FBS at a density of 6000 cells / well. overnight. The next morning, add the formula in 100% DMSO to the analysis board by sound wave distribution(I) Compound. At 37 ℃ and 5% CO2 After incubation for 1 h, add 40 nl of 3 mM 4NQO in 100% DMSO to all wells by sonic distribution, except for the minimum control wells that were not treated with 4NQO to generate a non-responsive control. Return the plate to the incubator and hold for another 1h. The cells were then fixed by adding 20 μl of 3.7% formaldehyde in PBS solution and incubating at r.t. for 20 min. Then add 20 μl of 0.1% Triton X100 in PBS and incubate at r.t. for 10 minutes to infiltrate the cells. The plate was then washed once with 50 μl / well PBS using a Biotek EL405 plate washer. Phospho-Chk1 Ser 345 antibody (Cell Signalling Technology No. 2348) was diluted 150-fold in PBS containing 0.05% polysorbate / Tween and 15 μl was added to each well and incubated overnight at r.t. The next morning, the plate was washed three times with 50 μl / well PBS using a Biotek EL405 plate washer, and then 20 μl secondary Ab solution containing Alexa Fluor® 488 goat anti-rabbit IgG diluted 500-fold in PBST (Molecular Probes code A -11008) and 0.002 mg / ml Hoeschst dye (Molecular Probes No. H-3570). After incubation for 2 h at r.t., the plate was washed three times with 50 μl / well PBS using a Biotek EL405 plate washer, and then the plate was sealed with a black plate seal until reading. The plate was read using an ArrayScan VTI instrument using an XF53 filter with a 10X objective lens. A dual laser setup was used to analyze nuclear staining by Hoeschst (405 nm) and secondary antibody staining of pChk1 (488 nm). Analysis c): PI3K cell efficacyprinciple : This analysis was used to measure PI3K-α inhibition in cells. PDK1 was identified as an activated cyclic kinase upstream of protein kinase B (Akt1), which is required for PKB activation. The activation of the lipid kinase phosphoinositide 3 kinase (PI3K) is crucial for PDK1 to activate the PKB line. After the ligand stimulation of the receptor tyrosine kinase, PI3K is activated, which converts PIP2 to PIP3, which is bound by the PH domain of PDK1, thereby causing PDK1 to recruit to the plasma membrane, where it phosphorylates the Thr308 in the activation loop Of AKT. This cell-based mode of action analysis aims to identify compounds that inhibit PDK activity by inhibiting PI3K activity or inhibit the recruitment of PDK1 to the membrane. After treatment with the compound for 2h, the phosphorylation of phospho-Akt (T308) in BT474c cells is a direct measurement of PDK1 and indirect measurement of PI3K activity.Method details : BT474 cells (human breast ductal carcinoma, ATCC HTB-20) were seeded into black 384-well plates (Costar, No. 3712) at a density of 5600 cells / well in DMEM containing 10% FBS and 1% glutamic acid And let it stick overnight. The next morning, the compound in 100% DMSO was added to the analysis plate by acoustic distribution. At 37 ℃ and 5% CO2 After incubation for 2h, the medium was agitated, and containing 25mM Tris, 3mM EDTA, 3mM EGTA, 50mM sodium fluoride, 2mM sodium orthovanadate, 0.27M sucrose, 10mM β-glycerophosphate, 5mM sodium pyrophosphate, 0.5% Triton X -100 and a buffer solution containing all protease inhibitor tablets (Roche No. 04 693 116 001, using 1 tablet / 50ml lysis buffer) to lyse the cells. After 20 minutes, the cell lysates were transferred to ELISA plates (Greiner No. 781077), which were pre-coated with anti-total-AKT antibodies in PBS buffer and using 1% BSA in PBS containing 0.05% Tween 20 Block non-specific binding. The plate was incubated overnight at 4 ° C. The next day, the plate was washed with PBS buffer containing 0.05% Tween 20 and further incubated with mouse monoclonal anti-phosphate AKT T308 for 2h. The plate was washed again as described above, after which horse anti-mouse-HRP conjugated secondary antibody was added. After incubation at r.t. for 2h, the plate was washed and QuantaBlu substrate working solution (Thermo Scientific number 15169, prepared according to the supplier's instructions) was added to each well. After 60 minutes, the development of the fluorescent product was stopped by adding a stop solution to the well. A Tecan Safire plate reader was used to read the plate using excitation at 325 nm and emission wavelength at 420 nm. Unless specified, the reagents included in the Path Scan Phospho AKT (Thr308) sandwich ELISA kit from Cell Signalling (No. 7144) were used in this ELISA analysis. Analysis d): mTOR cell efficacyprinciple : Phosphorylation-AKTser473 cell analysis was performed in the MDA-MB-468 cell line, a PTEN-free breast adenocarcinoma human cell line. Due to the lack of PTEN, pAKT is activated constitutively, which does not require stimulation to induce phosphorylation.Method details : MDA-MB- is cultured in a cell culture medium consisting of DMEM (Dubek's Modified Eagle's Medium, code D6546), 10% (v / v) fetal bovine serum, and 1% (v / v) L-glutamic acid 468 cells. After harvesting, cells were distributed into black 384-well Costar plates (No. 3712, Corning) to produce 1500 cells / well in a total volume of 40 μl of cell culture medium at 37 ° C, 90% relative humidity and 5% CO2 Incubate overnight in a rotating incubator. The compound is then tested by one of the two analysis schemes A or B:Program A : The cell plates were then incubated at 37 ° C for 2 h, then fixed by adding 3.7% formaldehyde (1.2% final concentration) in 20 µl PBS / A, followed by incubation at room temperature for 40 minutes, and then using BioTek ELx406 plate washer with 150 µl PBS / A (phosphate buffered saline) washes twice. The cells were permeabilized and blocked with 20 µl of analysis buffer (0.5% Tween 20 + 1% milk powder in PBS / A) at room temperature for 1 h, and then washed once with 50 µl of PBS / A. Dilute primary phosphorylation-AKT (Ser473) 736E11 rabbit monoclonal antibody (No. 3787, Cell Signaling Technology) 1: 500 in analysis buffer, add 20µl per well, and incubate the plate at 4 ° C overnight. Wash the cell plate with 200µl PBS / T (phosphate buffered saline containing 0.05% Tween-20) 3 times, then add 20µl Alexa Fluor® 488 goat anti-rabbit IgG secondary antibody (No. A11008, Molecular Probes, Life Technologies) to each well ) 1: 1000 dilution in analysis buffer and 1: 5000 dilution of Hoechst 33342. After incubating at room temperature for 2 h, the plate was washed 3 times with 200 µl PBS / T, and 40 µl PBS / A was added to each well. The stained cell plate was covered with a black seal, and then read on an Acumen (TTP Labtech) plate reader. Use the main channel (green fluorescent, 488nm) to set the maximum / minimum cut-off intensity settings to allow analysis of weekly changes using staining and "AKT +: number in object (number)" Analyze data and use Genedata Screener® Software calculation IC50.Program B : The cell plate was then incubated at 37 ° C for 2 h, then fixed by adding 3.7% formaldehyde (1.2% final concentration) in 20 µl PBS / A, followed by incubation at room temperature for 30 minutes, and then using BioTek ELx406 plate washer with 150 µl PBS / A Wash twice. The cells were permeabilized and blocked with 20 µl of analysis buffer (0.1% Triton X-100 + 1% BSA in PBS / A) at room temperature for 1 h, and then washed once with 50 µl of PBS / A. Dilute primary phosphorylation-AKT (Ser473) D9E XP® Rabbit Monoclonal Antibody (No. 4060, Cell Signaling Technology) 1: 200 in assay buffer, add 20µl per well, and incubate the plate at 4 ° C overnight. Wash the cell plate 3 times with 200µl PBS / T, then add 20µl Alexa Fluor® 488 goat anti-rabbit IgG secondary antibody (No. A11008, Molecular Probes, Life Technologies) in the analysis buffer at 1: 750 and 1: 5000 dilution of Hoechst 33342. After incubation at room temperature for 1 h, the plate was washed 3 times with 200 μl PBS / T, and 40 μl PBS w / o Ca, Mg and Na Bicarb (Gibco No. 14190-094) were added to each well. The stained cell plate was covered with a black seal, and then read on a Cell Insight imaging platform (Thermo Scientific) using a 10x objective. Use the main pass (Hoechst blue fluorescent 405nM, BGRFR_386_23) to autofocus and count the number of events (this will provide information about the cytotoxicity of the compounds tested). The secondary channel (green 488nM, BGRFR_485_20) measured pAKT staining. Analyze data and use Genedata Screener® Software calculation IC50. Analysis e): DNAPK cell efficacyCompound disposal : Use Echo 555 sonic distributor (Labcyte Inc ™) to distribute all compounds or DMSO (dimethyl sulfonate) analyzed by DNAPK cell ELISA directly from the source plate containing 100% (v / v) DMSO or 10 mM compound in 100% DMSO To the analysis board. A fixed tip 96-head Agilent Vprep liquid handler (Agilent Technologies, Santa Clara, CA) was used to dilute the 10 mM compound stock solution 1: 100 to produce four intermediate dilutions (10 mM, 100 μM, 1 μM, 10 nM). Use Echo to use this intermediate plate to dispense compound and DMSO directly into the cell plate in a 12-point dose range (30, 10, 3.125, 1.25, 0.3, 0.1, 0.03125, 0.0125, 0.003, 0.001, 0.0003125, 0.00003µM) To calculate compound IC50 , Where the total DMSO concentration in the analysis is 0.3%.Method details : DNA-PK cell ELISA analysis was performed in HT29 colorectal cancer cell line. HT29 cells were cultured in a cell culture medium consisting of MEM (Eagle's minimal essential medium, Sigma number M2279), 10% (v / v) fetal bovine serum, and 1% (v / v) 200 mM L-glutamic acid. After harvesting, cells were dispensed into black 384-well Costar plates (No. 3712, Corning) to produce 15,000 cells / well in 40 ul total volume of cell culture medium at 37 ° C, 90% relative humidity and 5% CO2 Incubate overnight in a rotating incubator. Greiner 781077 all black high-binding 384-well ELISA plate was coated with DNA-PK antibody (Abcam number ab1832) in 0.5 µg / ml PBS at 4 ° C overnight. The next day, the Greiner ELISA plate was washed 3 times with PBS-T and blocked with 3% BSA / PBS for about 2h, and then washed 3 times with PBS-T. A Labcyte Echo 555 sonic distributor was used to administer the test compound and reference control directly to the cell plate. The cell plates were then incubated at 37 ° C for 1 h, after which they received a radiation dose of 8 Gy (XRAD 320, stage height 65). The cells were incubated for another 1 h, after which the cell culture medium was removed. Dissolve the lysis buffer (prepared in-house, add protease inhibitor mixed lozenges, Roche No. 04 693 116 001) at 25 µl / well and incubate the plate at 4 ° C for 15-20 min. Transfer the cell lysate (20µl / well) to the DNA-PK antibody-coated ELISA plate using CyBio Felix liquid handling platform, and incubate the ELISA plate at 4 ° C overnight. The next day, the ELISA plate was washed 3 times with PBS-T and the internal pS2056-DNA-PK antibody (0.5 µg / ml in 3% BSA / PBS) was dispensed at 20 µl / well. The plate was incubated with antibody at room temperature (RT) for 1.5 h, and then washed 3 times with PBS-T. Dispense goat anti-rabbit HRP secondary antibody (1: 2000 dilution in 3% BSA / PBS; Cell Signaling No. 7074) at 20 µl / well and incubate the plate at room temperature for 1 h, then wash with PBS-T 3 times. Dispense QuantaBlu working substrate solution (Thermo Scientific No. 15169, prepared according to the manufacturer's instructions) at 20 µl / well and incubate the plate at room temperature for 1 h, then dispense the kit at 20 µl / well (Thermo Scientific No. 15169) QuantaBlu stop solution provided in. The PerkinElmer EnVision plate reader was used to measure the fluorescence intensity of individual wells. Analyze data and use Genedata Screener® Software calculation IC50. Table 4: Analysis of the efficacy data of examples 1-12 in a)-e) Table 5 shows comparative data of certain compounds of CN102399218A and CN102372711A in analysis a) to e). Table 5: Analysis of the efficacy data of certain compounds of CN102399218A and CN102372711A in a) -e)

圖 1 ：8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮之形式A之X射線粉末繞射圖案。圖 2 ：8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮之形式A之DSC溫度記錄圖。圖 3 ：8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮之形式C之X射線粉末繞射圖案。圖 4 ：8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮之形式C之DSC溫度記錄圖。圖 5 ：8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮之形式D之X射線粉末繞射圖案。圖 6 ：8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮之形式D之DSC溫度記錄圖。 Figure 1 : 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1,3-di X-ray powder diffraction pattern of Form A of hydrogen-2H-imidazo [4,5-c] quinolin-2-one. Figure 2 : 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1,3-di Hydrogen-2H-imidazo [4,5-c] quinolin-2-one, Form A DSC thermogram. Figure 3 : 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1,3-di X-ray powder diffraction pattern of Form C of hydrogen-2H-imidazo [4,5-c] quinolin-2-one. Figure 4 : 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1,3-di DSC thermograph of Form C of Hydrogen-2H-imidazo [4,5-c] quinolin-2-one. Figure 5 : 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1,3-di X-ray powder diffraction pattern of Form D of hydrogen-2H-imidazo [4,5-c] quinolin-2-one. Figure 6 : 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1,3-di DSC thermograph of Form D of Hydrogen-2H-imidazo [4,5-c] quinolin-2-one.

Claims (15)

一種式(I) 之化合物， (I) 或其醫藥上可接受之鹽，其中：R1 係4-氟六氫吡啶-1-基或3-氟吡咯啶-1-基；且R2 係甲基或氫。A compound of formula (I) , (I) or a pharmaceutically acceptable salt thereof, wherein: R 1 is 4-fluorohexahydropyridin-1-yl or 3-fluoropyrrolidin-1-yl; and R 2 is methyl or hydrogen. 如請求項1之式(I) 化合物或其醫藥上可接受之鹽，其中R1 係4-氟六氫吡啶-1-基。The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 1 is 4-fluorohexahydropyridin-1-yl. 如請求項1之式(I) 化合物或其醫藥上可接受之鹽，其中R1 係3-氟吡咯啶-1-基。The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 1 is 3-fluoropyrrolidin-1-yl. 如請求項1之式(I) 化合物或其醫藥上可接受之鹽，其中R1 係(S )-3-氟吡咯啶-1-基。The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 1 is ( S ) -3-fluoropyrrolidin-1-yl. 如請求項1之式(I) 化合物或其醫藥上可接受之鹽，其中R1 係(R )-3-氟吡咯啶-1-基。The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 1 is ( R ) -3-fluoropyrrolidin-1-yl. 如請求項1至5中任一項之式(I) 化合物或其醫藥上可接受之鹽，其中R2 係甲基。The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein R 2 is methyl. 如請求項1至5中任一項之式(I) 化合物或其醫藥上可接受之鹽，且其中R2 係氫。The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, and wherein R 2 is hydrogen. 如請求項1之式(I) 化合物或其醫藥上可接受之鹽，其中該化合物選自： 8-(6-(3-(4-氟六氫吡啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮； (S )-8-(6-(3-(3-氟吡咯啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮；及 (R )-8-(6-(3-(3-氟吡咯啶-1-基)丙氧基)吡啶-3-基)-1-異丙基-3-甲基-1,3-二氫-2H-咪唑并[4,5-c]喹啉-2-酮。The compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: 8- (6- (3- (4-fluorohexahydropyridin-1-yl) propoxy) pyridine -3-yl) -1-isopropyl-3-methyl-1,3-dihydro-2H-imidazo [4,5-c] quinolin-2-one; ( S ) -8- (6 -(3- (3-fluoropyrrolidin-1-yl) propoxy) pyridin-3-yl) -1-isopropyl-3-methyl-1,3-dihydro-2H-imidazo [4 , 5-c] quinolin-2-one; and ( R ) -8- (6- (3- (3-fluoropyrrolidin-1-yl) propoxy) pyridin-3-yl) -1-iso Propyl-3-methyl-1,3-dihydro-2H-imidazo [4,5-c] quinolin-2-one. 一種醫藥組合物，其包含如請求項1至8中任一項之式(I) 化合物或其醫藥上可接受之鹽及至少一種醫藥上可接受之賦形劑。A pharmaceutical composition comprising the compound of formula (I) according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. 如請求項1至8中任一項之式(I) 化合物或其醫藥上可接受之鹽，其用於療法中。The compound of formula (I) according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, for use in therapy. 如請求項1至8中任一項之式(I) 化合物或其醫藥上可接受之鹽，其用於治療癌症。The compound of formula (I) according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer. 如請求項11之用於治療癌症之式(I) 化合物或其醫藥上可接受之鹽，其中該式(I) 化合物係與放射療法同時、分開或依序投與。The compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of cancer according to claim 11, wherein the compound of formula (I) is administered simultaneously, separately, or sequentially with radiation therapy. 如請求項11之用於治療癌症之式(I) 化合物或其醫藥上可接受之鹽，其中該式(I) 化合物係與至少一種選自以下之額外抗腫瘤物質同時、分開或依序投與：順鉑(cisplatin)、奧沙利鉑(oxaliplatin)、卡鉑(carboplatin)、戊柔比星(valrubicin)、伊達比星(idarubicin)、多柔比星(doxorubicin)、吡柔比星(pirarubicin)、伊立替康(irinotecan)、托泊替康(topotecan)、胺柔比星(amrubicin)、泛艾黴素(epirubicin)、依託泊苷(etoposide)、絲裂黴素(mitomycin)、苯達莫司汀(bendamustine)、氮芥苯丁酸(chlorambucil)、環磷醯胺(cyclophosphamide)、異環磷醯胺(ifosfamide)、卡莫司汀(carmustine)、美法侖(melphalan)、博來黴素(bleomycin)、奧拉帕尼(olaparib)、MEDI4736、AZD1775及AZD6738。The compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment of cancer according to claim 11, wherein the compound of formula (I) is administered simultaneously, separately or sequentially with at least one additional antitumor substance selected from With: cisplatin, oxaliplatin, carboplatin, valrubicin, idarubicin, doxorubicin, pirarubicin ( pirarubicin), irinotecan, irinotecan, topotecan, amrubicin, epirubicin, etoposide, mitomycin, benzene Damdamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan, bo Bleomycin, olaparib, MEDI4736, AZD1775 and AZD6738. 一種如請求項1至8中任一項之式(I) 化合物或其醫藥上可接受之鹽的用途，其用於製造用於治療癌症之藥劑。A use of the compound of formula (I) according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating cancer. 一種用於治療需要治療之溫血動物之癌症之方法，其包含向該溫血動物投與治療有效量之如請求項1至8中任一項之式(I) 化合物或其醫藥上可接受之鹽。A method for treating cancer of a warm-blooded animal in need of treatment, which comprises administering to the warm-blooded animal a therapeutically effective amount of a compound of formula (I) according to any one of claims 1 to 8 or a pharmaceutically acceptable Salt.
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